Massachusetts General Hospital Psychiatry Update & Board Preparation [4th Edition] 9780985531898

Table of contents :
Title......Page 4
Copyright......Page 6
Table of Contents (by chapter)......Page 8
Contributors......Page 18
Preface......Page 38
Acknowlegments......Page 39
Section 1: Test-Taking Strategies......Page 40
Section 2: Approach to Psychiatric Diagnosis and Psychiatric Conditions......Page 89
Section 3: Neurologic Disorders......Page 734
Section 4: Treatment Approaches......Page 888
Section 5: Special Topics in Psychiatry......Page 1279
Section 6: Questions and Answers......Page 1532
Review Questions......Page 1533
Review Answers......Page 1599
Index......Page 1646

Citation preview

Massachusetts General Hospital Psychiatry Update and Board Preparation

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Massachusetts General Hospital

PSYCHIATRY Update & Board Preparation FOURTH EDITION

EDITORS THEODORE A. STERN, MD Psychiatrist and Chief Emeritus, Avery D. Weisman Psychiatric Consultation Service Director, Thomas P. Hackett Center for Scholarship in Psychosomatic Medicine Director, Office for Clinical Careers Massachusetts General Hospital Ned H. Cassem Professor of Psychiatry in the field of Psychosomatic Medicine/Consultation Harvard Medical School Editor-in-Chief, Psychosomatics Boston, Massachusetts

JOHN B. HERMAN, MD Associate Chief, Massachusetts General Hospital Department of Psychiatry Distinguished Scholar of Medical Psychiatry Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts

DAVID H. RUBIN, MD Director, Child and Adolescent Psychiatry Residency Training

Massachusetts General Hospital and McLean Hospital Director, Postgraduate Medical Education, Department of Psychiatry Massachusetts General Hospital Executive Director, Massachusetts General Hospital Psychiatry Academy Massachusetts General Hospital Lecturer in Psychiatry Harvard Medical School Boston, Massachusetts

Massachusetts General Hospital Psychiatry Update and Board Preparation, Fourth Edition

Copyright ©2018 by The Massachusetts General Hospital Psychiatry Academy . All rights reserved. Printed in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher. Previous edition copyright ©2000, ©2004 by The McGraw-Hill Companies, Inc. and ©2012 by The General Hospital Corporation. ISBN-10: 0-9855318-9-4 (print) ISBN-13: 978-0-9855318-9-8 (print) ISBN-10: 0-9991483-0-3 (ebook) ISBN-13: 978-0-9991483-0-3 (ebook) Book Production: Dianne Russell, Octal Publishing, Inc . Copyeditor: Bob Russell, Octal Publishing, Inc. Cover Design: Falcone Creative Design, LLC . Production Managers: Jane Pimental and Grace Shanks, MGH Psychiatry Academy

To life-long learners everywhere, and especially to those course participants who for more than 40 years have held us to our mission: speak straight and teach clearly. TAS JBH DHR

Contents

Contributors Preface Acknowledgments

Section One: Test-Taking Strategies CHAPTER 1 Test-Taking Strategies and Combating Test Anxiety JEFF Q. BOSTIC, MD, EDD AND TRISTAN GORRINDO, MD

CHAPTER 2 The Psychiatric Interview EMILY K. GRAY, MD; BRADFORD M. LEWIS, MD; AND EUGENE V. BERESIN, MA, MD

Section Two: Approach to Psychiatric Diagnosis and Psychiatric Conditions CHAPTER 3 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition JUSTIN A. CHEN, MD, MPH AND SUNI JANI, MD, MPH

CHAPTER 4 Child and Adolescent Development ANDREA E. SPENCER, MD AND ANNAH N. ABRAMS, MD

CHAPTER 5 Child and Adolescent Disorders MICHELLE CHANEY-CATCHPOLE, MD AND ANNAH N. ABRAMS, MD

CHAPTER 6 Tics and Tourette Disorder

ERICA L. GREENBERG, MD AND DAVID H. RUBIN, MD

CHAPTER 7 Autism Spectrum Disorders ARSHYA VAHABZADEH, MD

CHAPTER 8 Delirium THOMAS H. MCCOY, JR., MD; JOHN B. TAYLOR, MD, MBA; AND SHAMIM H. NEJAD, MD

CHAPTER 9 Dementia ZEINA CHEMALI, MD, MPH; ROY H. PERLIS, MD, MSC; AND WILLIAM E. FALK, MD

CHAPTER 10 Intellectual Disability NORA D.B. FRIEDMAN, MD; ROBERT E. ACCORDINO, MD, MSC; AND JOHN JULIAN, MD, MS

CHAPTER 11 Mental Disorders Due to Another Medical Condition BJ BECK, MSN, MD AND KATHRYN TOMPKINS, MD

CHAPTER 12 Alcoholism and Alcohol Use Disorders PETER R. JACKSON, MD; JOHN A. RENNER, MD; AND KARSTEN KUEPPENBENDER, MD

CHAPTER 13 Substance-Related Disorders: Cocaine and Opioids JOHN MATTHEWS MD, MSC

CHAPTER 14 Psychosis and Schizophrenia HANNAH E. BROWN, MD AND DAPHNE J. HOLT, MD, PHD

CHAPTER 15 Depressive Disorders JOHN D. MATTHEWS, MD, MSC AND CHRISTOPHER M. CELANO, MD

CHAPTER 16 Bipolar Disorder SHARMIN GHAZNAVI, MD, PHD AND FRANKLIN KING, IV, MD

CHAPTER 17

Anxiety Disorders ERIC BUI, MD, PHD; BRIAN J. SCHULMAN, MD; DAN V. IOSIFESCU, MD, MSC; AND MARK H. POLLACK, MD

CHAPTER 18 Obsessive-Compulsive and Related Disorders NOAH CHASE BERMAN, PHD; ERIN CURLEY, BA; AND SABINE WILHELM, PHD

CHAPTER 19 Trauma and Post-Traumatic Stress Disorder ERIC BUI, MD, PHD; BRIAN J. SCHULMAN, MD; RAFAEL D. ORNSTEIN, MD; AND ROGER K. PITMAN, MD

CHAPTER 20 Somatic Symptom and Related Disorders NICHOLAS KONTOS, MD

CHAPTER 21 Deception Syndromes: Factitious Disorder and Malingering SCOTT R. BEACH, MD; ADELE C. VIGUERA, MD; AND THEODORE A. STERN, MD

CHAPTER 22 Dissociative Disorders STEVEN C. SCHLOZMAN, MD

CHAPTER 23 Sexual Disorders and Sexual Dysfunction LINDA C. SHAFER, MD

CHAPTER 24 Eating Disorders LAZARO V. ZAYAS, MD; JENNIFER J. THOMAS, PHD; AND ANNE E. BECKER, MD, PHD, SM

CHAPTER 25 Sleep Disorders JOHN W. WINKELMAN, MD, PHD; TED AVI GERSTENBLITH, MD; PATRICK SMALLWOOD, MD; AND THEODORE A. STERN, MD

CHAPTER 26 Disruptive, Impulse-Control, and Conduct Disorders CHRISTOPHER M. TANGREN, MD AND MEREDITH CAITLIN BRADY, MD

CHAPTER 27 Adjustment Disorders, Grief, and Bereavement GUY MAYTAL, MD AND ANA IVKOVIC, MD

CHAPTER 28 Personality Disorders GUY MAYTAL, MD AND ANA IVKOVIC, MD

CHAPTER 29 Psychiatric Disorders Associated with the Female Reproductive Cycle RUTA M. NONACS, MD, PHD; CHARLOTTE HOGAN, MD; HELEN G. KIM, MD; ADELE C. VIGUERA, MD, MPH; AND LEE S. COHEN , MD

CHAPTER 30 HIV Infection and AIDS OLIVER FREUDENREICH, MD; JOHN QUERQUES, MD; AND RAJESH GANDHI, MD

CHAPTER 31 Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome SCOTT R. BEACH, MD; BRAD REDDICK, MD; GREGORY L. FRICCHIONE, MD; AND THEODORE A. STERN, MD

CHAPTER 32 Neuroimaging in Psychiatry JOAN A. CAMPRODON MD, MPH, PHD; DARIN D. DOUGHERTY, MD; AND SCOTT L. RAUCH, MD

CHAPTER 33 Diagnostic Rating Scales and Psychiatric Instruments DAVID MISCHOULON, MD, PHD AND MAURIZIO FAVA, MD

CHAPTER 34 Psychological Assessment SAMUEL JUSTIN SINCLAIR, PHD; MICHAEL J. ROCHE, PHD; SHEILA M. O’KEEFE, EDD; AND MARK A. BLAIS, PSYD

CHAPTER 35 Neuropsychological Assessment SAMUEL JUSTIN SINCLAIR, PHD; MARK A. BLAIS, PSYD; AND JANET C. SHERMAN, PHD

CHAPTER 36 Laboratory Tests and Diagnostic Procedures FRANKLIN KING, IV, MD; FELICIA A. SMITH, MD; AND MENEKSE ALPAY, MD

Section Three: Neurologic Disorders CHAPTER 37 Functional Neuroanatomy NICHOLAS KONTOS, MD AND JOAN CAMPRODON, MD, MPH, PHD

CHAPTER 38 The Neurologic Examination JOAN A. CAMPRODON, MD, MPH, PHD

CHAPTER 39 Neuropsychiatric Dysfunction NICHOLAS KONTOS, MD

CHAPTER 40 Clinical Neurophysiology and Electroencephalography RANI SARKIS MD, MSC; SHAHRAM KHOSHBIN, MD; AND ZEINA CHEMALI, MD, MPH

CHAPTER 41 Seizure Disorders RANI SARKIS MD, MSC; ZEINA CHEMALI, MD, MPH; AND SHAHRAM KHOSHBIN, MD

CHAPTER 42 Headache SHAMIM H. NEJAD, MD; JOHN DENNINGER, MD, PHD; EDWARD R. NORRIS, MD; AND MARTIN A. SAMUELS, MD

CHAPTER 43 Pain SHAMIM H. NEJAD, MD AND MENEKSE ALPAY, MD

CHAPTER 44 Stroke JAMES A. JENKINS, MD; SCOTT R. BEACH, MD; AND ALICE W. FLAHERTY, MD, PHD

CHAPTER 45 Movement Disorders FRANKLIN KING IV, MD; SCOTT R. BEACH, MD; AND ALICE W. FLAHERTY, MD, PHD

Section Four: Treatment Approaches CHAPTER 46 Basic Psychopharmacology SHARMIN GHAZNAVI, MD, PHD AND JAMES A. JENKINS, MD

CHAPTER 47 Treatment of Anxiety Disorders ERIC BUI, MD, PHD; BRIAN J. SCHULMAN, MD; DAN V. IOSIFESCU, MD, MSC; AND MARK H. POLLACK, MD

CHAPTER 48 Antipsychotic Drugs ABIGAIL L. DONOVAN, MD; DAVID C. HENDERSON, MD; AND OLIVER FREUDENREICH, MD

CHAPTER 49 Antidepressants and Somatic Therapies SHARMIN GHAZNAVI, MD, PHD AND MARIZIO FAVA, MD

CHAPTER 50 Electroconvulsive Therapy CARLOS FERNANDEZ-ROBLES, MD AND CHARLES A. WELCH, MD

CHAPTER 51 Neurotherapeutics TRACY A. BARBOUR, MD AND JOAN A. CAMPRODON, MD, MPH, PHD

CHAPTER 52 Lithium ANA IVKOVIC, MD AND THEODORE A. STERN, MD

CHAPTER 53 Anti-Epileptic Drugs and Psychiatric Illness ALLISON S. BAKER, MD AND SCOTT R. BEACH, MD

CHAPTER 54 Stimulants, Atomoxetine, Beta-Adrenergic Blocking Agents, and AlphaAdrenergic Blocking Agents JEFFERSON B. PRINCE, MD AND NICHOLAS H. CAGGIANO, BS

CHAPTER 55 Drug–Drug Interactions in Psychopharmacology JONATHAN E. ALPERT, MD, PHD

CHAPTER 56 Cardiovascular and Other Side Effects of Psychiatric Medications CHRISTOPHER M. CELANO, MD; SCOTT R. BEACH, MD; JEFF C. HUFFMAN, MD; AND THEODORE A. STERN, MD

CHAPTER 57 Natural Medications in Psychiatry DAVID MISCHOULON, MD, PHD AND ANDREW A. NIERENBERG, MD

CHAPTER 58 Suicide

REBECCA WEINTRAUB BRENDEL, MD, JD; KATHERINE A. KOH, MD, MSC; ROY PERLIS MD, MSC; AND THEODORE A. STERN, MD

CHAPTER 59 Psychiatry and the Law I: Informed Consent, Competency, Treatment Refusal, and Civil Commitment RONALD SCHOUTEN, MD, JD

CHAPTER 60 Psychiatry and the Law II: Criminal Issues and the Role of Psychiatrists in the Legal System RONALD SCHOUTEN, MD, JD

CHAPTER 61 Patient Adherence LARA TRAEGER, PHD; JOHN B. HERMAN, MD; AND THEODORE A. STERN, MD

CHAPTER 62 An Overview of the Psychotherapies STEVEN C. SCHLOZMAN, MD

CHAPTER 63 Brief Psychotherapy JOHANNA C. MALONE, PHD; MARK A. BLAIS, PSYD; AND JAMES E. GROVES, MD

CHAPTER 64 Couples Therapy ANNE K. FISHEL, PHD

CHAPTER 65 Family Therapy ANNE K. FISHEL, PHD AND DAVID H. RUBIN, MD

CHAPTER 66 Group Psychotherapy KATHLEEN H. ULMAN, PHD AND ANNE ALONSO, PHD

CHAPTER 67 Cognitive-Behavioral Therapy JOHN D. MATTHEWS, MD

CHAPTER 68 Mind–Body Medicine

JONATHAN P. ZEBROWSKI, MD; MICAELA B. OWUSU, MD MSC; GREGORY L. FRICCHIONE, MD; AND JOHN W. DENNINGER, MD, PHD

CHAPTER 69 Geriatric Psychiatry M. CORNELIA CREMENS, MD, MPH AND JAMES M. WILKINS, MD, DPHIL

Section Five: Special Topics in Psychiatry CHAPTER 70 Psychiatric Epidemiology ALBERT YEUNG, MD, SCD AND TRINA CHANG, MD, MPH

CHAPTER 71 Statistics in Psychiatric Research THOMAS H. MCCOY, JR., MD AND CHRISTINA BORBA, PHD

CHAPTER 72 Psychiatric Research Methodology THOMAS H. MCCOY, JR., MD AND DANA CHARLES MCCOY, PHD

CHAPTER 73 Genetics and Psychiatry TAMAR C. KATZ, MD, PHD; DANIEL H. EBERT, MD, PHD; CHRISTINE T. FINN, MD; AND JORDAN W. SMOLLER, MD, SCD

CHAPTER 74 Psychiatry and the Law III: Malpractice and Boundary Violations RONALD SCHOUTEN, MD, JD

CHAPTER 75 Psychiatric Consultation to Medical and Surgical Patients SEAN GLASS, MD; JOHN QUERQUES, MD; AND THEODORE A. STERN, MD

CHAPTER 76 Organ Transplantation LAURA M. PRAGER, MD

CHAPTER 77 Chronic Mental Illness ABIGAIL L. DONOVAN, MD; ALICIA D. POWELL MD; AND DAVID C. HENDERSON, MD

CHAPTER 78 Intimate Partner Violence (IPV)

BJ BECK, MSN, MD AND NADA MILOSAVLJEVIC MD, JD

CHAPTER 79 Abuse and Neglect NADA MILOSAVLJEVIC MD, JD AND REBECCA WEINTRAUB BRENDEL, MD, JD

CHAPTER 80 Lesbian, Gay, Bisexual, Transgender, and Queer (LGBTQ) Mental Health ALEX S. KEUROGHLIAN, MD, MSC

CHAPTER 81 Culture and Psychiatry ANDREA MADU, BA; JUSTIN A. CHEN, MD, MPH; DAVID C. HENDERSON, MD; AND NHI-HA T. TRINH, MD, MPH

CHAPTER 82 Approaches to Collaborative Care Psychiatry and Primary Care BJ BECK, MSN, MD AND JUDITH PUCKETT, MD

CHAPTER 83 Community Psychiatry BJ BECK, MSN, MD AND DAVID L. BECKMANN, MD, MPH

CHAPTER 84 Psychiatric Care of Military Personnel and Returning Veterans MARY C. VANCE, MD; MARIA D. RUBIO, MD, PHD; NAOMI M. SIMON, MD, MSC; AND MIREYA NADAL, MD, PHD

CHAPTER 85 Sports Psychiatry NICOLE DANFORTH, MD AND PETER NEWBERRY, MD

CHAPTER 86 Global Mental Health: Concepts and Personnel KAVITHA KOLAPPA, MD, MPH; SONALI SHARMA, MD, MSC; MELVYN FREEMAN, MA; GIUSEPPE RAVIOLA, MD, MPH; CARMEN MARTÍNEZ-VICIANA, MSC

CHAPTER 87 Quality Assurance and Quality Improvement NICOLE M. BENSON, MD AND JOHN B. TAYLOR, MD, MBA

CHAPTER 88 Ethical Considerations in Psychiatry Throughout the Life-span MARTA D. HERSCHKOPF MD, MST AND M. CORNELIA CREMENS, MD, MPH

Questions and Answers Review Questions Review Answers Index

Contributors

Annah N. Abrams, MD [4, 5] Associate Psychiatrist Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Robert E. Accordino, MD, MSc [10] Resident in Child and Adolescent Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Anne Alonso, PhD* [66] Former Director, The Center for Psychoanalytic Studies and the Endowment for the Advancement of Psychotherapy Massachusetts General Hospital Clinical Professor of Psychology, Department of Psychiatry Harvard Medical School (*Deceased) Menekse Alpay, MD [36, 43] Clinical Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Jonathan E. Alpert MD, PhD [55] Dorothy and Marty Silverman University Chair Department of Psychiatry and Behavioral Science Professor of Psychiatry, Neuroscience and Pediatrics Psychiatrist-in-Chief Montefiore Medical Center Albert Einstein College of Medicine Bronx, New York

Allison S. Baker, MD [53] Attending Psychiatrist, Ammon-Pinizzotto Center for Women’s Mental Health Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Tracy A. Barbour, MD [51] Assistant Massachusetts General Hospital Research Fellow Harvard Medical School Charlestown, Massachusetts Scott R. Beach, MD [21, 31, 44, 45, 53, 56] Psychiatrist, Avery D. Weisman Psychiatric Consultation Service Massachusetts General Hospital Program Director, MGH/McLean Adult Psychiatry Residency Training Program Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts BJ Beck, MSN, MD [11, 78, 82, 83] Assistant Professor of Psychiatry, (Part Time) Harvard Medical School Department of Psychiatry Massachusetts General Hospital Staff Member, Robert B. Andrews Unit Massachusetts General Hospital Boston, Massachusetts Anne E. Becker, MD, PhD, SM [24] Founding Director, Eating Disorders Clinical and Research Program Massachusetts General Hospital Vice-Chair, Department of Global Health and Social Medicine Harvard Medical School Maude and Lillian Presley Professor of Global Health and Social Medicine Harvard Medical School Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts David L. Beckmann, MD, MPH [83] Chief Resident, Public and Community Psychiatry Massachusetts General Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Nicole M. Benson, MD [87] Clinical Fellow in Child and Adolescent Psychiatry Massachusetts General Hospital

Boston, Massachusetts Eugene V. Beresin, MD [2] Executive Director, the Massachusetts General Hospital Clay Center for Young Healthy Minds Senior Educator in Child and Adolescent Psychiatry, Department of Psychiatry Massachusetts General Hospital Professor of Psychiatry Harvard Medical School Boston, Massachusetts Noah Chase Berman, PhD [18] Assistant in Psychology Massachusetts General Hospital Assistant Professor of Psychology, Department of Psychiatry Harvard Medical School OCD and Related Disorders Program Massachusetts General Hospital Boston, Massachusetts Mark A. Blais, PsyD [34, 35, 63] Director of the Psychological Evaluation and Research Laboratory (PEaRL) Massachusetts General Hospital Associate Chief of Psychology Massachusetts General Hospital Associate Professor of Psychology in the Department of Psychiatry Harvard Medical School Boston, Massachusetts Christina P.C. Borba, PhD, MPH [71] Director of Research, Division of Global Psychiatry Massachusetts General Hospital Assistant Professor of Psychology in the Department of Psychiatry Harvard Medical School Boston, Massachusetts Jeff Q. Bostic, MD, EdD [1] Director, School Psychiatry Massachusetts General Hospital Associate Professor of Psychiatry, (Part Time) Harvard Medical School Boston, Massachusetts Meredith Caitlin Brady, MD [26] Child Psychiatrist Massachusetts General Hospital & McLean Hospital Boston, Massachusetts Rebecca Weintraub Brendel MD, JD [58, 79] Associate Psychiatrist Massachusetts General Hospital Director, Master of Bioethics Degree Program Assistant Professor of Psychiatry

Harvard Medical School Boston, Massachusetts Hannah E. Brown, MD [14] Director of Research, First Episode and Early Psychosis Program of the Schizophrenia Clinical and Research Program Department of Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Eric Bui, MD, PhD [17, 19, 47] Assistant in Research Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Nicholas H. Caggiano, BS [54] Tufts University Psychology Boston, Massachusetts Joan A. Camprodon, MD, MPH, PhD [32, 37, 38, 51] Director, Program in Neuropsychiatry and Neuromodulation Massachusetts General Hospital Director, Transcranial Magnetic Stimulation (TMS) Clinical Service Massachusetts General Hospital Attending Physician, Division of Behavioral Neurology Attending Physician, Division of Neuropsychiatry Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Christopher M. Celano, MD [15, 56] Assistant Psychiatrist, Psychiatric Consultation Service Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Michelle Chaney-Catchpole, MD [5] Resident in Child and Adolescent Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Trina Chang, MD, MPH [70] Director of Community-Based Studies, Depression and Clinical Research Program Massachusetts General Hospital

Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Zeina Chemali, MD, MPH [9, 40, 41] Director, Massachusetts General Hospital Behavioral Neurology-Neuropsychiatry Fellowship Massachusetts General Hospital Associate Professor of Psychiatry Massachusetts General Hospital Boston, Massachusetts Justin A. Chen, MD, MPH [3, 81] Assistant Psychiatrist Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Massachusetts General Hospital Depression Clinical and Research Program Boston, Massachusetts Lee Cohen, MD [29] Director, Ammon-Pinizzotto Center for Women’s Mental Health Massachusetts General Hospital Edmund and Carroll Carpenter Professor of Psychiatry Harvard Medical School Boston, Massachusetts M. Cornelia Cremens, MD, MPH [69, 88] Geriatric Psychiatrist, Senior Health Practice Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Erin Curley, BA [18] Clinical Research Coordinator Massachusetts General Hospital OCD and Related Disorders Program Boston, Massachusetts Nicole Danforth, MD [85] Director of Outpatient Programs Division of Child and Adolescent Psychiatry Newton-Wellesley Hospital Newton, Massachusetts John W. Denninger, MD, PhD [42, 68] Director of Research, Benson-Henry Institute for Mind Body Medicine Massachusetts General Hospital Co-Director, Massachusetts General Hospital-McLean Psychiatry Residency Research Concentration Program Instructor in Psychiatry Harvard Medical School

Boston, Massachusetts Abigail L. Donovan, MD [48, 77] Director, First Episode and Early Psychosis Program Massachusetts General Hospital Associate Director, Acute Psychiatry Service Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Darin D. Dougherty, MD [32] Director, Neurotherapeutic Division Associate Director, Psychiatric Neuroimaging Research Department of Psychiatry Massachusetts General Hospital Associate Professor Psychiatry Harvard Medical School Boston, Massachusetts Daniel H. Ebert, MD, PhD [73] Assistant Professor of Psychiatry and Behavioral Sciences Assistant Professor of Neuroscience Johns Hopkins School of Medicine Baltimore, Maryland William E. Falk, MD [9] Geriatric Psychiatrist Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston Massachusetts Maurizio Fava, MD [33, 49] Executive Vice-Chair, Department of Psychiatry Executive Director Massachusetts General Hospital Clinical Trials Network & Institute Founding Director, Depression and Clinical Research Program Massachusetts General Hospital Slater Family Professor of Psychiatry Harvard Medical School Boston, Massachusetts Carlos Fernandez-Robles, MD [50] Attending Psychiatrist, Somatic Therapies Service and the Psychiatric Consultation Service Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Christine T. Finn, MD [73] Director, Psychiatry Residency Training Program

Director, Crises and Consultation Service Assistant Professor Giesel School of Medicine at Dartmouth Lebanon, New Hampshire Anne K. Fishel, PhD [64, 65] Director, Family and Couples Therapy Program Massachusetts General Hospital Associate Professor of Psychiatry, (Part Time) Harvard Medical School Boston, Massachusetts Alice W. Flaherty, MD, PhD [44, 45] Associate Neurologist Massachusetts General Hospital Director, Movement Disorders Fellowship Program Massachusetts General Hospital Associate Professor of Neurology and Psychiatry Harvard Medical School Boston, Massachusetts Melvyn Freeman, MA [86] Department of Health, South Africa University of the Witwatersrand Johannesburg, South Africa Oliver Freudenreich, MD [30, 48] Director, Infectious Disease Psychiatric Consultation Service Massachusetts General Hospital Co-Director, Schizophrenia Clinical and Research Program Erich Lindemann Mental Health Center Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Gregory L. Fricchione, MD [31, 68] Associate Chief, Department of Psychiatry Director Emeritus, Division of Psychiatry and Medicine Director of Chester M. Pierce, MD Division of Global Psychiatry Director, Benson-Hemry Mind-Body Institute Senior Scientist, Pierce Division of Global Psychiatry Massachusetts General Hospital Mind-Body Medical Professor of Psychiatry Harvard Medical School Boston, Massachusetts Nora D.B. Friedman, MD [10] Assistant Psychiatrist, Lurie Center for Autism Instructor in Psychiatry Harvard Medical School Massachusetts General Hospital

Lexington, Massachusetts Rajesh Gandhi, MD [30] Director, HIV Clinical Services and Education Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts Ted Avi Gerstenblith, MD [25] Instructor of Psychiatry and Behavioral Sciences The Johns Hopkins Hospital Baltimore, Maryland Sharmin Ghaznavi, MD, PhD [16, 46, 49] Psychiatrist, Bipolar Clinic and Research Program Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Sean Glass, MD [75] Psychiatrist Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Tristan Gorrindo, MD [1] Deputy Medical Director, Office of the Medical Director Director, Division of Education American Psychiatric Association Arlington, Virginia Emily K. Gray, MD [2] Medical Director of the Pediatric and Adolescent UCSD Eating Disorder Program Assistant Clinical Professor University of California, San Diego School of Medicine San Diego, California Erica L. Greenberg, MD [6] Staff Psychiatrist Massachusetts General Hospital Pediatric Neuropsychiatry and Immunology Program OCD and Related Disorders Program Instructor in Psychiatry Harvard Medical School Boston, Massachusetts James E. Groves, MD [63] Psychiatrist Massachusetts General Hospital

Associate Clinical Professor of Psychiatry Harvard Medical School Boston, Massachusetts David C. Henderson MD [48, 77, 81] Professor and Chair, Department of Psychiatry Boston University School of Medicine Psychiatrist-in-Chief, Division of Psychiatry Boston Medical Center Boston, Massachusetts John B. Herman, MD [61] Associate Chief, Department of Psychiatry Massachusetts General Hospital Medical Director, Partners Employee Assistance Program Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Marta D. Herschkopf MD, MSt [88] Attending Psychiatrist, Consultation Service Beth Israel Deaconess Medical Center Instructor in Psychiatry, (Part Time) Harvard Medical School Boston, Massachusetts Charlotte Hogan, MD [29] Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Daphne J. Holt, MD, PhD [14] Co-Director, Schizophrenia Clinical and Research Program, Department of Psychiatry Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Jeff C. Huffman, MD [56] Director, Cardiac Psychiatry Research Program Clinical Director, Department of Psychiatry Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Dan V. Iosifescu, MD, MSc [17, 47] Director Clinical Research, Nathan Kline Institute Associate Professor of Psychiatry New York University School of Medicine

New York, New York Ana Ivkovic, MD [27, 28, 52] Director, Transplant Psychiatry Assistant Psychiatrist, Acute Psychiatric Services and Consultation-Liaison Psychiatry Massachusetts General Hospital Instructor of Psychiatry Harvard Medical School Boston, Massachusetts Peter R. Jackson, MD [12] Fellow in Child and Adolescent Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Suni Jani, MD, MPH [3] Fellow, Child and Adolescent Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts James A. Jenkins, MD [44, 46] Medical Director, East Cambridge Residence McLean Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts John Julian, MD, MS [10] Assistant Child Psychiatrist McLean Hospital Assistant Professor of Psychiatry Harvard Medical School Belmont, Massachusetts Tamar C. Katz, MD, PhD [73] Resident in Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Alex S. Keuroghlian, MD, MSc [80] Kraft Fellow in Community Health Leadership Massachusetts General Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts

Shahram Khoshbin, MD [40, 41] Neurologist Brigham & Women’s Hospital Associate Professor of Neurology Harvard Medical School Boston, Massachusetts Helen G. Kim, MD [29] Director, Hennepin County Women’s Mental Health Program Minneapolis, MN Franklin King IV, MD [16, 36, 45] Fellow in Psychosomatic Medicine/Consultation Massachusetts General Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Katherine A. Koh, MD, MSc [58] Resident in Psychiatry Massachusetts General Hospital and McLean Hospital Adult Residency Training Program Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Kavitha Kolappa, MD, MPH [86] Clinical Research Fellow Chester M. Pierce Division of Global Psychiatry Psychiatry Consultation/Liaison Service Massachusetts General Hospital Boston, Massachusetts Nicholas Kontos, MD [20, 37, 39] Director, Fellowship in Psychosomatic Medicine Massachusetts General Hospital Attending Physician Avery D. Weissman Consultation Psychiatry Service Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Karsten Kueppenbender, MD [12] Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Bradford M. Lewis, MD [2] Associate Hospital Medical Director Chief of Somatic Therapies, Pembroke Hospital Affiliate Physician in the Department of Psychiatry

North Shore Medical Center Pembroke, Massachusetts Andrea Madu, BA [81] Senior Research Assistant The Disparities Solutions Center Massachusetts General Hospital Boston, Massachusetts Johanna C. Malone, PhD [63] Psychologist Massachusetts General Hospital Instructor in Psychology in the Department of Psychiatry Harvard Medical School Boston Massachusetts Carmen Martínez-Viciana, MsC [86] Médecins Sans Frontières, International Mental Health Working Group Geneva, Switzerland John D. Matthews, MD, MSc [13, 15, 67] Assistant Psychiatrist Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Guy Maytal, MD [27, 28] Medical Director, Division of Outpatient Psychiatry Director, Primary Care Psychiatry and Urgent Care Psychiatry; Palliative Care Psychiatry Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Thomas H. McCoy, Jr., MD [8, 71, 72] Psychiatrist Massachusetts General Hospital Assistant Professor of Psychiatry and Medicine Harvard Medical School Boston, Massachusetts Dana Charles McCoy, PhD [72] Assistant Professor Harvard Graduate School of Education Cambridge, Massachusetts Nada Milosavljevic MD, JD [78, 79] Department of Psychiatry Massachusetts General Hospital Director, Integrative Health Program Chelsea HealthCare Center

Chelsea, Massachusetts Instructor in Psychiatry Harvard Medical School Boston, Massachusetts David Mischoulon, MD, PhD [33, 57] Psychiatrist Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Mireya Nadal, MD, PhD [84] Center for Anxiety and Traumatic Stress Disorders & Medical Director Home Base, Red Sox Foundation and Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Shamim H. Nejad, MD [8, 42, 43] Medical Director, Division of Psychosocial Oncology Swedish Cancer Institute Swedish Medical Center Seattle, Washington Peter Newberry, MD [85] Staff Psychiatrist Newton-Wellesley Hospital Boston, Massachusetts Andrew A. Nierenberg, MD [57] Thomas P. Hackett, MD Endowed Chair in Psychiatry Massachusetts General Hospital Director, Bipolar Clinic and Research Program Massachusetts General Hospital Professor of Psychiatry Harvard Medical School Boston, Massachusetts Ruta M. Nonacs, MD PhD [29] Department of Psychiatry Massachusetts General Hospital Instructor in Psychiatry, Harvard Medical School Boston, Massachusetts Edward R. Norris, MD [42] Vice Chairman, Department of Psychiatry Lehigh Valley Health Network Lehigh Valley Physician Group LVPG-Psychiatry Allentown, Pennsylvania

Sheila M. O’Keefe, EdD [34] Director of Psychology Training Massachusetts General Hospital Assistant Professor of Psychology/Psychiatry Harvard Medical School Boston, Massachusetts Rafael D. Ornstein, MD [19] Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Brookline, Massachusetts Micaela B. Owusu, MD MSc [68] Resident in Psychiatry Massachusetts General Hospital/McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Roy H. Perlis, MD, MSc [9, 58] Director, Pharmacogenomics Research Massachusetts General Hospital Director, Center for Experimental Drugs and Diagnostics Department of Psychiatry Massachusetts General Hospital Professor of Psychiatry Harvard Medical School Boston, Massachusetts Roger K. Pitman, MD [19] Psychiatrist Massachusetts General Hospital Professor of Psychiatry Harvard Medical School Charlestown, Massachusetts Mark H. Pollack, MD [17, 47] Chairman and Grainger Professor of Psychiatry Rush University Medical Center Chicago, Illinois Alicia D. Powell, MD [77] Assistant Medical Director Vinfen Cambridge, Massachusetts Laura M. Prager, MD [76] Psychiatrist Massachusetts General Hospital Lung Transplant Team Associate Professor of Psychiatry Harvard Medical School

Boston, Massachusetts Jefferson B. Prince, MD [54] Attending, Child Psychiatry Massachusetts General Hospital Director of Child Psychiatry Massachusetts General for Children at North Shore Medical Center, Salem, Massachusetts Vice-Chairman Department of Psychiatry North Shore Medical Center, Salem, Massachusetts Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Judith Puckett, MD [82] Resident in Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts John Querques, MD [30, 75] Chief, Inpatient Services, Department of Psychiatry Tufts Medical Center Visiting Assistant Professor of Psychiatry Tufts University School of Medicine Boston, Massachusetts Scott L. Rauch, MD [32] Chair, Partners Psychiatry and Mental Health President and Psychiatrist-in-Chief McLean Hospital Professor of Psychiatry Harvard Medical School Belmont, Massachusetts Giuseppe Raviola, MD, MPH [86] Partners in Health, Boston Children’s Hospital Harvard Medical School Boston, Massachusetts Brad Reddick, MD [31] Eastover Psychiatric & Psychiatric Group President, North Carolina Council of Child and Adolescent Psychiatry Distinguished Fellow, American Academy of Child and Adolescent Psychiatry Medical Director, Alexander Youth Network Charlotte, North Carolina John A. Renner, MD [12] Consultant, Department of Psychiatry Massachusetts General Hospital Professor of Psychiatry Boston University School of Medicine

Boston, Massachusetts Michael J. Roche, PhD [34] Assistant Professor of Psychology Penn State Altoona Altoona, Pennsylvania David H. Rubin, MD [6, 65] Director, Child and Adolescent Psychiatry Residency Training Massachusetts General Hospital and McLean Hospital Director, Postgraduate Medical Education, Department of Psychiatry Massachusetts General Hospital Executive Director, Massachusetts General Hospital Psychiatry Academy Massachusetts General Hospital Lecturer in Psychiatry Harvard Medical School Boston, Massachusetts Maria D. Rubio, MD, PhD [84] Resident in Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Martin A. Samuels, MD [42] Chair, Department of Neurology Brigham & Women’s Hospital Professor of Neurology Harvard Medical School Boston, Massachusetts Rani Sarkis MD, MSc [40, 41] Neurologist, Brigham & Women’s Hospital Instructor in Neurology Harvard Medical School Boston, Massachusetts Steven C. Schlozman, MD [22, 62] Associate Director, The Clay Center for Young Healthy Minds Course Director, Psychiatry and Psychopathology, Health Science and Technology Program Harvard Medical School and MIT Staff Psychiatrist and Consultant, Pediatric Solid Organ Transplant Team Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Ronald Schouten, MD, JD [59, 60, 74] Director, Law and Psychiatry Service Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School

Boston, Massachusetts Brian J. Schulman, MD [17, 19, 47] Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Linda C. Shafer, MD [23] Psychiatrist, Massachusetts General Hospital Assistant Professor of Psychiatry, Harvard Medical School Massachusetts General Hospital Boston, Massachusetts Sonali Sharma, MD, MSc [86] Director of the Mental Health Service Corps New York, New York Janet C. Sherman, PhD [35] Clinical Director, Psychology Assessment Center Massachusetts General Hospital Assistant Professor of Psychology/Psychiatry Harvard Medical School Boston, Massachusetts Naomi M. Simon, MD, MSc [84] Director, Center for Anxiety and Traumatic Stress Disorders & Chief Medical Officer Home Base, Red Sox Foundation and Massachusetts General Hospital Professor of Psychiatry Harvard Medical School Boston, Massachusetts Samuel Justin Sinclair, PhD [34, 35] Staff Psychologist and Assistant in Psychology Massachusetts General Hospital Assistant Professor of Psychology/Psychiatry Harvard Medical School Boston, Massachusetts Patrick Smallwood, MD [25] Medical Director, Adult Psychosomatic Medicine and Emergency Mental Health Service UMass Memorial Medical Center Assistant Professor of Psychiatry University of Massachusetts Medical School Worcester, Massachusetts Felicia A. Smith, MD [36] Director, Division of Psychiatry and Medicine Director, Avery D. Weisman Psychiatry Consultation Service Massachusetts General Hospital Assistant Professor of Psychiatry, Harvard Medical School

Boston, Massachusetts Jordan W. Smoller, MD, ScD [73] Director, Psychiatric Genetics and Associate Vice-Chair, Department of Psychiatry, Department of Psychiatry Massachusetts General Hospital Professor of Psychiatry Harvard Medical School Boston, Massachusetts Andrea E. Spencer, MD [4] Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Theodore A. Stern, MD [21, 25, 31, 52, 56, 58, 61, 75] Psychiatrist and Chief Emeritus, Avery D. Weisman Psychiatric Consultation Service Director, Thomas P. Hackett Center for Scholarship in Psychosomatic Medicine Director, Office for Clinical Careers Massachusetts General Hospital Ned H. Cassem Professor of Psychiatry in the field of Psychosomatic Medicine/Consultation Harvard Medical School Boston, Massachusetts Christopher M. Tangren, MD [26] Psychiatrist in Charge, Proctor House 2 Inpatient Unit McLean Hospital Instructor in Psychiatry Harvard Medical School Belmont, Massachusetts John B. Taylor, MD, MBA [8, 87] Psychiatrist Massachusetts General Hospital Associate Director, Massachusetts General Hospital Psychosomatic Medicine Fellowship Massachusetts General Hospital Assistant Training Director, Massachusetts General Hospital/McLean Adult Psychiatry Residency Training Program Massachusetts General Hospital Attending Psychiatrist, Acute Psychiatry Service, Inpatient Consultation Service, Outpatient Resident Clinic Massachusetts General Hospital Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Jennifer J. Thomas, PhD [24] Co-Director, Eating Disorders Clinical and Research Program Massachusetts General Hospital Associate Professor of Psychology, Department of Psychiatry Harvard Medical School

Boston, Massachusetts Kathryn Tompkins, MD [11] Psychiatrist Boston Medical Center Boston, Massachusetts Lara Traeger, PhD [61] Psychologist, Department of Psychiatry Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Nhi-Ha T. Trinh, MD, MPH [81] Director Massachusetts General Hospital Psychiatry Center for Diversity Massachusetts General Hospital Director Multicultural Studies and Clinical Services, Massachusetts General Hospital Depression and Clinical Research Program Massachusetts General Hospital Assistant Professor of Psychiatry Harvard Medical School Boston, Massachusetts Kathleen H. Ulman, PhD [66] Clinical Assistant in Psychiatry (Psychology) Massachusetts General Hospital Massachusetts General Hospital Director, Center for Group Psychotherapy Massachusetts General Hospital Assistant Professor of Psychiatry (Psychology) Harvard Medical School Boston, Massachusetts Arshya Vahabzadeh, MD [7] Instructor in Psychiatry Harvard Medical School Boston, Massachusetts Mary C. Vance, MD [84] Resident in Psychiatry Massachusetts General Hospital and McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts Adele C. Viguera, MD, MPH [21, 29] Associate Director of the Perinatal and Reproductive Psychiatry Program, Assistant Professor, Department of Psychiatry Cleveland Clinic Cleveland, Ohio Charles A. Welch, MD [50]

Attending Psychiatrist, Somatic Therapies Service Assistant Professor of Psychiatry Harvard Medical School McLean Hospital Belmont, Massachusetts Sabine Wilhelm, PhD [18] Chief of Psychology Massachusetts General Hospital Professor of Psychology, Department of Psychiatry Harvard Medical School OCD and Related Disorders Program Massachusetts General Hospital Boston, Massachusetts James M. Wilkins, MD, DPhil [69] Assistant Medical Director, Cognitive Neuropsychiatry Unit McLean Hospital Instructor in Psychiatry Harvard Medical School Belmont, Massachusetts John W. Winkelman MD, PhD [25] Chief, Sleep Disorders Clinical Research Program Departments of Psychiatry and Neurology Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Albert Yeung, MD, ScD [70] Director of Clinical Studies, Depression Clinical and Research Program Massachusetts General Hospital Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts Lazaro V. Zayas, MD [24] Staff Psychiatrist, Eating Disorders Clinical and Research Program Assistant in Psychiatry Massachusetts General Hospital Instructor in Psychiatry, (Part Time) Harvard Medical School Boston, Massachusetts Jonathan P. Zebrowski, MD [68] Resident in Psychiatry Massachusetts General Hospital/McLean Hospital Clinical Fellow in Psychiatry Harvard Medical School Boston, Massachusetts

Preface

More than 40 years ago our then Chief of Psychiatry at the Massachusetts General Hospital inspired our department to embark upon a mission which then seemed bold: to offer annual comprehensive courses on psychiatry. Through the years our attendees urged us to create a companion text (with board-style questions and answers) as a tool to aid in their studies and to serve as a basic reference for everyday clinical practice. Nearly 20 years ago the first edition of this text, Massachusetts General Hospital Psychiatry Update and Board Preparation , was compiled. Now that our review course can be accessed on-line and via mobile devices, our review book has been designed for e-book readers. This book, now in its fourth edition, has been a team effort. More than 100 authors have updated and revised this text (consistent with the terminology used in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ). Thoroughly indexed, it is designed for quick access to specific areas of inquiry, while providing a broad, in-depth review of our field, as well as informative questions and annotated answers.

Acknowledgments

Like our courses, the contents of this updated text were mined from the rich ore of a mountain of collaborators. Without their yeoman’s efforts this effort would not have been possible. At the MGH Psychiatry Academy, who produce our annual review courses and who publish this book, we were thankful for the incredible efforts of Grace Shanks, Jane Pimental, Rose Desilets, and David Rubin, MD. And, the eagle eyes of Dianne and Bob Russell at Octal Publishing, Inc. were invaluable in reaching our goal. We owe special thanks to our colleagues, who time after time dig down to find the gems in the literature and to bring them forth for all of us to see. TAS JBH DHR

Test-Taking Strategies

S E C T I O N O N E

CHAPTER 1 Test-Taking Strategies and Combating Test Anxiety JEFF Q. BOSTIC, MD, EDD AND TRISTAN GORRINDO, MD

KEY POINTS The Board Examination is designed for candidates to successfully demonstrate they have learned the core knowledge of their field. The Initial Certification Examination (ICE) currently includes 480 items to be taken over nine-and-a-half hours in one day. The Maintenance of Certification (MOC) Examination currently includes 220 items to be taken over five hours in one day. Study is most effective over long intervals, simulating test conditions with similar types of items, making contracts with oneself and others, and devising questions as one reads/reviews material. You can diminish test anxiety by enhancing your positive attitude about the exam, replacing distracting and negative thoughts with focused thoughts, employing healthy practices surrounding the exam, and practicing relaxation technique

Overview The Board Examination is not designed to fail candidates. Instead, it allows candidates to demonstrate that they understand, and now remain abreast of, the core terminology and knowledge of psychiatry. Each candidate has had at least 3 years of accredited psychiatry training to prepare one to know and implement this knowledge. The Board Examination aims to assure that candidates have the required knowledge of an appropriate (not perfect), practicing psychiatrist.

Components of the Psychiatry Certification Examinations

The most updated information, including examination format and content, about the Psychiatry Initial Certification Examination (ICE) and the Maintenance of Certification Examination (MOC ) are available at www.abpn.com . The ICE examination is currently offered on one date each year, so applicants should review information aware that one is expected to apply approximately 7 months before the examination date; for 2016, the application deadline was February 2, 2016 to take the examination September 22–23, 2016. The MOC examination is usually offered twice per year, in February and October through November.

The Psychiatry ICE The ICE examination changed for graduates on or after July 1, 2007, so candidates should review their status with the program from which they completed certification. The oral examination was discontinued for graduates after July 1, 2007. The ICE consists of 480 multiple-choice questions administered via computer in three timed sections. Nine-and-a-half hours (510 minutes of examination time) are allotted for the day. The examination is currently comprised of 8 sections, each of 50 to 60 questions, with “breaks” allowed between each section. Examinees can take up to 50 minutes of breaktime over the course of the examination, including a lunch break. Questions are of two types: (1) stand-alone multiple-choice questions with one best answer, and unrelated to other questions; (2) vignette multiple-choice questions, which include a text, video , or audio vignette and then 2 to 10 accompanying multiple-choice questions. (headphones are provided at the test site). Examinees can flag and return later to the stand-alone questions, but not the vignette questions (since some of the answers may be revealed amidst that vignette’s “set” of questions). Questions may also have multiple correct answers. For example, a candidate might be asked to pick three treatment options from a list of six potential interventions. Because of this format, answers to alreadyanswered items may be revealed in subsequent questions and candidates will not be able to skip items , change answers, or flag them for later review. There is no penalty for guessing , and the American Board of Psychiatry and Neurology (ABPN) emphasizes that examinees should answer every question. There is no pre-defined “pass percentage,” and the ABPN website makes clear that “no candidate is expected to obtain a perfect score.”

The Psychiatry MOC Examination

The candidate must pass the MOC examination once every 10 years after having passed the ICE. This examination includes 220 multiple choice standalone (non-vignette) items, in four sections each of 50 to 60 questions, to be taken within a maximum of 5 hours (300 minutes). After a section is completed, the candidate cannot return to items in that section. The candidate can take breaks after any section, but the entire examination must be completed within five hours. Like the ICE examination, there is no penalty for guessing, the ABPN emphasizes that examinees should answer every question, there is no predefined “pass percentage,” and the ABPN website makes clear that “no candidate is expected to obtain a perfect score.”

Examination Preparation To become a hurdler, you should hurdle. To become a test-taker, you should take tests. Nothing prepares one better to do a task than practice. Taking written tests such as the Psychiatry Residency in Training Examination (PRITE ) or other review tests is helpful. Educational research suggests that familiarity with a testing format predicts success better than studying longer or harder. The more one can simulate the test-taking situation, the more likely success will occur on the actual exam. Successful preparation strategies include the following: Study over a longer time (3 months) with smaller material (e.g., 10 pages per day). This strategy is more effective and diminishes test anxiety more than studying intensively over a shorter interval (e.g., 30 pages per night during the month prior to the test). Time management and self-testing throughout the study process are particularly important predictors of success for high-stakes examinations. Practice examinations in the mornings with the same time constraints as the actual examination; this optimally simulates the actual test-taking situation. You should take the first exam early in the preparation process (months before the exam), and subsequent tests about 3–4 weeks before the actual exam. Make study plans known and even “write contracts” with yourself or others (e.g., your spouse or colleagues) to increase both study time and scores on multiple-choice examinations. Ask others who have taken the exams about what was helpful, including

what notes were useful, what materials they found helpful, and what was both most helpful and challenging as they prepared. Devise your own multiple-choice questions at varying levels of complexity to score better on these types of exams. As you read and review materials, anticipate how this information might be asked, and create questions to again review later. Specifically, “guess” at what the answers will be to content that you’re about to study; for example, “this section is on depression treatment—my ‘guess’ is that men are more depressed than women, older more than younger patients, and treatment with selective serotonin re-uptake inhibitors (SSRIs) is much better than psychotherapy or other medications.” Even “wrongful” guessing appears to prime the brain to focus on and retain important content. Some questions assess basic facts, whereas others require higher levels of synthesis or analysis. Study recent (within the past 5 years) textbooks and review articles that best capture the content of the exam.

Test-Taking Skills As in any high-stakes examination, there are basic skills that you can apply to improve your odds of success. A systematic approach on examination day might include the following: Concentration: Sustained concentration appears to be the variable that most positively affects performance on medical board examinations. You can enhance your ability to focus on the item at hand with minimal distractions by dividing study sessions into shorter segments (12 to 18 minutes) and then pausing and reflecting for approximately 2 minutes on the material just studied and how you can apply and recall it. In addition, when you notice that your focus is diminishing, practicing taking test questions like board exams (e.g., the PRITE) and extending effort to three to five items can improve concentration. Setting: Familiarity with the setting and test site enhances comfort while taking an exam. Although it is unlikely that you will be able to visit the computer testing room prior to the exam, you should practice the drive to the testing center and visualize yourself entering the building to take the exam. Look around the environment and scout out places where you might have lunch or relax during scheduled breaks. To minimize distractions by others or outside noises, you should consider

using earplugs during the exam. You also should wear earplugs while studying during the week leading up to exam so that you can habituate to the feeling of having them in your ears. Pace yourself. People who finish faster do not score higher than people who finish slower; proceed at your own pace. Most people answer questions more quickly as the test progresses and as the task becomes more familiar; being behind initially warrants little concern. A pace that allows 5 to 10 minutes at the end for review of difficult questions is optimal. Questions: Creating questions about the content you study improves retention of information. Students given more study material to read fared less well than those students who took actual test questions after short segments of studying or instruction. Embedding “question-making” (like board-type questions) helps anchor information and recognize relevant distinctions in new content. When you create questions, adhere to the standard multiple-choice format (one best answer—no “combinations” [e.g., 1 and 3 are correct, all of the above, none of the above]) because non-standardized type formats are more difficult to understand (and anchor) and because they will not be used on the Board Examinations. Focus on keywords in both item stems (i.e., the question) and answers to clarify the purpose of each question. Determine what is the important information or concept being sought in each question. Often, keywords in the stem provide clues about what is being sought in the answer. Example Question 1: Which of the following medications would be the most appropriate monotherapy for a depressed psychotic patient? A) Fluoxetine; B) Nortriptyline; C) Paroxetine; D) Amoxapine; E) Amitriptyline. Careful reading of the stem indicates that only one medication must address depression and psychosis, but also that no specific diagnosis is provided. Thus, the best answer is D , because this could be a psychotic patient now depressed as well as a patient with an affective disorder. Deductive reasoning strategies are based on choosing the best answer to each question. Similar answers might be present, thereby eliminating multiple answers. Board questions sometimes have multiple answers pertaining to symptoms of anticholinergic crisis or neuroleptic malignant syndrome. For example, the preceding example question illustrates this

because choices A and C are both SSRIs, and choices B and E are both tricyclic antidepressants. Only choice D is substantially different from the other choices. Example Question 2: Rimfodine is used to treat: A) psychiatric disorders complicated by a thought disorder; B) psychotic disorders; C) depression with psychotic features; D) impaired reality-testing; or E) anxiety disorders. Answers A through D all indicate treatment of psychosis, making E the best answer (no drug named rimfodine exists). Specific determiners, such as “always,” “never,” are less likely to be correct than are choices that include words such as “sometimes, often, rarely.” Because many issues in psychiatry remain ambiguous, longer answers with more qualifiers are more often correct. However, question writers know this and will occasionally include longer answers as distractors.

Avoid Making Mistakes For items to be revisited if time permits (afternoon session only), flag answers and review them after you have answered all of the other questions. You no longer need to worry about forgetting to fill in bubbles on paper answer sheets, but you do need to remember to go back and complete all questions previously “flagged” but not initially answered on the computer.

Increase Accuracy Levels Even when instructed to not change their answers, college students scored better when they went back and changed answers . The more rapidly you complete a test, the more reasonable it is to go back and change an answer. In addition, changing answers benefited medical students on multiple-choice exams when they changed their answers because they recalled new information (oftentimes, subsequent test items aided recall useful for earlier items) or reread the question more carefully.

Analyze Items Perceived as Difficult Consider why this item is important enough to be on the exam. Return later to difficult items to allow information from other items to clarify answers and allow the item to be read afresh. Because each item counts the same, proceed to simpler items (e.g., matching) rather than spending excessive time trying to reason through one item.

Guess There are no penalties for guessing ; at least a 20% chance of guessing the correct answer is preferable to 0% (not filling in anything). There is no pattern to use when guessing (e.g., always choosing “B”); instead, attempt to eliminate wrong choices to increase the probability of choosing a correct answer from the remaining reasonable choices.

Test Anxiety Among medical students, test anxiety was positively related to academic success. On written exams, test anxiety is most impairing for those who also have negative mood (dreading the exam and feeling inadequate for months). Thus, efforts to both improve optimism toward the exam as well as efforts to decrease test anxiety are necessary. “Distraction” from the question, by other thoughts, unrelated to the item, competing and interfering with focus and working memory, negatively affect test performance. Accordingly, sustaining focus on the task at hand by ignoring or minimizing distracting attention and by cueing oneself about the test itself each improve test performance. Specifically, anxiety impedes mental processing efficiency, including inhibition and shifting, thus requiring more energy and time to answer an item. Test anxiety does not usually intensify throughout exams, but rather diminishes from the halfway point.

Managing Anxiety and Optimizing Performance Preparation for an exam comes in stages. The better prepared you are, the less anxious you will feel.

Weeks to Months Before the Examination Engaging in relaxation training (deep-muscle techniques) improves test scores, although it is less effective for reducing “state” anxiety during an examination. That is, relaxation techniques are preferred before exams rather than during the exam. If you “freeze up” during the exam, a brief (less than a minute) exercise can be helpful. Systematic desensitization (by determining what factors on a test cause the greatest anxiety reactions and practicing relaxation responses to these, starting with those factors that cause the least anxiety and then working up to the factors causing the greatest anxiety) has been helpful both to decrease anxiety and to improve test performance.

Practice does not make perfect—practice makes permanent. Accordingly, practice with items by simulating the test-taking situation (e.g., timed and seated at a small carrel in a library or other public place, during the same hours as the actual test) enhances performance. Similarly, rehearsal and retrieval practice, by considering how information could appear on actual questions, from simple definitions to nuanced differences between similar constructs, to applications in case examples, all improve your facility in accessing and recalling information across diverse contexts. You should practice refuting unhelpful, distracting, negative thoughts. For example, if interfering thoughts emerge, preparation ahead of time with positive self-talk can help diminish interference on the test. Table 1-1 provides some ideas on how you can address negative thoughts. Table 1-1: Converting Negative Thoughts to Positive Thoughts Negative Thought

Positive Thought

“I’ve never been a good test-taker, so “This is my chosen career and I have studied and used this information this one will likely be a disappointment, successfully for years now—I should remember what I’ve learned to do.” as well.” “This test will have questions to trick me and make me look stupid.”

“This test is designed for psychiatrists to demonstrate their special knowledge and training compared to other specialties.”

“Oh no—I don’t know the answer to this question—I’m too stupid to pass this test.”

“I don’t have to know every answer, and will know most of these items; how is this question trying to test what a practicing psychiatrist knows?”

“Oh my gosh, this is the third question “The questions are randomly arranged, not from easy to hard so stay focused on that I’m not sure about; what am I doing how this question seeks to distinguish between psychiatrists from those in other here?” specialties.”

Performance improves when an examination is perceived as an opportunity for self-growth and as a demonstration of knowledge. Examination performance decreases when the examination is perceived as a threat to the individual’s aptitude or self-esteem. Accordingly, studying information of your chosen profession should be perceived as valuable and time well spent that will improve patient care. Priming for the exam by imagining the type of person who would do well on this examination and then identifying the traits of those likely to be successful, and even writing down how this person would likely feel and manage the exam, can be helpful if you are prone to being anxious and self-disparaging. In addition, if you experience significant test anxiety, literally writing about it has proven effective; specifically, writing about worries and fears, and about the

perceived impacts of the test diminish anxiety and interference with cognitive effort during high-stakes tests. Organize weeks to months before the test to review relevant information. If you have had dense coursework and experience with topics (e.g., a 6-month rotation recently on substance abuse), identifying other areas to emphasize for studying might prove more fruitful than “going through” a general psychiatry textbook. Selective emphasis and review on those topics more distant or less well covered might warrant increased attention in the weeks or months before the examination. Try to simplify work schedules and outside pressures the month before testing. Surgical residents who took vacations the month before taking the annual surgical residency training examination scored significantly better than those who did not.

The Night Before the Examination Aerobic exercise diminishes test-anxiety, so plan a light aerobic exercise the night before an exam. Studying the night before the examination is not usually helpful; time is better spent reinforcing familiarity with the format of the test. Relax with friends if possible or doing activities that favor ease of sleep and being physically rested even if keyed up (which is common and not to be feared; even if it feels like you “can’t sleep,” lying down and relaxing/attempting sleep can still yield rest. If you cannot avoid studying, broad review of the major psychiatric diagnoses and treatments is preferred to reading journal articles or reviewing PRITE tests. Use of alcohol or sleep agents is dissuaded because they impair short-term memory as well as diminish early morning attention the next day.

The Morning of the Examination Eat a normal breakfast; this is preferable to eating nothing or to eating something atypical. Drink the same amount of caffeine as you normally drink (to avoid increased anxiety but also to prevent withdrawal discomfort). No formal research has been conducted on the use of caffeine, alcohol, or nicotine to enhance Board performance. Still, initiating use (or abuse) of a substance is not perceived as beneficial prior to the exam. Similarly, deciding to stop smoking immediately prior to the exam will not diminish anxiety. Do not study on the morning of the test, because this makes you less confident and more anxious.

During the Examination

Unlike many standardized tests, the items are not arranged in order of difficulty. You should not become demoralized if the first items appear difficult. During breaks, discussion of test items increases anxiety. Truth does not occur by consensus, and negative effects on confidence outweigh the benefits of any knowledge item clarification. Eat lunch with friendly, familiar others (who do not discuss test items). Greasy or fatty foods can cause tiredness, so you should avoid them. Similarly, sugar snacks or candy bars are preferred in the afternoon session rather than in morning sessions.

Suggested References 1. Baghdady M, Carnahan H: Test-enhanced learning and its effect on comprehension and diagnostic accuracy. Med Educ. 2014; 48: 181-188. 2. Caldwell DJ, Pate AN: Effects of question formats on student and item performance. Am J Pharm Educ. 2013; 77: 71. 3. Cizek GJ, Burg SS: Addressing Test Anxiety in a High-Stakes Environment: Strategies for Classrooms and Schools . Thousand Oaks, CA: Corwin Press; 2006. 4. Kingston R, Coumaravelou S: The effectiveness of psychoeducation and systematic desensitization to reduce test anxiety among first-year pharmacy students. Am J Pharm Educ. 2014; 78: 163-168. 5. Lang JWB, Lang J: Priming competence diminishes the link between cognitive test anxiety and test performance. Psychological Sci. 2010; 21: 811-819. 6. Ramirez G, Beilock SL: Writing about testing worries boosts exam performance in the classroom. Science. 2011; 331: 211-213. 7. Sugar JG, Chu QD: Effect of January vacations and prior night call status on resident ABSITE performance. J Surg Educ. 2013; 70: 720-724. 8. West C, Kurz T: Are study strategies related to medical licensing exam performance? Int J Med Educ. 2014; 5: 199-204. 9. West C, Sadoski M: Do study practices predict academic performance in medical school? Med Educ. 2011; 45: 696-703. 10. Yan VX, Yu Y: Why does guessing incorrectly enhance, rather than impair,

retention? Mem Cognit. 2014; 42: 1373-1383. 11. Zhang J, Peterson RF, Ozolins IZ: Student approaches for learning in medicine: What does it tell us about the informal curriculum? BMC Medical Education. 2011; 11: 87. ( http://www.biomedcentral.com/14726920/11/87 ).

CHAPTER 2 The Psychiatric Interview EMILY K. GRAY, MD; BRADFORD M. LEWIS, MD; AND EUGENE V. BERESIN, MA, MD

KEY POINTS Introduction This chapter presents a comprehensive review of the shift in 2011 by the American Board of Psychiatry and Neurology (ABPN) shift in 2011 from the traditional, ABPN-administered oral board examination to a more decentralized and geographically local system of evaluation. Although this broad movement from regional to residency was designed to assess and provide meaningful feedback on the same core skills, the mechanics and pragmatics of the testing process has become the burden of individual training programs. Clinical Skills Verification (CSV) versus Annual Oral Examination (AOE) Format, Purpose, and Focus: Each examination’s global structure is detailed, as are targeted similarities and important differences between the two. Attention is paid to each test’s respective evaluation goals, standardized format, and clinical focus of evaluation. Testing Criteria and Grading: Fundamental aspects of the interview and case presentation are examined here. Quick establishment of patient rapport and effective conveyance by the trainee of the comprehensive clinical, diagnostic, and treatment pearls are discussed. An outline of the current grading methodology is provided, highlighting the ongoing, interpretive variability among residency educators today. Test Preparation, Practice, and the Script: Essential preparation tools and examination strategies are outlined. Utilizing these pearls, a well-prepared examinee will confidently and accurately present to the examiner a comprehensive and cohesive presentation in the time allotted. The CSV and AOE—Clinical Interview Provided in more detail are effective strategies to quickly establish rapport with the patient, as well as an interview structure that covers the essential

spheres of content in a short period. Themes of active listening, integrating the patient’s affective cues, and keeping all participants focused during the examination are discussed. An appreciation of interpersonal psychodynamics is coupled with the aforementioned skills to foster a stronger doctor–patient dialogue. The CSV and AOE—Case Presentation The importance of rapidly and effectively conveying an organized, logical, and comprehensive case presentation is addressed. Detailed here is how to demonstrate the structured presentation format integrating both DSM-5 nosology and key biopsychosocial elements. High-stakes clinical topics and strategies are highlighted. Furthermore, the Treatment Plan and its structural components as defined by the AOE are outlined and discussed. Helpful Tips on Presentation and Discussion Strategies for managing unexpected examiner questions during the oral presentation itself are covered, as well as tips for coping with test-taking anxiety.

Introduction In 2011, the ABPN eliminated the Oral Board Examination for psychiatry residents who entered training on or after July 1, 2007 (PGY-1) or July 1, 2008 (PGY-2). To become Board-eligible, residents are now required to pass three CSVs that are administered by the residency programs themselves at their respective training locations (www.acgme.org ). The previous, centralized oral examination format developed a reputation of conjuring substantial pre-test anxiety and subsequent notoriety of a relatively disappointing pass rate. Many examinees felt inadequately prepared after successful completion of residency training, ostensibly raising concerns about the adequacy and quality of individual training programs. In addition, the ABPN faced an increasing number of logistical concerns and financial burden just to maintain the examination process it created. Furthermore, some critics expressed concern that the examination format produced a “Hawthorne effect,” in which an individual’s testing performance did not reflect their true clinical skills, instead coloring the examinee’s behavior in the specific testing condition to produce a favorable outcome: a passing score.

Consequently, there was a significant shift toward objectively assessing one’s clinical skills throughout training , yielding an evaluation process more comparable to an examinee’s true clinical practice, involving real patients and providing real-time feedback. These evaluative objectives were then echoed in both the ABPN and the Accreditation Council for Graduate Medical Education (ACGME) clinical skills requirements: residents are now required to pass the CSV exams to become Board-eligible and the ACGME requires residency programs to administer CSVs as well as an annual oral examination AOE.

CSV versus AOE The CSV , developed by the ABPN, and the AOE , developed by the ACGME, serve to test similar yet different skills (see Table 2-1). The CSV was developed to assess competency in the following three core areas: the physician-patient relationship; the psychiatric interview (including a mental status examination); and case presentations (www.abpn.com/forms.html ). The AOE, as defined by the Psychiatry Review Committee of the ACGME, builds on the same core competencies but then also expands to include formulation with differential diagnosis and treatment planning. Given that the AOE has the three required portions of the CSV, it can serve as a CSV. However, the CSV, as defined by the ABPN, cannot serve as an AOE, because it lacks the formulation and treatment-planning components. Although the previous apprehension of preparing for the oral portion of the Board examination has been shifted to residency training, the videotape/audiotape format of the new Board examination draws on a similar skill set as the clinical interview, requiring the examinee to make observations, to postulate or appreciate issues of importance, and to consider elements of a mental status examination, formulation, and differential diagnosis, as well as to make treatment decisions. Therefore, the CSV and AOE are the best opportunity to prepare for this portion of the test. The purpose of this chapter is to help clarify the goals and objectives of both the CSV and the AOE and to help to provide a framework to approach the interview (including principles of preparation and presentation). Table 2-1: CSV versus AOE Assessed Competency Components CSV AOE Physician–patient relationship

✓

✓

Psychiatric interview

✓

✓

Case presentation

✓

✓

Formulation and differential diagnosis

✓

Treatment planning

✓

CSV: Clinical Skills Verification (required by ABPN and ACGME) AOE: Annual Oral Exam (required by ACGME)

Format The minimum CSV requirements (for both adult and child psychiatry) consist of a 30-minute interview of a live patient followed by a 10- to 15-minute case presentation (i.e., the evaluation session lasts 45 minutes). For the child psychiatry examination, the interview can last 45 minutes. Each of the three CSVs needs to be completed using a previously unknown patient that changes for each evaluation. The child psychiatry CSV requires that the three patients also need to fall into different age groups (pre-school, school-aged, and adolescent). The evaluator must be an ABPN-certified psychiatrist, and at least two different evaluators are required for the three verifications. There are two different versions of the verification form (Psych CSV v1 and Psych CSV v2; see Tables 2-2 and 2-3) provided on the ABPN website) and those of the American Association of Directors of Psychiatry Residency Training (AADPRT). See Tables 2-4 and 2-5 for sample evaluation forms developed by these organizations, respectively. Other programs might develop their own forms, but these forms must be approved by the ABPN.

Tables 2-4 and 2-5: Examples of CSV Forms Developed by the American Association of Directors of Psychiatry Residency Training (AADPRT)

The AOE has similar guidelines to the CSV regarding patient selection and the evaluators. However, there are no other explicit AOE requirements outside of the identified six skill areas of assessment, which include: 1) the ability to interview patients and families; 2) the ability to establish an appropriate doctor–patient relationship; 3) the ability to elicit an appropriate present and past psychiatric, medical, social, and developmental history; 4) the ability to assess the mental status; 5) the ability to provide a relevant formulation, differential diagnosis, and

provisional treatment plan; and, 6) the ability to make an organized presentation of the pertinent history, including the mental status examination (ACGME Psychiatry Training Requirements V.A.1 f)1-6). Some programs have made the AOE their standard clinical skills examination, using the three required parts of the CSV and then adding two sections (making all of the CSVs into AOEs). However, for purposes of the Boards, passing only the first three sections is required. The Massachusetts General Hospital Child and Adolescent Psychiatry (CAP) Clinical Skills Evaluation form (see Table 2-6) meets the requirements of the AOE (and includes sections that are necessary to meet the requirements for a CSV). The full version of the AOE is well suited to prepare you for the level of competency required in the Board examination. This form has been adopted by all three Harvard CAP programs. It was vetted by the ABPN and by the Psychiatry Review Committee and approved for clinical assessment. The MGH’s clinical skills evaluation consists of a 30-minute patient interview, followed by a 30-minute case presentation, formulation, differential diagnosis, and treatment plan. Following a similar protocol to the previous Oral Board Examination format, you will be introduced to the patient by name, but given no additional identifying data. There are no directions as to how to conduct the interview, and it is up to you to keep track of time. However, most residents and examiners have become familiar with the CSV assessment form that in some fashion outlines the major clinical issues that require assessment. Because the “long” AADPRT and MGH forms are quite specific in demonstrating the appropriate “anchors” in each area of the interview, we suggest that these forms be utilized as the most extensive and detailed educational experiences. Residents are encouraged to review them in detail, and faculty are required to have training either in their home institution or at a national meeting to develop some uniformity in rating residents. A five-minute warning can be given before the end of the allotted time for the interview; after the interview is complete, there will be a few minutes for you to collect your thoughts, before being asked to present the case. This interview is different from an office-based or inpatient diagnostic interview; it is more similar to that of an emergency room visit or a crisis intervention evaluation, and it is imperative that you become familiar with this format.

Purpose and Criteria for Evaluation The purpose of the clinical interview and the presentation is to demonstrate that you are a safe provider. The age-old standard of care, “physician, do no harm,”

was the gold standard of the Boards and is the spirit of the CSV and the AOE. However, we should ask, “What does safety in such an interview entail?” The best way to think of this is to imagine that the patient you are examining comes into your emergency room or office, and you have only 30 minutes to make a reasonable assessment and a plan for follow-up. Naturally, in such a short period of time spent with a complete stranger and without collateral sources of information, you need to look for the most serious problems, and to understand that, a fair amount of important clinical and historical information will be lacking. What does such an interview require? First, one needs to form an alliance around the situation at hand. The relationship with the patient (and the parent if the patient is a child or a teen and is present for the interview) is the single most important element in an attempt to collect accurate historical and current symptoms. In a clinical setting, the alliance would be formed around the nature of the crisis. You would naturally attempt to develop rapport and comfort, respecting and listening to the patient. The clinician should elicit present and past data relevant to the current illness and develop a differential diagnosis based on the data available, which will lead to a treatment plan. You would want to be sure that after the patient leaves your presence, you are confident that you have a good idea of the nature of the clinical problems, that the patient is in no imminent danger, and that your prescription for treatment and follow-up are consistent with the data collected. This is exactly what previous Board examiners, and now CSV and AOE assessors, are looking for. They want to see that you are careful, thoughtful, and, most important, that your clinical reasoning is based on the data collected, and that it is logical and clinically sound. If you are taking a three-part CSV, the examiner wants to be sure that you have established a strong relationship, have done a good interview and mental status examination (that includes collecting sufficient information to produce a sound formulation and differential diagnosis), and can present the case without necessarily producing the latter two sections. Based upon our experience, we strongly believe that the full AOE is the best CSV in that it provides not only the first three sections, but the additional components of a comprehensive review. The examiners are very interested in the way you think—the way you organize your clinical approach, and the way you base your clinical hypotheses on the data obtained. Examiners want to know that you have a logical, coherent, systematic way of organizing data, considering possible areas of concern that were not elicited in the interview.

Table 2-6: MGH CAP Long Forms

Focus Because you have only 30 minutes and the most important issue is safety, the primary concern is the present illness: its diagnosis, its differential diagnosis, and its management. After you feel comfortable knowing the current clinical situation, it is important to examine how it relates to the past psychiatric history; the medical history; and the developmental, family, and social history.

Grading Each section of the CSV is graded . Depending on the form, a resident must pass all three sections for the CSV to count as a successful examination. On the

short form, the examiner rates sub-sections under each section (using a scale of 1 to 8), and you need an average of ≥ 5 on all sub-sections (of each of the three major domains) to pass. For example, if you fall below a 5 on one section but score in the 7 to 8 range on all other sections, an examiner might grade the overall section with a passing grade. There is controversy in the field about this method. Some feel that an overall average is good enough for a resident to pass. Others argue that although a resident might rate highly on most sections, if he fails to ask critical questions, such as those relating to high-risk behaviors (e.g., suicide, homicide, trauma, and substance abuse), this trumps the overall average. This debate extends beyond the psychiatric CSV to all oral examinations. We believe that the averaging method is viable; however, critical errors can result in personal danger or danger to others, and this over-rides the average score.

Preparation and Books to Review Although examiners are interested in your presentation being supported by a solid knowledge base, they are not interested in psychiatric facts and figures from the literature. The best study guide is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); you should formulate your presentation using the criteria outlined within this manual. In such a short interview, you will have time to collect only the sufficient data to produce a reasonable differential diagnosis (not asked for in the CSV) and to run though plausible diagnostic criteria in an AOE. Details of the epidemiology, course, and co-morbidities are not required for these exams. It also might be helpful to read the DSM-5 Clinical Cases to see how data is put together from clinical vignettes. You do not need any other “book” study.

Practice To successfully navigate the required CSVs (acceptable in each of the three core competencies), practice is crucial . The same is true for the AOE. There are no penalties for an unacceptable performance on these exams, and the residency program takes on the responsibility of administering any needed remediation activities. In fact, we recommend CSVs or AOEs on as many services as possible throughout training. A major goal of the ABPN and ACGME for these exercises is to generate observational feedback and evaluation in real time with real patients. The intent is to begin to make in-residency “examinations” a seamless part of integrated clinical care and assessment. Even though they count

as “examinations,” they should also be educational experiences. The “gold standard” would be an ongoing real-time assessment with an outcome assessment of patient care. This process significantly reduces the pressure and stress of the evaluation. One important reason for failing the Oral Boards in years’ past was being unfamiliar with the format and practicing too little. You should practice several of these special interviews to become comfortable with the time limitation of the interview as well as the stress of conducting an observed clinical examination and presentation. It would be best to find Boardcertified colleagues who you do not regularly work with (to simulate the stress of evaluation by attendings who do not regularly supervise your clinical care). They should make the practice examinations as close to the real thing as possible: use patients unknown to you, and do not have them give feedback until after the interview and the discussion.

Script It is essential to prepare and practice a systematic way of handling the interview , the presentation, and the discussion. This amounts to a model for establishing a relationship with the patient, gathering data, presenting the psychiatric history, the mental status examination, the differential diagnosis, and the treatment plan. A script is essential because it represents an outline of clinical categories and, therefore, you can readily discern any gaps in the interview or discussion because they will be left out of the conceptual framework. We recommend the standard medical model for taking the history and the biopsychosocial model for discussion of the differential diagnosis. When presenting the case, it is helpful to think back to your presentations during internship, as in the following example: Chief Complaint: This is a 64-year-old married Caucasian female presenting with shortness of breath, three pillow orthopnea, four-plus pitting edema, and palpitations. History of Present Illness: Cardiac: Mrs. Jones sustained her first myocardial infarction 4 years ago, having complained of progressive angina. She was brought to County General… Trainees were questioned by the attending physicians about their clinical reasoning. This is exactly the mind and skill set needed for excellent performance in the CSV.

The Clinical Interview

The clinical interview’s form and scope is influenced by the doctor–patient relationship.

Doctor–Patient Relationship (CSV and AOE) The doctor–patient relationship is an essential element in any patient encounter, and forming an alliance is critical for this evaluation. During the process of obtaining a history, the examiner is looking at your ability to establish rapport, to follow the patient’s lead, to ask relevant questions, and to control the direction of the interview. Establishing rapport is a crucial part of being a safe, effective psychiatric history-taker and treater. Before conducting the interview, you should consider the setup of the room, making adjustments to the seating so that you can help the patient feel comfortable in the environment as well as thinking of safety for both the patient and yourself. Introduce yourself, and explain the nature of the interview. Cooperation should be invited. For example: Hello, my name is Dr. Beresin. Has anyone told you about the nature of this interview? Let me explain. I am taking a clinical examination, and this doctor is watching me to see how effective I am in talking with you and understanding your problems. I want to thank you for coming here today. If there is anything you do not feel comfortable talking about, please feel free to tell me, and you do not have to talk about it. We will have 30 minutes to talk, and so there might be times that I will interrupt you, for the sake of time, and at the end I will offer you a chance to ask me any questions you have. Form an alliance around the task of exploring the current illness. Help the patient feel comfortable. Demonstrate politeness, empathy, concern, responsiveness, and respect. Respond honestly to the patient’s questions/comments. Thank the patient for cooperating. Maintain eye contact and avoid using medical/psychiatric jargon. If you’re used to taking notes, this is not a problem, so long as you maintain eye contact and do not look down too much.

Conducting the Interview It is crucial to appreciate that no interview of this nature can be complete— some data will not be obtained. Moreover, you need to be flexible with different patients and, in the case of children and adolescents, with different

developmental stages. Remember, if questions are not asked or data is not collected, there is always an opportunity to make up for this in the presentation. After your introduction, begin with open-ended questions for about five minutes. For example, you could begin with, “What concerns brought you to the clinic today?” and after the patient has had time to fully respond, follow with, “anything else?” It is valuable to see what is most important to the patient, and what his/her associations entail. This can give you important clues about diagnosis and/or disposition. In addition, it gives you an opportunity to demonstrate empathic skill, respect, and concern for the patient’s priorities (following their informational cues). Furthermore, from a psychodynamic standpoint, which is still highly valued by examiners, you can develop a window into the mindset as well as cognitive and affective styles of the patient. After the initial five minutes, you should start to hone in on specific areas of concern and detailed questions. A simple statement that affirms the patient and then refers to the time limitations and the goal of the interview can help frame this transition. For example: Ms. Smith, it sounds like this has been a difficult time for you, and I feel like what you are sharing is important. However, we need to keep in mind that we only have 30 minutes to speak and there are some specific areas I do not want to miss. When patients ramble, or are tangential or circumstantial, gentle re-direction is often necessary. The examiner is assessing your ability to control and direct the interview while following the patient’s informational and affective cues. Focus on the primary concern, the present illness (e.g., symptoms, precipitants, social setting and supports, current and past treatment, and complications). Listen to the patient: follow that patient’s leads, be flexible, and clarify the patient’s use of terms (e.g., Patient: “I was really nervous”; Examiner: “What do you mean by nervous?”) and deal sensitively to the patient’s affective responses. Collect relevant clinical data (if possible) such as past psychiatric history (previous disorders, therapies, hospitalizations, medications [their benefits and adverse effects]), suicide ideation and attempts, homicidal ideation, alcohol and drug use), medical history, family history (particularly psychiatric history), development, social history (including marital history, work, and interpersonal relationships). Never forget to ask about the potential for suicide and homicide, trauma (including physical and sexual abuse), as well as alcohol and drug use. Remember that the mental status examination is a cornerstone of the

psychiatric interview. This should be a core part of the interview—but you should spend no more than five minutes on this component, because much of the differential diagnosis will be based on the history. Whether to perform a formal cognitive examination is controversial; however, it is essential to perform an organized, brief assessment of cognition. You should perform this type of highly structured examination if there is any suspicion for an organic etiology or for psychosis, with or without depression. If you do not perform a formal cognitive examination, you should be able to say why it was not necessary; for example: I did not perform a formal, quantifiable cognitive examination, such as the Mini-Mental State Exam, because the patient was lucid, well-oriented, and in his/her normal conversation there was no evidence of a thought disorder, or impairment in memory, attention, concentration, or judgment. When in doubt, perform the examination. Always close the interview by asking the patient if he/she has any questions and by thanking the patient for their participation.

The Case Presentation (CSV and AOE) Format You should begin with a formal, concise, medical-style presentation that includes the following categories. If data is not available in a particular category, you should make mention of this and include a statement that indicates which material you would have obtained if you had more time. This signals to the examiners that you know what is needed in each relevant area. Figure 2-1 offers a schematic for the format for both a core CSV as well as the addition of elements adapted by the AOE. This is one of the most challenging parts of the presentation. What follows are a few tips for a coherent, inclusive biopsychosocial case discussion. Begin with the descriptive signs and symptoms. Build your diagnostic possibilities around constellations of specific symptoms. In other words, move from the specific to the generic. Begin with the most likely possibilities and consider the pros and cons of all other possible psychiatric conditions. You should look at all categories, even the very unlikely ones. A core concept for this exam is the following: If you do not mention a diagnostic or treatment category, the examiners will assume that you did not know it exists. Thus, it is imperative

to be over-inclusive. You should incorporate all diagnostic categories from the DSM-5 into the discussion. Although the DSM-5 no longer utilizes the five axes framework, the current model has considered that categories might not be discrete, but rather a continuum that combines the first three axes into an area of consideration, and maintains Axes IV and V; thus, it is still recommended to use the multi-axial framework as the script for the discussion. Always run through the major mental diagnoses, ruling-in or ruling-out major illnesses (such as schizophrenia, mood disorders, substance-related disorders, anxiety disorders) including each of the sub-categories of disorders within each of the major classes. This is best thought of as the psychiatric biological axis . In addition, take into account intellectual disability as well as personality traits or disorders and include a psychodynamic formulation. Despite our reliance on DSM-5 for psychiatric nosology, good clinical care requires an understanding of the inner world of the patient. Although it is often difficult in a 30-minute interview to make a personality disorder diagnosis, or fully understand the complexity of intrapsychic structure, this is a place to discuss hypotheses about common defense mechanisms, personality trait disturbances, and possible intrapsychic conflicts, all of which can be important in treatment planning and determination of a prognosis. Finally, consider possible medical illness that might be causes or complicating entities in the clinical picture. Drug-drug interactions, allergies, and other medical issues should be raised here. The second area of importance is to discuss the social/environmental and cultural dimension (e.g., the nature of object relations, the impact of ethnicity and cultural heritage, the precipitants, supports, life stressors). It is always useful to attempt to rate an approximate current level of disability and global assessment of functioning (GAF) or you can utilize the World Health Organization Disability Assessment Schedule (WHODAS 2.0). The key to the discussion is to let the examiners know that you have an organized way of moving from specific clinical data through the various diagnostic possibilities and that you consider and integrate the biological, psychological, and social/environmental/cultural components of psychiatric health and illness. An important concept to keep in mind is that making the “correct” diagnosis is not as crucial as having a systematic approach to obtaining it. It is always valuable to indicate your omissions; for example, “I would have liked to explore

this area further, if I had more time,” or, “I didn’t ask about _______, and this might have helped establish a diagnosis of ________.” It is essential to provide a safety assessment in the formulation. This assessment should consider both the patient’s strengths as well as risk factors that contribute to their level of risk. Risk assessment can vary over time. Keep things simple: use a system that specifies low, moderate, and high ranking, along with the descriptors that contribute to the assessment. This is also where you can use countertransference to describe a “gut” feeling.

Treatment Plan (AOE) Be sure the treatment plan includes multi-modal components. Remember that each modality has multiple specific components, and each should be mentioned, even if not appropriate for the case at hand. Along with each recommendation, a risk and benefit analysis should also be considered and, if important, articulated with the presentation. Figure 2-2 outlines the essential domains of a comprehensive treatment plan as defined by the AOE, along with common examples that can be utilized as part of a multi-faceted treatment approach.

Helpful Tips on the Presentation and Discussion Interruptions and Questions Remember to keep the script in mind for the history and differential diagnosis. Begin with the formal presentation, as indicated earlier. The examiners will, at times, interrupt and ask questions. Do not assume that you have made an error or that the examiners are questioning your reasoning. There are many reasons why examiners ask questions. It is not up you to figure them out. Try not to become rattled by interruptions. It is most useful to respond to an examiner’s questions and then continue where you left off with your scripted presentation (again, a structured script is very reassuring in such situations, particularly if you are answering a difficult question). It is vital to demonstrate that you know the basics about psychiatric diagnosis and treatment. Then, if time permits, and if based on the nature of their questions you feel that the examiners want you to go into greater depth, you can discuss the fine points, controversial issues, or current research data. For the most part, such detail is beyond the scope, goals, and objectives of this examination. If you do not know the answer to a question, do not attempt to guess. Such a response is an indicator that you might not be safe. It is important to be comfortable saying, “I don’t know the answer to that question, but I would get

assistance by asking an expert colleague, looking up the topic in _____ journal or ______ textbook.” Making references to specific journals, articles, or texts is useful here. Remember, the examiners do not expect you to know everything, and the hallmark of a safe physician is knowing where to quickly get the information needed and appropriate consultations.

Coping with Anxiety With the elimination of the Oral Boards, the pressure and anxiety of an observed interview has now shifted into residency . The CSV and AOE can bring about severe anxiety, especially if this is the first time you have been examined in this format or if you have had difficulty passing previous CSVs. In either of these cases, it is useful to practice the clinical exam to know what makes you anxious (e.g., which types of patients, which countertransference responses, what kinds of questions from examiners). After you discern the factors that heighten your anxiety, you should practice a desensitization approach by facing such situations before the CSV. For example, if you have problems interviewing rambling, vague, and tangential patients, find as many of these patients as possible to interview ahead of time. Beyond desensitization, there are other techniques to reduce anxiety (e.g., deep breathing before the exam or talking to yourself to calm down). For some, note-taking in a scripted format helps. For example, dividing your pad into three vertical sections, one for obtained clinical data, one for missing data, and one for diagnostic categories might help. The most important form of self-reassurance is to know that you have done many other exams successfully and you know what works well for you. An important method for reducing anxiety is keeping good track of your time. Too often, under pressure, an examinee loses sense of time and, upon hearing there remains only five minutes, needs to cram in a cognitive examination as well as cover several specific questions for one or more diagnostic categories. Monitor your style under stress. Each of us invokes coping mechanisms under pressure. Be sure to appreciate the ways that you tend to react to stressful situations. Some examinees become argumentative, joke, or provide noncommittal or vague responses in examination situations. Practice examinations are the best ways to determine how you tend to respond under such conditions. If you disagree with an examiner (e.g., where you know the literature on a topic in depth and could get into a controversial discussion or argument with the examiner) it is best to avoid power struggles and to proceed with conventional clinical wisdom and to avoid controversy.

Suggested Readings 1. Beresin EV, Gordon C: The psychiatric interview. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby Elsevier; 2016: 8– 19. 2. Beresin E, Phillips M, Gordon C: The psychiatric interview. In: Stern, TA, Fricchione GL, Cassem NH, et al, eds.: The Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Mosby Elsevier; 2010: 25–38. 3. Gordon C, Beresin EV: The doctor-patient relationship. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby Elsevier; 2016: 1–7. 4. Gordon C, Phillips M, Beresin E: The doctor-patient relationship. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: The Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Mosby Elsevier; 2010: 15–23.

Approach to Psychiatric Diagnosis and Psychiatric Conditions

S E C T I O N T W O

CHAPTER 3 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition JUSTIN A. CHEN, MD, MPH AND SUNI JANI, MD, MPH

KEY POINTS Overview The DSM has undergone multiple revisions since the publication of its first edition in 1952. The most recent edition, DSM-5, was published in May 2013, following a 14year revision process. It replaced the previous edition, DSM-IV-TR. DSM-5 Revision Process The revision process began in 1999 with a report commissioned by the APA evaluating DSM-IV-TR’s strengths and weaknesses. The report was published in 2002 as A Research Agenda for DSM-V . Field trials were conducted to test the reliability of proposed diagnostic criteria, including for the first time in two contrasting settings: large academic medical centers and routine clinical practices. DSM-5 for the first time included a public review process in which proposed changes in diagnostic criteria were posted on the Internet and feedback was solicited from the public, including mental-health clinicians, patients, and mental-health advocates. Organization DSM-5’s organization is intended to improve clinical utility and facilitate research into relationships and patterns among mental illnesses. The manual is divided into three major sections and an appendix. Section I introduces the organizational structure of the manual and describes changes from DSM-IV-TR, including the revision process. Section II lists the 541 Diagnostic Criteria Codes. Section III provides additional tools and techniques to enhance the process of clinical decision-making. The Appendix contains

glossaries of technical terms and cultural concepts of distress. The Diagnostic Criteria in Section II are divided into 20 chapters, organized sequentially using alpha-numeric codes, with conceptually-related disorders located adjacent to one another. The diagnoses have been harmonized with the World Health Organization’s International Statistical Classification of Diseases and Related Health Problems , 10th Revision (ICD-10). The total number of chapters has increased, and new chapters have been created to group disorders based on shared neurocircuitry pathways (e.g., Obsessive-Compulsive and Related Disorders.). Major Conceptual Changes DSM-5 has eliminated the multi-axial diagnostic system. Diagnosis now consists of the former Axes I-III; that is, psychiatric diagnoses, including personality disorders, as well as any medical conditions that might have a bearing on the individual’s mental illness. The former Axis IV is replaced using specific relevant ICD-10-CM “Z codes” corresponding to psychosocial and contextual factors affecting illness. The former Axis V Global Assessment of Functioning has been replaced by a global measure of disability, the WHODAS 2.0. DSM-5 adopts a dimensional, clustering approach to diagnosis with the intention of facilitating research geared toward gaining a better understanding of pathophysiology and commonalities among disorders. DSM-5 provides an enhanced focus on the role of culture in psychiatry. Within the text discussions of each disorder, multi-cultural explanations for similar symptoms are directly cross-referenced. The term “culture-bound syndromes” has been eliminated and replaced by three related concepts: cultural syndrome, cultural idiom of distress, and cultural explanation or perceived cause. Diagnostic Changes Some chapters bring together diagnoses that were formerly scattered through other chapters (e.g., the new chapter on Neurodevelopmental Disorders encompasses Autism Spectrum Disorder, Intellectual Developmental Disorder, Attention-Deficit/Hyperactivity Disorder, and Tic Disorders). Other chapters were created based on improved understanding of underlying shared neurocircuitry pathways (e.g., Obsessive-Compulsive and Related Disorders now constitutes its own chapter rather than being subsumed under the broader category of Anxiety Disorders). The diagnosis of schizophrenia now requires two or more Criterion A symptoms for a significant portion of the time during 1 month.

The diagnosis of bipolar disorder now requires both elevated, expansive, or irritable mood and increased goal-directed activity or energy. The grief exclusion has been eliminated for Major Depressive Disorder. Acute Stress Disorder and Post-traumatic Stress Disorder no longer require Criterion A2 (that “the person’s response involves intensive fear, helplessness or horror”). Somatic Symptom Disorder replaces multiple former diagnoses, including Somatization Disorder, Hypochondriasis, Pain disorder, and Undifferentiated Somatoform Disorder. There is also less emphasis on which specific symptoms must be present to establish the diagnosis, and more emphasis on the distress the symptoms cause as well as abnormal thoughts, feelings, or behaviors in response. Several disorders have been expanded to apply to all ages (e.g., Pica, Rumination Disorder, Avoidance/Restrictive Food Intake Disorder). The former chapter “Sexual and Gender Identity Disorders” has been separated into three distinct chapters: Sexual Dysfunctions, Gender Dysphoria, and Paraphilic Disorders. Substance Abuse and Substance Dependence have been combined into the broader diagnosis of Substance Use Disorder, with severity determined by the number of criteria met by the individual with the disorder. Personality Disorders have remained categorical and largely unchanged, though a dimensional approach is included for further study in Section III. Criticism and Controversy Like prior revisions of the manual, DSM-5 has been criticized for contributing to the over-pathologization of ordinary human experience and the propagation of “fad diagnoses.” Unlike prior revisions, DSM-5 also has been criticized for its decision to collapse certain diagnoses into more dimensional categories. For instance, consumer groups argued that patients formerly diagnosed with Asperger’s Disorder under DSM-IV-TR but who no longer meet criteria for the same diagnosis under DSM-5 might be at risk of losing eligibility for services.

Introduction The Diagnostic and Statistical Manual of Mental Disorders (DSM ) is one of the most well-known and widely utilized psychiatric classifications in the world. Since the release of its first edition in 1952, the American Psychiatric

Association (APA) has continued to maintain a central role in over-seeing and publishing successive revisions of the manual. From 2000 to 2013, the version of the DSM in widespread use was called DSM-IV-TR (the text revision of the fourth edition). The nearly 400 disorders and associated diagnostic criteria laid out in this manual had been utilized for more than a decade by a variety of stakeholders to serve a wide range of functions, including communication between mental health and other medical professionals, forensic and legal affairs, clinical and basic research, epidemiology and public health applications, and reimbursement by third-party payers. The fifth and latest edition of the DSM, published in May 2013 following a 14year revision process, is referred to as the DSM-5. This edition was the result of significant collaborative and leadership efforts, including the 1999 APA and National Institute of Mental Health (NIMH) Research Planning Conference as well as a 2007 Task Force convened by the same organizations and responsible for developing and testing new proposed classification changes. Although an exhaustive analysis of updates and changes in DSM-5 is beyond the scope of a single chapter, in Table 3-1, we attempt to summarize the most salient points. We begin by describing the revision process itself, then provide an overview of the organization of the manual, major conceptual changes, a summary in table format of specific diagnostic changes (with side-by-side comparisons between DSM-IV-TR and DSM-5), and controversy. DSM-IV-TR and DSM-5 differ in their basic definitions of mental illness. Like DSM-IV-TR, DSM-5 describes mental illness as a clinically-significant disturbance in cognition, emotion, or behavior that results from a dysfunction, as opposed to mere clusters of symptoms. However, DSM-5 notes the dysfunction must be the result of psychological, biological, or developmental processes that contribute to mental illness, and cannot merely reflect behavioral dysfunction, as was permissible in DSM-IV-TR. DSM-5 also notes that mental disorders are “usually associated with” social or occupational distress but no longer requires such distress for evidence of the disorder. Both DSM-IV-TR and DSM-5 agree that an expected or culturally-sanctioned response to a common stressor is not a mental disorder, but DSM-5 now explicitly states that socially-deviant behavior (e.g., of a political, religious, or sexual nature) that does not result from an individual dysfunction is also not a mental illness. Finally, DSM-5 acknowledges that “boundaries between disorders are more porous than originally perceived” and notes that many, if not most, disorders

exist on a spectrum with one another. The updated organization and “dimensional approach” of the manual reflects this understanding.

The DSM-5 Revision Process In 1999, the APA commissioned an extensive evaluation of DSM’s strengths and weaknesses, in collaboration with key stakeholders including the World Health Organization (WHO), the World Psychiatric Association, and the NIMH. The results of these investigations were published in 2002 as A Research Agenda for DSM-V . In 2006, the APA named David J. Kupfer, MD, as chair of the DSM-5 task force, and Darrel A. Regier, MD, MPH, as vice-chair. Kupfer and Regier then recommended chairs for the 13 diagnostic work groups as well as additional task force members, all of whom underwent an additional screening process overseen by the APA Board of Trustees to avoid conflicts of interest, particularly financial. The final task force included 28 members; the work groups comprised more than 130 voting members, with an additional 400 nonvoting members. Each work group developed proposals for revision of diagnostic criteria within their purview based on literature reviews, professional expertise, and the findings of the 2002 Research Agenda . Subsequently, field trials were conducted to empirically demonstrate reliability of the proposed diagnoses—a practice that has been in place since DSM-III. Unique to DSM-5 was the implementation of field trials in two contrasting settings: 1) large, diverse academic medical centers throughout North America, and 2) routine clinical practices (using volunteer clinicians in the community, who ranged from psychiatrists to licensed clinical social workers). Another unique feature of DSM-5 was the inclusion of a public review process. The APA launched a website in 2010 (dsm5.org) which posted for a 2-month period all draft proposals for diagnostic criteria to facilitate open feedback, including feedback from patients and mental health advocates. The more than 8,000 on-line submissions were systematically reviewed and incorporated as revisions. The APA carried out a second posting in 2011. The DSM has always been designed with the conscious goal of promoting concordance with the WHO’s International Statistical Classification of Diseases and Related Health Problems , or the ICD. The ICD is an internationally-utilized medical classification and clinical communication system used for the coding of diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or disease. The ICD includes a

standardized code for diagnosis of medical and psychiatric disorders worldwide, while acknowledging that language, culture, and approach to treatment can vary significantly from one country to another. DSM-5 is specifically designed to harmonize with the eleventh revision of the ICD (ICD-11). However, because at the time of DSM-5’s release ICD-11 was not yet in use, the manual lists codes from the ICD-10, clinical modification (ICD-10-CM), within each disorder’s description (generally, a letter followed by a number in gray font—e.g., F42 for Hoarding Disorder) as well as the older ICD-9 codes. Because ICD codes are generally preferred in the United States for the purposes of reimbursement by third-party payers (i.e., public and private health insurers), this in-text crossreferencing presents a useful feature for clinicians.

Organization DSM-5 is organized into three major sections and an appendix. Section I introduces the organizational structure of the manual and provides a more comprehensive discussion of the changes from DSM-IV-TR. Section II lists the 541 Diagnostic Criteria Codes. Section III provides additional tools and techniques to enhance the process of clinical decision-making, including the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), the Cultural Formulation Interview (CFI), alternative models for personality disorders, and conditions requiring further study (e.g., Attenuated Psychosis Syndrome). Finally, the Appendix contains several glossaries of technical terms and cultural concepts of distress, which have replaced the former nomenclature of “culture-bound syndromes” as well as more condensed listings of DSM-5, ICD-9, and ICD-10 diagnostic codes. The grouping and organization of disorders was not generally considered scientifically important in previous versions of the DSM. However, the creators of DSM-5 viewed enhancement of the manual’s organization as a key priority for both improving its clinical utility and facilitating research into relationships and patterns among mental illnesses. The DSM-5’s introductory chapter explains that this focus on organization was conceived at least in part to address high rates of co-morbidity within and across DSM chapters. This was done to reduce clinicians’ reliance on the “not otherwise specified” (NOS) criteria and to improve integration with the latest scientific research findings that shed light on common neural substrates underlying psychiatric disorders. To those ends, DSM-5 adopts a greater focus than DSM-IV-TR on genetic risk factors, family traits, biomarkers, temperamental antecedents, processing abnormalities, illness

course, co-morbid factors, and shared treatment response. Chapters in the revised manual are organized sequentially using alpha-numeric codes, with conceptually-related disorders located adjacent to one another. All 20 chapters share a similar format based on developmental stages, beginning with disorders typically diagnosed in childhood, followed by adolescence, adulthood, and later life. The separate chapter in DSM-IV-TR, “Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence,” has consequently been eliminated. The total number of chapters has increased in order to improve the classification of disorders based on known similarities or to improve representative nosology. A key example of this is the new Neurodevelopmental Disorders chapter, which includes autism spectrum disorders, intellectual developmental disorder, attention-deficit/hyperactivity disorder, and tic disorders such as Tourette’s Disorder. Based on their distinct neurocircuitry pathways, new chapters were also created for ObsessiveCompulsive and Related Disorders, Depressive Disorders, and Bipolar and Related Disorders, which previously had been subsumed under the less-specific categories of Anxiety Disorders and Mood Disorders. In this way, DSM-5 represents an attempt to move away from a purely phenomenological organizational scheme, toward a more neurobiologically-coherent framework, in line with recent calls from the National Institute of Mental Health Research Domain Criteria (RDoC) project.

Major Conceptual Changes Elimination of the Multi-Axial System DSM-5 has eliminated the diagnostic system that uses five separate axes, which was introduced in DSM-III. Under the new system, the psychiatric diagnosis is established by combining the former Axes I through III—i.e., psychiatric diagnoses, including personality disorders, as well as any medical conditions that might have a bearing on the individual’s mental illness. This simplified diagnostic scheme is an attempt to demonstrate the equal importance of primary mental illness, developmental conditions, and medical conditions contributing to the patient’s presentation. The former Axis IV, representing psychosocial and contextual factors affecting illness, is replaced using specific relevant ICD-10-CM “Z codes.” Finally, the former Axis V Global Assessment of Functioning has been eliminated (due to questionable psychometric properties and conceptual lack of clarity) and replaced by a global measure of disability, the

WHODAS 2.0. The DSM-5 Disability Study Group determined that this instrument, developed by the International Classification of Functioning, Disability, and Health (ICF), was the best current measure of disability for routine clinical use as opposed to payer justification.

Dimensional Approach to Diagnosis DSM-5 cites the preponderance of NOS diagnoses under earlier editions of the manual to argue that traditionally too much emphasis has been placed on excluding false-positive diagnoses, resulting in categories that were overly narrow and not clinically useful—especially in the areas of eating disorders, personality disorders, and autism spectrum disorders. Additionally, in light of increasing scientific research calling into question the categorical structure of prior editions of the manual, DSM-5 has moved toward a dimensional, “clustering” approach to diagnosis based on the best available knowledge (see the section “Diagnostic Changes ,” coming up in this chapter). Such groupings are created with the intention of facilitating future genetic, neurobiological, and epidemiologic research geared toward gaining a better understanding of pathophysiology and commonalities between disorders. In this way, DSM-5 is designed as a framework for ongoing adaptation based on future discoveries—a “living document.”

Expanded Emphasis on Culture Some of the most significant conceptual changes in DSM-5 are in the area of cultural psychiatry. DSM-5 explicitly states that “all forms of distress are locally shaped, including the DSM disorders.” As such, rather than being appended to the manual, multi-cultural explanations for similar symptoms are directly crossreferenced within the discussion of each disorder (e.g., the description of Panic Disorder contains a discussion of ataque de nervios and refers the reader to the glossary of common cultural syndromes). The concept of “culture-bound syndromes” has been eliminated, and replaced by three related concepts that are proposed to have greater clinical utility: cultural syndrome, cultural idiom of distress, and cultural explanation or perceived cause. However, a “Glossary of Cultural Concepts of Distress” is still included in the Appendix, and outlines some of the most common cultural syndromes familiar from DSM-IV-TR. Finally, the Cultural Formulation Interview (CFI) has been updated to be more practical for clinicians. These changes are reviewed in greater detail in Chapter 81 .

Diagnostic Changes Like DSM-IV-TR, DSM-5 is a descriptive classification system outlining specific clinical features that must be present for the reliable diagnosis of a disorder by a clinician. DSM-5 adopts a more dimensional approach commonly seen in other medical specialties by allowing the incorporation of symptom severity, with the goal of discouraging the use of NOS diagnoses for cases that don’t meet the full criteria for a particular condition. Both DSM-IV-TR and DSM-5 allow multiple diagnoses for individuals who present with symptoms that meet criteria for more than one disorder, with the caveat that a more pervasive disorder accounting for both sets of criteria might be present. Certain disorders might not be diagnosed if another primary mental or medical illness is present. Neither DSM-IV-TR nor DSM-5 address etiology or treatment. Table 3-2 presents a summary of major changes. Note that the chapter headings and disorders listed in the leftmost column reflect the updated DSM-5 nomenclature. This table is intended to highlight major changes; it does not provide full criteria for any diagnosis or provide an exhaustive list of all diagnoses.

Criticism and Controversy The DSM frequently finds itself the subject of significant debate and controversy, within the mental health field as well as in the lay press. A common criticism is that the steady proliferation of diagnosable mental conditions leads to the “pathologization of ordinary life.” DSM-5 was no exception to this attack, but it also experienced the reverse charge due to its decision to collapse certain diagnoses into more dimensional categories. For instance, consumer groups argued that patients formerly diagnosed with Asperger’s Disorder under DSMIV-TR and who no longer met criteria for the same diagnosis under DSM-5 might be at risk of losing eligibility for services. Allen Frances, the psychiatrist and chair of the task force that produced DSM-IV, has been vocal in joining the chorus of voices arguing that DSM-5 over-pathologizes ordinary human experiences (citing for example removal of the grief exception from the diagnostic criteria for MDD) and contributes to “fad diagnoses.” He also argues that the APA has an inherent conflict of interest in both creating and benefiting from the profits of a scientific manual whose use is intended for the public trust.

References 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Press; 2013. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 4th ed. Washington, DC: American Psychiatric Press; 1994. 3. Blashfield RK, Keeley JW, Flanagan EH, et al: The cycle of classification: DSM-I through DSM-5. Annual Review Clin Psychology . 2014; 10: 25–51. 4. Donovan AL, Kearns ME: The DSM-IV: A multi-axial system for psychiatric diagnosis. In: Stern TA, Herman JB, Gorrindo T, eds. Massachusetts General Hospital Psychiatry Update & Board Preparation, 3rd ed . Boston: Massachusetts General Hospital Psychiatry Academy; 2012. 5. Feighner JP, Robins E, Guze SB, et al: Di agnostic criteria for use in psychiatric research. Arch Gen Psychiatry . 1972; 26: 57–63. 6. Nemeroff CB, Weinberger D, Rutter M, et al: DSM-5: A collection of psychiatrist views on the changes, controversies, and future directions. BMC Medicine . 2013; 11: 202.

CHAPTER 4 Child and Adolescent Development ANDREA E. SPENCER, MD AND ANNAH N. ABRAMS, MD

KEY POINTS Overview This chapter outlines normal childhood development and environmental stressors that can affect the continuum of development from infancy through adolescence. Theoretical Basis Object Relations Theory describes how an infant’s relationship to primary caretakers shapes later relationships. Major theorists include Melanie Klein and Donald Winnicott. Attachment Theory refers to the bonding between infant and caregiver. Mary Ainsworth observed three attachment patterns and John Bowlby described separation anxiety. In Separation-Individuation Theory , Margaret Mahler outlined phases of an infant’s dependence on an ultimate ability to separate from the caregiver. In his Psychosexual Model of Development , Sigmund Freud described five psychosexual stages through which a child must successfully progress to avoid later psychopathology. Erik Erikson’s Epigenetic Theory presents eight stages of psychosocial development that a child must complete to avoid future psychosocial problems. Jean Piaget described a four-stage theory of Cognitive Development . Chess and Thomas’ Theory of Temperament describes a child’s innate personality style, examined also by Jerome Kagan in studies of infant reactivity. Theorists of Moral Development include Lawrence Kohlberg and Carol Gilligan. Environmental Influences

The environment plays an important role affecting normal development. Significant stressors include separation from caregivers, child maltreatment, bullying, and the media. Brain Development Recent technological advances are rapidly improving our understanding of brain development, including the maturation process of white matter (axonal growth and myelination) and gray matter (synaptogenesis followed by synaptic pruning) as well as the biological basis of adolescent risk-taking.

Introduction This chapter outlines the normal development of a child, which occurs along a continuum. Each age group is associated with physical, social, sexual, and cognitive changes. Pediatricians and child psychiatrists use developmental screening tests to measure (monitor) the developmental tasks a child should achieve by a given age. Table 4-1 outlines the developmental milestones as might appear in a screening test. Theories of child development describe and explain the social, sexual, and cognitive changes that occur for the child. The most often-cited theorists in child development include Sigmund Freud, Erik Erikson, and Jean Piaget, who are discussed here. Table 4-2 provides an overview of each theorist’s approach to the development of the child. Table 4-1: Developmental Milestones that Might be Used in Screening Tests Age

Social

6 weeks

Social smile

2 months

Recognizes mother

Gross Motor

Fine Motor

Language

Follows past mid-line

Responds to bell

Sits with head steady Reaches for object

4 months

Rolls over

Holds a rattle

6 months

Sits alone

Passes cube hand to hand Laughs

Stranger anxiety

Stands

Thumb-finger grasp

Plays peek-a-boo

Creeps

Drinks from a cup

Walks

Dada/mama specific

Throws ball overhand Four-cube tower

Combines two different words

8 to 10 months

12 months

14–18 months Imitates housework

Coos

Dada/mama non-specific

24 months

Plays interactive games

Rides a tricycle

3 years 4 years

Dresses with supervision Hops on one foot

Eight-cube tower

Knows 50-plus words

Copy a “0”

Gives first and last name

Copy a “+”

Recognizes colors

Draws man in three parts 5 years

Dresses alone

Copies a square

Table 4-2: Theorists ’ Approach to Child Development

Ages Birth to 12 months

Cognitive Stages — Psychosocial Stages— Piaget Erikson

Psychosexual Stages— Freud

Sensorimotor stage

Trust versus mistrust

Oral

Autonomy versus shame

Anal

1 to 2 years

Doubt 3 to 5 years

Pre-operational thought

Initiative versus guilt

Phallic

6 to 10 years

Concrete operations

Industry versus inferiority

Latency

11 to 18 years

Formal operations

Identity versus role confusion

Adolescence

Infancy Infancy begins at birth and lasts until the child is verbal (age 2-plus years). During this phase, the major emotional milestone is attachment. Attachment is the connection that develops between the infant and the primary caretaker. Bowlby and Mahler are key theorists who describe the stages of attachment and separation. Multiple developmental milestones in social, motor, and language skills are met (see Table 4-1).

Pre-School (Ages 2½ to 6 Years) Important aspects of the child’s emotional and cognitive development during the pre-school phase include egocentricity, magical thinking, and body-image anxiety. Egocentricity is the child’s perception that all life events revolve around him. Magical thinking is the creative weaving of reality and fantasy to explain how things occur in the world (associative logic). Imaginary friends are common. Pretend play begins around the age of 2 years with the ability to symbolize. Children under 3 interact in parallel play (when children play on their own but in physical proximity), and by age 4 they cooperate in activities. Body-

image anxiety is a result of the child’s immature sense of body integrity. The preschooler feels that his entire body is vulnerable when any body part is injured (e.g., my arm is broken, therefore I am broken). Gender identity also forms by age 3.

School Age/Latency (Ages 6–12 Years) Latency is the phase of development that is characterized by mastery of skills. Children are gaining skills in many areas: academic, athletic, artistic, and social. School and peer groups play a fundamental role for the child. Status within the peer group depends on a child’s abilities and how they compare with those of his/her peers. During this phase, children develop best friends. Cognitively, the child can use logical thinking (causal logic) and to appreciate another person’s point of view. The disorders that present during this phase are often related to school performance and peer relationships.

Adolescence (Ages 12–18 Years) The emphasis during adolescence is on autonomy and sexuality. The adolescent is struggling to create a sense of identity that is separate from his or her parents. His/her emerging identity relies on the peer group to determine what is “in” and what is “out.” Attractiveness is a key component of self-esteem. There is tremendous self-consciousness, heightened by the range of maturation at any given age. Adolescents are reaching new levels both cognitively and emotionally. At this stage, they are capable of abstract thinking.

Theories of Development Object Relations Theory Object relations theory describes the development of the mind in relation to others, and describes how the infant’s relationship to primary caretakers shapes how she will relate to others later in life. The infant has mental representations of self and others (i.e., objects), initially perceived only as part-objects that are ultimately integrated. Melanie Klein described the depressive position, achieved as early as 3–6 months, as the stage at which the infant is able to experience others as whole, understanding that opposing qualities (e.g., good and bad) can be found within the same object. The infant begins to understand ambiguity and to develop the capacity to empathize with others.

Donald Winnicott extended object relations theory with his descriptions of the infant-mother dyad: holding environment, transitional object, good-enough mother concept, and true self. He described the initial mother-infant dyad as one entity, with the baby existing only as part and with the love of his primary caregiver. By providing reliable and consistent parenting, the caregiver provides a holding environment within which the baby feels safe and can grow to be autonomous. The good-enough mother, caring optimally but sometimes making mistakes or perceived as failing, teaches the infant that occasional failures do not discount her love and reliability. This prepares the infant to understand the depressive position and to develop a true self, accepting the experience of having a range of feelings and learning how to manage them. Winnicott described the child’s use of transitional objects that represent the primary caregiver, safety, and love to be able to separate from the caregiver.

Bowlby’s Attachment Theory John Bowlby’s attachment theory describes the reciprocal process of bonding that is based on the care and the relationship that develop between the infant and his primary caregiver. Attachment is the observable behavior of an infant responding to his caregiver. The infant at 6 to 8 weeks of age smiles in recognition of the caregiver and imprints the caregiver’s face as the person to whom he will turn. A mutual connection and admiration has formed between the infant and the caregiver. The result of this attachment behavior is an infant who feels and is protected by his caregiver. Bowlby asserts that attachment evolved to protect helpless infants from potential predators. Regarding infants separated from their caregivers, Bowlby described three stages of separation anxiety: protest, despair, and detachment. In “protest,” the infant is separated from the caregiver and cries or calls out. In “despair,” the infant gives up hope that the caregiver will return. Finally, in “detachment,” the infant has emotionally separated himself from the caregiver. Mary Ainsworth created a model to determine the quality and strength of the attachment between infant and caregiver called “strange situation.” This sevenstep process follows a sequence (the infant and mother are together in a room → stranger enters the room → mother leaves the room → infant is left alone with the stranger → mother returns and the process is repeated). Based on her observations, Ainsworth described three patterns of attachment: secure, insecureavoidant, and insecure-ambivalent. A fourth type, disorganized, was added later.

Ainsworth concluded that more than 60% of infants have secure attachments by the age of 24 months.

Mahler’s Separation-Individuation Process Margaret Mahler described the process separation-individuation that occurs between a mother (primary caregiver) and a child. This theory is based on behavioral observations. Mahler described the first phase as symbiosis (birth to 5 months), during which the infant does not differentiate from the mother. The separation-individuation process begins at approximately 5 months of age and follows four stages through the first 3 years of life: differentiation, practicing, rapprochement, and consolidation and object constancy. During “differentiation” (5–10 months), physical movement away from the mother begins to occur. The infant begins to explore through play with his/her own body, and stranger anxiety develops. During the “practicing” (10–15 months) stage, the infant gains physical distance through walking. Greater exploration occurs, as does separation anxiety. In “rapprochement” (18–24 months), self-awareness begins to develop. This increased self-awareness leads to anxiety and conflict because the child wants to stay close to the primary caregiver but also wants to explore. Finally, during “consolidation and object constancy” (24–36 months) phase, the child is able to maintain an internal representation of the primary caregiver and thus tolerates separations from the caregiver, knowing that they will be reunited.

Freud’s Psychosexual Model of Development Sigmund Freud outlined the psychosexual development of the child from a psychoanalytic perspective. According to Freud, the sexual goal of each stage is to derive pleasure and to relieve pain. Accordingly, the infant is first soothed by the mother’s breast and derives satisfaction orally; hence the first stage is the oral stage. Freud described five psychosexual stages (oral, anal, phallic, latency, and adolescent) based on the child’s development of sexual drives, body maturation, and nervous system development. In the “oral phase” (birth to 1 year), the infant’s urges are focused on feeding and sucking at the breast, which is the source of all the infant’s satisfaction and frustration. In the “anal phase” (1–3 years), the child’s urges are centered on bowel function, and his ability to have control over his bodily functions becomes the main issue in the relationship between the child and the caregiver. During the “phallic (genital) phase” (3–5 years), the genitals become the child’s focus for pleasure and satisfaction. Masturbation is used as a way of releasing tension and leads to anxiety and guilt. The “Oedipus Complex” describes the child’s competition with the same-sex

parent for the parent of the opposite sex. The child wants to have exclusive possession of the parent and wants to eliminate the other parent. (This term was initially applied to boys, and Jung coined the term “Electra Complex” describing the same phenomenon in girls). Castration anxiety is the boy’s fear that his father will cut off his penis in retaliation for the boy’s coveting his mother. This anxiety leads to repression of the sexual desire for the mother. Penis envy is a girl’s curiosity and desire to have a penis. Resolution of the Oedipus complex occurs when the child identifies with the same sex parent and begins to form relationships with same sex peers. During the next phase, “latency” (6–11 years, sexual development is relatively stagnant. In adolescence (12–18 years), genital sexuality develops and proceeds into adulthood.

Erikson’s Epigenetic Model of Development Erik Erikson presented an epigenetic model of development from birth to old age. The epigenetic principle holds that the eight stages of the life cycle are sequential, each stage relying on the next. For successful development, a person must complete one stage before moving on to the next stage. If a stage is not completed, the unresolved issues continue to arise and create problems in subsequent stages. Each stage addresses cognitive, ego, sexual, social, and societal issues, and offers positive and negative adaptations. In “basic trust versus basic mistrust” (birth to 1 year), a sense of basic trust is derived from the attachment that forms between the child and the parent who provides consistent care. Mistrust develops when the child is unable to rely on his or her parent for basic care, which leads to feelings of emptiness and despair. In “autonomy versus shame and doubt” (1–3 years), the trust developed in the first stage gives the child freedom to explore, for which he is able to separate briefly from the primary caregiver without significant distress. During this stage, the child’s sense of self is in part based on his/her ability to control his/her bodily functions (e.g., anal sphincter control). Shame and doubt develop when the child is required to perform but is unable. In “initiative versus guilt” (3–6 years), the child takes steps toward establishing a special relationship with the parent of the same sex. Fantasy allows the child to feel both the pleasure and the pride of being powerful and the guilt of having the imagined power to do harm to others. The stage of “industry versus inferiority” (6–12 years) corresponds to entering school, when the main tasks for the child are ones of learning and doing. The child strives for a sense of accomplishment and develops a sense of mastery and

control of his environment (i.e., school), avoiding failure at all costs. The child begins to understand that his family is a part of a larger society. Parents are no longer perceived as the only authorities. Feelings of inferiority develop when the child is unable to master all tasks. The next stage, “identity versus role confusion” (12–20 years), occurs during adolescence, a phase of development characterized by multiple physical and social changes with the potential for significant growth as well as crisis. Adolescents are at a fragile point of finding themselves at the same time as losing themselves; they must identify within themselves and with the society at large. In this stage, normative crises can evolve into disruptive and pathological behavior but are not inherently maladaptive. Development of a reasonable sense of self/personal identity is necessary for the establishment of a stable love relationship, the main task in the stage of “intimacy versus isolation” (20–40 years). Although the fear of intimacy can lead one to choose isolation, the mature individual chooses the vulnerable position of intimacy over the loneliness of isolation. These adaptations also apply to a person’s career aspirations. In the stage of “generativity versus stagnation” (40–65 years), adults can be generative through child rearing and mentoring in the community, passing along to the next generation what they have learned and achieved. Stagnation occurs when the adult is unable to give to others and remains isolated and self-involved. Finally, in “ego integrity versus despair” (65 years and older) ego integrity develops for a person who feels that he/she has led a fulfilled life and is content with his/her place in the life cycle. Despair occurs for those who feel that life had no meaning. Death becomes a feared end to an unfulfilled life.

Piaget’s Model of Cognitive Development Jean Piaget focused on the cognitive development of the child. In this model, the child follows a continuous pattern of behavior of adapting and responding to the various stimuli in the environment (stimulus-response-awareness). A behavioral pattern or loop is based on a schema—a mental framework that is formed as the child interacts with the environment. The development of the child’s cognitive abilities is categorized in four stages: sensorimotor , preoperational , concrete operational , and formal operational . In the sensorimotor stage (birth through 18–24 months), the child experiences the world through movement and senses, and the body reacts to sensory stimuli in a stereotyped way. In the second year of life, object permanence develops, and

the child can maintain a mental image of the object and understand that it exists even when out of sight. After this develops, the child will look for a toy where it has disappeared. In the pre-operational stage (2–6 years), the child develops symbolic functions, being able to create mental images of objects and occurrences and keep them in mind for later use. The child continues to develop motor skills, and language development changes the child’s ability to interact. The child is unable to use logic to understand how and why they know what they know, but develops egocentric thinking (the perception that everything revolves around them), and magical thinking (in which reality and fantasy are interwoven to explain the world around them). Moral thought also develops, based on something being good or bad. In the concrete operational stage (7–11 years), the child develops rational and logical thought. He/she is no longer egocentric, applies a more conceptual framework to the world, and can understand someone else’s point of view. The child understands the concept of conservation, the ability to understand the combination of two variables. An example of a beaker experiment is often used. In this exercise, water is placed in two identical beakers (A and B). Next, water from beaker B is transferred into a taller, narrower beaker C. The child is then asked if the amount of water in beakers A and C is the same or different. A child at this stage of development will understand that the amount of water present in beakers A and C is the same even though the levels in the beakers are different. In the formal operational stage (12+ years), the child develops abstract thinking (ability to manipulate ideas and theoretical constructs), deductive reasoning (ability to go from the general to the particular), and conceptual thinking (ability to define concepts or ideas).

Chess and Thomas’ Theory of Temperament Stella Chess and Alexander Thomas described children as having individual, innate styles that influence their development and adaptation throughout their lives. The temperament of the child considers nine observed behaviors and categorizes children as “easy,” “difficult,” and “slow to warm up.” These behaviors include activity level, rhythmicity, approach or withdrawal response (initial reaction), adaptability to change in the environment, threshold of responsiveness (sensory sensitivity), intensity of reaction, mood, degree of distractibility, and persistence in the face of obstacles. They describe children as being active participants in their own development and experience.

Jerome Kagan studied the temperamental characteristic of reactivity. In his longitudinal study, he classified 4-month-old infants as low versus high reactive and showed that low-reactive infants are more likely to be behaviorally inhibited (timid and shy) as children, whereas high-reactive infants were more likely to be uninhibited (outgoing and fearless). Using Kagan’s longitudinal sample, Carl Schwartz discovered that based on brain MRI scans at the age of 18 years, subjects with low-reactive infant temperaments had a thicker left orbitofrontal cortex and a thinner right ventromedial prefrontal cortex than those who had high-reactive infant temperaments.

Kohlberg’s Model of Moral Development Lawrence Kohlberg described three major levels of development of moral judgment. His theory has been criticized for being culture-bound, middle-class, and male-oriented. In Level I, pre-morality (or pre-conventional morality ), the child follows the rules set forth by his parents. Parents are the authority figures and they establish the standards of punishment and obedience. In Level II, morality of conventional role-conformity , the child conforms to the norms of the group to gain acceptance and to maintain relationships. In Level III, morality of self-accepted principles , the child voluntarily follows rules based on the concept of ethical principles and makes exceptions when they are determined to be appropriate.

Gilligan’s Model of Morality Carol Gilligan presented a view of the development of morality that includes alternate pathways to the same moral pinnacle. She proposed that girls have a greater sense of connection and concern with relationships than with rules and meet the highest level of moral development through other routes.

Environmental Stress Divorce M ore than one million children in the United States each year are affected by divorce . Marriages end in divorce after an average of 6 to 7 years. The impact of divorce on children is significant and depends on multiple factors, including the parents’ attention to the child and the child’s age. Half of children have difficulties during the first year after divorce; factors that contribute to an adjustment period longer than 1 year include parental discord, parental psychiatric illness, and poverty. The impact on family is also significant. Higher

rates of depression occur in parents after divorce. The mother is the custodial parent 90% of the time, and women experience significant drops in their disposable income.

Child Maltreatment Physical abuse (any inflicted rather than accidental injury) and child neglect (the major needs of the child [such as nutrition, shelter, protection, health care, education, and emotional needs], are not met) occur to more than one million children in the United States each year. More than 3,000 deaths are caused by child abuse each year. A child is at increased risk for abuse if he or she has suffered from low birth weight, handicap (e.g., intellectual disability), and behavioral disturbance. In families, risk factors for abuse and neglect include low socioeconomic status, substance abuse, and domestic violence. The abuser is most commonly a parent, often one who was abused in childhood himself or herself. Victims of childhood maltreatment are at increased risk for academic, social, and behavioral disturbances. They are also at increased risk for future intimate partner violence, teenage pregnancy, parenting difficulties, and worse physical health. Sexual abuse occurs when the child is engaged in sexual activities that the child cannot comprehend, for which the child is developmentally unprepared to give consent, and/or which violates the social and legal taboos of society. In the majority of cases the perpetrator is known to the victim and most often is a father, stepfather, or surrogate father. The median age of victims is between 9 and 10 years. Risk factors include physical or sexual abuse history of the perpetrator, substance abuse, impulsivity, sexual deviancy, and violent tendencies. Children who are maltreated by parents can be placed into foster care and often experience multiple out-of-home placements, increasing their risk for behavior problems, including antisocial behaviors and anxiety. Institutionalization of children also constitutes a form of deprivation with dire consequences as demonstrated in the Bucharest Early Intervention Project (BEIP ), the first randomized controlled trial of foster care for institutionalized children. This study demonstrated significant benefit across a range of outcomes for children placed in foster care at any point. Children placed under 24 months generally had improved outcomes, suggesting the existence of a sensitive period.

Bullying Bullying is the use of strength or power to harm or intimidate those who are

weaker. About half of children are bullied at some point in their school years, and 10% are bullied recurrently. Bullying can be physical or verbal; with girls, it is more often verbal, whereas physical bullying is more common with boys. Bullies are often victims of abuse or bullying themselves and generally thrive on dominating others, whereas victims are usually more passive, younger, smaller, easily intimidated, and have few friends. Bullies are at increased risk for psychiatric illness, substance abuse, personality disorders, and criminal behavior. Being bullied also raises a child’s risk for major mental health problems (including psychotic symptoms, selfharm, and violent behavior). It is also associated with worse physical health and social functioning. School anti-bullying programs have been applied with success in some cases, leading to reduced bullying and fewer victims.

Media Children are immersed in electronic media, including TV, video games, smartphones, and computers and the many methods of communication they provide (e.g., messaging, email, and social networking). This culture comes with advantages including socialization, communication, and access to knowledge. But, it also entails disadvantages, including increased uncontrolled exposure to influences (such as pornography, cyber-bullying, cyber-sex, and sexting [sending sexually-explicit messages or pictures via text message]) as well as risk of social contagion including copycat suicides.

Brain Development in Childhood and Adolescence Most rapid brain growth occurs before age 2, and by age 7 the child’s brain is nearly the size of an adult brain. Maturation of white matter (growth and myelination of axons) occurs throughout childhood and continues into adulthood. The volume of gray matter increases via synaptogenesis until adolescence, when pruning of cortical synapses (many of which are excitatory glutamatergic and dopaminergic) results in loss of gray matter. Maturation of the prefrontal cortex occurs later than maturation of the limbic system, which could explain increased risk-taking behavior in adolescence.

Suggested Readings 1. Bos K, Zeanah CH, Fox NA, et al: Psychiatric outcomes in young children with a history of institutionalization. Harv Rev Psychiatry . 2011; 19(1):

2. 3. 4. 5.

6. 7. 8. 9. 10. 11.

12. 13.

15–24. Bowlby J: Attachment and Loss . Vol. 1: Attachment. New York: Basic Books; 1969. Erikson E: Childhood and Society . 2nd ed. New York: WW Norton; 1963. Gilligan C: In a Different Voice: Psychological Theory and Women’s Development . Cambridge, MA: Harvard University Press; 1982. Hazen EP, Abrams AN, Muriel AC: Child, adolescent, and adult development. In: Stern TA, Fava M, Wilens TE, Rosenbaum JF, eds. MGH Comprehensive Clinical Psychiatry , 2nd ed. Philadelphia: Elsevier; 2016. Kliegman RM, Stanton BF, St. Geme JW, et al, eds.: Nelson’s Pediatrics, 19th ed . Elsevier Saunders; 2011. Kohlberg L: The Psychology of Moral Development: The Nature and Validity of Moral Stages . San Francisco: Harper and Row; 1984. Mahler MS, Pine F, Bergman A: The Psychological Birth of the Human Infant: Symbiosis and Individuation . New York: Basic Books; 1975. Thapar A, Pine D, Leckman J, et al, eds.: Rutter’s Textbook of Child and Adolescent Psychiatry . Oxford: Blackwell; 2015. Thomas A, Chess S, Birch HG: Temperament and Behavior Disorders in Children . New York: New York University Press; 1968. Vaughn MG , Fu Q , Bender K , et al: Psychiatric correlates of bullying in the United States: findings from a national sample. Psychiatr Q . 2010; 81(3): 183–195. Wallerstein JS, Kelly JB: Surviving the Breakup: How Children and Parents Cope with Divorce . New York: Basic Books; 1980. Winnicott DW: The depressive position in normal emotional development. In: Through Paediatrics to Psycho-analysis . New York: Basic Books; 1975.

CHAPTER 5 Child and Adolescent Disorders MICHELLE CHANEY-CATCHPOLE, MD AND ANNAH N. ABRAMS, MD

KEY POINTS Approximately 12% to 22% of the child and adolescent population suffer from a psychiatric disorder. When psychiatric illnesses present in childhood, they tend to be more familial and chronic, and are associated with greater morbidity. Many of the disorders that present during childhood are responsive to medication. However, the use of medications in children is not as well established as it is in adults. The use of medications in children should occur only after completion of a thorough diagnostic evaluation (which includes a full psychiatric assessment, use of structured psychiatric interviews and rating forms (as indicated), and relevant laboratory studies to rule-out underlying medical conditions).

Overview Approximately 12% to 22% of the child and adolescent population suffers from a psychiatric disorder (Center for Mental Health Services, 2010). When psychiatric illnesses present in childhood, they tend to be more familial and chronic, and associated with greater morbidity. This chapter outlines the disorders of infancy, childhood, and adolescence and presents them in the diagnostic categories as outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). In addition, treatment for these childhood-onset psychiatric disorders is addressed.

Neurodevelopmental Disorders Attention Deficit Hyperactivity Disorder Diagnosis

Attention Deficit Hyperactivity Disorder (ADHD ) is the most common psychiatric disorder in children; its prevalence is 5–11% in school-aged children (Polanczyk et al, 2007). It often presents with a classic triad of inattention, hyperactivity, and impulsivity. However, some children might be primarily hyperactive, whereas others are primarily inattentive. Symptoms must include at least six signs of inattention and/or six signs of hyperactivity–impulsivity for 6 months. For adolescents 17 and older and adults, at least five symptoms are required. Symptoms of inattention include: failure to pay close attention to details; difficulty sustaining attention to tasks or activities; failure to listen when spoken to directly; difficulty organizing tasks; avoidance of activities that require mental effort; losing things necessary for tasks or activities; distractibility; and, forgetfulness in daily activities. Symptoms of hyperactivity include: fidgeting with the hands or feet; inability to sit still; running around when it is not appropriate; difficulty engaging quietly in leisure activities; feeling “on the go” or “driven by a motor”; and, talking excessively. Symptoms of impulsivity include: blurting out answers before questions are completed; having trouble waiting one’s turn; and, interrupting others. The diagnosis is specified as either combined type, predominately inattentive type, or predominately hyperactive–impulsive type. The pattern of behavior must be more frequent and severe than that observed in other children of the same developmental level. The symptoms of the disorder must be present before the age of 12 years. Many children are diagnosed after this age, but the symptoms often have been present for years prior to the diagnosis being established. Impairment must cross situations and must be noted in at least two settings (e.g., school and home). The symptoms must not be exclusively present when another disorder (such as depression) is present.

Prevalence The prevalence is between 8% and 11% among school-aged children. The disorder persists into adolescence and adulthood in about half of those who are affected. According to the 2011 National Survey of Children’s Health, the male to female ratio is 4:1 (predominately hyperactive type) and 2:1 (predominately inattentive type), depending on the type of ADHD and the setting. The 2011 National Survey of Children’s Health found the male to female ratio was 4:1 for

the predominantly hyperactive type and 2:1 for the predominantly inattentive type.

Treatment Medication is the first-line of treatment for ADHD in school-aged children and adolescents. There is a 70% to 80% response rate to psychostimulants (Wilens et al, 1998) (e.g., methylphenidate [MPH], dextroamphetamine [Dexedrine], and amphetamine sulfate). For pre-school-aged children (5 and under), behavioral interventions are initially recommended. Medications can be considered for preschool-aged children if they fail to respond to behavioral interventions and functional impairment persists.

Psychostimulants MPH (Ritalin ) should be started at 2.5 to 5 mg twice daily (before breakfast and lunch), and, if necessary, increased weekly by 2.5 to 5 mg/day (reaching an optimal dose of 1 mg/kg/day and a maximal dose of 2 mg/kg/day). Side effects include insomnia, decreased appetite, mood disturbance, tics, headache, gastrointestinal (GI) distress, and psychosis (rare). Longer-acting MPH preparations, including Ritalin-XR, Ritalin LA, Metadate, and Metadate CD (intermediate-acting), and Concerta, Daytrana, Focalin XR, Aptensio XR, and Quillivant XR (long-acting), release MPH immediately followed by a sustained/second release with resulting plasma levels of MPH lasting approximately 4 to 12 hours, depending on the preparation. Amphetamine sulfate (Adderall ) should be started at 2.5 to 5 mg once or twice daily and it can be increased by 5 mg/week (reaching an optimal dose of 0.5–1 mg/kg/day). Dextroamphetamine is twice as potent as amphetamine. Amphetamines have a similar side effect profile to MPH. Longer-acting amphetamine preparations include Adderall XR, Dyanavel XR, Dexedrine spansule, and Vyvanse (formulated as a pro-drug to reduce the risk of abuse); both last approximately 12 hours. The stimulants carry a “black box warning” regarding the potential for dependence and abuse. In addition, a cardiovascular safety warning has been issued by the United States Food and Drug Administration (FDA) regarding the risk of sudden cardiovascular death in children and adolescents with structural heart abnormalities or other serious cardiovascular conditions. Patients should be screened for a personal history of cardiovascular problems and for a family history of sudden cardiac death; in addition, a physical exam should be performed. Further evaluation, including an electrocardiogram (EKG), is

recommended if there is a cardiac history or an abnormal cardiac exam; however, an EKG is not necessary in the absence of cardiovascular risk factors. (Perrin, 2008). Antihypertensive medications (which are α -agonists) can also be used to treat ADHD, especially if a tic disorder or aggression is present. Clonidine should be initiated at 0.025 mg BID, and can be dosed up to 4–5 μcg/kg/day total. Side effects include sedation, depression, and rebound hypertension. Clonidine also comes in an extended-release preparation (Kapvay) to reduce sedation. The initial dose of extended-release clonidine is 0.1 mg at bedtime. It should be titrated in increments of 0.1 mg at weekly intervals (maximum, 0.4 mg /day). Guanfacine (Tenex ) is similar to clonidine, but less potent and less sedating. It is administered in doses up to 1–2 mg TID. Intuniv is a long-acting preparation of guanfacine, dosed once daily. Atomoxetine (Strattera ) is a selective norepinephrine re-uptake inhibitor. For those under 70 kg, the starting dose is 0.5 mg/kg/day increased after at least 3 days to a target dose of 1.2 mg/kg/day. For those above 70 kg, the starting dose is 40 mg, with a target dose of 80 mg and a maximum dose of 100 mg. Side effects include GI distress, sedation, decreased appetite, and irritability. It carries a black-box warning for liver injury.

Antidepressants Tricyclic antidepressants (TCAs ) and bupropion (Wellbutrin ) may also be used for the treatment of ADHD. TCAs have been effective in 60% to 70% of patients (Wilens et al, 1998).

Intellectual Disabilities Intellectual Disability (Intellectual Developmental Disorder) Diagnosis Diagnosis is based upon sub-average general intellectual and adaptive functioning deficits in conceptual, social, and practical domains. A federal statute (Public Law 111-256, Rosa’s Law) replaces the term mental retardation with intellectual disability. Severity level is no longer determined predominantly from a standardized intelligence test (IQ), but from overall deficits across the domains. Four diagnostic severity levels of intellectual disability are described:

Mild (previously IQ range of 50–55 to 70): Children with mild intellectual disability can develop social and communication skills, and can function relatively normally as adults. The individual is immature in social interactions compared with typically developing peers and needs some support with complex tasks of daily living. They will generally need support to make health-care decisions and legal decisions as an adult. Moderate (previously IQ range of 35–40 to 50–55): Children with moderate intellectual disability have limited social awareness. They can be trained to care for most personal needs and to work in sheltered job placements; however, support is often needed. Moderate supervision (e.g., a group home) is usually required. Severe (previously IQ range of 20–25 to 35–40): Children with severe intellectual disability have slow and poor motor development. They have limited to no speech and require close supervision. Profound (previously IQ falls below 20–25): Children with profound intellectual disability have poor cognitive and social capacities. Speech is often absent. Constant supervision is needed (e.g., special-care setting). Co-occurring sensory and physical impairments are frequent barriers. The onset of intellectual disability must occur before the age of 18 years. The prevalence is 2% to 3% of the school-aged population.

Global Developmental Delay This diagnosis is used when an individual under the age of 5 fails to meet expected developmental milestones in several areas of intellectual functioning and cannot undergo systematic assessments (too young to participate or unable to participate). Re-assessment is recommended.

Communication Disorders Disorders of communication include deficits in language , speech, and communication. According to the DSM-5, speech is “the excessive production of sounds and includes an individual’s articulation, fluency, voice, and resonance quality.” Language includes “the form, function, and use of a conventional system of symbols in a rule-governed manner for communication.” Communication includes “any verbal or non-verbal behavior that influences the behavior, ideas, or attitudes of another individual.”

Language Disorder Diagnostic features of a language disorder are difficulties in the acquisition and use of language due to deficits in the comprehension or production of vocabulary, sentence structure, and discourse (ability to use vocabulary and connect sentences to explain a topic or have a conversation). Language abilities are substantially and quantifiably below those expected for age resulting in functional limitations. The difficulties are not attributable to sensory impairment (e.g., being hard of hearing), motor dysfunction, or another medical or neurological condition, and are not better explained by intellectual disability or global developmental delay, (DSM-5, 2013).

Speech Sound Disorder Diagnostic features of a speech sound disorder include persistent difficulty with speech sound production that interferes with speech intelligibility or prevents verbal communication of messages. The disturbance causes limitations in effective communication that interfere with social participation, academic achievement, or occupational performance. The onset is in the early developmental period, and the difficulties are not due to congenital or acquired conditions like cerebral palsy, cleft palate, deafness, traumatic brain injury, use of medications, or neurological conditions. The etiology is heterogeneous and includes phonological disorder and articulation disorder. Overall, speech should be intelligible by age 4 years in typically developing children. At age 2, only 50% might be understood.

Childhood-Onset Fluency Disorder (Stuttering) The main feature of this disorder is a disturbance in the normal fluency and time patterning of speech that is inappropriate for the individual’s age and language skills. It must persist over time and have frequent occurrences of one or more of the following: sound and syllable repetitions, sound prolongations of consonants as well as vowels, broken words (pauses within a word), audible or silent sentence blocking, circumlocutions (word substitutions to avoid problem words), words produced with an excess of physical tension, and monosyllabic whole-word repetitions. The disturbance must cause anxiety about speaking or limitations in effective communication. Onset occurs by age 6 for 80% to 90% of affected individuals (Mansson, 2000). Almost all cases present before the age of 10 years. The prevalence is 1% in prepubertal children, with a male to female ratio of 3:1. The symptoms often remit in adolescence. There is a familial pattern

for the disorder with the risk for a first-degree biological relative developing stuttering at three times the risk observed in the general population.

Specific Learning Disorder Learning disorders are associated with below-expected abilities in academic achievement in reading, mathematics, and/or writing, based on the child’s chronological age, measured intelligence, and age-appropriate education. The symptoms must persist for at least 6 months, despite the provision of interventions that target those difficulties. Difficulties can include inaccurate or slow word reading, difficulty understanding the meaning of what is read, difficulties with spelling, difficulties with written expression, difficulties mastering number sense or calculation, and difficulties with mathematical reasoning. The clinician must specify all academic domains that are impaired. This includes impairment in reading, impairment in written expression, and impairment in mathematics. The difference between achievement and IQ must be at least 1.5 standard deviations below the mean. Reading, mathematics, and writing disorders are often co-morbid. The disorder is usually diagnosed during or after the first grade when reading, math, and writing are being taught in school. Children with learning disorders have a school drop-out rate of 40% (approximately 1.5 times the average). The prevalence of learning disorders ranges from 5% to 15% among school-aged children across different languages and cultures, with approximately 5% of school children in the United States carrying a diagnosis of a learning disorder. Treatment involves tutoring and providing appropriate school accommodation for the learning disability.

Motor Disorders Developmental Coordination Disorder This is a disorder with an impaired ability to perform daily activities due to a coordination difficulty not accounted for by a medical condition (e.g., cerebral palsy, hemiplegia). Afflicted children might be slow to crawl or walk and/be clumsy with fine and gross motor skills. Often this disorder is seen in premature infants. The prevalence is 6% in school-aged children. The course is variable and can persist into adulthood. These children benefit from occupational and physical therapy.

Depressive Disorders

Mood disorders in children are classified as unipolar or bipolar, with major and minor levels of severity. Juvenile mood disorders tend to be more chronic and more refractory to pharmacologic interventions than are adult-onset mood disorders. The prevalence of these disorders increases with age. Mood disorders are not classified as childhood disorders in the DSM-5. For treatment of mood disorders in children, see Table 5-1. Table 5-1. Characteristics and Treatment of Child and Adolescent Disorders Disorder

Main Characteristics

Treatment Therapy

Medication

Disruptive Behavior Disorders Conduct Disorder

Patterns of aggressive and antisocial behavior

Behavioral therapy

No specific medications for core symptoms; assess and treat co-morbid conditions; may treat aggression and agitation with α -agonists, β -blockers, mood stabilizers, and antipsychotics

Oppositional Defiant Disorder

Pattern of negative, hostile, and defiant behavior

As for Conduct Disorder

As for Conduct Disorder

Psychotherapy, CBT

SSRIs, TCAs, atypical antidepressants

Supportive psychotherapy

Mood stabilizers, antipsychotics (typical and atypical)

Depressive Disorders Depression

Sad or irritable mood and/or loss of interest in usual activities; neurovegetative symptoms; age-specific associated features (e.g., school refusal)

Disruptive Mood Dysregulation Disorder Bipolar and Related Disorders Bipolar Disorder

Extreme irritability or explosive mood; neurovegetative symptoms as seen in adults

Anxiety Disorders Separation Anxiety Disorder

Excessive anxiety when a child is separated from caretaker

CBT

BZDs, buspirone, SSRIs

ObsessiveCompulsive Disorder

Recurrent obsessions and compulsions, severe and distressing

CBT, psychotherapy

Clomipramine, SSRIs

Social Phobia

Fear of embarrassment in social situations

CBT

Generalized Anxiety Disorder

Excessive anxiety and worry

CBT

BZDs, buspirone, SSRIs

Psychotherapy, dialectical behavioral therapy

α -agonists, SSRIs, BZDs, occasionally antipsychotics

Trauma and Stressor-Related Disorders Post-Traumatic Trauma followed by Stress Disorder hypervigilance, autonomic reactivity, and avoidance Psychotic Disorders

Delusions, hallucinations, bizarre behavior, thought disorder, and negative symptoms (inattention and anhedonia, avolition, apathy, and alogia)

Antipsychotics (typical and atypical)

Neurodevelopmental Disorders Attention Deficit Hyperactivity Disorder

Inattention, hyperactivity, impulsivity

Autism Spectrum Disorder

Impairment in multiple areas: Behavioral therapy; treat comotor, language, social, and morbid disorder. Important academic interventions include appropriate school placement, OT/PT, and speech and language therapy

Specific Learning Disorder

Specify with impairment in reading, written expression, mathematics

Communication Language Disorder, Speech Disorders Sound Disorder, ChildhoodOnset Fluency Disorder (Stuttering), Social (Pragmatic) Communication Disorder

Stimulants, TCAs, α -agonists, atypical antidepressants

Appropriate school accommodation for the learning disability; tutoring Appropriate school accommodation; tutoring; speech therapy; see ASD chapter for more on social communication disorder

Elimination Disorders Encopresis

Fecal incontinence

Behavioral therapy

Medical management of constipation and diarrhea

Enuresis

Urinary incontinence

Behavioral therapy (bell and pad conditioning)

TCAs (imipramine), ddAVP

Feeding Disorders Pica

Eating of non-nutritional substances

Rumination Disorder

Re-chewing or regurgitation of food

Tic Disorders

Behavioral therapy Treatment of medical consequences of disorder

Persistent Either motor or vocal tics (Chronic) Motor or Vocal Tic Disorder

α -agonists, antipsychotics

Tourette’s

α -agonists, antipsychotics

Multiple motor and one or more vocal tics; co-morbid with OCD and ADHD

Other Disorders of Childhood Selective Mutism

Does not speak in some social Psychotherapy, CBT situations, but fluent in others

Reactive Attachment Disorder and Disinhibited Social Engagement Disorder

Disturbed ability to relate socially

SSRIs

Consistent placement/caregivers, infant– parent work

Key: ADHD: Attention Deficit Hyperactivity Disorder; BZD: benzodiazepine; CBT: cognitive–behavioral therapy; ddAVP: vasopressin; OCD: Obsessive–Compulsive Disorder; OT/PT: occupational/physical therapy; SSRI: selective serotonin re-uptake inhibitor; TCA: tricyclic antidepressant.

Major Depressive Disorder Diagnosis In children, Major Depressive Disorder (MDD ) can present with a sad or irritable mood and/or a loss of interest or pleasure in the child’s usual activities. Child-specific symptoms include school difficulties, school-refusal, somatic complaints, and aggressive/antisocial behavior patterns. Physiologic changes, such as weight change or sleep pattern disruption, might also be present. Psychotic symptoms might be present in a depressed child.

Prevalence The prevalence of MDD is 0.5% in pre-schoolers, 1% to 2% in school-aged children, and 3.5% to 11% in adolescents. Females experience 1.5- to 3-fold higher rates of depression than males beginning in early adolescence ( Kessler et al, 2003; Avenevoli et al, 2015 ).

Treatment Pharmacologic management utilizes the same medications as are used in adult depression. Of the antidepressants, only fluoxetine (Prozac ) and escitalopram (Lexapro) are FDA-approved for use in adolescents. Fluoxetine is approved for

children aged 8 and above; escitalopram is approved for ages 12 and above. However, the other SSRIs are widely used in clinical practice.

Bipolar Disorder Diagnosis Mania in children often presents as an extremely irritable or explosive mood with poor psychosocial functioning. Children can exhibit unrestrained high energy, over-talkativeness, racing thoughts, decreased sleep, and increased goaldirected activity. Poor judgment, as manifested by reckless thrill-seeking behavior, might also be present. It is important to differentiate juvenile mania from ADHD, Conduct Disorder (CD), MDD, and psychotic disorders that commonly occur with mania (Liu et al, 2011).

Prevalence Recent epidemiologic studies have estimated the prevalence of bipolar disorder in children and adolescents at 1.8%. The rate of bipolar disorder increases with advancing age (2.7% for adolescents aged 12–18 years) (Van meter et al, 2011). However, depending on the setting, referral source, and methodology used to ascertain the symptoms of bipolar disorder, the prevalence in youth has been reported as anywhere between 0.6% and 20% (Pavuluri et al, 2005).

Treatment Pharmacologic treatment for pediatric bipolar disorder follows guidelines that are similar to those for adult bipolar disorder; however, not all medications are approved for use in children and adolescents (see Table 5-1). Lithium is approved for acute mania and for maintenance treatment of bipolar disorder for children aged 12 to 17 years. Aripiprazole , risperidone , quetiapine , and asenapine are approved for children and adolescents 10 to 17 years old. Olanzapine is approved for adolescents aged 13 to 17 years. Lamotrigine and divalproex have not been approved for pediatric use by the FDA, but they are used commonly in clinical practice. Divalproex is less often used in adolescent girls due to its risk of causing polycystic ovarian syndrome.

Anxiety Disorders Separation Anxiety Disorder Diagnosis

Separation anxiety is defined as excessive anxiety that occurs when a child is separated from home or from significant attachment figures. Afflicted children also have excessive worry about losing someone or about something untoward happening to their primary caretaker. Such anxiety occurs as part of normal development in children around the age of 2 years. However, when the symptoms have an onset later during childhood and the symptoms become excessive to the point of impairing function, a disorder is diagnosed. Symptoms must last for at least 4 weeks and the onset must occur before the age of 18 years.

Prevalence The prevalence is 4% in school-aged children and 1% in adolescents. It occurs equally in boys and girls.

Treatment Treatment includes cognitive –behavioral therapy (CBT) and use of medications ( selective serotonin re-uptake inhibitors [SSRIs], buspirone, and benzodiazepines (although this class of medication is not approved for use in children with this disorder.

Selective Mutism The child with this disorder will not speak in specific social situations even though their speech is fluent in other settings (e.g., home). The child usually communicates non-verbally (e.g., via eye contact or head nodding) in these settings. The diagnosis should not be made if the child is not comfortable with the spoken language (e.g., an immigrant child). The symptoms must be present for at least 1 month. It is associated with anxiety and shyness. The disorder is uncommon and occurs in less than 1% of children. Treatments include psychotherapy, CBT, and the use of SSRIs.

Social Anxiety Disorder (Social Phobia) Social phobia involves a fear of embarrassment in social situations. Children might exhibit their fears by crying or by staying close to familiar adults. They might appear very shy and often are on the periphery in social situations (e.g., not participating on the playground). Unlike adults, children are often unable to avoid the situations (e.g., school) that cause the anxiety and/or are unable to identify the source of the anxiety. The symptoms can interfere with class performance and social activities. The phobia must be present in same-age peer

group situations and not just with adults. The course of the condition depends on the age at which it presents. If the onset is in childhood, it can lead to a failure to achieve, if it occurs in adolescence, a decline in function can result (see Table 51).

Generalized Anxiety Disorder The main features of Generalized Anxiety Disorder (GAD ) are excessive anxiety and worry that are present for at least 6 months. Children tend to worry about their ability to perform. The worries might be focused on school or athletic performance, even when they are not being evaluated. The anxiety also might be focused on catastrophic events (e.g., a hurricane). Frequently, afflicted children are perfectionistic, which causes them to re-do tasks and to seek constant reassurance that they have done well. The prevalence of GAD in children and adolescents is 2% to 4%. For treatment, see Table 5-1.

Obsessive–Compulsive and Related Disorders Obsessive–Compulsive Disorder Diagnosis Obsessive–Compulsive Disorder (OCD ) is manifest by recurrent, distressing, and intrusive thoughts (obsessions). These can lead to repetitive and purposeful behaviors (compulsions). Children’s thoughts might include fears of contamination or feelings of self-doubt or guilt. Children also commonly have a fear of a catastrophic family event (such as the death of a parent). The resulting compulsive behaviors that alleviate the obsessions include checking, counting, hand-washing, and touching. Parents are often involved in children’s rituals, especially those that involve reassurance-seeking.

Prevalence The prevalence of the disorder is approximately 1% to 2%. Childhood OCD is characterized by a male predominance (3:2). By adolescence, the adult pattern with a slight female predominance emerges. The disorder often presents during childhood and adolescence. The mean age of presentation in the United States is 19.5 years, but 25% of cases start by age 14 (Kessler et al, 2005; Ruscio et al, 2010). Treatment issues are the same as in adults (see Table 5-1).

Trauma and Stressor-Related Disorders

Post-Traumatic Stress Disorder Children with Post-Traumatic Stress Disorder (PTSD ) experience or witness a traumatic event and develop symptoms of the disorder after that trauma. The symptoms of the disorder include re-experiencing of the event (e.g., recurrent intrusive recollections or recurrent distressing dreams of the event), autonomic arousal (e.g., increased heart rate or blood pressure) and avoidance of any stimuli associated with the trauma. In children 6 years and younger, exposure to trauma can include directly experiencing the traumatic event, witnessing the event in person, or learning that an event occurred to a parent or caregiving figure. Intrusive memories might not be distressing and can be expressed as play reenactment. For treatment, see Table 5-1.

Attachment and Engagement Disorders In the DSM-IV, Reactive Attachment Disorder had two sub-types of emotionally withdrawn/inhibited and indiscriminately social/disinhibited. These are now distinct disorders: Reactive Attachment Disorder and Disinhibited Social Engagement Disorder . The child with these conditions has a disturbed and developmentally-inappropriate ability to relate socially as a result of social neglect or situations that limit appropriate social interaction and formation of selective attachments. The child must have a developmental age of at least 9 months. In Reactive Attachment Disorder, the symptoms must be present prior to 5 years of age. There is a consistent pattern of inhibited, emotionally-withdrawn behavior toward adult caregivers. The child seeks comfort minimally when distressed or responds minimally to comfort when distressed. In Disinhibited Social Engagement Disorder, the child actively approaches and interacts with unfamiliar adults in an overly familiar way. Treatment for both includes consistent placement and work with the caregiver and infant/child dyad.

Schizophrenia Spectrum and other Psychotic Disorders Diagnosis Psychosis can (rarely) present in childhood . It refers to abnormal behavior that is accompanied by impaired reality-testing. Psychosis is defined by the presence of positive symptoms, which include delusions, hallucinations, bizarre behavior, disordered thought, and negative symptoms of inattention, anhedonia, avolition, apathy, and alogia (poverty of speech). Developmental issues complicate the diagnosis of a child with a psychotic disorder. Normal children have rich fantasy

lives in their pre-school and latency years. Therefore, differentiating normal fantasies from delusions can be difficult. In addition, normal pre-school and latency-aged children have speaking patterns that could be described as looseness of associations due to their language and cognitive development. However, if a child is psychotic, he or she has extreme degrees of disordered thought. The diagnosis of a psychotic disorder in children should be reserved for those who are consumed with fantasy and who do not recognize how fantasy differs from reality. Children have visual hallucinations more commonly than do adults. These usually occur with auditory hallucinations. In addition, children can have delusions, but they are less fixed than are the delusions in adults.

Prevalence Childhood-onset schizophrenia occurs rarely (in roughly 1/10,000 children) and develops insidiously over more than 6 months, though the initial symptoms are often overlooked, resulting in a seemingly acute presentation. The male to female ratio ranges from 3:1 to 5:1 (Frazier et al, 1997). Most children who present with psychotic symptoms have a primary affective disorder. Although presentation in childhood is rare, onset in late adolescence and early adulthood is the rule for a first-episode of psychosis.

Treatment The cornerstone of treatment for psychotic disorders in children is antipsychotic medication. Given the lower risk of tardive dyskinesia associated with atypical neuroleptics, they are now being used as first-line treatment. Adjunctive medications should be used according to the symptoms present (e.g., antidepressants for depression or mood stabilizers for bipolar disorder) and their side effect profiles (e.g., benztropine for parkinsonian symptoms).

Elimination Disorders Encopresis This condition is manifest by the repeated passage of feces into inappropriate places (intentional or involuntary); it is not due to a medical condition. This behavior occurs at least once per month for 3 months. Encopresis can occur with or without constipation and overflow incontinence. There are two types of this disorder: primary (i.e., never toilet-trained) and secondary (i.e., regressed after being toilet-trained). The child must be at least 4 years of age (chronologically and developmentally). The prevalence is 1% of 5-year-olds. It is more common

in boys than in girls. The treatment of encopresis is behavioral therapy. Some children need medical intervention for constipation and diarrhea.

Enuresis Diagnosis Enuresis is manifest by the repeated voiding of urine into the bed or clothes (intentional or involuntary) that is not due to a medical condition. This occurs at least twice each week for 3 consecutive months or causes significant distress or social impairment for the child. Enuresis can be nocturnal, diurnal, or both. Like encopresis, there are two types of the disorder (primary and secondary). The child must be at least 5 years of age (chronologically and developmentally).

Prevalence The prevalence varies with age ranging from 7% of 5-year-old boys and 3% of 5-year-old girls to 1% of 18-year-old boys and less than 1% of 18-year-old girls.

Treatment Treatment should begin with behavioral therapies. Techniques include star charts and the bell-and-pad technique (i.e., a pad is placed on the bed; when the pad becomes wet, the bell sounds). If these methods are not successful, medication is the next step. Imipramine and vasopressin (ddAVP ) have been shown to be effective. Enuresis can remit spontaneously; it is therefore important not to continue these medications indefinitely.

Feeding and Eating Disorders Pica Pica is the persistent eating of a non-nutritional substance for at least one month. This behavior is developmentally and culturally inappropriate and is often associated with intellectual disability, poverty, and nutritional deficiencies. A medical etiology for the disorder must be ruled-out. Behavioral techniques are used for treatment.

Rumination Disorder Rumination disorder involves the repeated regurgitation and re-chewing of food occurring for at least 1 month following a period of normal eating. This disorder can be associated with neglect and with developmental delay. The symptoms are not due to a GI or medical condition. This disorder develops

between the ages of 3 and 12 months. The prevalence is rare. Outcomes range from spontaneous remission to death secondary to malnutrition (mortality rates are as high as 25%). Treatment must address the medical consequences of the illness, such as dehydration and malnutrition, as well as the etiology of the illness, whether it is neglect or developmental delay.

Other Significant Issues During Childhood Suicide Suicide is the third leading cause of death in all children and adolescents in the United States, including those aged 10 to 19 years (Kochanek et al, 2012). In 2007, the death rate from suicide for children aged 10–14 years was 0.9/100,000, and for adolescents, 15 to 19 years, it was 6.9/100,000. As with adults, the ratio of males to females for completed suicide is 4:1 and the reverse is true for attempted suicide (i.e., 4:1 female to male). The most common successful means used is firearms for both males and females. Other means include hanging, suffocation, and poisoning/overdose (OD). Risk factors include a previous attempt (25%), substance abuse, chronic illness, depression, psychosis, gender identity issues (homosexuality), and family issues including history of suicide, discord, and psychiatric illness/substance abuse. Suicidal ideation is greater in high school girls than in boys with female students more likely than male students to have a specific suicide plan. The rates of having a specific plan are similar between the genders in college students. Among adolescents, suicide attempts are also more common in girls than boys (one study found that the 1-year prevalence was twice as great in females than males) Adolescent males are more likely to complete suicide than are females. Girls tend to choose less lethal means, such as cutting or overdose, whereas boys tend to choose firearms and hanging (Brent et al, 1999). In 2005, the FDA issued a black-box warning for antidepressants of all classes regarding the potential for emergence or worsening of suicidality in children and adolescents with depression treated with these medications. As untreated depression is also a risk factor for adolescent suicide, careful clinical consideration of the risks and benefits should be explicitly weighed. Adolescents and guardians should be aware of this risk and should be counseled on the need to monitor for any increase in suicidal thoughts.

Eating Disorders

Chapter 24 examines anorexia, bulimia, and avoidant restrictive food intake disorder.

Child-Specific Pharmacologic Issues Many of the disorders that present during childhood are responsive to medication. However, the use of medications in children is not as well established as it is in adults. The use of medications in children should occur only after completion of a thorough diagnostic evaluation. This process includes a full psychiatric assessment, use of structured psychiatric interviews and rating forms (as indicated), and relevant laboratory studies to rule-out underlying medical conditions. Children often benefit significantly from the initiation of medications for the treatment of psychiatric disorders. Medication can decrease the symptoms of a disorder, effect a positive change in the social/emotional and behavioral presentation of the child, and optimize the developmental trajectory of the child. The following basic pharmacologic principles should be considered when medications are used in children: children metabolize most medications more efficiently than adults and might require two-fold greater weight-corrected doses of medications; children can have higher peak plasma concentrations; and, children can have lower trough plasma concentrations.

Conclusion This chapter under-scores that psychopathology occurs in children and adolescents and that this inherently involves some de gree of developmental deviance. It is important to be able to recognize the disorders and how they present in childhood to initiate appropriate therapeutic interventions. The aim of these interventions is to decrease the child’s symptoms and to facilitate development.

Suggested Readings 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders , 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Avenevoli S, Swendsen J, He JP, et al: Major depression in the national comorbidity survey-adolescent supplement: prevalence, correlates, and

treatment. J Am Acad Child Adolesc Psychiatry . 2015 Jan; 54(1): 37– 44.e2. Epub 2014 Oct 29. 3. Brent DA, Baugher M, Bridge J, et al: Age- and sex-related risk factors for adolescent suicide. J Am Acad Child Adolesc Psychiatry . 1999; 38(12): 1497. 4. Centers for Disease Control and Prevention (CDC). Prevalence of autismspectrum disorders-autism and developmental disabilities monitoring network, 14 sites, United States, 2008. Surveillance Summaries, Morbidity and Mortality Weekly Report ; March 30, 2012/61(SS03): 1–19. 5. Frazier JA, Spencer T, Wilens T, et al: Childhood onset schizophrenia: the prototypic psychotic disorder of childhood. In: Dunner DL, Rosenbaum JF, eds.: Psychiatric Clin North Am: Annual of Drug Therapy . Philadelphia: WB Saunders, 1997; 4: 167–193. 6. Kochanek KD, Kirmeyer SE, Martin JA, et al: Annual summary of vital statistics: 2009. Pediatrics . 2012; 129(2): 338. 7. Liu H, Potter M, Woodworth Y, et al: Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry 2011; 50(8): 749–762. 8. Pavuluri MN, Birmaher B, Naylor MW: Pediatric bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry . 2005; 44(9): 846. 9. Perrin JM, Friedman RA, Knilans TK: The Black Box Working Group and the Section on Cardiology and Cardiac Surgery. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics. 2008; 122: 451–453. 10. Pfeffer CR: Suicidal behavior in children and adolescents: causes and management. In: Lewis M, ed. Child and Adolescent Psychiatry: A Comprehensive Textbook . 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007: 529–538. 11. Randall JR, Nickel NC, Colman SO: Contagion from peer suicidal behavior in a representative sample of American adolescents. J Affect Disord . 2015 Nov; 186: 219–225. Epub 2015 Jul 26. 12. Van Meter A, Moreira A, Youngstrom E: Meta-analysis of epidemiologic studies of pediatric bipolar disorder. J Clin Psychiatry. 2011; 72(9): 1250–

1256. 13. Wilens T, Spencer TJ, Frazier JA, et al: Child and adolescent psychopharmacology. In: Ollendick T, Hersen M, eds. Handbook of Child Psychopathology . 3rd ed. New York: Plenum Press; 1998: 603–636. 14. Thapar A, Pine D, Leckman J, et al, eds.: Rutter’s Textbook of Child and Adolescent Psychiatry . Oxford: Blackwell; 2015. 15. Thomas A, Chess S, Birch HG: Temperament and Behavior Disorders in Children . New York: New York University Press; 1968. 16. Vaughn MG, Fu Q, Bender K, et al: Psychiatric correlates of bullying in the United States: findings from a national sample. Psychiatr Q . 2010; 81(3): 183–195. 17. Wallerstein JS, Kelly JB: Surviving the Breakup: How Children and Parents Cope with Divorce . New York: Basic Books; 1980. 18. Winnicott DW: The depressive position in normal emotional development. In: Through Paediatrics to Psycho-analysis . New York: Basic Books; 1975.

CHAPTER 6 Tics and Tourette Disorder ERICA L. GREENBERG, MD AND DAVID H. RUBIN, MD

KEY POINTS Overview Tics are brief, recurrent, non-rhythmic movements, and are either motor or vocal and simple or complex in nature. Tourette disorder is a neurodevelopmental disorder characterized by: multiple motor and one or more vocal tics at any time during the illness (not necessarily concurrently); tics that persist for at least one year (allowing for waxing and waning in frequency); and tics with an onset before age 18 years. Persistent (chronic) motor or vocal tic disorder differs from Tourette disorder only in that the affected individual has motor or vocal tics, but not both, and they have never met criteria for Tourette disorder. Provisional tic disorder is characterized by tics that are present for < 1 year, and the individual has never met criteria for Tourette disorder. Roughly 25% of children experience tics. The volition behind tics is somewhere between involuntary and voluntary. Epidemiology and Co-morbidity Tourette disorder is highly heritable, affecting between 0.3% and 0.9% of the general population. Approximately 50% of patients with Tourette disorder will have obsessivecompulsive disorder. Approximately 50% of patients with Tourette disorder will have attentiondeficit hyperactivity disorder. Treatment Management of Tourette disorder’s co-morbid conditions (e.g., obsessivecompulsive disorder, attention-deficit hyperactivity disorder) is often more important than is treatment of the tics. There are three tiers of tic treatment. The higher the tier, the greater the efficacy and side-effect burden. Tier 1 uses alpha antagonists for mild tics. Tier

2 uses atypical antipsychotics, and Tier 3 uses typical antipsychotics, haloperidol and pimozide. Comprehensive Behavioral Intervention for Tics (CBIT) is a very effective and well-studied behavioral treatment for tics. It incorporates Habit Reversal Therapy (HRT) and function-based intervention with psycho-education, parent-training and relaxation training.

Introduction Tourette disorder , also known as Tourette syndrome, or Tourette’s, is a developmental neuropsychiatric disorder characterized by the presence of tics. Tics are brief, recurrent, non-rhythmic movements, and are either motor or vocal and simple or complex in nature.

Background Tourette disorder is in the section “Neurodevelopmental Disorders ” in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). It is manifest by multiple motor and one or more vocal tics at any time during the illness (not necessarily concurrently); tics that persist for at least one year (allowing for waxing and waning in frequency); and tics with an onset before age 18 years. Moreover, the disorder is not secondary to physiologic effects of a substance or another medical condition. All of the above criteria are required to qualify for the diagnosis. In addition to Tourette disorder, other tic disorders include persistent (chronic) motor or vocal tic disorder and provisional tic disorder . Persistent motor or vocal tic disorder differs from Tourette disorder only in that the affected individual has motor or vocal tics but not both, and they have never met criteria for Tourette disorder. Provisional tic disorder is characterized by tics that are present for less than 1 year, and the individual has never met criteria for Tourette disorder. Up to 25% of children experience a tic at some point. If an adult first notices onset of tics after the age of 18 years, it is likely that this person had tics when younger but they had spontaneously remitted. Few changes were made to Tourette disorder in DSM-5. The criterion of never being tic-free for more than three consecutive months was eliminated. Transient Tic Disorder was changed to Provisional Tic Disorder, and Tic Disorder NOS

was separated into Other Specified Tic Disorder and Unspecified Tic Disorder.” Tic criteria were standardized throughout the tic disorders. Tics wax and wane in frequency , change location, occur singularly or in bouts, and are temporarily suppressible. An itch or a sneeze is a common analogy for tics. Tics are often described as “unvoluntary,” meaning that their volition is somewhere between voluntary and involuntary. Tics are often categorized as motor tics or vocal tics, and simple tics or complex tics, as presented in Table 6-1. Motor tics involve voluntary muscle groups and create movement. Vocal tics lead to a sound. Many experts believe that there is little difference between motor and vocal tics because vocal tics are created by moving muscles to pass air. However, the distinction persists. Simple tics involve one muscle group, whereas complex tics involve the coordination of multiple muscle groups. Although the movements might look purposeful, they are not necessarily voluntary. Though coprolalia (uncontrolled swearing) is typically thought of as a hallmark of Tourette disorder, it arises in only in 15% of those with Tourette disorder. Tics are more often simple and motor (versus complex and vocal); variations include simple motor tics (e.g., blinking, shoulder shrugging), complex motor tics (e.g., tapping, rubbing), simple phonic tics (e.g., sniffing, throat clearing), and complex phonic tics (e.g., vocalizing phrases and words). Table 6-1: Categorization of Tics

Tourette disorder is more common than previously thought, affecting between 0.3% and 0.9% of the general population. Persistent (chronic) tics disorders affect an additional 1% to 2% of the population. Tic disorders, including Tourette disorder, are three to four times as common in boys than girls. The typical age of onset of tics is 5 to 7 years old. However, the peak age of Tourette disorder severity is between 10 to 14 years. It is more commonly seen in nonHispanic whites; however, a selection bias might skew these results. Following

mid-adolescence, tics often remit, and by adulthood, one can employ the “rule of thirds.” For about one-third of individuals, tics (essentially) resolve; for another one-third, they improve; and for the final third, symptoms remain the same or worsen. About 10% of adults with Tourette disorder have persistent, disabling tics. With Tourette disorder, it is helpful to think of the progression of tics as going from head to toe, from simple to complex, and from motor to vocal. Initially tics commonly involve the face (e.g., eye blinking). Tics in Tourette Disorder most often affect the face, neck, and/or shoulders. Typically, just prior to the tic, individuals will experience a “premonitory urge,” which is described as an itch or a tension that only the tic can relieve. It is usually described as a feeling of “not just right” or “incompleteness.” The tic often provides relief; however, it tends to be temporary, with the urge to tic returning rapidly. The premonitory urge frequently is the target of behavioral treatments. In general, medications target the tics, not the premonitory urges. Tics wax and wane over time (with periodicity!), but there are also common exacerbating and alleviating factors. Individuals with tics commonly find that tics improve with relaxation, intense concentration, and acting or singing. Common exacerbating factors include anxiety, fatigue, and boredom. Tics are also known to “jump”; that is, they frequently change location, number, type, complexity, and severity. They also diminish during sleep. Although psychosocial morbidity is often seen in a host of psychiatric conditions, more than two-thirds of children with Tourette disorder report impaired peer relations, difficulty with friendships, and bullying secondary to Tourette disorder. Studies show that the quality of life in children with Tourette disorder is worse compared to those in a normative sample (and/or a sample of children with a chronic, non-psychiatric disorder, such as diabetes mellitus, Type 1). Although roughly 60–80% of patients with Tourette disorder experience a decline in tics after reaching adulthood, some investigators feel that its symptoms are under-reported in adults. Because having Tourette disorder as an adult can lead to significant impairment, it is important to evaluate and assess quality-of-life measures in any patient with a history of tics.

Pathophysiology The pathophysiology of tics and Tourette disorder is complex. Tourette disorder has been called a disorder of disinhibition or a failure of cortical inhibition; this is observed in both the motor and limbic systems. Tourette

disorder is thought to be secondary to dysfunction in the fronto-striatal-thalamocortical circuits—circuits that connect the cortex to the basal ganglia to the thalamus and back to the cortex. Dopamine, and, more recently, glutamate, are the neurotransmitters typically associated with Tourette disorder. For that reason, dopamine-blocking agents typically are employed to treat Tourette disorder.

Genetics The genetics of Tourette disorder are complex. It is highly heritable, although the inheritance pattern remains unclear. Both genetic and non-genetic risk factors are postulated. Tourette disorder is believed to be polygenic; that is, there are no specific susceptibility genes that have been identified in Tourette disorder. If a family member has the disorder, there is a 10% to 20% chance that a first-degree relative will have it (about 20% of offspring, and 8% of siblings), and an additional 10% to 20% risk of having chronic tics. First-degree family members of those with Tourette disorder also have an elevated rate of early-onset o bsessive–compulsive disorder (OCD ). There are elevated rates of a ttention deficit hyperactivity disorder (ADHD) in first-degree family members in those with Tourette disorder.

Co-Morbidities In Tourette disorder, commonly occurring co-morbidities (e.g., OCD and ADHD) are often the most problematic and debilitating for patients. OCD is seen in about 50% (11%–80%) of individuals with Tourette disorder. Symptoms of OCD typically start shortly after the onset of tics. As described in the previous section, OCD is common in first-degree family members of those with Tourette disorder, and Tourette disorder and OCD are thought to be genetically linked. Symptoms of OCD in those with tic disorders and OCD typically involve symmetry; aggression; sexual and religious obsessions; and checking, touching, and evening up compulsions. About 50% (21%–90%) of those with Tourette disorder also have ADHD. Symptoms of ADHD typically start shortly before the onset of tics and persist into adulthood (related to worse psychosocial outcome). In about one-third of patients with Tourette disorder, individuals have a combination of tics, OCD, and ADHD. Though the tics might be the most observable, OCD and ADHD are often most troubling to patients.

The life-time prevalence of having co-morbid psychiatric disorders with Tourette disorder is high. A recent study showed that 79% to 90% of those with Tourette disorder have at least one co-morbid condition (e.g., a mood disorder, anxiety disorder, learning disorder, or disruptive behavior disorder). Autism spectrum disorders and body-focused repetitive behaviors (found in Obsessive– Compulsive and Related Disorders) are also more common in those with Tourette disorder.

Diagnostic Evaluation The diagnosis of Tourette disorder is made largely by the patient’s history and knowledge of the patient’s family history (of either Tourette’s and/or OCD). The physical and neurological examinations are usually normal. No routine labs or imaging are necessary unless the history is atypical or the exam abnormal. When taking the history, it is helpful to understand the development, potential stressors and triggers, and/or any physical consequences of tics, as well as to ask whether the tics have any relationship to infection (see the discussion on “PANDAS/PANS” in the next section). The most commonly used scale to assess and follow tics is the Ya le Global Tic Severity Scale (YGTSS).

Secondary Causes of Tics Secondary causes of tics include use of medications and substances (e.g., cocaine, amphetamines, methamphetamines), infectious diseases (e.g., infectious encephalitis), neurodegenerative syndromes and toxins (e.g., steroids, organophosphates), neuroacanthocytosis and autoimmune conditions (e.g., NMDA receptor encephalitis), and medical conditions (e.g., diabetic ketoacidosis, thyroid conditions). Associated symptoms and conditions that look like tics but that are not tics include stereotypies, compulsions, myoclonic jerks, and body-focused repetitive behaviors. Stereotypies are typically seen in those less than 3 years of age, are constant and fixed, are prolonged and rhythmic, and are not preceded by a premonitory urge. It can be difficult to differentiate tics from compulsions found in OCD; asking whether the movement is preceded by a thought (compulsion) or a physical feeling (tic) can help guide the diagnosis. Pe diatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS ) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS ) are two conditions that also are associated

with tics. They are poorly understood conditions, characterized by rapid, newonset OCD and/or tic symptoms in a previously healthy child, with a temporal association to a Group A Strep infection . Note that although sudden onset tics can be associated with PANDAS, PANS is identified by the sudden appearance of obsessive–compulsive symptoms and/or severe food restriction. PANDAS and PANS are hypothesized to be autoimmune disorders induced by Group A Strep infection, wherein autoimmune cells cross-react with CNS proteins. Symptoms that differentiate PANS/PANDAS from typical Tourette disorder and OCD are the concurrent sudden onset of separation anxiety, changes in motor function, and changes in urinary frequency. Current practice almost always involves treating PANS/PANDAS with the same tools you would use to treat Tourette disorder and OCD. Anti-inflammatory and antibiotic agents are occasionally used as well.

Treatment Because there is no cure for Tourette disorder , treatment is aimed at symptom reduction. Treating tic disorders can be difficult, given the natural fluctuation of tic severity and frequency. Management of its co-morbid conditions (e.g., OCD and ADHD) is often more important than is treatment of the tics themselves. Treatment should be initiated when the tics/premonitory urges are causing physical pain or impairment, social and/or functional impairment, and/or leading to psychological distress (e.g., depressive and anxious symptoms, low selfesteem, withdrawal). Two primary tactics (i.e., behavioral and pharmacological) are used to treat Tourette disorder. Though both can be effective, the two have not been compared. Ha bit Reversal Therapy (HRT ) is the central type of behavioral treatment for Tourette disorder. HRT involves the therapist helping the patient to develop “competing responses”—movements incompatible with the tics. For example, with a shoulder-shrugging tic, the patient would practice pulling down his shoulders when he feels the urge to tic. HRT utilizes detection of premonitory urges, which means that the patient must have an awareness before tics begin for this approach to work. Comprehensive Behavioral Intervention for Tics (CBIT ) is a very effective and well-studied behavioral treatment for tics. It incorporates HRT and functionbased intervention with psycho-education, parent training, and relaxation training. Function-based intervention involves determining the contextual factors that might worsen tics. Studies have shown that the effects of CBIT are

comparable to that of pharmacotherapy, specifically use of atypical antipsychotics. Few pharmacological trials have been conducted, with only three FDAapproved treatments (pimozide , haloperidol , and aripiprazole ). All other medications employed are for off-label uses. Three tiers of medications categorize treatment of tics . The first tier uses αagonists (e.g., clonidine, guanfacine) that have few side effects and are effective for mild tics. Because many children with Tourette disorder have ADHD, the αagonists can also reduce symptoms of ADHD. The second tier involves use of atypical antipsychotics (e.g., risperidone, aripiprazole), which are more effective but have more short- and long-term side effects. The final tier is comprised by use of typical antipsychotics (e.g., haloperidol, pimozide); these are commonly used when other medication trials and behavioral therapy fail. Providers often wonder whether they can use stimulants in patients with Tourette disorder. Although it was believed that stimulants would exacerbate or even cause tics, several studies have shown no association between new-onset or worsening of tics with stimulant use. Stimulants have been found to be effective in improving symptoms of ADHD regardless of whether one has Tourette disorder. Tourette disorder might worsen on stimulants. If that occurs, one can stop the stimulant, while considering the natural waxing and waning pattern of tics, and consider whether the stimulant is improving the symptoms that are more distressing to the patient.

Conclusion In summary, Tourette disorder is a common neuropsychiatric disorder. Its onset is in childhood, but about one-third of adults continue to have tics. Tourette disorder is rarely an isolated tic disorder. Up to 90% of those with the disorder have at least one co-morbid condition, most frequently OCD or ADHD; moreover, the co-morbidities are typically more impairing than are the tics themselves. Although there are some pharmacologic treatments for Tourette disorder, behavioral treatments (most notably CBIT) have been shown to be effective.

Bibliography 1. American Psychiatric Association: Highlights of Changes from DSM-IV-

TR to DSM-5. 2013. 2. American Psychiatric Association: The Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 3. Cohen S, Leckman JF, Bloch MH: Clinical assessment of Tourette syndrome and tic disorders. Neurosci Biobehav Rev . 2012; 37(6): 997– 1007. 4. Cohen S, Mulqueen J, Ferracioli-Oda E, et al: Meta-analysis: Risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry. 2015; 54(9): 728–736. 5. Egolf A, Coffey BJ: Current pharmacotherapeutic approaches for the treatment of Tourette syndrome. Drugs of Today. 2014, 50(2): 159–179. 6. Ganos C, Martino D: Tics and Tourette syndrome. Neurol Clin. 2015; 33: 115–136. 7. Hallett M: Tourette syndrome: Update. Brain & Development. 2015; 37: 651–655. 8. Hassan N, Cavanna AE: The prognosis of Tourette syndrome: implications for clinical practice. Functional Neurology 2012; 27(1): 23–27. 9. Hirschtritt ME, Lee PC, Pauls DL, et al: For the Tourette Association International Consortium for Gene tics. Lifetime prevalence, age of risk, and genetic relationships of co-morbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry . 2015; 72(4): 325–333. 10. McGuire JF, Piacentini J, Brennan EA, et al: A meta-analysis of behavior therapy for Tourette syndrome. J Psychiatric Res. 2014; 50: 106–112. 11. Robertson MM: Tourette Syndrome 1: A personal 35-year perspective on Gilles de la Tourette prevalence, phenomenology, co-morbidities, and coexistent psychopathologies. Lancet Psychiatry. 2015; 2 :68–87. 12. Robertson MM: Tourette syndrome 2: A personal 35-year perspective on Gilles de la Tourette syndrome: assessment, investigations, and management. Lancet Psychiatry. 2015; 2: 88–104. 13. Serajee FJ, Huq AHM: Advances in Tourette syndrome: Diagnoses and treatment. Pediatr Clin N Am. 2015; 62: 687–701. 14. Walkup JT, Ferrao Y, Leckman JF, et al: Tic disorders: Some key issues for DSM-V. Depression and Anxiety. 2010; 27: 600–610.

15. Yael D, Vinner E, Bar-Gad I: Pathophysiology of tic disorders. Movement Disorders , 2015; 30(9): 1171–1178.

CHAPTER 7 Autism Spectrum Disorders ARSHYA VAHABZADEH, MD

KEY POINTS Overview Autism spectrum disorder (ASD) is a diagnostic term used to categorize individuals with pervasive developmental disorders (PDDs). Epidemiology ASD occurs in approximately 1 in 68 children in the United States, accounting for a prevalence of 14.6 per 1,000 children. The prevalence of ASD has been rising steadily in recent years, and it is about 4.5 times more common in males than females. Clinical Features Diagnostic criteria for ASD now focus on two domains: social communication impairment and restricted/repetitive patterns of behavior. Etiology ASD is a neurodevelopmental disorder with a complex etiology comprising both genetic and environmental factors. Family and twin studies have identified ASD as being highly heritable. Differential Diagnosis Several psychiatric disorders (e.g., anxiety disorders, mood disorders, disorders of attention, obsessive–compulsive disorders) need to be considered when evaluating a person with marked deficits in social communication and social relationships. Co-Morbidity Common co-morbid conditions include intellectual disability, attention deficit

hyperactivity disorder (ADHD), and seizure disorders. Evaluation An assessment of an ASD diagnosis necessitates both a behavioral evaluation and the review of collateral information (e.g., from caregivers and the educational setting). Although ASD remains a clinical diagnosis, screening and diagnostic assessments, such as the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) might support the diagnosis. Treatment Treatment options for ASD include behavioral interventions and pharmacologic treatments. Early behavioral interventions, such as those provided by applied behavioral analysis, have been effective in reducing behavioral and functional impairments. The primary focus on pharmacotherapy in ASD is on the use of selected antipsychotics for the treatment of irritability associated with ASD.

Overview Autism spectrum disorder (ASD) is a diagnostic term introduced by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) to categorize individuals with PDDs. The predecessor to the DSM, the DSM-IV, had categorized several PDDs, including Asperger’s disorder, autistic disorder, and PDD not otherwise specified (PDD-NOS). The transition to ASD as a single umbrella diagnosis was believed to improve the diagnosis of ASD without altering the sensitivity of its criteria. Research suggested that 91% of children with DSM-IV–based autism-related diagnoses would meet criteria for a DSM-5 ASD diagnosis (Huerta et al, 2012). Although some DSM-IV diagnoses, such as PDD-NOS, have a lower likelihood of meeting DSM-5 ASD criteria than others (e.g., autistic disorder and Asperger’s disorder), per the DSM-5, individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s disorder, or PDD-NOS should be grandfathered into an ASD diagnosis.

Epidemiology ASD occurs in approximately 1 in 68 children in the United States according to data from the Centers for Disease Control and Prevention (CDC), accounting for a prevalence of 14.6 per 1,000 children. The prevalence of ASD has been rising steadily in recent years, and it is about 4.5 times more common in males than females. It has been suggested that most of the rise in prevalence can be attributed to greater awareness, and broadening of the diagnostic criteria, as opposed to biologic or environmental factors. The median age of when ASD is diagnosed in the United States is 50 months (Christensen et al, 2012); this finding was based on research conducted on DSM-IV PDD criteria. Individuals with a diagnosis of autistic disorder had an earlier diagnosis (46 months) compared to those with a PDD-NOS diagnosis (49 months), and Asperger disorder (74 months). ASD is present in all racial and ethnic groups although the estimated prevalence appears to be higher in non-Hispanic white children compared to Hispanic, Asian/Pacific Islander, and non-Hispanic black children (Christensen et al, 2012).

Clinical Features As noted above, the DSM-5 created a new diagnostic category (ASD), with the removal of previously classified PDDs. Diagnostic criteria for ASD now focus on symptoms in two domains instead of three. These two domains are social communication impairment and restricted/repetitive patterns of behavior ; these replaced the previous domains of social reciprocity , communication , and restricted/repetitive behavior . An individual must have had these symptoms since early childhood. Additionally, the new ASD category allows for a diagnosis to have severity specifiers (Level 1: requiring support; Level 2: requiring substantial support; Level 3: requiring very substantial support). Diagnoses also can be made with specifiers as to their associated symptoms (e.g., intellectual impairment, language impairment, catatonia, association with a mental/genetic/environmental factor, and association with another mental or behavioral disorder).

Social Communication Social communication impairment includes deficits in social–emotional reciprocity, non-verbal communication, and developing interpersonal relationships. Social–emotional reciprocity deficits can include: failure of back-

and-forth communication; reduced sharing of interests, emotions, or affect; or failure to respond to social interactions. Non-verbal communication deficits include difficulty understanding facial expressions, body language, and, eye contact. Deficits in developing and understanding relationships include adjusting behavior based on social context, difficulty in engaging in imaginative play, or difficulty in making friends.

Restricted or Repetitive Patterns of Behavior Restricted and repetitive patterns of behavior include stereotyped or repetitive motor movements, speech, or use of objects. Additionally, individuals might have rigid routines and insist on sameness; for example, adopting a greeting ritual or struggling with small changes to normal activities. Afflicted individuals might also have increased or decreased sensory input, or pay special attention to sensory aspects of the environment. The consideration of abnormal sensory processing is novel for the DSM-5. Individuals might also demonstrate an abnormal intensity of interest in a narrow range of fixed topics.

Gender and Co-Morbidity Although the prevalence of ASD is lower in females than in males, females with ASD have been noted to have a greater impairment in social communication, lower cognitive abilities, and more difficulty externalizing problems than do males (Frazier et al, 2014). ASD is often co-morbid with intellectual disability (Christensen et al, 2016; Volkmar and McPartland, 2014; Geschwind and State, 2015), ADHD (Davis and Kollins, 2012), and seizure disorders (Amiet et al, 2008).

Etiology ASD is a neurodevelopmental disorder with a complex etiology comprising both genetic and environmental factors. Family and twin studies have identified ASD as being highly heritable, and much of the etiologic research into ASD has focused on genetic factors. Twin concordance studies have suggested that ASD can have a heritability of 37% to more than 90%, with approximately 15% of cases attributed to a known genetic mutation. Aside from specific gene mutations, ASD is thought to be a polygenic condition wherein many inherited gene variants contribute a small additive risk for development of the disorder. A range of genetic disorders (e.g., tuberous sclerosis complex, Fragile X syndrome, Phelan-McDermid Syndrome) have been linked to an increased risk of ASD.

Neuroimaging research has found that ASD is often associated with an atypical trajectory of brain maturation, with accompanying changes in neuroanatomy and neurocircuitry. Additional findings have highlighted altered neurotransmitter levels across multiple systems, immune dysfunction, and neuroinflammation. One of the areas of greatest controversy has focused on whether certain childhood vaccinations cause ASD; however, the current evidence suggests that ASD is not associated with childhood vaccinations (Jain et al, 2015). Recent research has highlighted several environmental factors that might be linked with ASD, including pre-natal exposure to antidepressants ( Boukhris et al, 2016) and valproate (Christensen et al, 2013) as well as particulate air pollution (Lam et al, 2016). ASD also has been linked to low birth weight and to both rising maternal and paternal age (Sandin et al, 2012; Sandin et al, 2016).

Differential Diagnosis Several other psychiatric disorders need to be considered when evaluating a person with marked deficits in social communication. Anxiety disorders, mood disorders, and disorders of attention, can all interfere with a person’s ability to build and engage in social relationships. Individuals who display repetitive behavior should also be differentiated from people with obsessive–compulsive disorder, or those with tics. Some who display symptoms of impaired social communication but who do not also have restricted or repetitive behaviors/interests associated with ASD might be diagnosed as having social (pragmatic) communication disorder (SCD ). SCD is a new diagnostic category introduced by the DSM-5 as a communication disorder . Research is limited into SCD, and there are no validated assessments or treatments for this new disorder. If criteria for ASD are met, an ASD diagnosis supersedes a SCD diagnosis. Selective mutism also might be considered in the differential diagnosis, although in such cases, early development is normal, and, within certain settings, a child might be able to have normative social communication and behavior. In selective mutism, social reciprocity continues, whereas repetitive behaviors are absent when a child is mute. People with schizophrenia also demonstrate deficits in social interactions, although schizophrenia is encountered only rarely in childhood, and it tends to manifest in adolescence or young adulthood. Even though those with schizophrenia might experience delusions and perceptual disturbances (such as

auditory hallucinations), these symptoms are not normally encountered in individuals with ASD.

Co-Morbidity Common co-morbid conditions include intellectual disability, ADHD, and seizure disorders. When seizure disorders occur in individuals with ASD, they can be refractory to treatment. Those with ASD might also have pronounced problems with sleep and gastrointestinal function (including constipation and disorders of food intake). The DSM-5 allows for a co-morbid diagnosis of an ASD and ADHD. A diagnosis of autistic disorder in the DSM-IV-TR precluded a co-morbid diagnosis of ADHD. This is important given that between 30% to 50% of individuals with ASD also demonstrate marked ADHD symptomatology. It also should be noted that about one-third of people with ASD have co-morbid intellectual disability.

Approaches to Evaluation An assessment of an ASD diagnosis necessitates both a behavioral evaluation and the review of collateral information (e.g., from caregivers and the educational setting). Although ASD remains a clinical diagnosis, there is a wide variety of screening and diagnostic assessments that might also support the diagnosis. The most well-known of these measures are the Autism Diagnostic Observation Schedule (ADOS ) and the Autism Diagnostic Interview-Revised (ADI-R ) (Gotham et al, 2008; Lord et al, 1994). A delay in spoken language is a common cause for younger children being referred for an ASD evaluation. It is prudent to ensure that a child has had normal hearing and vision tests because these senses are important in communication and social interactions. Some clinicians also ask for genetic testing, especially if there are dysmorphic characteristics that might suggest the presence of a syndrome. It is also worthwhile to review a patient’s educational history and prior neuropsychological testing. A sudden change in behavior or presentation should alert clinicians to look for medical and psychiatric causes, especially if the patient is non-verbal or has pronounced limitations of their communication skills.

Treatment

Treatment options for ASD include behavioral interventions and pharmacologic treatments. Early behavioral interventions, such as those provided by applied behavioral analysis (ABA ), have been effective in reducing behavioral and functional impairments. Early behavioral interventions are strongly recommended in children diagnosed with ASD. Co-morbid psychiatric and medical conditions should also be treated. The primary focus on pharmacotherapy in ASD is on the use of selected antipsychotics for the treatment of irritability associated with ASD. Many psychiatrists resort to using psychiatric medications off-label to control behavioral symptoms (e.g. irritability, mood swings, or sleep disturbance). Evidence-based behavioral interventions vary depending on methodology and delivery (therapist versus parent versus technological). ABA techniques that utilize reinforcement, extinction, and prompting are common, as are approaches involving communication training, pivotal response training, and functional behavior assessments. Many of those with ASD benefit from occupational, physical, and speech and language therapy services.

Pharmacotherapy There are currently no medications that address the social communication deficits seen in ASD. There are only two FDA-approved medications (risperidone and aripiprazole ) for ASD-related symptoms; both atypical antipsychotics approved to treat irritability in children. Children with ASD often have other co-morbid psychiatric conditions, such as ADHD or anxiety, and, if present, these should be treated. Some clinicians use other medications, such as selective serotonin re-uptake inhibitors (SSRIs) to target ASD-related repetitive behaviors. However, there is no consensus as to their effectiveness, and any use would be considered off-label.

References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. American Psychiatric Publishing; 2013. 2. Amiet C, Gourfinkel-An I, Bouzamondo A, et al: Epilepsy in autism is associated with intellectual disability and gender: evidence from a metaanalysis. Biol Psychiatry . 2008; 64: 577–582. 3. Autism Spectrum Disorder Fact Sheet. NINDS.NIH.GOV, 2016. (Accessed

Oct 31 2016, at https://www.ncbi.nlm.nih.gov/pubmed/ ). 4. Boukhris T, Sheehy O, Mottron L, et al: Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatrics . 2016; 170: 117–124. 5. Canitano R: Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry . 2007; 16: 61–66. 6. Christensen DL, Baio J, Van Naarden Braun K, et al: Prevalence and characteristics of autism spectrum disorder among children aged 8 years-Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ . 2016; 65: 1–23. 7. Christensen J, Gronborg TK, Sorensen MJ, et al: Pre-natal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA . 2013; 309: 1696–1703. 8. Davis NO, Kollins SH: Treatment for co-occurring attention deficit/hyperactivity disorder and autism spectrum disorder. Neurotherapeutics . 2012; 9: 518–530. 9. Ecker C, Bookheimer SY, Murphy DG: Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan. Lancet Neurol . 2015; 14: 1121–1134. 10. Fountain C, King MD, Bearman PS: Age of diagnosis for autism: individual and community factors across 10 birth cohorts. J Epidemiol Community Health . 2011; 65: 503–510. 11. Frazier TW, Georgiades S, Bishop SL, et al: Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J Am Acad Child Adolesc Psychiatry . 2014; 53: 329–340 e1-3. 12. Geschwind DH, State MW: Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol 2015; 14: 1109–1120. 13. Gotham K, Risi S, Dawson G, et al: A replication of the Autism Diagnostic Observation Schedule (ADOS) revised algorithms. J Am Acad Child Adolesc Psychiatry . 2008; 47: 642–651. 14. Hallmayer J, Cleveland S, Torres A, et al: Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry . 2011; 68: 1095–1102. 15. Huerta M, Bishop SL, Duncan A, et al: Application of DSM-5 criteria for

16.

17.

18.

19.

20.

21.

22. 23.

24.

25. 26.

autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. Am J Psychiatry . 2012; 169: 1056–1064. Jain A, Marshall J, Buikema A, et al: Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA . 2015; 313: 1534–1540. Kim YS, Leventhal BL: Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry . 2015; 77: 66–74. Kim YS, Leventhal BL, Koh YJ, et al: Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry . 2011; 168: 904– 912. Lam J, Sutton P, Kalkbrenner A, et al: A systematic review and metaanalysis of multiple airborne pollutants and autism spectrum disorder. PLoS One . 2016; 11:e0161851. Lord C, Rutter M, Le Couteur A: Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord . 1994; 24: 659–685. Sandin S, Hultman CM, Kolevzon A, et al: Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry . 2012; 51: 477–486 e1. Sandin S, Lichtenstein P, Kuja-Halkola R, et al: The familial risk of autism. JAMA . 2014; 311: 1770–1777. Sandin S, Schendel D, Magnusson P, et al: Autism risk associated with parental age and with increasing difference in age between the parents. Mol Psychiatry . 2016; 21: 693–700. de la Torre-Ubieta L, Won H, Stein JL, et al: Advancing the understanding of autism disease mechanisms through genetics. Nat Med . 2016; 22: 345– 361. Volkmar FR, McPartland JC: From Kanner to DSM-5: autism as an evolving diagnostic concept. Annu Rev Clin Psychol . 2014; 10: 193–212. Warren Z, McPheeters ML, Sathe N, et al: A systematic review of early intensive intervention for autism spectrum disorders. Pediatrics . 2011; 127:

e1303–1311. 27. Wong C, Odom SL, Hume KA, et al: Evidence-based practices for children, youth, and young adults with autism spectrum disorder: A comprehensive review. J Autism Dev Disord . 2015; 45: 1951–1966.

CHAPTER 8 Delirium THOMAS H. MCCOY, JR., MD; JOHN B. TAYLOR, MD, MBA; AND SHAMIM H. NEJAD, MD

KEY POINTS Overview Delirium is a clinically significant and common illness. Delirium might best be thought of as acute brain failure and a sign that an underlying illness results in end-organ (brain) dysfunction. Epidemiology Delirium is a common diagnosis, estimated to affect 15% to 60% of all inpatients. Meta-analyses show that roughly one-third of intensive care unit (ICU) patients become delirious, and among patients who are intubated, the rate of delirium can exceed 80%. Clinical Features The hallmark of delirium is impaired attention and orientation. The delirious patient often has perceptual disturbances. Symptoms of delirium fluctuate over a short period and should not be explicable in terms of a pre-existing neurocognitive condition. Etiology The pathophysiology of delirium is not fully understood. It appears likely that systemic illnesses yield brain dysfunction through inflammation, oxidative stress, and neuroendocrine responses to stress hormone levels. Although the precise final common pathway—if it exists—is unclear, there is mounting evidence for an important role of alterations in neurotransmitter levels and network disconnection. Withdrawal from alcohol is a particularly common and understood cause of delirium that requires specific identification and attention.

The mnemonic WWHHHHHIMPS is helpful in identifying life-threatening causes of delirium. Prevention and Treatment Delirium is definitively treated when its underlying cause is treated. It appears to be preventable through a range of pharmacological and behavioral interventions. After delirium has developed, reversal of the acute insult is the cornerstone of treatment. Delirium due to alcohol withdrawal requires focused treatment. Delirium in general can be symptomatically managed with antipsychotics and melatonin agonists.

Overview Delirium is a condition with far-reaching consequences for patients and hospitals alike. For patients, delirium might best be thought of as acute brain failure and a sign of an underlying illness that results in end-organ (brain) dysfunction. Sequelae of this dysfunction include persistent cognitive deficits, prolonged hospital stays, and an increased likelihood of in-hospital death and death in the six-months following the diagnosis of delirium. For hospitals, delirium often results in increased length of stays with accompanying financial consequences. The annual cost of delirium is estimated to be upward of $150 billion. For primary medical and surgical teams, the agitated and delirious patient is a common source of frustration and uncertainty.

Epidemiology Delirium is a common diagnosis in general hospitals, estimated to affect 15% to 60% of all inpatients. Meta-analyses show that roughly one-third of intensive care unit (ICU) patients become delirious; among patients who are intubated, the rate of delirium can exceed 80%. Geriatric patients are particularly susceptible to delirium. Among the elderly, 15% to 50% of post-operative patients develop delirium, and up to 80% of those in the ICU develop delirium, regardless of whether they are intubated. Although the literature on risk factors for delirium continues to evolve, current approaches divide risk into pre-hospital and intra-hospital risks. Reliably

demonstrated pre-hospital risk factors include age, pre-existing brain compromise (e.g., dementia, stroke, traumatic brain injury), sensory impairments, and alcoholism. Reliable in-hospital risk factors include, severity of illness, unplanned or emergency surgery, use of opioids, metabolic derangement, and reduced mobility following surgery. Although not studied in meta-analyses, hypertension, multiple medical problems, and the use of anticholinergic medications also appear to contribute to risk of delirium.

Clinical Features To make the diagnosis of delirium, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) requires the following: A disturbance of attention and awareness or orientation An alteration in cognition or the development of a perceptual disturbance Evolution of these symptoms over a short span (generally hours to days), with fluctuation during the day Symptoms that are not attributable to a pre-existing neurocognitive condition or that occur in the setting of grossly reduced arousal (e.g., coma) Evidence that the disturbance is caused directly by a general medical condition The hallmark of delirium is impaired attention. Patients are easily distracted and unable to focus on the conversation. Cognitive impairment is frequently identified by: an inability to recall events, both recent and remote; disorientation to place and time; effortful production and comprehension of speech; and difficulty with reading and writing. An underlying medical problem—usually more than one—is always present (though not always identified). The presentation of delirium is wide-ranging and can be heralded by few and subtle disturbances. Symptoms that traditionally mark a psychotic illness— especially auditory and visual hallucinations and paranoid delusions—are frequently present. Patients can exhibit a broad range of activity (from hyperactive and agitated to psychomotorically retarded), which can be insidious and often be confused with depression. Other principal features include acute onset and disturbance of the sleep-wake cycle. Sundowning is not uncommon. The course often waxes and wanes with periods of lucidity that are interspersed

with periods of beclouded sensorium. In addition, afflicted patients frequently have impaired insight into their condition. Physical findings also can signify brain dysfunction, though these findings are not specific to delirium. The presence of frontal release signs (e.g., grasp, snout, palmomental, suck, glabellar reflexes) can indicate frontal lobe compromise. The Luria hand sequence can detect subtle dysfunction in the premotor cortex. Various bedside tests can be used to objectify patients’ cognitive problems. The Folstein Mini-Mental State Examination (MMSE ) is a well-studied questionnaire that screens for cognitive impairment; it can be used over both short and long time spans to track changes in functioning. The Montreal Cognitive Assessment (MoCA ) features a wider range of tasks than the MMSE, and it has a higher sensitivity for identification of mild cognitive impairment; it is available in numerous languages and forms. Clock-drawing, a component of the MoCA, can be administered as a stand-alone task and is appealing because it is unaffected by education level, cultural differences, and language barriers (yet tests a wide range of cognitive domains, including comprehension, planning, visual memory, visuo-spatial ability, motor programming and execution, abstraction, concentration, and response inhibition).

Mechanism The mechanisms by which delirium is caused are not fully understood; however, several inter-connected mechanisms attempt to explain its development. Systemic illness is thought to yield brain dysfunction through inflammation, oxidative stress, and neuroendocrine responses to stress hormone levels. Sensitivity to the downstream consequences of these illnesses is likely increased by aging and by diurnal dysregulation. Although the precise final common pathway is unclear, there is mounting evidence for an important role of alterations in neurotransmitter levels and network disconnections. Delirium, depending on its etiology, appears to be associated with reduced acetylcholine (ACh), reduced melatonin, increased dopamine, increased glutamate, and increased norepinephrine. It is postulated that there is dysfunction in the reticular activating system (RAS), a set of neurons associated with alertness and mediated by ACh. Diminished ACh could cause dysfunction in the RAS, leading to the fluctuation in consciousness that is the hallmark of delirium. This might explain why anticholinergic medications often exacerbate delirium or predispose to its development.

Delirium also has been associated with hyper-dopaminergia. It is hypothesized that this is caused by stress, which has been shown to increase dopamine release in the mesocortical and mesolimbic tracts. Therefore, D2 -blocking agents (e.g., both typical and atypical antipsychotics) are often effective in controlling symptoms of delirium. Melatonin is a hormone released by the pineal gland in anticipation of darkness and is an important regulator of circadian rhythm. Although sleep disruption is an important risk factor for delirium and melatonin supplementation can be therapeutic, the exact mechanism is unclear. Alcohol withdrawal is an illustrative example of the roles of norepinephrine and glutamate. Alcohol use appears to be one of the strongest risk factors for development of delirium and, from a physiological standpoint, alcohol is the most commonly encountered source of chronic exogenous g -aminobutyric acid (GABA ) agonism. Long-term exposure to GABAA agonists (e.g., benzodiazepines, barbiturates, alcohol) leads to adaptation in glutamate, norepinephrine, and GABA. Glutamate is the most common excitatory neurotransmitter in the human brain, and it acts on several types of receptors, of which the N -methyl-D -aspartate (NMDA) receptor is the most studied. Chronic exposure to GABAA substrates results in reduced GABA activity and increased glutamate activity. In the setting of abrupt discontinuation of GABA agonists, the decrease in GABA activity leads to restlessness, anxiety, panic, tremor, nausea, and malaise, whereas the hyperglutamatergic state results in neuroexcitability that activates the locus ceruleus (the primary source of noradrenergic neurons in the brain). The subsequent release of norepinephrine leads to tachycardia, hypertension, diaphoresis, tremor, and fever. Furthermore, due to the hyper-glutamatergic state, dopamine is released in the mesolimbic tract resulting in confusion, agitation, and paranoia, as well as visual and tactile hallucinations. If these symptoms continue to worsen, seizures and delirium—what is termed complicated withdrawal —can occur. The timing and severity of symptoms depend on the substance from which the patient is withdrawing, the duration and severity of its use, and the patient’s baseline physiological reserve.

Important Illnesses that Cause Delirium Any illness or stress to the body can cause delirium. In general, as insults mount, the greater the likelihood, duration, and severity of delirium. Life-

threatening causes can be remembered using the mnemonic,“WWHHHHHIMPS” (see Table 8-1). Because the consequences of these etiologies could be dire, they should be ruled-out first when developing a differential diagnosis. A broader differential, encompassing many potential causes of delirium, can be recalled using the mnemonic, “I WATCH DEATH” (see Table 8-2). Table 8-1. Life-Threatening Causes of Delirium: WWHHHHHIMPS W ithdrawal (from alcohol, benzodiazepines, barbiturates, and, less frequently, opioids) W ernicke’s encephalopathy H ypoxia H ypoglycemia H ypertensive urgency or emergency H yper- or hypothermia H ypoperfusion (e.g., hypotension) I ntracerebral hemorrhage M eningitis/encephalitis P oisoning S tatus epilepticus

Table 8-2. Causes of Delirium: I WATCH DEATH I nfection

Local or systemic infection

W ithdrawal

Alcohol, benzodiazepines, barbiturates, and (less frequently) opioids

A cute metabolic Electrolyte and fluid derangements, renal failure, hepatic failure, acid-base disturbances T rauma

Head injury, burns, post-operative state

C NS pathology

Anywhere in the neurological axis

H ypoxia

Anemia, hypotension, hypoperfusion, respiratory failure, carbon monoxide poisoning, pulmonary embolism

D eficiencies

Vitamin B12 , folate, thiamine, niacin

E ndocrinopathies

Hyper- or hypoglycemia; increase or decrease in activity of pituitary, thyroid, parathyroid, or adrenal glands

A cute vascular

Hypertensive urgency/emergency, myocardial infarction, stroke, shock

T oxins/drugs

Medications, pesticides, solvents

H eavy metals

Lead, manganese, mercury

The diversity of these illnesses speaks to the need for a broad differential and work-up of the delirious patient. Depending on the presentation, this work-up might include serology, cell counts, cultures, electrophysiological tests, and radiographic data.

Prevention The literature on delirium prevention is rapidly growing and suggests that delirium is preventable. Most literature on prevention focuses on very high-risk patients. This literature can be divided into pharmacological and nonpharmacological interventions. The most robust pharmacological prophylaxis literature is for the pre-operative administration of antipsychotics in high-risk patients. For example, in one such study of olanzapine in patients undergoing hip or knee replacement surgery, perioperative administration of olanzapine 10 mg was associated with a significantly lower incidence of delirium in the 5 days after surgery (Larsen et al, 2010). Other benefits included reduced need for opioids and greater likelihood of being discharged to home instead of to a rehabilitation facility. Several similar studies have been conducted, allowing for meta-analysis of peri-operative antipsychotic administration, which yielded a number-needed-to-treat (NNT) ranging from 4 to 12. Although far from established, a few interesting studies that await replication hint at future means of pharmacological prophylaxis. Ramelteon (a melatonin receptor agonist) might be protective in elderly patients with significant medical illness. Non-pharmacological interventions to prevent delirium also appear effective on meta-analysis. Most interventions in this literature are based on the Hospital Elderly Life Program, which focuses on re-orientation, mobilization, activity, hydration, nutrition, sleep, and mitigation of sensory impairments (e.g., with use of hearing aids and glasses). These interventions appeared to have a pooled NNT of 10 to 20.

Treatment Delirium is definitively treated when its underlying cause is treated. As the agitated delirious patient presents a risk to himself and others, symptomatic management is appropriate in the interim. Symptoms can be managed using

medications to minimize the patient’s confusion, agitation, and likelihood of causing inadvertent injury to self or others. Adjunctive neuroleptic medication is commonly used to control symptoms in both hypoactive and hyperactive delirium. The most commonly used neuroleptic in this setting is haloperidol , usually in its intravenous (IV) formulation. The IV formulation is less frequently associated with development of extrapyramidal symptoms (EPS ), such as dystonia and akathisia, and can usually be safely given in high doses. Typical total daily doses range from 1 to 20 mg, usually divided in two or four doses per day, though higher doses are sometimes necessary. A serial doubling protocol, whereby a previous ineffective dose can be doubled every 30 minutes until the patient is calm, is best reserved for cases of florid agitation that compromises critical treatments and when a clinician with experience in the management of severe delirious agitation is on hand. As the delirium resolves, the dose can be tapered over several days. If IV access cannot be established, it is better to use an atypical agent rather than haloperidol orally or intramuscularly (IM), as the risk of EPS with these routes of administration is too great. Atypical antipsychotics also can be used to treat delirium. None are available as an IV formulation. Several (olanzapine, risperidone, and aripiprazole) have orally-disintegrating formulations that might prove useful for an agitated patient; these are not absorbed sublingually (but enterally) and a lag between time of administration and onset of action will occur as with any other oral medication. Some (olanzapine, ziprasidone, and aripiprazole) also have IM formulations that act quickly. Because delirious patients are often paranoid and uncooperative, it can be unhelpful to subject them to the pain of an IM injection that they neither want nor understand; IM injections are best used in acute behavioral emergencies. IM olanzapine should not be co-administered with an IM/IV benzodiazepine, because numerous case reports document a risk of respiratory depression.

Treatment of GABA Withdrawal GABA withdrawal is a particularly important cause of delirium, given that the treatment of the underlying cause of the delirium—discontinuation of exogenous GABA—is often the primary responsibility of the psychiatrist. Treatment of GABA-agonist withdrawal can be thought of as having a prevention stage and a management stage.

The prevention stage requires systematic return of exogenous GABA in a tapering fashion. This taper of exogenous GABA allows for a gradually controlled reversal of the physiological adaptation that occurred to chronic exogenous GABA. Benzodiazepines , such as lorazepam and diazepam (both available in oral and IV formulations), as well as chlordiazepoxide and oxazepam (available orally), are most often used to treat GABA-agonist withdrawal delirium. Although benzodiazepines often effectively address the symptoms of hyperarousal seen in withdrawal states, they can produce untoward effects, such as respiratory depression, when used in exceedingly high doses or when administered to patients unable to metabolize the medications adequately (e.g., patients with chronic liver dysfunction). Chlordiazepoxide has a half-life of several days and has several metabolites that are metabolically active; its overuse in treating withdrawal can lead to benzodiazepine intoxication over extended periods. Lorazepam and oxazepam have short half-lives, do not require hepatic oxidation, and do not have active metabolites; therefore, they are more frequently used in geriatric patients and in patients with liver disease. Benzodiazepines are not the only option for controlled taper of exogenous GABA to prevent withdrawal. Phenobarbital, a barbiturate, is the antiepileptic drug (AED) most commonly used worldwide to treat seizures. As with all barbiturates, phenobarbital binds to the GABAA receptor at a binding site distinct from where GABA and benzodiazepines bind. In addition to this GABA-ergic effect, barbiturates also block the α -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) and kainate receptors , sub-types of glutamate receptor implicated in the development of complicated alcohol withdrawal. Phenobarbital’s long half-life, lack of cross-tolerance in alcohol-dependent patients, cross-reactivity with alcohol and benzodiazepines, reliable pharmacokinetics that allows targeting of a serum level, suppression of glutamate hyperactivity, and decreased tendency to cause altered mental status compared with benzodiazepines make it a reasonable choice for the treatment of GABA-mediated delirium. Its administration for GABA-agonist withdrawal resembles its administration for epilepsy: a loading dose of 15 mg/kg based on the patient’s ideal body weight is given IM with a desired serum level of 6 to 15 mcg/mL, followed by a 6-day taper. If prophylaxis through a taper is not possible or is unsuccessful and symptomatic withdrawal develops, an exogenous GABA taper is unlikely to be sufficient. Nevertheless, a controlled return of exogenous GABA remains important. In these more difficult cases, agents with direct effects on the

glutamate system (phenobarbital and propofol) are of increased utility. Propofol can be an appropriate agent for patients who are already in an ICU or have treatment-resistant GABA-mediated withdrawal delirium. Propofol appears to have less cross-tolerance to, but is cross-reactive with, benzodiazepines and alcohol, is easily titrated, and is rapidly cleared from the body. As with alcohol, propofol affects GABAA and glutamate receptors. Maintenance of sedation (by infusion at 25–75 mcg/kg/minute) or anesthesia (at 100–300 mcg/kg/min) can be achieved and titrated to the patient’s response. Recovery from propofol is quick; typically, within 30 minutes of discontinuation, propofol concentrations drop to < 1 mg/L. There is no standard protocol for the taper of propofol when it is used for the control of GABA-mediated withdrawal states; some clinicians abruptly discontinue the infusion, whereas others prefer to wean the drug over a few hours to minimize the potential of emergent agitation. Dexmedetomidine is a lipophilic imidazole derivative approved by the U nited States Food and Drug Administration (FDA) in 1999 for sedation in ICUs. Its affinity for α2-adrenoceptors is 1,620 times higher than for α1-receptors and eight times higher than clonidine’s affinity for the former; clonidine is the other α2-agonist drug available in the United States. Dexmedetomidine works by binding pre-synaptic α2-adrenergic receptors and decreasing the release of norepinephrine from the locus ceruleus. Dexmedetomidine’s sedative, anxiolytic, and analgesic effects are produced through selective activation of post-synaptic α2-adrenoreceptors. Dexmedetomidine has been found to be an excellent alternative for sedation in ICUs; studies suggest it significantly reduces the development of post-operative GABA-related withdrawal states. Given that α 2 -agonist agents effectively control the autonomic manifestations of the alcohol w ithdrawal syndrome (AWS) and have been shown to reduce agitation and other behavioral manifestations of AWS, their use in the management of severe GABA-mediated withdrawal should be considered for patients in the ICU or for patients with treatment-resistance to more conventional forms of treatment. Treatment with dexmedetomidine usually involves a continuous infusion at 0.2 to 1.4 mcg/kg/hr, without a loading dose, to avoid unnecessary hypotension and bradycardia.

Conclusion With a wide-ranging presentation and frequently obscured underlying etiology, delirium is a challenging condition to diagnose and to manage in general

hospitals. Its morbidity and mortality necessitate timely diagnosis so that its cause can be appropriately treated. Delirium is best managed using antipsychotics; GABA-agonist withdrawal delirium is best managed by using a different set of medications, most of which act on the GABA receptor and manage noradrenergic excess. Although the pre-emptive administration of antipsychotics is not yet the standard of care, data showing improved outcomes with antipsychotic use before certain surgical procedures that predispose to delirium are accumulating.

Suggested Readings 1. Elie M, Cole MG, Primeau FJ, et al: Delirium risk factors in elderly hospitalized patients. J Gen Intern Med . 1998; 13: 204–212. 2. Fok MC, Sepehry AA, Frisch L, et al: Do antipsychotics prevent postoperative delirium? A systematic review and meta-analysis. Int J Geriatr Psychiatry . 2015; 30: 333–344. 3. Hshieh TT, Yue J, Oh E, et al: Effectiveness of multi-component nonpharmacological delirium interventions: A meta-analysis. JAMA Intern Med . 2015; 175: 512–520. 4. Larsen KA, Kelly SE, Stern TA, et al: Administration of olanzapine to prevent post-operative delirium in elderly joint-replacement patients: A randomized, controlled trial. Psychosomatics . 2010; 51: 409–418. 5. Maldonado JR: Neuropathogenesis of delirium: Review of current etiologic theories and common pathways. Am J Geriatric Psychiatry . 2013; 21: 1190–1222. 6. Markowitz JD, Narasimhan M: Delirium and antipsychotics: A systematic review of epidemiology and somatic treatment options. Psychiatry (Edgmont). 2008; 5: 29–36. 7. van Meenen LCC, van Meenen DMP, de Rooij SE, et al: Risk prediction models for post-operative delirium: A systematic review and meta-analysis. J Am Geriatr Soc . 2014; 62: 2383–2390. 8. Mu JL, Lee A, Joynt GM: Pharmacologic agents for the prevention and treatment of delirium in patients undergoing cardiac surgery: Systematic review and meta-analysis. Crit Care Med . 2015; 43: 194–204. 9. Querques J: Disordered consciousness: Delirium in the intensive care unit.

J Critical Care . 2006; 25: 219–224. 10. Salluh JIF, Wang H, Schneider EB, et al: Outcome of delirium in critically ill patients: Systematic review and meta-analysis. BMJ . 2015; 350: h2538.

CHAPTER 9 Dementia ZEINA CHEMALI, MD, MPH; ROY H. PERLIS, MD, MSC; AND WILLIAM E. FALK, MD

KEY POINTS Overview Dementia is a syndrome with multiple etiologies. It is characterized by a disabling decline in memory as well as impairment in at least one other higher cortical activity (e.g., aphasia, apraxia, executive dysfunction). Epidemiology The incidence of dementia increases with age. Dementia affects 15% to 20% of those > 65 years of age, and up to 45% of those beyond the age of 80 years. Alzheimer’s dementia accounts for 60% to 70% of cases, whereas vascular dementia accounts for 20% of cases. Differential Diagnosis Conditions that can mimic certain features of dementia include delirium, depression, as well as vascular conditions, infectious diseases, neoplastic conditions, degenerative diseases, inflammatory disorders, endocrine disorders, metabolic disorders, exposure to toxins, Central nervous system (CNS) trauma, and normal pressure hydrocephalus (NPH). Approach to Evaluation Evaluation should include a detailed history (including the nature of the presentation, the course, associated physical and psychiatric symptoms, a review of symptoms, the past medical and psychiatric history, medications, the family history, the social and occupational history), as well as a physical, neurological, and cognitive exam (e.g., Mini-Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA]), and laboratory testing (e.g., HIV screening, MRI scan). Treatment

Reversible etiologies should be addressed first. Psychosocial and behavioral interventions are essential and include education and support of the patient and the family. Pharmacological treatments (e.g., donepezil, rivastigmine) should be attempted.

Introduction New nomenclature in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) places the dementias and amnestic disorder under the heading of major neurocognitive disorders (NCD). In addition, the DSM-5 now recognizes a less-severe entity called “mild NCD.” The disorders will be initially designated as major or mild and then be followed by their etiological sub-types; for example, NCD due to dementia of the Alzheimer’s type, NCD due to frontotemporal dementia (FTD), Lewy bodies, traumatic brain injury, Parkinson’s disease, HIV infection, Huntington’s disease, prion disease, another medical condition, or to multiple etiologies. Substance- or medicationinduced NCD as well as unspecified NCD are also included in the list of diagnoses.

Epidemiology Estimates of the prevalence of dementia vary widely depending on which set of diagnostic criteria is utilized. Alzheimer’s disease (AD ), which accounts for up to 70% of cases of dementia, affects approximately 5.4 million people in the United States. The payment for providing care for patients with dementia exceeds $200 billion each year, but the cost of unreimbursed care (e.g., incurred by families) is even greater.

Demographic Factors The incidence of dementia increases with age; dementia affects 15% to 20% of individuals above the age of 65 years, and up to 45% of those beyond the age of 80 years. Most elderly individuals with chronic dementia have AD. Vascular dementia (VaD ) accounts for 20% of cases and is relatively frequent in AfricanAmericans and in patients with diabetes and hypertension. Dementia with Lewy bodies (DLB ), like VaD, is also quite common in the elderly as is any combination of these disorders (so-called “mixed dementias”). FTD is less

common than is AD, VaD, or DLB. Younger patients more often develop dementia of metabolic origin (e.g., alcohol-related dementia).

Trends As the average life expectancy increases, the number of patients with dementia is expected to increase dramatically. Unless significant progress is made in treating or slowing the progression of these disorders, as many as 15 million Americans will be afflicted by mid-century, creating a public health catastrophe.

Identification of Dementia Normal aging is associated with mild changes in cognition (mostly in processing speed). Those changes are not progressive and do not affect daily function; memory retention is intact even if problems are noted in acquisition and retrieval. On the other hand, individuals with dementia might have difficulties with learning new information, handling complex tasks (e.g., balancing the checkbook), reasoning (when faced with new or complex issues), language (word-finding difficulties), spatial orientation (getting lost), and behavior.

Differential Diagnosis Confounding Disorders As noted earlier, the diagnostic criteria for dementia require that a number of confounding disorders be ruled-out; chief among these is delirium . Other psychiatric illnesses, including major depressive disorder (MDD), might also resemble dementia. Differences in presentation can be useful in distinguishing delirium or depression from dementia. Delirium differs from dementia in several important ways: its onset is acute or sub-acute (hours to days); its course often fluctuates; areas of cognitive deficits (including level of consciousness and attention) can be impaired. However, having a diagnosis of dementia can predispose a patient to delirium; thus, further evaluation of cognition is often required after delirium has been treated successfully. Depression can be difficult to distinguish from dementia because the two diagnoses are often co-morbid. In addition, depression alone can cause cognitive impairment; in such cases, it can presage AD by several years. Certain features favor a diagnosis of depression (e.g., a better pre-morbid level of function, a

more acute onset, poor motivation and/or prominent negativity on mental status testing, a family history that is positive for depression). Of note, depressed patients might state that they are unable to perform relatively easy tasks, yet succeed at more difficult ones.

Reversible Conditions Establishing a precise etiology whenever possible allows for more focused treatment and for an accurate estimation of prognosis (Table 9-1). Even though a reversible cause will be identified in fewer than 15% of cases, having a diagnosis can be comforting to patients and their families as well as be useful in their planning for the future. Table 9-1: Etiology of Dementia Organ System

Conditions

Vascular

Stroke, chronic sub-dural hemorrhages, post-anoxic injury, diffuse white matter disease

Infectious

HIV-infection, neurosyphilis, progressive multi-focal leukoencephalopathy (PMLE), Creutzfeldt-Jakob disease (CJD), tuberculosis, sarcoidosis, Whipple’s disease

Neoplastic

Primary versus metastatic carcinoma, paraneoplastic syndrome

Degenerative AD, FTD, DLB, Parkinson’s disease (PD), progressive supranuclear palsy (PSP), multi-system degeneration, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, multiple sclerosis (MS) Inflammatory Vasculitis Endocrine

Hypothyroidism, adrenal insufficiency, Cushing’s syndrome, hypo/hyperparathyroidism, renal failure, liver failure

Metabolic

Thiamine deficiency (Wernicke’s encephalopathy), B12 deficiency, inherited enzyme defects

Toxins

Chronic alcoholism, drugs/medication effects, heavy metals, dialysis dementia (aluminum)

Trauma

Dementia pugilistica

Other

Normal-pressure hydrocephalus (NPH), obstructive hydrocephalus

Evaluation of the Patient with Suspected Dementia General Approach Most patients with dementia do not present with complaints of memory loss. A family member or spouse usually brings their concerns to the physician’s attention. In fact, self-reported memory loss does not appear to correlate with

dementia although an informant reporting memory loss is a good predictor of the presence or development of dementia. History can be obtained from the patient but must also come from family members or others who have observed the patient; ideally these informants should be interviewed separately from the patient because they can more freely express their observations and concerns.

History Nature of the Presentation An abrupt or precipitous onset of cognitive decline favors the diagnosis of a vascular event, whereas an insidious onset suggests the diagnosis of AD. Behavioral symptoms that precede cognitive ones can herald a FTD.

Course A step-wise progression is more consistent with a VaD, whereas a gradual course suggests a progressive process (such as occurs with AD), and a fluctuating course accompanied by visual hallucinations and disordered sleep points to DLB. Associated physical symptoms might favor a particular diagnosis (e.g., incontinence and gait apraxia are seen in NPH). Associated psychiatric symptoms (such as hallucinations, paranoia, or personality change) might also implicate a particular diagnosis. The review of systems should focus on incontinence, gait disturbance, falls, and activities of daily living (ADLs ) and instrumental activities of daily living (IADLs ). The past medical history can reveal risk factors for stroke (e.g., hypertension, obesity, hypercholesterolemia, cigarette smoking, diabetes mellitus, postmenopausal status) or other general medical or neurologic etiologies. The past psychiatric history can suggest co-morbid illness (e.g., depression or alcohol abuse, particularly if prior episodes of psychiatric illness are elicited). Medications (e.g., anticholinergics, antihypertensives, psychotropics, sedativehypnotics, narcotic/analgesics) are implicated in up to 30% of cases of dementia; any drug (including over-the-counter agents) should be suspect if its first use and the initiation of symptoms are temporally related. A family history is a significant risk factor for developing certain dementias (including AD and FTD).

A social and occupational history is useful when assessing pre-morbid intelligence and education (both of which can confound cognitive screens for dementia) as well as a change in the level of function.

Physical Examination A general medical examination , with a particular focus on the cardiovascular system, is an essential part of the evaluation of dementia. Endocrine, inflammatory, and infectious etiologies, for example, might also be suggested by physical findings. A complete neurologic examination , including function of the cranial nerves, sensory and motor function, deep-tendon reflexes, and cerebellar function, can reveal focal findings, which might suggest a VaD or Parkinson’s disease (PD) (e.g., with cogwheel rigidity, tremors). Vision and hearing screening can reveal losses that can masquerade as, or exacerbate, cognitive decline.

Psychiatric Examination The Mini-Mental State Examination (MMSE ) (Table 9-2) can reveal evidence of delirium, depression, or psychosis; documentation of particular findings, in addition to the overall score, allows cognitive function to be followed over time. A total maximum score on the MMSE is 30. A score < 24 has a sensitivity of 87% and a specificity of 82% regarding the detection of dementia. The MMSE contributes to a diagnosis of dementia in low prevalence settings , but it should not be used in isolation to confirm or exclude disease. For accuracy of diagnosis within a specific context, we recommend that future work evaluate cognitive tests, bearing in mind the diagnostic pathway experienced by the patient. Of note, the MMSE is influenced by age and education. The MMSE can have utility in assessing decision-making capacity, as MMSE scores of ≥ 23 and ≤ 19 are highly predictable, respectively, for capacity and incapacity in decision-making. Other tests of cognitive function are also available (Table 9-3). Alternatively, the MoCA is a brief screening tool for mild cognitive impairment that can be employed. Table 9-2: Mini-Mental State Examination Task

Instructions

Date “Tell me the date” Orientation

Scoring One point each for year, season, date, day of week, month

Place “Where are you?” Orientation

One point each for state, county, town, building, floor/room

Register 3 objects

Name three objects, ask patient to repeat them.

One point for each correctly repeated

Serial sevens

Ask the patient to count backward from 100 by 7. Stop after five answers. (Or ask patient to spell “WORLD” backward)

One point for each correct answer or letter

Recall three objects

Ask the patient to recall the registered objects

One point for each correct object

Naming

Point to watch, ask “what is this?” Repeat with a pencil.

One point for each correct answer

Repeating a phrase

Ask patient to say, “No ifs, ands, or buts”

One point if successful on first try

Verbal Give the patient a piece of paper, and say “Take this paper in your right commands hand, fold it in half, and put it on the floor”

One point for each correct action (out of three total)

Written Show the patient a piece of paper with the words “CLOSE YOUR commands EYES”

One point if the patient’s eyes close

Writing

Ask the patient to write a sentence

One point if the sentence has subject, verb, and makes sense

Drawing

Ask the patient to copy a pair of intersecting pentagons

One point if the figure has ten corners, two intersecting lines Total number of points: 30

Table 9-3: Supplemental Mental State Testing for Patients with Dementia Area

Test

Memory

Recall name and address: “John Brown, 42 Market Street, Chicago” Recall three unusual words: “tulip, umbrella, fear”

Language

Naming parts: “lab coat: lapel, sleeve, cuff; watch: band, face, crystal” Complex commands: “Before pointing to the door, point to the ceiling” Word-list: “In one minute, name all the animals you can think of.”

Praxis

“Show me how you would slice a loaf of bread”; “Show me how you brush your teeth”

Visuospatial “Draw a clock face with numbers, and mark the hands to say 11:10” Abstraction “How is an apple like a banana?”; “How is a canal different from a river?”; proverb interpretation

Clinical Dementia Rating The Clinical Dementia Rating (CDR ) was designed to assess the severity of dementia in longitudinal studies. It explores six domains (memory, orientation, judgment and problem-solving, home and hobbies, as well as personal care), and it is given to the patient and to his or her caregiver. The deficits are scored as

none, questionable, mild, moderate, and severe (0, 0.5, 1, 2, and 3, respectively). The CDR is often used as a benchmark for decision-making (e.g., in driving assessment).

Clock-Drawing Asking the patient to draw-a-clock and to place the hands of the clock at a certain time (e.g., ten to two) is a quick examination that correlates well with the MMSE score. It is not a sensitive test for mild dementia but can reveal deficits in executive function otherwise missed on the MMSE.

Laboratory Evaluation The American Academy of Neurology’s (AAN) guidelines for the evaluation of dementia recommend screening for B12 deficiency and for hypothyroidism. However, there is no clear data to support or refute measurement of the complete blood count, electrolytes, glucose, BUN, creatinine, and liver function. Screening for syphilis is not routinely recommended. The AAN recommends obtaining a computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the brain (without contrast) for the evaluation of dementia. The CT scan also can be useful to rule-out a sub-dural hematoma, hydrocephalus, stroke, or a tumor. Additional investigations are indicated if the initial work-up is uninformative, if a particular diagnosis is suspected, or when the presentation is atypical (Table 9-4). Such investigations are particularly important in younger patients and/or in those with rapidly progressive dementia. Table 9-4: Supplemental Laboratory Investigations What?

When?

Why?

Neuropsychological testing

Patient’s deficits are mild or difficult to characterize

The sensitivity of the MMSE for dementia is poor, particularly in highly educated or intelligent patients (who can compensate for deficits)

Lumbar puncture, including routine studies and cytology

Known or suspected cancer, Look for infection, elevated pressure, abnormal immunosuppression, suspected CNS infection proteins or vasculitis, hydrocephalus by CT, rapid or atypical course

MRI with gadolinium

Any atypical findings on the neurologic exam More sensitive than CT for tumor, stroke

EEG

Suspected toxic-metabolic encephalopathy, partial complex seizures, CJD

Look for diffuse slowing (encephalopathy) versus focal seizure activity

HIV-testing

Risk factors or opportunistic infections

Up to 20% of patients with HIV-infection develop dementia, though it is unusual for dementia to be the presenting sign

Heavy-metal screening, screening for Wilson’s disease or autoimmune disease

Suggested by history, physical exam, laboratory findings

Might be reversible

Neuropsychological testing is useful to diagnose dementia and differentiate between its sub-types, especially in cases where a patient’s deficits are mild or difficult to characterize. It involves extensive evaluation of multiple cognitive domains. A MRI scan of the brain is sensitive for assessment of recent stroke and should be considered when focal findings are detected on the neurologic examination and/or in a younger patient. General or focal atrophy as seen on MRI scans are common in AD, whereas non-specific white matter lesions suggest VaD. The value of obtaining a PET scan to assist with the differential diagnosis is under study. An electroencephalogram (EEG) can be used to identify toxic-metabolic encephalopathy, partial complex seizures, or CJD. A lumbar puncture may be informative when cancer, CNS infection, hydrocephalus, or vasculitis is suspected. HIV testing is indicated in a patient with risk factors for HIV-infection; up to 20% of patients with HIV-infection develop dementia. However, dementia is uncommon as a presenting sign of HIV-infection. Heavy-metal screening as well as tests for Wilson’s disease or autoimmune diseases, should be reserved for patients with reasons to suspect these etiologies. Biomarkers are currently used to help in the accurate diagnosis of neurodegenerative diseases (Table 9-5). Current biomarkers are divided into two categories: those that signal underlying amyloid pathology ( cerebrospinal fluid [CSF] amyloid β or amyloid PET); and, those that signal neurodegeneration (hippocampal atrophy on MRI, CSF tau, and fl uoro deoxyglucose [FDG]PET). Several “gold-standard” biomarkers exist; three are neuroimaging measures and three are CSF assays (CSF Aβ1-42 (Aβ1-42), also expressed as Aβ1-42): Aβ140 ratio, T-tau, and P-tau Thr 181, and Thr 231 proteins. Both CSF tau and MRI hippocampal volume are equal in their ability to predict cognitive decline, as CSF amyloid β in patients with mild cogni tive impairment. Core markers have been shown to predict risk of progression in prodromal mild cognitive

impairment and AD. When all three biomarkers are normal, AD can be ruledout. CSF tau is also a useful marker of tau pathology and has been used to monitor the efficacy of disease-modifying treatment. P-tau also has been found in spines of patients with ALS and is measured as a CSF biomarker for AD. In addition, neuroimaging biomarkers now can be checked for tau PET tracers. Table 9-5: Selected Human Brain Neurodegenerative Diseases As Proteinopathies Disease

Protein

Locus

AD

Amyloid β - protein Tau

Plaques-extracellular Tangles-neuronal cytoplasm

FDP—Chromosome 17

Tau

Tangles-neuronal cytoplasm

CJD

Prion Protein (PrPc)

Plaques-extracellular Oligomers-inside cells

Parkinson’s disease

Α -synuclein

Neuronal cytoplasm

Amyotrophic lateral sclerosis

Superoxide dismutase

Neuronal cytoplasm

Polyglutamine expansion diseases: Huntington’s disease

Long glutamine stretches with different proteins

Neuronal and nuclei cytoplasm

Genetic testing for dementia is currently the subject of considerable debate; however, it’s use is highly questionable given its rates of false positives and negatives. Thus, ApoE4 testing is not currently recommended as a screen for AD. Brain biopsy has a limited role in the diagnosis of dementia. Typically, it is reserved for younger patients with atypical presentations of dementia.

Mechanisms of Neurodegenerative Diseases Over the past 30 years, investigators thought that the accumulation of Aβ in the brain was central to the pathogenesis of AD, because amyloidogenic processing of APP produces Aβ peptides from the sequential actions of β - and γ -secretase yielding mostly Aβ 1−40 and Aβ 1−42 . However, the level of Aβ depends on the rate of production and the rate of removal via various clearance pathways, including enzyme-mediated degradation that increases the production of the less soluble Aβ 1−42 or increases the ratio of Aβ 1−42 : Aβ 1−40 (creating a cascade of pathological processes that leads to the development of AD). A simplified view of the

hallmark pathological lesions of AD pointed to the fact that extracellular Aβ 1−42 is prone to aggregate is more toxic than Aβ 1−40 , precipitates as “plaques” in brain parenchyma, and induces the development of neuritic and neurofibrillary tangle pathology, whereas the less toxic Aβ 1−40 reaches the cerebral blood vessels and can precipitate, leading to cerebral amyloid angiopathy (CAA ).

The Story of Tau Tau is abundant in neurons. Tau’s role is to promote the assembly of the microtubule protein subunit, tubulin, into microtubules and to stabilize their structure. Tau proteins form highly soluble microtubule-associated proteins (MAP ). Tau proteins are encoded from a single gene “MAPT” located on chromosome 17q21. Mis-sense mutations in the MAPT gene are found in inherited cases of FTD with parkinsonism that is linked to chromosome 17 (FTDP-17). The mutated tau is a favorable substrate for hyperphosphorylation and it also has pro-aggregant properties. The main regulator of tau phosphorylation is PP2A which controls ~70% of the total tau phosphatase activity in the brain. The tauopathies are underpinned by a variety of etiologies, at least some of which converge on reduced PP2A activity and the development of abnormally hyperphosphorylated tau. Toxic species of soluble tau are involved in the pathogenesis of AD and the enzyme activity of hyperphosphorylated tau that is compromised in AD. Indeed, this phosphorylation disrupts normal tau function in regulating axonal transport and leads to its aggregation into paired helical filaments (PHFs) . PHFs are manifest as neurofibrillary tangles (NFTs) in the neuronal soma and as neuropil threads in neuritis. PHFs are dystrophic neurites that surround an amyloid-β (Aβ ) core in neuritic plaques. It is noteworthy that NFT density is directly correlated to disease severity, and total tau levels are increased several-fold in AD patients’ brains. Diseased cells continue to produce regular tau to restore function.

Metabolic Effects Metabolic effects have been viewed as being among the contributors to a chronic-pro-inflammatory state. By now, we know that diabetes, obesity, hypertension, as well as brain ischemia and hypoxia (chronic traumatic encephalopathy, too) lead to acidosis in the affected brain areas that activate segments that interact with PP2Ac and inhibit its activity. Ischemia combined with deprivation of oxygen and glucose has been associated with increased Aβ in animal and cell culture models of AD. Changing lifestyles and dietary habits

affects metabolic health. Poor nutritional habits lead to metabolic disorders that cause meta-inflammation and a series of disorders and diseases (such as hypertension, metabolic syndrome, cardiovascular disease, stroke, insulinresistance, type 2 diabetes mellitus, and depression). They increase inflammatory markers (IL-6, CRP, and adipokines) and lead to chronic inflammatory states and trigger a neurodegeneration cascade.

Depression and Dementia Increased symptoms of depression and anxiety have been found to increase cognitive dysfunction in the elderly and the obese. In addition, patients with depression are more likely to develop dementia, coronary artery disease, and type 2 diabetes. Depression also complicates the prognosis of other chronic diseases. Having said that, the biological mechanisms that underlie depression remain poorly understood.

Mild Cognitive Impairment Mild Cognitive Impairment (MCI ) is a stage between normal aging and dementia. According to an MCI Consensus, only 16% of individuals who were positive for both biomarkers (amyloid and neurodegeneration) progressed to dementia. Since Petersen and associates coined the term MCI in 1999, its diagnostic criteria have evolved to include abnormal memory function for the person’s age (in association with memory complaints), normal general cognitive function, and normal ADLs. Although MCI can constitute a prodromal form of AD, afflicted individuals have no signs of dementia. Currently, we understand that memory impairment is not considered necessary for the diagnosis. MCI can affect several cognitive domains such as learning and memory, complex attention, executive function, language and perceptual-motor domains, and social cognition. Often a single domain is affected. Along with advancing age, an accepted risk factor for MCI is the presence of the APOE4 allele. A recent cross-sectional analysis from the Framingham Heart study found an association between APOE4 and MCI, particularly among those > 65 years. Cardiovascular and cardio-metabolic risk factors as well as gender are currently under investigation. The annual incidence rate of MCI is 5.5% to7.7% of persons aged > 60 years, and 15% to 41% of MCI cases progress to AD or other dementias each year. Amnestic MCI progresses at a rate of 30/100 person-years, whereas non-amnestic MCI progresses at ~20/100 person-years.

A four-year study by Lonie and co-workers advanced a mean annual conversion rate of 11% with ACE. Converters tended to be older (76.1 ± 4.2 years) with an MMSE average score of 27.4 (whereas non-converters had a MMSE score > 27) and had more atrophy on imaging (70% as compared to 42% for non-converters), whereas non-converters had an MMSE score > 27. Of note, up to 44% of patients with MCI had a non-MCI diagnosis a year later, suggesting that it can be viewed as unstable. The list of modifiable risk factors for MCI continues to grow, with moderate exercise decreasing MCI, whereas smoking, lower education, and depression (current and life-time) increases the risk of MCI. Alcohol intake exhibits a U-shape curve, whereas sensory impairment can impact MCI negatively. Mental stimulation and social participation are both related to better cognitive function. There is no approved treatment for MCI, and to date no drugs can reverse its cognitive impairment. Trials have been conducted with acetylcholinesterase inhibitors, testosterone, and omega-3 fatty acids. Testosterone supplements can have a short-term effect. Given the heterogeneity of MCI, future studies should test different compounds in all MCI sub-types before a firm conclusion can be drawn. Moreover, the instability and spontaneous reversion to non-MCI levels of cognition (44% within a year) increases the difficulty to the interpretation of results.

New Diagnostic Criteria for Dementia New criteria for dementia (McKann et al, 2011) have been considered as having impairment in two or more core cognitive/behavioral domains: memory (impaired ability to acquire and remember new information); executive functions (impaired reasoning and handling of complex tasks, poor judgment); visual function and praxis (impaired visual and spatial abilities or apraxia); language (impaired speaking, reading or writing); and, personality, behavior or comportment (uncharacteristic mood fluctuations such as agitation, apathy, social withdrawal, loss of empathy, compulsive-obsessive behaviors, and socially unacceptable behaviors).

Alzheimer’s Disease (AD); Dementia of the Alzheimer’s Type AD is the main cause of dementia in middle-aged and elderly individuals. AD is typically a disease of older age; it is unusual for AD to begin before the age of 60 years. It has an insidious onset with a progressive deterioration in cognition (memory, thinking, and perception), function, behavior, and mood. AD is slightly more common in women than in men. Major risk factors for AD include

advancing age and a positive family history; other risk factors include a history of head trauma and Down syndrome. Autosomal dominant forms of AD account for < 5% of cases and are associated with younger onset, strongly positive family history, and typically have a more rapid progression. Less than 1% of AD cases are familial and related to mutations in amyloid precursor protein (APP), pres enilin 1 or presenilin 2 genes. Early-onset AD also could be caused by increased production of APP, as in trisomy-21 or by duplication in the APP locus on chromosome 21. Moreover, the inheritance of 1 to 2 apolipoprotein E (APoE ) ε 4 alleles increases the risk of AD by ~3.5-fold in the presence of one allele, and by 10-fold for homozygous (2) alleles. Of note, the exact cause of AD, in the remaining cases of sporadic AD (90% of cases) is not yet understood.

New Diagnostic Criteria for AD Dementia The initial and most prominent cognitive deficits of AD are provided by the history and physical examination. Presentations include: an amnestic presentation, which is the most common or typical type (with deficits that include impairments in learning and recall of recently learned information along with deficits in other cognitive domains); language presentation (with prominent deficits in word finding as well as deficits in other cognitive domains); visuospatial presentation (with prominent deficits in spatial cognition, including agnosia, impaired face recognition, simultagnosia, and alexia); and, executive dysfunction (with prominent deficits in impaired reasoning, judgment, and problem solving) (McKann et al, 2011).

New Diagnostic Criteria for AD Dementia (NCD) (DSM-5, 2013) Impairment is apparent in ≥ 2 core cognitive/behavioral domains, including: complex attention (with sustained or divided attention and processing speed); executive function (with impairment of planning, decision-making, working memory, inhibition, mental flexibility, responding to feedback/error correction); learning and memory (both episodic and semantic memory); language (with expressive and receptive language affected); perceptual–motor (with visual perception, visual construction, praxis, gnosis); and social (with impairment in the recognition of emotion).

Diagnosis A diagnosis of probable AD is made when a patient meets the criteria for dementia (after other etiologies have been ruled-out) with a gradual and

progressive course. A definite diagnosis of AD requires histopathologic confirmation and is generally made on post-mortem examination. Memory impairment is a core feature in AD, and it is often its first symptom. The pattern of memory loss is highly suggestive of AD when declarative memory (for facts and events) is severely affected, whereas procedural memory (e.g., for motor learning) is relatively spared until late in the disease. Declarative memory is highly dependent on mesial temporal and neocortical structures. Episodic memory is impaired, especially for recent events, hence pointing further to the hippocampi, the entorhinal cortex, and related structures in the mesial temporal lobe. Long-term memory and immediate memory (encoded by the frontal lobes) are spared. Word-finding difficulties are often early features of AD and can be the presenting feature. These difficulties progress into paraphasic errors, agrammatism, and impaired comprehension. Semantic memory for vocabulary and concepts is also lost. When asked to generate words, patients with AD generally perform worse on category listings (e.g., animals, fruits, vegetables) rather than on letter fluency tests (e.g., generate words beginning with the letter, F, A, and S). Loss of visuo-spatial skills (i.e., tasks that require hand–eye coordination) is often seen early in AD. An inability to recognize faces (prosopagnosia) and recognize objects (visual agnosia) tends to occur later in the disease, as does difficulty at performing motor tasks (e.g., apraxia). In the early stages of AD, impairment of executive function tends to be subtle, although it can be the presenting symptom in younger patients with AD. In addition, poor insight parallels the severity of dementia and decreases the ability to think abstractly, solve problems, reason, and offer sound judgment. Psychiatric symptoms are often prominent in AD. Depression and anxiety can be presenting complaints in up to 40% of cases. Delusions (often related to theft or to other family members) are also common, affecting up to 50% of patients. Hallucinations (most often visual) affect up to 25% of patients. Changes in personality and agitation are also frequent.

Atypical Presentations of AD Posterior Cortical Atrophy Patients might present to optometrists with visual complaints and with difficulty in reading and driving. Examination reveals an inability to integrate scenes (simultagnosia), an inability to direct gaze (ocular apraxia), and an

inability to reach accurately at visual target (optic ataxia) in addition to memory impairment. Alexia, acalculia, and anomia are also common. The neuropathology and PET scanning results in this form of AD reveal deposition in the visual association areas and the primary cortex.

Primary Progressive Aphasia-Primary Non-Fluent Aphasia This finding is more suggestive of FTD than AD, although up to one-third of afflicted patients have AD. Its age of onset is < 60 years and behavioral symptoms are often prominent. One also can have word-finding difficulties without grammar issues (logopenia), whereas comprehension is typically preserved. With this condition, the MRI might show left peri-Sylvian fissure involvement.

Mixed Dementias (Involving AD + VaD, AD + PD, or AD + DLB) Histopathology The cardinal histopathological changes in AD are senile plaques and NFTs. Plaques are extracellular and contain beta amyloid, whereas tangles are intracellular and contain cytoskeletal filaments. Other changes include synaptic degeneration and loss of cortical and sub-cortical neurons, particularly in the entorhinal cortex, hippocampus, and nucleus basalis. Neuron loss affects several neurotransmitter systems. However, death of cholinergic neurons in the basal forebrain causes a particularly prominent decrease in levels of cortical acetylcholine.

Course The average survival after the onset of symptoms in AD is 8 to 10 years. Predictors of time-to-nursing-home care or death include the presence of extrapyramidal symptoms (EPS), the pres ence of psychotic symptoms, younger age at onset, current cognitive dysfunction, and the duration of illness.

Other Selected Etiologies Vascular Dementia (VaD) VaD (formerly referred to as multi-infarct dementia ) accounts for up to 20% of cases of dementia ; along with DLB it is the second most common form of dementia after AD. Typical features include a step-wise progression of cognitive deficits with associated focal signs and symptoms (e.g., deficits in sensory or motor function). Clinically, these features are often incorporated into an

“ischemic score;” the diagnosis is confirmed by brain imaging. Unlike AD, VaD has no specific pathologic criteria. Risk factors for VaD are those associated with vascular disease, vasculitis, or embolic disease (including atrial fibrillation). The metabolic syndrome (manifest by obesity, hypertension, insulin-resistance, dyslipidemia) has been linked with VaD; it might be better termed a prodromal state for vascular cognitive impairment. A single (strategically-placed), infarct, multiple infarcts, or white matter ischemia can all yield dementia; however, population-based studies are in conflict regarding the risk of dementia after a stroke. A meta-analysis showed a two-fold increase in dementia risk in younger but not older (> 85 years) adults. The presence of white matter lesions is strongly associated with hypertension and age and is common in patients with ischemic stroke.

Related Conditions Cerebral amyloid angiopathy (CAA ) is a disorder characterized by the accumulation of amyloid in cerebral vessels leading to strokes, microbleeds, or hemorrhages. In other respects, the neuropathology of CAA is identical to that of AD. Cerebral autosomal dominant arteriopath y (CADASIL ) is caused by genetic mutations on chromosome 19 that produces infarcts. Patients ultimately develop VaD in the fifth to seventh decade of life. Common features include migraine with aura and psychiatric symptoms in the absence of cardiovascular risk factors and a history of multiple members affected in a given family. Pathology reveals extensive white matter disease. Treatment of VaD focuses on its secondary prevention by addressing underlying risk factors.

Parkinson Disease Dementia (PDD) Parkinson’s disease is associated with dementia in up to 70% of cases. The association of Parkinson disease dementia (PDD) and DLB is somewhat arbitrary. If parkinsonism is present for > 1 year before the onset of dementia, it is termed PDD. Clinically, PDD and DLB present with similar symptoms. Several other dementias with parkinsonism (e.g., Huntington’s disease) might be manifest by both neurologic and psychiatric features and in early-onset presentations as with catatonia.

Dementia with Lewy Bodies (DLBs)

DLB might be more prevalent than previously thought due to presence of Lewy bodies (round, eosinophilic intraneuronal inclusions) in up to 25% of dementia cases. Lewy bodies can be found in both cortical and sub-cortical structures in patients with PD and AD as well as in a small number of well-elderly individuals. Clinically, DLB shares features of both AD and PD with progressive cognitive decline plus consensus criteria for a clinical diagnosis that requires at least two of the following for a probable diagnosis: recurrent visual hallucinations (which are often well formed) that occur in two-thirds of those with DLB; parkinsonism; and fluctuating cognition (with variation in attention and alertness). Caregivers often describe episodes of loss of consciousness, increased confusion, or bizarre behavior. Sometimes, patients also can have speech arrest or become highly somnolent. Patients with DLB present early with impairments of attention as well as executive and visuo-spatial function, and, later, with overt memory impairment. Moreover, features suggestive of DLB include rapid eye movement (REM) sleep disorder (with vivid dreams without atonia), during which dream enactment can lead to injury of the patient and/or the patient’s partner. Patients with DLB might suffer from repeated falls and be unusually sensitive to untoward effects of typical neuroleptics. Common psychiatric symptoms include depression and systematized delusions. Risk factors for DLB are not yet well understood. There might be a genetic predisposition. The disease is more prevalent in men by a factor of 2:1; the age at onset ranges from 50 to 80 years. PET scans show generalized hypoperfusion and decreased metabolism in the occipital lobes (with a sensitivity and specificity of 80% and 90%, respectively). DOPA-PET scans show low dopamine uptake in the basal ganglia. There is no specific treatment for DLB, although patients might respond to cholinergic agents.

Frontotemporal Dementias (FTDs) FTD is the term for a group of clinical and neuropathological heterogeneous disorders characterized by focal atrophy in the frontal and/or temporal lobes. For many years, this clinical syndrome was known as Pick’s disease . Unlike most other dementias that present initially with cognitive change, FTD presents insidiously with changes in personality, social behavior, or language. A subset of patients also shows EPS. Typical changes include: a decline in personal hygiene (e.g., incontinence and voiding in inappropriate places without any concern for it); disinhibition,

impaired social awareness, lack of concern and insight (termed the Behavioral Variant FTD [Bv-FTD ]) with emotional blunting and a loss of empathy; impulsivity; inflexibility and rigidity; repetitive behaviors (particularly involving an obsessive focus on certain foods) as well as hoarding, counting, humming, and pacing; and depression, anxiety, and delusions. Language impairments are also seen, including abundant speech, echolalia, repetition, and perseveration. In late stages mutism can occur. Typically, the age of onset in FTD is the late 50s or early 60s; a family history of early-onset dementia is often present. In some cases, a familial linkage has been shown to chromosome 17. Because not all mutations underlying FTD have been found, a genetic testing currently is not recommended. Behavioral changes are presumed to involve the orbitofrontal systems and the right hemisphere. In contrast, memory and visuospatial skills are relatively well preserved. The diagnosis is made by clinical assessment. Neuropathological changes include loss of cortical neurons, particularly in the frontal and anterior temporal lobes, and intra-neuronal inclusions, known as Pick bodies. Structural neuroimaging demonstrates atrophy in these areas in 40% to 70% of patients; PET studies are more sensitive than are MRI scans, and they reveal frontal lobe hypoperfusion. Neuropsychological testing is frequently helpful. Biomarkers are currently used to facilitate accurate diagnosis in FTD. Treatment relies on the management of behavior; however, it is often of minimal benefit. The cornerstone of treatment should be on offering support to the patient and the patient’s caregiver. In progressive non-fluent aphasia, anomia often appears first, with speech errors and phonemic paraphasic errors. However, behavior is often preserved. Semantic dementia (or temporal variant FTD) shows speech disturbances with normal fluency but with impaired comprehension and semantic paraphasia. Repetition is often intact. Motor neuron disease can follow or precede BvFTD. This disease presents with progressive muscular atrophy, flaccidity, fasciculations, and bulbar symptoms. Progression to death is rapid. Dementia presentation could be atypical such as in primary progressive aphasia, logopenic progressive aphasia, and posterior cortical atrophy (focal neurodegenerative disorder affecting occipital and occipito-parietal cortex; it is visual variant of AD (in 80% of cases). Corticobasal ganglionic degeneration , also an atypical presentation, is a syndrome of asymmetric rigidity and apraxia. According to the new consensus

on CBGD, alien limb syndrome could be present, though it is not exclusive for the criteria diagnosis of CBGD. Cognitive impairment follows. There has been a new consensus for CBGD.

Progressive Supranuclear Palsy (PSP) PSP is a clinical syndrome of vertical gaze palsy, bradykinesia, rigidity, and falls. Motor findings are symmetric. Some patients with PSP develop behavioral features. Several other dementias (e.g., Huntington’s disease) are manifest by both neurologic and psychiatric features.

Normal Pressure Hydrocephalus (NPH) NPH typically presents with a “magnetic gait” followed by urinary incontinence and dementia. Cognitive deficits include impaired concentration and mild deficits of memory. On CT scans of the brain, ventriculomegaly and diffuse cortical atrophy might be noted. Diagnosis relies on clinical improvement following serial lumbar punctures (known as the Miller Fisher Test ) or placement of a lumbar drain. A neuropsychiatric test battery (attending to tasks of attention and memory and timing the pace of patient gait) is done pre- and post-drain placement. If a patient derives benefits from the procedure, a ventriculo-peritoneal shunt sometimes provides more persistent improvement.

Young- Onset Dementia Young-onset dementia (or commonly coined as early-onset dementia) should have a chapter of its own, given that this entity can present differently than does late-onset dementia. Symptoms of young-onset dementia are typically present for > 2 years before clinical contact. The presentation with MCI or depression is associated with a doubling of the time-to-dementia diagnosis in young-onset dementia. Clinicians need to communicate clearly with patients and their families when MCI converts to a dementia diagnosis. Time-to-diagnosis is greater in dementias other than AD and FTD. This delay often leads to decreased quality of life and strained family systems.

Prevention Prevention of dementia remains an active area of investigation. Studies have yielded inconsistent results or have been inconclusive. The most promising

finding to date is for the secondary prevention in VaD by controlling vascular risk factors and by stopping smoking.

Treatment Reversible Etiologies Reversible etiologies should be addressed first. Thus, any co-morbid medical problems identified in the initial evaluation must be treated regardless of whether they contribute directly to the dementia. At the same time, drugs with cognitive side effects should be minimized and eliminated altogether whenever possible; as noted earlier, medications are implicated in 10–30% of cases of dementia.

Psychosocial or Behavioral Interventions Psychosocial or behavioral interventions are essential in the treatment of patients with dementia. The patient and the family should be educated in a supportive and caring way, as presentation of an initial diagnosis can be extremely frightening. The family’s advice should be sought on how to inform the patient. Informing both the patient and the family that driving is, or might become, impossible should ensure the patient’s safety. Driving evaluations are very helpful in this regard. The CDR is a highly reliable tool in the evaluation of driving safety. When the CDR = 0, it is safe to drive. When the CDR = 0.5 to 1, an individual is at higher risk for at-fault motor accidents, though 40% to 80% will be judged as safe to drive. When the CDR is ≥ 2, it is unsafe to drive. Families should be educated about wandering and becoming lost because the risk of wandering is real. And because wandering and becoming lost can be lifethreatening, a safe-return bracelet for the patient should be suggested; notifying local police of the problem also can be helpful. Legal issues (such as wills, health-care proxies, and durable power of attorney) should be addressed early. Financial capacity also should be addressed. Assistance with financial management (such as bill-paying) might be needed. Routine health-maintenance visits every 3 to 6 months should be continued. When appropriate, the possibility of placement should be raised, given that nearly three-fourths of those with dementia will require placement in a long-term care facility. Other options include adult day care, respite care, and use of home health aides, outreach services, and homemakers. Behavioral problems (e.g., agitation, screaming, incontinence, aggression, psychosis) should be addressed. Most commonly these issues, rather than

cognitive decline, precipitate nursing home placement. Although pharmacotherapy can be beneficial in some cases, behavioral interventions remain a mainstay of treatment.

Pharmacologic Treatment Pharmacologic treatment should target specific symptoms; this strategy allows for more accurate assessment of treatment response over time. The MMSE or the MoCA can be used to screen for cognitive status, although other scales exist for behavioral assessment. Functional measures include the ADL and the IADL scales (Table 9-6). However, none of these measures is especially sensitive to change. Clinicians therefore need to follow a patient’s activities, such as hobbies, for which treatment effects can be more noticeable. In multiple aggregate trials, no evidence was found to support any class of medication as preventing cognitive decline or the transformation of MCI into dementia. Table 9-6: Activities of Daily Living Basic

Instrumental

Bathing

Shopping

Dressing

Cooking

Walking

Managing finances

Toileting

Housework

Feeding

Using the telephone

Transfers (to/from bed, chair) Taking medications Traveling outside of home

It remains unclear if galantamine, rivastigmine or donepezil should be used by patients with severe AD and whether memantine is the optimal treatment for severe AD. One should not forget that those medications—for example, cholinesterase inhibitors—have side effects such as bradycardia and syncope. Donepezil has little peripheral cholinergic activity and is generally well tolerated. It is dosed at 5, 10, and 23 mg QD. It is also available in a disintegrating-pill form that is of benefit to those with swallowing difficulty. Rivastigmine appears to be beneficial in mild-to-moderate AD, but has notable peripheral effects, and the pill form should be taken with food. It is also FDAapproved for dementia associated with PD. A once-a-day patch has fewer side effects, but caregivers must remember to remove it before another is applied. It

is better to take it with meals. Galantamine is used in mild-to-moderate AD with once-a-day dosing up to 32 mg per day. Memantine is another drug approved for moderate-to-severe AD, modulating the glutamatergic (excitatory) NMDA receptors; it is typically used in conjunction with AchEIs for moderate-to-severe AD, and is dosed most often as 10 mg twice a day. In addition, AD patients might respond differently to the medication based on the severity of AD and their sex; hence severity and sex could be considered treatment effect modifiers. All choline esterase inhibitors can have an action on improving behavior rather than any direct action of cognitive decline. Donepezil improved behavior and rivastigmine improved function in AD. These effects were associated with higher doses of rivastigmine, suggesting that dose might be a treatment effect modifier.

Duration of Therapy All of the aforementioned agents are used for symptomatic treatment and not as disease-modifying agents. They should be administered for 8 weeks and then reassessed with the results/improvements corroborated by family members or caregivers. Only if improvement is noticeable should they be continued. There is no evidence that cholinesterase inhibitors are of clinical benefit in moderate-toadvanced disease, although from a tolerance point of view they could be continued indefinitely. Occasionally, some patients decline further after stopping ChEIs. It is unclear whether this is linked to any benefit from the drug. Reintroducing the drug for possible benefits is reasonable, but sometimes improvement is not achieved. Drugs that treat psychiatric or behavioral symptoms can be quite important. For depressive symptoms, selective serotonin re-uptake inhibitors (SSRIs ) are considered as first-line agents because of their relative safety. For hallucinations and psychosis, antipsychotic drugs (at low doses) can be helpful, but patient and family should be advised of the FDA black-box warning about increased risk of cerebrovascular events and death. Agitation and anxiety might respond to SSRIs or antipsychotics. Benzodiazepines should be avoided because they can cause disinhibition and can further impair cognition.

Research Trials Over the past 20 years, AD drug development efforts focused on Aβ -based therapeutic approaches: inhibition of Aβ synthesis, inhibition of Aβ aggregation, and clearance of Aβ plaques by immunotherapy. To date trials on Aβ have been negative. Another therapeutic approach to AD would be to pharmacologically

shift the balance from neurodegeneration to regeneration of the brain by using brain-derived neurotrophic factor (BDNF) which attenuates phosphorylation of tau and APP. Recent research on rescue of PP2A activity, which seems to have a central involvement in the pathogenesis of AD and other tauopathies, has been a promising therapeutic approach. Other laboratories are promoting passive and active tau immunization. It is worth noting, that four main tau-based therapeutic approaches have been proposed: inhibition of tau hyperphosphorylation (BDNF, for example), inhibition of tau aggregation, clearance of tau and tau pathology, and rescue of neuronal plasticity by stabilizing the microtubule network or promoting regeneration. Although tau pathology is intraneuronal, the spread of tau pathology is believed to involve an extracellular stage during which tau seeds are released from dead or dying tangle-bearing neurons and are ingested by naive neurons close by in a random manner making the disease spread transsynaptically.

Caregiver Burden and Burnout Psychological and emotional struggles such as social isolation are common as progressive disability and changes in behavior inhibit the patient and caregiver from interacting with others. Care for the caregiver is essential (by providing referral to support groups or other sources of information and coping skills). More than 50% of caregivers will develop clinically-significant depression. Caregivers reported poor scores in physical and mental health, severe emotional burden, high levels of depressive and anxiety symptoms, decreases in leisure time activities, and a decrease in economic profile.

Referral Referral to a geriatric psychiatrist, a neuropsychiatrist, or a memory disorder unit can be helpful. Patients with atypical presentations, with unusual symptoms, or rapid progression, as well as those in whom no etiology can be identified also should be referred. In some cases, families might request a referral, particularly when they are interested in undertaking genetic counseling and/or participating in a research protocol. The team caring for the patient needs to screen and treat the co-morbidities, especially depression, as well as initiate social work referral to help patients and families deal with the diagnosis and perhaps guide them toward day programs and long-term care. Cognitive occupational therapy in the early stages of the disease could be helpful in providing alternative strategies, as can speech and language and organizational skills.

Raising Awareness and Dementia As a Public Health Problem Dementia is a major public health problem that should be a global priority.

Suggested Readings 1. Alladi S, Xuereb J, Bak T, et al: Focal cortical presentations of Alzheimer’s disease. Brain . 2007; 130: 2636–2645. 2. Ahmed RM, Irish M, Piguet O, et al: Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism. Lanet Neurol . 2016: January 25, 2016; http://dx.doi.org/10.1016/ S1474-4422(15)00380-4. 3. Apostolo J, Holland C, O’Connell M, et al: Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing (EIPAHA). Maturitas . 2016; 83: 83–93. 4. Awasthi M, Singh S, Pandey VP, Dwivedi UN: Alzheimer’s disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products. J Neurological Sci. 2016; 361: 256–271. 5. Baird AL, Westwood S, Lovestone S: Blood-based proteomic biomarkers of Alzheimer’s disease pathology. Frontiers in Neurology. 2016; 6(236): 1–16. 6. Bang J, Spina S, Miller B: Frontotemporal dementia. Lancet. 2015; 386: 1672–1682. 7. Belza MG, Urich H: Cerebral amyloid angiopathy in Down’s syndrome. Clin Neuropathol. 1986 Nov-Dec; 5(6): 257–260. 8. Berti V, Polito C, Lombardi G, et al: Rethinking on the concept of biomarkers in preclinical Alzheimer’s disease. Neurol Sci . doi: 10.1007/s10072-016-2477-1. 9. Boersma I, Miyasaki J, Kutner J, Kluger B: Palliative care and neurology: time for a paradigm shift. Neurology . 2014 Aug 5; 83(6): 561–567. 10. Boxer AL, Miller BL: Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord . 2005; 19 (Suppl 1): S3–6.

11. Cabrejo L, Guyant-Maréchal L, Laquerrière A, et al: Phenotype associated with APP duplication in five families. Brain . 2006 Nov; 129(Pt 11): 2966– 2976. 12. Cai Z, Wang C, He W, et al: Cerebral small vessel disease and Alzheimer’s disease. Clin Interventions in Aging . 2015; 10: 1695–1704. 13. Calo L, Wegrzynowicz M, Santivañez-Perez J, Spillantini MG: Synaptic failure and a -synuclein. Movement Disorders . 2016: 1–8. 14. Capuron L, Poitou C, Machaux-Tholliez D, et al: Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation. Psychol Med . 2011 Jul; 41(7): 1517–1528. 15. Carr DB, Gray S, Baty J, et al: The value of informant versus individual’s complaints of memory impairment in early dementia. Neurology . 2000; 55: 1724–1726. 16. Caselli RJ: Current issues in the diagnosis and management of dementia. Semin Neurol . 2003; 23(3): 231–240. 17. Cavedo E, Lista S, Khachaturian Z, et al: The road ahead to cure Alzheimer’s disease: Development of biological markers and neuroimaging. Methods for prevention trials across all stages and target populations J Prev Alzheimers Dis . 2014 Dec; 1(3): 181–202. 18. Chatterjee S, Peters SAE, Arango SM, et al: Type 2 diabetes as a risk factor for dementia in women compared with men: A pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care . 2016; 39: 300–307 | doi: 10.2337/dc15-1588. 19. Cherbuin N, Kim S, Anstey KJ: Dementia risk estimates associated with measures of depression: a systematic review and meta-analysis. BMJ Open . 2015; 5:e008853. doi:10.1136/bmjopen-2015- 008853 20. Creavin ST, Wisniewski S, Noel-Storr AH, et al: Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations (Review). Cochrane Database Syst Rev . 2016 Jan 13;1:CD011145. doi: 10.1002/14651858.CD011145.pub2. 21. Cummings JL, Vinters HV, Cole GM, et al: Alzheimer’s disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities, Neurology . 1998; 51(suppl. 1): S2–S17.

22. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 23. Draper D, Cations M, White F, et al: Time to diagnosis in young-onset dementia and its determinants: the INSPIRED study. Int J Geriatr Psychiatry . 2016 Jan 25; doi: 10.1002/gps.4430. [Epub ahead of print] 24. Eisenmenger LB, Huo EJ, Hoffman JM, et al: Advances in PET imaging of degenerative, cerebrovascular, and traumatic causes of dementia. Semin Nucl Med . 2016; 46: 57–87. 25. Fiala M, Terrando N, Dalli J: Specialized pro-resolving mediators from omega-3 fatty acids improve amyloid-β phagocytosis and regulate inflammation in patients with minor cognitive impairment. J Alzheimers Dis . 2015; 48(2): 293–301. 26. Filippi M, Agosta F, Ferraro PM: Charting frontotemporal dementia: From genes to networks. J Neuroimaging . 2016; 26: 16–27. 27. Greig SL: Memantine ER/donepezil: A review in Alzheimer’s disease. CNS Drugs . 2015; 29: 963–970. 28. Hay J, Johnson VE, Smith DH, Stewart W: Chronic traumatic encephalopathy: The neuropathological legacy of traumatic brain injury. Annu Rev Pathol Mech Dis . 2016. 11: 21–45. 29. Hardy J: Amyloid, the presinilins and Alzheimer’s disease. Trends Neurosci. 1997 Apr; 20(4): 154–159. 30. Iqbal K, Liu F, Gong C-X: Tau and neurodegenerative disease: the story so far. Nat Rev Neurol . 2016; 12: 15–27. 31. Jarrett JT, Berger EP, Lansbury PT Jr: The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry . 1993 May 11; 32(18): 4693–4697. 32. Jefferson AL, Beiser AS, Seshadri S, et al: APOE and mild cognitive impairment: the Framingham Heart Study. Age Ageing. 2015 Mar; 44(2): 307–311. 33. Kalia LV, Lang AE: Parkinson’s disease. Lancet . 2015; 386: 896–912. 34. Kalaria RN, Ihara M: Vascular and neurodegenerative pathways—Will they meet. Nat Rev Neurol . 2013; 9: 487–488. 35. Kapasi A, Schneider JA: Vascular contributions to cognitive impairment,

clinical Alzheimer’s disease, and dementia in older persons, Biochem Biophys Acta . 2016; http://dx.doi.org/10.1016/j.bbadis.2015.12.023. 36. Lonie JA, Tierney KM, Ebmeier KP: Screening for mild cognitive impairment: a systematic review. Int J Geriatr Psychiatry . 2009 Sep; 24(9): 902–915. 37. Maioli F, Coveri M, Pagni P, et al: Conversion of mild cognitive impairment to dementia in elderly subjects: a preliminary study in a memory and cognitive disorder unit. Arch Gerontol Geriatr . 2007; 44 (Suppl 1): 233–241. 38. Majumdar SR, McAuley G, Tricco AC: Comparative safety and effectiveness of cognitive enhancers for Alzheimer’s dementia: protocol for a systematic review and individual patient data network meta-analysis. BMJ Open . 2016; 6: e010251. doi: 10.1136/bmjopen-2015-010251 39. McKeith IG, Dickson DW, Lowe J, et al: Diagnosis and management of dementia with Lewy Bodies: 3rd report of the DLB consortium. Neurology . 2005; 65: 1863-1872. 40. Morris JC: The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology . 1993; 43: 2412–2414. 41. McKhann GM, Knopman DS, Chertkow H, et al: The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement . 2011 May; 7(3): 263–269. 42. Miners JC, Palmer JC, Tayler H, et al: Aβ degradation or cerebral perfusion? Divergent effects of multi-functional enzymes. Frontiers in Aging Neuroscience. 2014; 238(6): 1–13. 43. Nasreddine ZS, Phillips NA, Bédirian V, et al: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc . 2005; 53(4): 695–699. 44. O’Brien JT, Thomas A: Vascular dementia. Lancet . 2015; 386: 1698–706 45. Petersen R, Smith GE, Waring SC, et al: MCI: Clinical characterization and outcome. Arch Neurol . 1999; 56(3): 303–308. 46. Pijnenburg YA, Schoonenboom SN, Barkhof F, et al: CSF biomarkers in frontotemporal lobar degeneration: relations with clinical characteristics,

47.

48.

49.

50.

51. 52.

53. 54.

55.

apolipoprotein E genotype, and neuroimaging. J Neurol Neurosurg Psychiatry . 2006 Feb; 77(2): 246–248. Plassman BL, Langa KM, McCammon RJ, et al: Incidence of dementia and cognitive impairment, not dementia in the United States. Ann Neurol . 2011 Sep; 70(3): 418–426. Qaseem A, Snow V, Cross JT, Jr, et al: Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2008; 148(5): 370–378. Sandu RE, Buga AM, Uzoni A, et al: Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology. Neural Regen Res . 2015 Sep; 10(9): 1349–1355. Savva GM, Stephan BC: Alzheimer’s Society Vascular Dementia Systematic Review Group. Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke. 2010; 41: e41–46. Scheltens P: Mild cognitive impairment—amyloid and beyond. Nat Rev Neurol. 2013; 9: 493–495. Segura B, Jurado MA, Freixenet N, et al: Mental slowness and executive dysfunctions in patients with metabolic syndrome. Neurosci Lett . 2009; 462(1): 49–53. Selkoe DJ: Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis . 2001; 3(1): 75–80 Trettel J, Chemali Z, Daffner KR: Management of neuropsychiatric manifestations of neurodegenerative complications (Revised for new edition). In: Hardiman O, Doherty C, eds. A Clinician’s Guide to Neurodegeneration . Dublin, Ireland: Springer; 2015. Veroniki AA, Straus SE, Ashoor HM, et al: Lewy Body Demenitas. Lancet . 2015; 386: 1683–1697.

CHAPTER Intellectual Disability 10 NORA D.B. FRIEDMAN, MD; ROBERT E. ACCORDINO, MD, MSC; AND JOHN JULIAN, MD, MS

KEY POINTS Overview Although intellectual disability and psychiatric illness have a shared lineage, they have been viewed quite differently over the centuries. In recent decades, with a shift in focus toward neurobiological psychiatry, the association between intellectual disability and psychiatric illness has generated more interest. Epidemiology The prevalence of intellectual disability is between 1% and 3% depending on the criteria used, the methods employed, and the populations sampled. Intellectual disability is a condition with diverse etiologies that can be of prenatal, peri-natal, or post-natal onset with more than 350 known causes of intellectual disability. Clinical Features The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM–5) replaced the term “mental retardation” with “intellectual disability (intellectual developmental disorder).” Intellectual disability, which presents during the developmental period, consists of impairments in intellectual and adaptive functioning in social, practical and conceptual domains. Etiology Down syndrome, fragile X syndrome, and fetal alcohol syndrome account for about 30% of identified cases. Down syndrome, the most common genetic cause of intellectual disability,

involves extra genetic material from chromosome 21, most commonly due to trisomy. Fragile X syndrome, resulting from expansion of the CGG trinucleotide repeat within the fragile X mental retardation 1 gene (FMR1 ) on the X chromosome, is the most common inherited form of intellectual disability caused by a single gene defect. Fetal alcohol syndrome, another common cause of intellectual disability, occurs through in utero alcohol exposure. Differential Diagnosis The differential diagnosis for intellectual disability includes physical disabilities, specific learning disorders, communication disorders, and borderline intellectual functioning. Approaches to Evaluation Neuropsychological and adaptive behavior testing, coupled with a history of adaptive functioning from ancillary sources, such as primary caregivers and school staff, serve as the cornerstones of an assessment. A thorough medical and neurological examination should be performed to ruleout potentially correctable causes of observed dysfunction (e.g., hearing impairment, vision impairment, seizures). Treatment It is unlikely that a psychiatrist will be asked to treat intellectual disability per se , as specialized education and training in adaptive functioning occur in schools and vocational settings. More likely, a psychiatrist will be called upon to evaluate and manage psychiatric or behavioral symptoms that interfere with adaptive functioning. The evaluation and differential diagnosis of psychiatric illness in this population is not as straightforward as the diagnosis of intellectual disability itself. Definitive diagnosis can be clinically and methodologically challenging due to limited self-reporting by a substantial proportion of the population.

Overview

Although intellectual disability (previously known as mental retardation) and psychiatric illness have a shared lineage, they have been viewed quite differently over the centuries . In the sixteenth century, the English Court of Wards and Liveries differentiated “idiots” from “lunatics.” Later, in his initial diagnostic scheme, Kraepelin described mental retardation as a distinct form of psychiatric illness. It was not until the late nineteenth century that mental retardation and psychiatric illness were noted, at times, to co-exist. The American Journal of Insanity used the phrase “imbecility with insanity” in 1888. Since then, intellectual disability with co-morbid psychiatric illness has continued to be investigated, but at a slower pace than other areas of psychiatry. In recent decades, with a shift in focus toward neurobiological psychiatry, the association between intellectual disability and psychiatric illness has generated more interest. Future investigations in this area are likely to shed light on complex issues, including behavioral phenotypes and the relationship between coping abilities and the vulnerability to mental illness.

Epidemiology and Etiology The prevalence of intellectual disability is between 1% and 3% depending on the criteria used, the methods employed, and the populations sampled. Intellectual disability is a condition with diverse etiologies that can be of prenatal, peri-natal, or post-natal onset. Even though more than 350 causes of intellectual disability are known, approximately 40% of cases have no clear etiology. Down syndrome , fragile X syndrome , and fetal alcohol syndrome account for about 30% of identified cases. Down syndrome, the most common genetic cause of intellectual disability, involves extra genetic material from chromosome 21, most commonly due to trisomy. Fragile X syndrome, resulting from expansion of the CGG trinucleotide repeat within the fragile X mental retardation 1 gene (FMR1 ) on the X chromosome, is the most common inherited form of intellectual disability caused by a single gene defect. Fetal alcohol syndrome, another common cause of intellectual disability, occurs via in utero alcohol exposure. Individuals with intellectual disability suffer from the full range of psychiatric illness and are likely afflicted at a rate 4 to 6 times higher than that seen in the general population. In institutionalized settings, upward of 10% of the population with intellectual disability have some form of psychopathology; percentages are less clear in community samples. One must be cautious when

interpreting data regarding this population due to a bevy of methodological problems encountered. The reasons for the higher prevalence of psychiatric illness among individuals with intellectual disability remain unclear. One theory centers on the idea that intellectual disability is a manifestation of damage to cortical and sub-cortical substrate, regardless of whether these insults can be identified with available technology. This damage confers a special vulnerability to psychiatric conditions. Another theory holds that individuals with intellectual disability have been chronically exposed to a confusing and stressful environment. Their decreased ability to cope with the demands of a complex society and their inadequate cognitive capacity to resolve emotional conflicts leads to increased psychiatric pathology. A third theory highlights the lack of psychiatric care for this population. It suggests that mental health clinicians might be less inclined to treat psychiatric illness in individuals with intellectual disability due to a prevailing view that behavioral disturbances and psychopathology are somehow more acceptable in this population.

Diagnostic Features The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM–5) replaced the term “mental retardation” with “intellectual disability (intellectual developmental disorder)” to reflect the common use of these terms among medical and educational professionals, advocacy groups, and the lay public. Intellectual disability, which presents during the developmental period, consists of impairments in intellectual and adaptive functioning in social, practical and conceptual domains. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) had defined significantly sub-average intellectual functioning as an intelligence quotient (IQ) of approximately 70 or below. Deficits in intellectual functioning are now more broadly defined as impaired reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience. DSM-5 notes that these should be determined through clinical assessment and standardized intelligence testing. Deficits in adaptive functioning cause a failure to meet developmentally appropriate and sociocultural standards for personal independence and social responsibility. These impairments interfere with a person’s activities of daily living, such as communication, social participation, and independent living across multiple environments (e.g., home, school, work, community).

Intellectual disability had previously been classified into four levels of severity —mild, moderate, severe, and profound—based on intellectual impairment, as measured by IQ scores. These categories, however, did not reflect functional capabilities, and IQ tests have a standard error of measurement of approximately 15 points. For this reason, the DSM-5 utilizes the same severity specifiers , but has replaced IQ cutoffs with qualitative descriptors of the severity of impaired adaptive functioning in conceptual, social, and practical domains. A proportion of individuals diagnosed with mild intellectual disability as children might lose this diagnosis in adulthood with improvement in their adaptive skills. Those who retain this label into adulthood tend to be affected more severely.

Evaluation and Differential Diagnosis The evaluation for a diagnosis of intellectual disability is relatively straightforward and based on the aforementioned DSM-5 diagnostic criteria. Neuropsychological and adaptive behavior testing, coupled with a history of adaptive functioning from ancillary sources, such as primary caregivers and school staff, serve as the cornerstones of an assessment. A thorough medical and neurological examination should be performed to rule-out potentially correctable causes of observed dysfunction (e.g., hearing impairment, vision impairment, seizures). These exams are also useful in discerning any physical features that might be associated with specific syndromes that have related psychiatric conditions. In spite of there being no specific laboratory markers associated with intellectual disability, some findings are linked to a variety of causes of intellectual disability, such as metabolic disturbances and chromosomal disorders. Identifying these abnormalities can also lead to the diagnosis of syndromes that might have associated psychiatric pathology. The differential diagnosis for intellectual disability includes physical disabilities, specific learning disorders, communication disorders, and borderline intellectual functioning. Although autism spectrum disorder (ASD) is a separate diagnostic category, individuals with ASD commonly present with co-morbid intellectual disability. DSM-5 has classified both conditions as neurodevelopmental disorders to reflect this overlap.

Treatment Considerations

It is unlikely that a psychiatrist will be asked to treat intellectual disability per se , as specialized education and training in adaptive functioning occur in schools and vocational settings. More likely, a psychiatrist will be called upon to evaluate and manage psychiatric or behavioral symptoms that interfere with adaptive functioning. The evaluation and differential diagnosis of psychiatric illness in this population is not as straightforward as the diagnosis of intellectual disability itself. Definitive diagnosis can be clinically and methodologically challenging due to limited self-reporting by a substantial proportion of the population. In a process known as diagnostic overshadowing, symptoms might be inappropriately attributed to intellectual disability rather than to a co-morbid psychiatric disorder. In addition, we must keep in mind that there are certain behavioral disorders and syndrome-associated disorders that occur in people with intellectual disability. Syndrome-associated disorders are specific disorders that have a high probability of being exhibited by individuals with a given syndrome. The terms pathobehavorial syndrome and behavioral phenotype have been used to try to conceptualize this phenomenon. What follows is a brief synopsis of traditional psychiatric disorders , behavioral disorders, and syndrome-associated disorders that present in individuals with intellectual disability. In each category, any differences in presentation or special treatment from that of the general population will be highlighted.

Affective Disorders Compared with those in the general population, diagnosing depression and bipolar spectrum disorders in individuals with intellectual disability might rely less on self-report and more on a change from baseline behavior, as assessed by caregivers and educators. Observable mood changes accompanied by quantifiable neurovegetative symptoms, such as using sleep charts and calorie counts, are helpful. Those with severe intellectual disability might present primarily with behavioral difficulties. Treatment can involve both medication and therapy, with the type of therapy chosen based on the individual’s strengths. Highly anticholinergic medications should be avoided if possible, due to the potential for these agents to cause cognitive blunting.

Anxiety Disorders The full spectrum of anxiety disorders has been reported in the population with intellectual disability. Somatic, more observable aspects of anxiety can be more helpful than a reliance on subjective reporting. The possibility of trauma must always be considered given the vulnerability of this population. Obsessive–

compulsive disorder (OCD) can be difficult to distinguish from stereotypy, given the critical need for self-reported ego-dystonic feelings. Treatment of anxiety disorders involves therapy and medication. Although benzodiazepines can be used in this population, their potential as contributors to disinhibition should be considered.

Schizophrenia Even though the co-occurrence of schizophrenia and intellectual disability has been noted since the days of Kraepelin and Bleuler, diagnostic clarity remains a problem. Observable behaviors related to psychosis must be present in addition to the chronic changes in baseline functioning associated with major mental illness. Antipsychotics are the drugs of choice, although clinicians need to be cognizant of their side effect profiles. Atypical antipsychotics, for instance, cause fewer extrapyramidal symptoms (EPS). It is not clear that EPS are worse or more prevalent among individuals with intellectual disability.

Behavioral Disorders Individuals with intellectual disability can present with several challenging behaviors. In this population, aggression is one of the prime reasons for psychiatric consultation. Pain and discomfort, environmental triggers, and/or psychopathology can precipitate aggression. Behavioral treatment is usually the first-line intervention for aggression, followed by use of medication for any underlying psychiatric or impulse-control disorder. Self-injurious behavior (SIB ) either potentially or actually causes damage to an individual’s body. It usually presents as idiosyncratic, repetitive acts that occur in an identical form. Whereas behavior therapy is the mainstay of treatment, there have been some reports of success using medications (e.g., selective serotonin re-uptake inhibitors [SSRIs], neuroleptics) to target these behaviors. Stereotypies are invariant, pathologic motor behaviors or action sequences without an obvious reinforcement pattern. They are often seen in circumstances of extreme stimulation or deprivation, and they are noted in many institutionalized patients with intellectual disability. Behavior therapy is the primary treatment. Although SSRIs are employed, their use requires further empirical validation. Copraxia consists of rectal digging, feces smearing, and coprophagia. It is a rare phenomenon that is usually found only in individuals with profound

intellectual disability. Behavior therapy is the first line of treatment after medical conditions have been ruled-out. Pica involves eating inedibles (e.g., dirt, paper clips, cigarette butts) and usually occurs in individuals with severe intellectual disability. Behavior therapy is the mainstay of treatment. It is unclear if dietary supplements are helpful. Rumination consists of repeated acts of vomiting, chewing, and re-ingestion of the vomitus. This condition occurs more often in the severely-to-profoundly intellectually disabled population. Behavior therapy is the treatment of choice; overfeeding should be included in the differential diagnosis.

Syndrome-Associated Disorders Several syndrome-associated disorders have been recognized. Individuals with Down syndrome , most commonly due to trisomy 21, have characteristic features, such as a round face, upward slanting palpebral fissures, flat nasal bridge, and short stature. Psychiatric co-morbidities include depression and Alzheimer’s dementia (which often begins after the age of 40 years). Features of fragile X syndrome include a long face, protuberant ears, prominent jaw, and macro-orchidism. Although the full range of psychiatric disorders has been reported in this population, the most prominent co-morbidity is attention deficit hyperactivity disorder (ADHD ), which occurs in approximately 80% of affected individuals. Thirty percent of males with fragile X syndrome meet the criteria for autism. Due to the role of X-chromosome inactivation, females with fragile X syndrome might present with milder phenotypes. Prader-Willi syndrome results from a loss of function of paternally-inherited genes on chromosome 15. Individuals with this condition exhibit short stature, hypogonadism, hyperphagia, and obesity. Common co-morbidities include compulsive behaviors and temper tantrums. At least 5% to 10% of individuals with Prader-Willi develop psychosis by young adulthood, with higher prevalence rates found among those with a maternal uniparental disomy sub-type. People with Williams syndrome , caused by a deletion on chromosome 7, present with elfin-like faces, a starburst iris, as well as supravalvular aortic stenosis and hypertension. They often have a loquacious communication style, known as cocktail-party speech. Co-morbidities include ADHD, anxiety, and depression. Fetal alcohol spectrum disorders (FASDs) refers to a range of physical, cognitive, and behavioral outcomes associated with pre-natal alcohol exposure. At the severe end of this spectrum, fetal alcohol syndrome consists of

dysmorphic facial features (e.g., short palpebral fissures, thin upper vermillion border, smooth philtrum), growth deficiency, and central nervous system involvement. Cognitive impairments, executive functioning deficits, difficulties with attention and hyperactivity, and social skill impairments occur in this population.

Conclusion There are several important points to consider in the area of intellectual disability and psychiatric illness. Intellectual disability is a prevalent condition with diverse etiologies that affects approximately 1% of the population. Three of the most common causes of intellectual disability are Down syndrome, fragile X syndrome, and fetal alcohol syndrome. People with intellectual disability are susceptible to the full range of psychiatric illness and likely suffer from psychiatric illness at a higher rate than do those in the general population. Certain pathobehavioral syndromes are associated with intellectual disability. From both a clinical and research perspective, this is an incredibly under-served population with regard to psychiatric morbidity.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Bouras N, ed: Psychiatric and Behavioral Disorders in Developmental Disabilities and Mental Retardation . New York: Cambridge University Press; 1999. 3. Cassidy SB, Driscoll DJ: Prader-Willi syndrome. Eur J Human Genetics . 2009; 13: 3–13. 4. Cooper SA, Smiley E, Morrison J, et al: Mental ill-health in adults with intellectual disabilities: prevalence and associated factors. Br J Psychiatry . 2007; 190: 27–35. 5. Gualtieri CT: Neuropsychiatry and Behavioral Pharmacology . New York: Springer-Verlag; 1990. 6. Julian JN: Intellectual Disability. In: Stern TA, Fava M, Wilens TE, et al, eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry .

7. 8.

9.

10. 11.

12.

Philadelphia, PA: Mosby/Elsevier; 2016: 198–204. King BH, State MW, Shah B, et al: Mental retardation: A review of the past 10 years. Part I. J Am Acad Child Adol Psychiatry . 1997; 36: 1656–1663. Matson JL, Bamburg JW, Mayville EA, et al: Psychopharmacology and mental retardation: A 10-year review (1990–1999). Res Developmental Disabilities . 2000; 21: 263–296. Munir K: The co-occurrence of mental disorders in children and adolescents with intellectual disability/intellectual developmental disorder. Curr Opin Psychiatry . 2016; 29: 95–102. State MW, King BH, Dykebs E: Mental retardation: A review of the past 10 years. Part II. J Am Acad Child Adol Psychiatry . 1997; 36: 1664–1671. Volkmar FR, Dykens EM, Hodapp RM: Mental retardation. In: Martin A, Volmkar FR, eds. Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook . 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007: 401–410. Volkmar FR, Lewis M: Mental retardation: Child and Adolescent Psychiatric Clinics of North America . Philadelphia, PA: WB Saunders Company; 1996: 5: 769–993.

CHAPTER Mental Disorders Due to 11 Another Medical Condition BJ BECK, MSN, MD AND KATHRYN TOMPKINS, MD

KEY POINTS Mental disorders due to another medical condition should be in the differential diagnosis for every psychiatric evaluation. A high degree of medical suspicion and familiarity with the categories of causative medical conditions will aid in the diagnosis. Psychiatric symptoms can precede, coincide with, or lag behind the physical manifestation of a medical condition. Psychiatric symptoms can resolve, lessen, or continue after appropriate treatment of the underlying medical cause, and they may require specific treatment. The course of some medical conditions might not be alterable, but rigorous treatment of psychiatric distress is part of palliation.

Introduction Mental disorders due to another medical condition (DTAMC ) are defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5) as psychiatric symptoms that are thought to be the direct, physiologic consequence of a non-psychiatric medical condition. The psychiatric symptoms themselves are severe enough to warrant recognition and treatment. This terminology is an attempt to replace the previously used functional versus organic dichotomy and its unfortunate suggestion that the former has no biologic or physiologic basis, or that the latter is unaffected by psychosocial or environmental influences. General qualifiers serve to separate mental disorders DTAMC from co-occurring medical and psychiatric conditions. Mental disorders DTAMC must be the direct pathophysiologic consequence of the medical condition, and they cannot be better accounted for by another primary mental disorder. The symptoms cannot occur solely during the course of delirium (i.e., a

disturbance of consciousness in association with cognitive deficits), nor can they be substance-induced (e.g., alcohol intoxication or cocaine-induced hallucinations). Meeting the diagnostic criteria for dementia (i.e., a syndrome with memory impairment and aphasia, apraxia, agnosia, or disturbances of executive function) precludes a diagnosis of DTAMC. Mental disorders DTAMC should be part of the differential diagnosis for any psychiatric syndrome. Alterations in cognition, behavior, or perception look much the same whether they derive from primary mental disorders, toxins, trauma, tumors, or seizures. For this reason, all but three of the individual disorders are listed in DSM-5 with disorders of similar symptomatology. These disorders are listed in Table 11-1, under the chapter titles in which they are located in the DSM-5. The three diagnostic categories that do not meet criteria for a similar psychiatric disorder are listed separately in their own chapter, “Mental Disorders DTAMC .” Table 11-1: Mental Disorders DTAMC Listed by Chapters in DSM-5 Schizophrenia Spectrum and Other Psychotic Disorders Psychotic Disorder DTAMC Catatonia DTAMC Bipolar and Related Disorders Bipolar and Related Disorder DTAMC Depressive Disorders Depressive Disorder DTAMC Anxiety Disorders Anxiety Disorder DTAMC Obsessive-Compulsive and Related Disorders Obsessive-Compulsive and Related Disorder DTAMC Neurocognitive Disorders Delirium DTAMC Major Neurocognitive Disorder DTAMC Mild Neurocognitive Disorder DTAMC Personality Disorders Personality Change DTAMC Other Mental Disorders

Other Specified Mental Disorders DTAMC Other Unspecified Mental Disorders DTAMC DTAMC= Due to Another Medical Condition.

Psychiatric Differential Diagnosis Primary Mental Disorders It can be difficult to ascertain whether the mental disorder in question is the direct physiologic consequence of the medical condition or whether the two merely co-exist. Correlation between the onset or severity of the medical and mental conditions is helpful, but inadequate, to establish a causal link. Psychiatric symptoms might be the first symptoms of a medical condition (e.g., depression as the first manifestation of pancreatic carcinoma) or be out of proportion to the severity of the medical condition (e.g., depression or irritability in patients with early or minimal sensorimotor symptoms of multiple sclerosis). Alternatively, the psychiatric symptoms might occur late in the course of the medical condition (e.g., psychosis years after the onset of epilepsy) or might not resolve simultaneously with the medical condition (e.g., depression that continues after hypothyroidism is corrected). When treatment of the medical condition dissipates the psychiatric symptoms, an etiologic relationship is supported. However, some mental disorders DTAMC are amenable to, and require, treatment (e.g., interictal depression); this does not imply the diagnosis of a primary mental disorder. Atypical features of a primary mental disorder support an etiologic relationship to the medical condition. Such features can include the age of onset (e.g., firstonset panic attacks in a 65-year-old man), the time course (e.g., sudden or abrupt onset of depression), or the uncharacteristic nature or severity of associated symptoms (e.g., cognitive deficits that are out of proportion to mildly depressed mood). Typical features of the primary mental disorder suggest that certain conditions can co-exist. A positive family history or prior episodes in the absence of the medical condition, for instance, weaken the plausibility of a causal link. The scientific literature supports the causal relationship between some medical conditions and the occurrence of certain psychiatric symptoms; that is, there is a greater than base-rate occurrence for a mental syndrome in a patient with a given medical condition, compared to an appropriate control group. Or, a mental syndrome might correlate with expected deficits or symptoms based on the

location of brain pathology or pathophysiology (e.g., disinhibition or decreased executive function with frontal lobe damage). Although such studies might support the causal relationship between medical and mental disorders, the diagnosis for a given patient must be considered individually. Less stringent, but helpful, are individual case studies that suggest a link between a given medical condition and a mental disorder.

Substance-Induced Disorders Prescription and over-the-counter medications , illicit drugs, or alcohol can be used, misused, or abused during the course of a general medical condition. A careful history, and possibly the use of urine or blood tests, should alert the clinician to drug use and abuse and be part of every evaluation. Use, intoxication, or withdrawal can cause mental symptoms that continue for up to a month after the discontinuation of a substance. The therapeutic use of some medications (e.g., steroids in a patient with systemic lupus erythematosus) causes psychiatric symptoms that mimic the symptoms (e.g., mood lability) of the disease itself. If mental symptoms seem to be substance-induced and DTAMC, both conditions should be coded. The “Unspecified” categories are reserved for symptoms characteristic of the given mental disorder that cause clinically significant distress or impairment but do not meet full criteria for any of the disorders in the identified diagnostic class, and where there is etiological uncertainty or insufficient information to make a more specific diagnosis.

Another Medical Condition The mnemonic ANother MEDical CONDITion (Table 11-2) should help the evaluating clinician recall the broad categories of medical conditions that can cause psychiatric syndromes. Table 11-2: Categories for Another Medical Condition A utoimmune N utritional deficit M etabolic encephalopathy E ndocrine disorders D emyelination I mmune

C onvulsions C erebrovascular disease O ffensive toxins N eoplasm D egeneration I nfection T oxins

Infectious Diseases Infection of the central nervous system (CNS), and especially the chronic meningitides, are increasingly prevalent as immune suppression is on the rise, either from acquired immunodeficiency syndrome (AIDS) or as a result of immune-suppressant therapy for malignancy or organ transplantation.

Herpes Simplex Virus Herpes simplex virus (HSV ) has a propensity for the temporal and inferomedial frontal lobes and is the most commonly encountered focal encephalopathy. Widely recognized as a cause of loss of the sense of smell (anosmia) as well as olfactory or gustatory hallucinations, the limbic distribution of HSV can also result in psychosis, bizarre behavior, or personality change. These personality changes, along with affective lability and decreased cognitive function, can persist. Simple or complex partial seizures might also develop.

Human Immunodeficiency Virus Human immunodeficiency virus (HIV)–infection is associated with neuropsychiatric symptoms of multiple etiologies, including, but not limited to, direct CNS infection (e.g., HIV-related metabolic derangements, endocrinopathies, medication side effects, tumors, opportunistic infections). Accepted terms for the neuropsychiatric syndromes of HIV CNS infection (e.g., HIV-1-associated cognitive/motor complex, AIDS dementia complex, dementia due to HIV disease) are inadequate descriptors for the range of reported symptoms. The presence, severity, and location of HIV-related CNS pathology does not correlate particularly well with the reported symptoms. Besides the deficits suggested by the aforementioned terms (i.e., cognitive deficits: attention, concentration, and visuospatial performance; motor deficits: fine motor control and speed; and dementia: short-term memory loss, word-

finding difficulties, and poor executive function), patients might experience depressed mood, apathy, social withdrawal, and a lack of energy, motivation, or spontaneity. Although much less common, mania and hypomania have also been reported. Psychosis is rarely reported as a new syndrome; when present, it generally occurs in the setting of advanced disease.

Rabies Rabies is an acute viral disease of the mammalian CNS. It is most often transmitted by exposure to infected saliva by means of an animal bite. Rare in the United States, human rabies is more commonly seen following domestic animal bites received during foreign travel. The virus travels centripetally along peripheral nerves to the CNS. The distance the virus travels, along with size of the inoculum and the degree of host defenses, is thought to be responsible for the extreme variability in the incubation period, from 10 days to a year; the mean incubation period is 1 to 2 months. The initial prodrome is like that of other viral illnesses, except for the distinct feature of local fasciculations or paresthesias at the inoculation site. After rabies proceeds to acute encephalitis, brainstem dysfunction, coma, and death usually follow within 4 to 20 days. The encephalitis is heralded by agitation and motor excitation, followed by periods of confusion, psychosis, and combativeness that can initially be interspersed with lucid periods. Half of infected individuals experience painful and violent spasms of the diaphragm as well as laryngeal, pharyngeal, and accessory respiratory muscles when attempting to swallow liquids; this leads to classic hydrophobia. There is autonomic dysfunction, upper motor neuron weakness and paralysis, cranial nerve involvement, and often vocal cord paralysis.

Lyme Disease Lyme disease is a tick-borne spirochetal infection most common in parts of Europe and the United States (especially the Northeast, upper Midwest, and Pacific Coastal states). Because of the confusing array, and unreliable results, of serologic tests as well as the prolonged, recurrent, and non-specific nature of the symptoms, clinicians must have a high level of awareness of the neuropsychiatric sequelae of Lyme disease. Diagnosis might require both Lyme enzyme-linked immunosorbent assay (ELISA) and Lyme Western blot tests, as well as a polymerase chain reaction assay (PCR) or culture. A flu-like syndrome and rash (erythema migrans) usually follows the initial tick (Ixodes scapularis ) bite, with hematogenous spread taking place over days

to weeks. After it is lodged in the target organs (e.g., heart, eyes, joints, muscles, peripheral or CNS), the organism (Borrelia burgdorferi ) can lie dormant for months to years, at which point memory of the initial event has often dimmed. Diagnostic delay is associated with a more chronic course, but even with early, aggressive, antibiotic treatment, symptoms might develop or recur months to years later. Lyme encephalitis can present with fatigue, mood lability, irritability, confusion, and sleep disturbance. Encephalomyelitis, which is rare, can mimic multiple sclerosis. A more chronic encephalopathy might develop with a large range of disturbances in personality, cognition (e.g., short-term memory, memory retrieval, verbal fluency, concentration and attention, orientation, processing speed), behavior (e.g., disorganization, distractibility, catatonia, mutism, violence), mood (e.g., depression, mania, lability), thought processes (e.g., paranoia), and perception (e.g., hallucinations, depersonalization, hyperacusis, photophobia). Strokes, seizures, and severe dementia are rare sequelae of neurologic Lyme disease.

Neurosyphilis Neurosyphilis , of the symptomatic , parenchymal, general paretic type, is a form of late (tertiary) syphilis seen in fewer than 10% of untreated syphilitics, 20 years after primary infection. Even more rare in the post-penicillin era, general paresis might be on the rise among individuals with AIDS. Antibiotics have also changed the classic picture, and patients might have mixed, subtler, symptoms of late syphilis. With diffuse, but particularly frontal lobe involvement, signs and symptoms of general paresis (Table 11-3) include personality change, irritability, poor judgment and insight, difficulty with calculations and recent memory, apathy, and decreased personal grooming. If untreated, mood lability, delusions of grandeur, hallucinations, disorientation, and dementia can follow, along with the classic neurological signs of tremor, dysarthria, hyperreflexia, hypotonia, ataxia, and Argyll-Robertson pupils (i.e., small, irregular, unequal pupils that accommodate, but do not react to light). Cerebral spinal fluid (with elevated protein and lymphocyte count, and a positive Venereal Disease Research Laboratory [VDRL] test) confirms the diagnosis. Table 11-3: Manifestations of General Paresis PARESIS Personality

Affect Reflexes (hyperactive) Eye (Argyll-Robertson pupils) Sensorium (illusions, delusions, hallucinations) Intellect (decreased recent memory, orientation, calculation, judgment, and insight) Speech Source: Lukehart SA, Holmes KK. Syphilis. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine . 14th ed. New York: McGraw-Hill; 1998:1027.

Chronic Meningitis Chronic meningitis is a potentially treatable condition that sadly presents with minimal (and subtle) physical signs and symptoms (e.g., low-grade fever, headache) which, especially in the immunocompromised patient, might be overlooked or attributed to an underlying condition (e.g., AIDS). Likewise, the common psychiatric concomitants (e.g., confusion, cognitive dysfunction, memory, behavioral problems) are non-specific. The most common cause of chronic meningitis is Mycobacterium tuberculosis ; common fungal agents include cryptococcus and coccidioides.

Chronic and Persistent Viral or Prion Diseases These diseases of the CNS are included here more for historic rather than practical significance. These tend to be increasingly rare disorders that, when manifest, lead unalterably to death in a matter of months to a few years. The neurologic signs can lag behind the psychiatric symptoms, but they are so extreme and rapidly debilitating that they are unlikely to be attributed to primary mental disorders.

Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis (SSPE ) occurs in children and adolescents (usually before the age of 11 years) following previous measles (rubeola) infection or, rarely, measles vaccination. SSPE has steadily declined since the advent of widespread measles vaccination. With a predilection for males (3:1, male/female), the first signs are often deterioration in school work, distractibility, behavioral change (e.g., opposition, temper tantrums), sleepiness, and hallucinations. Neurologic signs, which appear within a few months, include myoclonic jerks, ataxia, seizures, and further intellectual deterioration. Patients are generally bed-ridden within 6–9 months, and death occurs within 1–3 years.

Creutzfeldt-Jakob Disease Creutzfeldt-Jakob Disease (CJD ) is a rare, and rapidly progressive, fatal, illness of primarily 50- to 70-year-olds. Most cases of this prion disease are sporadic, though 5% to 15% can be familial. There is also evidence of person-toperson transmission through corneal transplantation as well as transmission through cadaveric human growth hormone or cadaveric gonadotropins. The hallmarks of the disease, dementia and myoclonus, can be preceded by intellectual decline (e.g., memory difficulties, mood instability, poor judgment), sensorimotor disturbance (e.g., dizziness, vertigo, gait problems), and perceptual abnormalities (e.g., visual illusions or distortions). Hallucinations, delusions, and confusion can follow. Patients become spastic, mute, and stuporous, and usually die in less than a year. Characteristic electroencephalographic (EEG) changes late in the course, along with cortical and cerebellar atrophy seen on head computed tomography (CT) scan, are suggestive of the diagnosis.

Kuru Kuru , or “trembling with fear,” is a fatal disorder of progressive dementia and extrapyramidal signs; it was endemic among a particular tribal group of New Guinea highlanders who ate the brains of their dead. As this ritual cannibalism declined, so did the incidence of Kuru.

Epilepsy Epilepsy is a common (3% life-time prevalence) neurologic disorder characterized by episodic, disorganized firing of electrical impulses in the cortex of the brain. The location of these impulses dictates the seizure phenomena that can include altered consciousness as well as motor, cognitive, behavioral, affective, perceptual, and/or memory disturbances. Seizures were often considered to be emotional problems prior to the use of the EEG (that demonstrated a correlation between behavioral and objective findings). It is not surprising that psychiatric and neurologic syndromes were confused; the CNS has only certain, non-specific modes of response to stimulation, regardless of the source of the input. However, seizures remain a clinical diagnosis, which might be supported but not ruled out by the EEG. Complex partial seizures, often of temporal lobe or other limbic origin, are of particular interest to the psychiatrist. It is estimated that 60% of the roughly two million individuals with epilepsy in the United States have non-convulsive seizures, which are most commonly partial seizures. Of those with partial

seizures, 40% do not show the classic, focal findings on the EEG. A high level of suspicion must be maintained by the psychiatrist not to uncritically accept the neurologist’s dismissal of the diagnosis based on a “normal” EEG. Depression occurs in slightly more than half of patients with epilepsy, as compared to 30% of matched (medical and neurologic outpatient) controls. The incidence is thought to be even higher in patients with partial complex seizures and left hemispheric foci, which suggests that depression might be caused by seizure-induced limbic dysfunction. The suicide rate in patients with epilepsy is five times that of the rate in the general public; in patients with temporal lobe epilepsy, the risk can be 25-fold higher than in the general population. Anxiety symptoms are also more closely associated with partial seizures than with other types of seizures. It can be particularly difficult to differentiate partial seizures from panic attacks. Both can occur “out of the blue,” with hyperarousal, intense fear, perceptual distortion, and dissociative symptoms (such as depersonalization or derealization). Both can be responsive to benzodiazepines. Both can appear to begin with hyperventilation, a common symptom of panic that also can lower the seizure threshold in susceptible individuals. However, in panic disorder, the fear of passing out is common, whereas the actual loss (or alteration) of consciousness is rare; auditory or visual distortions can occur, but usually not olfactory or gustatory hallucinations; automatisms (e.g., chewing or lip-smacking movements) are not common; and there is usually no period of confusion following the episode. Panic attacks generally last 10 to 20 minutes, with memory of the event intact. It is precisely this memory that leads to the fear of the next attack and promotes the development of agoraphobia. In contrast, complex partial seizures often begin with cognitive (e.g., déjà vu , jamais vu , forced thinking), affective (e.g., fear, depression, pleasure), or perceptual (e.g., illusions, olfactory, or gustatory hallucinations) auras, followed by a brief cessation of activity and then a minute or less of automatisms and unresponsiveness, concluding with a brief period (less than a minute to a half hour) of a lack of, or decreased, awareness. There is often incomplete memory of the episode, and agoraphobia is rare. Psychosis is also more prevalent in patients with complex partial seizures. The risk of psychosis in patients with epilepsy can be as much as 6 to 12 times that of the rate in the general public. Besides the psychotic symptoms experienced as auras or as post-ictal delirium, there are brief episodic as well as unremitting chronic psychoses that are thought to result from sub-ictal, temporal lobe dysrhythmias. The most common symptoms are hallucinations, paranoia, and

thought disorders (e.g., circumstantiality, as opposed to the more common schizophrenic symptoms of thought blocking, derailment, and tangentiality). Psychosis often appears after many years of epilepsy, and can be preceded by personality changes. A notable difference in psychotic presentation is that the epileptic’s affect is generally intact and warm, as compared to the affective flattening seen in schizophrenia. Personality symptoms associated with temporal lobe epilepsy are commonly described, but controversial, and not supported by controlled studies using structured, diagnostic tools. Nonetheless, the inter-ictal traits reported include hyperreligiosity, hypergraphia, hyposexuality, dependence, obsessionality, and a marked humorlessness. There is better agreement about a sticky, or viscous, conversational style from which it is difficult to disengage. Violence should be considered a rare ictal event, which is never an organized, purposeful act. Episodic dyscontrol is a controversial syndrome, described as recurrent outbursts of uncontrollable rage, in response to minor irritations that can occur more frequently in patients with early onset of temporal or frontal lobe epilepsy. However, such outbursts are also associated with psychosis and multiple psychosocial, educational, intellectual, socioeconomic, and family deficits, as well as a history of abuse. The overwhelming probability is that such attacks are related to (interictal or primary) psychopathology or brain injury (which might also be the cause of seizures), and should not be attributed to seizure activity per se . The significance of epilepsy in psychiatric practice goes beyond its neuropsychiatric manifestations; it includes the psychosocial ramifications of living with a seizure disorder, the cognitive and affective side effects of common antiepileptic medications, and the seizure threshold-lowering effect of certain neuroleptic and tricyclic antidepressant medications. Thus, the presence of, for instance, mood symptoms and a seizure disorder does not automatically make the diagnosis of mood disorder due to epilepsy. Yet, interictal mood symptoms deserve to be treated, even when they are most likely caused by the seizure disorder. Finally, the difficulty or inability of confirming the clinical diagnosis of a seizure disorder, in the setting of psychiatric symptoms resistant to the usual treatments, should prompt a trial of an appropriate antiepileptic medication.

Nutritional Deficits Niacin

Niacin (nicotinic acid) deficiency and deficiency of its precursor, tryptophan, lead to pellagra, which, when untreated, leads to a chronic wasting, diarrheal, neurologic (e.g., encephalopathy, peripheral neuropathy), and dermatologic (e.g., sun-exposed skin rash, angular stomatitis, glossitis) syndrome. The early symptoms are non-specific and can easily be mistaken for depression: insomnia, fatigue, irritability, anxiety, and depressed mood. Untreated, this progresses to mental slowing, confusion, psychosis, and dementia that can be accompanied by a spastic spinal syndrome with leg weakness, hyperreflexia, clonus, and extensor plantar responses. Pellagra is rare since the advent of niacin fortification of cereals, but still occurs in alcoholics, refugee populations, and vegetarians in less-developed nations. Most symptoms reverse quickly with niacin repletion. Dementia, however, a sign of severe and prolonged deficit, might clear slowly or incompletely.

Thiamine Thiamine (vitamin B1 ) deficiency occurs in two forms: beriberi in areas of poverty or famine, and Wernicke-Korsakoff syndrome in alcoholism. There are cardiovascular, neuropathic, and cerebral signs and symptoms that generally occur in combination but can present less frequently as isolated forms. Few alcoholics or malnourished individuals develop clinical deficiency, and other factors (e.g., activity, total calorie intake) affect the presentation. The syndrome can be precipitated by the administration of glucose to asymptomatic, thiaminedeficient patients. The early symptoms might include decreased concentration, apathy, mild agitation, and depressed mood. Confusion, amnesia, and confabulation are late signs of severe, prolonged deficit.

Cobalamin Cobalamin (vitamin B12 ) deficiency, from lack of absorption (e.g., from absence of intrinsic factor in pernicious anemia or after gastric surgery) or a vegetarian diet, leads to megaloblastic macrocytic anemia and neurodegenerative changes in the peripheral and CNS. Neuropsychiatric symptoms, which can precede hematologic findings, include apathy, irritability, depression, and mood lability. Less common, and indicative of more severe disease, is megaloblastic madness, a delirium with prominent hallucinations, paranoia, and intellectual decline. Neurologic signs include peripheral numbness and paresthesias, sphincter dyscontrol, abnormal reflexes, and decreased position and vibratory

sensation. Because the axonal demyelination and neurodegenerative changes lead ultimately to cell death, not all neurologic findings clear with treatment.

Metabolic Encephalopathy Metabolic encephalopathy should be considered whenever sudden or abrupt changes in mentation, orientation, behavior, or level of consciousness occur. Although the waxing and waning presentation of delirium might eventually be evident, early memory impairment, passivity, withdrawal, or anxiety, and agitation, can be wrongly attributed to a primary psychiatric disorder.

Hepatic Encephalopathy Hepatic encephalopathy can result from acute, subacute, or chronic hepatocellular failure, with a range of neuropsychiatric symptoms from mild personality change to coma, many of which can precede the more classic neurologic or physical findings (e.g., asterixis or icterus, respectively). Earliest signs, apparent only to close family and friends, are mild intellectual difficulties, often covered by intact verbal ability. Objective mental slowing, mild confusion, decreased concentration, depressed or labile mood, irritability, sleep–wake reversal, and decreased personal grooming are common early signs. There can be periods of intermittent disorientation, inappropriate behavior, and outbursts of rage before the progressive deterioration in consciousness, speech, cognition, and memory leave the patient somnolent, incoherent, disoriented, confused, and amnestic. The final stage is coma.

Renal Insufficiency Renal insufficiency , acute or chronic, is associated with neuropsychiatric symptoms. Acute renal failure is most notable for delirium, often with bizarre visual hallucinations. Chronic renal insufficiency is associated with a wide range of symptoms, from mild difficulties in concentration, problem-solving, or calculation, to more severe cognitive impairment and lethargy. Whereas adequate dialysis can improve cognitive function, there are also problems of memory, concentration, and mental slowness associated with dialysis (even though the removal of aluminum has nearly eradicated the incidence of dialysis dementia). Depression also seems more prevalent in renal insufficiency and in dialysis patients, although associated endocrine dysfunction (e.g., hyperparathyroidism) and disordered neurotransmission are thought to be contributing factors. Finally, uremia is associated with seizures, and complex

partial seizures can be an occult cause of altered behavior, affect, perception, cognition, and consciousness.

Hypoglycemic Encephalopathy Whether from excess endogenous or exogenous insulin, hypoglycemic encephalopathy can present with confusion, disorientation, or hallucinations and bizarre behavior. Often, but not always, these symptoms are preceded by restlessness or apprehension. Physical signs and symptoms include nausea, hunger, diaphoresis, and tachycardia. Untreated, stupor and coma follow. Repeated hypoglycemic episodes can cause permanent amnesia from hippocampal involvement.

Diabetic Ketoacidosis Diabetic ketoacidosis can also present with non-specific symptoms of fatigue and lethargy, before the “three Ps” (polyphagia, polydipsia, and polyuria), headache, nausea, and vomiting appear. In a poorly controlled, elderly, diabetic patient, osmotic fluid shifts can cause a slowly resolving delirium that primarily affects cognitive function.

Acute Intermittent Porphyria Acute i ntermittent porphyria (AIP ) is a rare, autosomal dominant enzyme deficiency that interferes with heme biosynthesis and causes the accumulation of porphyrins. More common in women than men, it is known for the classic triad of episodic, acute, colicky abdominal pain, motor polyneuropathy, and psychosis, usually with onset in the 20- to 50-year-old age range. However, AIP can present with only psychiatric symptoms: insomnia, anxiety, mood lability, depression, and psychosis. A small percentage of chronic psychiatric patients have been found to have undiagnosed porphyrias. Neurologic effects, hyponatremia, and other electrolyte imbalances (from vomiting and diarrhea) can lead to seizures. Attacks can be precipitated by drugs, alcohol, low calorie diets, or gonadal steroids (endogenous or exogenous). Porphyrinogenic drugs include most antiepileptic medications, meprobamate, sulfonamide antibiotics, and ergot derivatives. Phenothiazines, bromides, narcotic analgesics, and glucocorticoids are among the safe medications for those with the disorder.

Endocrine Disorders Endocrine disorders are associated with psychiatric symptoms, most commonly depression and anxiety. In the past, when endocrinopathies were diagnosed later

in their course, delirium and dementia were more common.

Thyroid Thyroid dysfunction in either direction is associated with the gradual onset of symptoms that overlap with those of common psychiatric disorders. Hypothyroidism, which is at least four times more prevalent in women than in men, has an insidious onset of non-specific symptoms such as fatigue, lethargy, weight gain, decreased appetite, depressed mood, cold intolerance, and slowed mental and motor activity. Later in the course, the physical signs are dry skin, thin and dry hair, constipation, stiffness, a coarse voice, facial puffiness, carpal tunnel symptoms, loss of the outer third of the eyebrow, loss of hearing, and a delayed relaxation phase of deep tendon reflexes. Early symptoms may be attributed to aging, depression, dementia, or Parkinson’s disease. Hallucinations and paranoia, the manifestations of the so-called “myxedema madness,” are late findings. Roughly 10% of patients have residual psychiatric symptoms after hormone replacement. Hyperthyroid patients appear restless, anxious, fidgety, or labile. Symptoms can overlap with those of anxiety or panic, with palpitations, tachycardia, sweating, irritability, tremulousness, decreased sleep, weakness, and fatigue. Weight loss occurs despite increased appetite. Elderly patients might manifest apathy, psychomotor retardation, and depression, rather than hyperactive symptoms; proximal muscle wasting and cardiovascular symptoms (failure and atrial arrhythmias) can predominate.

Parathyroid Parathyroid dysfunction is closely linked to perturbations in calcium, phosphate, and bone metabolism. However, attempts to correlate symptoms with absolute serum calcium levels have been inconclusive. Hyperparathyroidism, and the resultant hypercalcemia, can be asymptomatic in as many as half of all patients, or present early on with non-specific signs of mental slowness, lethargy, apathy, decreased attention and memory, and depressed mood. Delirium, disorientation, and psychosis are also reported. In hypoparathyroidism, a gradual onset of hypocalcemia can cause personality change, or delirium, without the characteristic tetany of a more precipitous drop in serum calcium.

Adrenal Insufficiency

Whether from autoimmune Addison’s disease (primary hypocortisolism) or the sudden withdrawal of prolonged glucocorticoid therapy (secondary hypocortisolism), adrenal insufficiency presents with initially mild psychiatric symptoms that can be attributable to depression: apathy; negativism; social withdrawal; poverty of thought; fatigue; depressed mood; irritability; and loss of appetite, interest, and enjoyment. Other signs and symptoms include nausea, vomiting, weakness, hypotension, and hypoglycemia. Psychosis, delirium, and eventually coma can develop. The treatment is glucocorticoid replacement, although psychiatric symptoms might not fully resolve and might require specific therapy, as well. Care should be taken to choose psychotropic medications that will not exacerbate hypotension. The relative roles of decreased glucocorticoids versus the increased levels of adrenoc orticotropic hormone (ACTH) and corticotropin-releasing factor (CRF) versus the lack of normal diurnal and stress modulation in glucocorticoid replacement, and in the development and continuation of psychiatric symptoms, are unclear. Hypercortisolism can result from chronic hypersecretion of ACTH (ACTHdependent) from a pituitary adenoma (Cushing’s disease) or a non-pituitary neoplasm (Cushing’s syndrome); or, less frequently, it can result from the direct, adrenal over-secretion of cortisol from a tumor or hyperplasia (ACTHindependent Cushing’s syndrome). The vast majority of patients will experience psychiatric symptoms that can precede the (often partial) development of the classical, Cushingoid, stigmata: truncal obesity, peripheral wasting, hirsutism, moon facies, acne, and striae. Psychiatric symptoms include anxiety (similar to that seen in general anxiety disorder [GAD] or panic disorder) and depression, with crying, extreme irritability, insomnia, as well as decreased interest, energy, concentration, and memory. Suicidal ideation might be prevalent. Although relatively rare, psychosis can develop. Prolonged administration of exogenous corticosteroids produces a similar syndrome, and patients might be extremely responsive, psychiatrically, to small dose adjustments. High-dose, exogenous corticosteroids might also precipitate mania. In patients with a history of corticosteroid-induced mania and a need for episodic corticosteroid treatment, the prophylactic use of a mood stabilizer is indicated.

Pituitary Dysfunction Pituitary dysfunction can disrupt the normal modulation of multiple systems in the body and thus can cause a wide range of psychiatric symptoms. The postpartum, hemorrhagic destruction of the pituitary (Sheehan’s syndrome), for

example, can cause depression, mental slowness, and mood lability. An overactive pituitary can lead to adrenal hyperplasia and all the symptoms of Cushing’s syndrome, described in the previous section.

Demyelinating Disorders Demyelinating disorders are associated with neuropsychiatric symptoms as well as motor and sensory changes. These disorders are relatively rare in the general public and can present initially with mild alterations in mood, behavior, cognition, or personality. When the early physical complaints are intermittent, subjective, and variable, they might be attributed to depression, anxiety, somatization, or even malingering. Multiple sclerosis is by far the most prevalent of these disorders (50–60 per 100,000), with amyotrophic lateral sclerosis a distant second (3–5 per 100,000). Others include metachromatic leukodystrophy, adrenoleukodystrophy, gangliosidoses, and SSPE.

Multiple Sclerosis Multiple sclerosis (MS ), an episodic, inflammatory, multi-focal, demyelinating disease of unknown etiology, affects the cerebral hemispheres, optic nerves, brain stem, cerebellum, and spinal cord. MS is more common in cold and temperate climates, with a predilection for women, and an onset between the ages of 20 and 40 years. Studies suggest that psychiatric symptoms are prevalent throughout the course of MS; do not clear during remission of physical symptoms; and correlate poorly with magnetic resonance imaging (MRI) findings, severity of physical symptoms, or length of illness. In order of prevalence, 95% of MS patients experience some of the following alterations in mood, behavior, or personality: depressed mood, agitation, anxiety, irritability, apathy, euphoria, disinhibition, hallucinations, aberrant motor behavior, or delusions. Depressive symptoms can occur in more than 75% of patients and are associated with an increased rate of suicide. Although the presence of depression does not vary by gender or age, the risk of suicide in MS is higher in men, the newly diagnosed, and those with onset prior to the age of 30 years. Despite the common wisdom that MS is associated with euphoria, only about a quarter of patients experience this mildly elevated mood at some point during the course of their illness, and persistent euphoria probably occurs in fewer than 10% of patients. Euphoria should not be considered synonymous with mania, which is rarely seen. Rather, what passes for euphoria in MS is more of an upbeat nature that can seem incongruent with the patient’s condition and pre-morbid personality style.

Mild to moderate cognitive deficits appear in more than half of MS patients, with more severe decline seen in 20% to 30%. Memory is most often affected, though severe dementia is not common.

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS ), the most common degenerative motor neuron disease, is still relatively rare, with an annual incidence of 1.6 per 100,000 population. It can begin with either upper or lower motor neuron involvement, but eventually both will be affected. It has a relentless course to death within 4 or 5 years, usually from diaphragmatic failure. The sporadic form is more common, although there are familial forms. Dementia can occur in familial ALS, but even with advanced sporadic disease, cognitive function remains intact. Uncontrollable laughing and crying (pseudobulbar affect) is the result of degenerative changes in the cortical bulbar projections to the brainstem.

Lipid Storage Disorders Lipid storage disorders are a group of rare, inherited (autosomal recessive) enzyme deficiencies that can present in adulthood with multiple psychiatric and neuromuscular signs and symptoms.

Metachromatic Leukodystrophy Metachromatic leukodystrophy (MLD ) is rapidly fatal when it presents in infancy. When it presents in adolescence or adulthood, however, it has an insidious, progressive course with cognitive decline, forgetfulness, deterioration of work or school performance, and personality changes. Mild cerebellar signs follow, with gait disturbances, masked facies, and strange postures. Patients become demented, and finally mute and bedridden.

Adrenoleukodystrophy Adrenoleukodystrophy (ALD ) also causes adrenal insufficiency (i.e., primary Addison’s disease). It can present with aphasia, dementia, asymmetric myelopathic findings (e.g., homonymous hemianopsia and hemiparesis), or the psychiatric symptoms of Addison’s disease. A progressive, more symmetric presentation follows, with spastic paraparesis or demyelinating polyneuropathy. Glucocorticoids treat the adrenal insufficiency, but there is no treatment for the overall disorder.

Gangliosidoses

Gangliosidoses are a group of lysosomal storage diseases that include the adult form of Tay-Sach’s disease. Lower motor neuron and spinocerebellar symptoms can present in childhood or adolescence as clumsiness or weakness, with normal intelligence and vision. However, in some patients, psychosis or seizures develop, whereas the neuromuscular effects are mild.

Mitochondrial Disease These maternally-inherited disorders of mitochondrial metabolic dysfunction usually present in children, but can become apparent in adulthood with a wide range of multi-system disease. Organs and tissues especially vulnerable are those heavily reliant on aerobic metabolism (e.g., CNS [including visual and auditory pathways], heart, liver, kidneys, skeletal muscles). Psychiatric symptoms are more prevalent among those with mitochondrial disorders (e.g.., depression, anxiety, mania, psychosis, cognitive impairment). There is also evidence for dysfunctional mitochondrial involvement in certain psychiatric disorders as well as neurodegenerative disorders. The acronym MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes ) refers to a syndrome of stroke-like episodes, migraines, diabetes, seizures, sensorineuronal hearing loss, short stature, and cardiomyopathy that usually presents in adolescence or early adulthood, but with rare cases of onset after the age of 40. MELAS has a relapsing-remitting pattern with the hallmark transient stroke-like episodes. Serum and CSF lactate are commonly elevated. Imaging reflects white matter involvement as well as characteristic, transient, cerebrocortical lesions that defy vascular territory.

Cerebrovascular Disease Cerebrovascular disease is the fourth most common cause of death in the United States, behind heart disease, cancer, and chronic lower-respiratory disease. The vast majority (85%) of strokes are ischemic, and about one-third of all strokes are the result of atherosclerotic thrombosis and cerebral embolism. Essential hypertension is the most common cause of hemorrhagic stroke; spontaneous aneurysmal rupture, or arteriovenous malformation, are much lessfrequent causes of parenchymal bleeding. Depression, either major depression or dysthymia, is the most common poststroke psychiatric syndrome, which occurs in more than half of patients. Roughly two-thirds of these patients experience depressive symptoms in the immediate post-stroke period, whereas the rest become depressed after about six months. The natural course of untreated post-stroke depression (PSD) is about a

year, whereas the course of dysthymia can be more protracted and variable. Although the severity of deficits does not correlate with the onset of depression, depression is correlated with poor recovery and with a decreased ability to participate in rehabilitative therapies. Standard antidepressant therapies have been shown to shorten the course of PSD, underscoring the importance of timely recognition and initiation of treatment. There is suggestive, but questioned, evidence that stroke location (left hemisphere frontal, prefrontal, or basal ganglia) predisposes to depression; previous stroke, sub-cortical atrophy, and personal or family history of mood disorder can also increase the risk of PSD. Aprosodia—the inability to affectively modulate speech and gestures (motor aprosodia), or the inability to interpret the emotional components of another’s speech or gestures (sensory aprosodia)—might follow right (non-dominant) hemisphere insults. The aprosodic patient often appears affectively blunted, or “flat,” but this is a disorder of expression , not mood, and it should be carefully differentiated from depression. Anxiety, as an isolated syndrome, is relatively rare in the post-stroke period. However, almost half of patients with PSD have concomitant anxiety symptoms. Mania, although rare, correlates with right-sided lesions of the orbitofrontal, basotemporal, basal ganglia, and thalamic areas. This secondary mania can be more common in those with preexisting sub-cortical atrophy, or a personal or family history of mood disorder. Affective incontinence might be seen, with multiple lacunar infarcts affecting the descending corticobulbar and frontopontine pathways. This release of cortical inhibition over lower brainstem centers results in uncontrollable outbursts of laughing or crying and loss of more moderate emotional expression, such as smiling. This affective dyscontrol occurs along with dysarthria, dysphagia, and bifacial weakness, which together comprise the syndrome of “pseudobulbar palsy.”

Toxins Toxins , of various types in miniscule amounts, are gaining notoriety as the putative cause of myriad non-specific symptoms in certain, sensitive individuals. Although there is little data to support the existence of multiple chemical sensitivity or environmental illness, there are syndromes from common environmental toxins, such as carbon monoxide or low-level lead exposure, that might be overlooked because of their similarity to common medical or primary mental disorders.

Carbon Monoxide Carbon monoxide (CO) poisoning , from faulty heating or exhaust systems, may cause a flu-like illness with cough, nausea, and general malaise. More chronic, low-level exposure can cause cognitive deterioration and depression. Severe, but sublethal poisoning can lead to memory dysfunction, visual problems, parkinsonism, confabulation, psychosis, and delirium.

Lead Lead a known toxin in young children, but it also poses a risk to adults who are exposed in a variety of occupational, recreational, and environmental settings. Potentially hazardous activities include home renovation, drinking from leaded crystal, and jogging in areas of heavy traffic. Stained glass, ceramic, and leadfigure artisans, as well as artists who use lead-based oil paints, and even art conservators, are at risk. Firearm enthusiasts should also monitor their lead levels. The psychiatric symptoms of low-level lead exposure are non-descript, and easily dismissed as depression: after-work fatigue, sleepiness, depressed mood, and apathy. At higher levels, cognition and memory can be impaired, along with sensorimotor symptoms, restlessness, and gastrointestinal complaints. Organic lead exposure from gasoline, solvents, and cleaning fluids can cause psychosis, restlessness, nightmares, and, at very high levels, seizures, and coma.

Mercury Exposure from organic mercury, such as from contaminated fish, results in a primarily neurologic syndrome, whereas exposure to inorganic mercury presents initially with psychiatric symptoms. Organic mercury poisoning causes prominent neurologic effects (e.g., motorsensory neuropathy, cerebellar ataxia, slurred speech, paresthesias, visual field defects), but the primary psychiatric symptoms (e.g., depression, irritability, mild dementia) might be less striking. With inorganic mercury poisoning (the Mad Hatter syndrome), the initial symptoms are depression, irritability, and psychosis, with less prominent headache, tremor, and weakness. Whereas exposure in the past was occupational or from broken thermometers, present-day sources can be less obvious. Mercury is found in readily purchased botanical preparations and folk medicines. It is also sold in easily-broken capsules with instructions to sprinkle it in the home or car, a practice of certain cultural or religious sects.

Drugs

Drugs (whether overdosed, herbal, non-prescription, prescribed, or recreational) should all be considered potential toxins when evaluating changes in cognition, behavior, consciousness, or personality. (These would be substance-induced mental disorders, which are discussed elsewhere.)

Neoplasm Neoplasm , unregulated focal or diffuse growth within the cranial confines, can produce any of the symptomatic presentations available to the CNS. As compared to ischemic infarcts, tumors affecting similar brain volume are less symptomatic. The clinical presentation can suggest the type, location, and primary versus metastatic nature of the lesion. Metastatic brain lesions are more prevalent in adults than are primary brain tumors. In addition, paraneoplastic syndromes of non-brain tumors also cause psychiatric symptoms.

Brain Tumors Brain tumors , such as gliomas, which account for 50% to 60% of primary brain tumors, tend to produce diffuse symptoms (e.g., cognitive decline) because they grow slowly and diffusely throughout the cortex. Multiple metastases or lymphoma also can present this non-focal pattern. Meningiomas (25% of primary brain tumors) grow extrinsically to the brain and compress a limited area, causing progressive, more focal symptoms. Seizure is the third presentation of intracranial lesions, which can be the result of abnormal excitation or interference of normal inhibitory mechanisms. Cortical invasion or compression, even from a relatively small meningioma, is more likely than sub-cortical tumors to cause seizures. Constitutional symptoms (e.g., fever, weight loss, fatigue) are more common with metastatic disease. Psychiatric symptoms occur in half of patients with brain tumors, and, of those, more than 80% have tumors in the frontal or limbic areas. Besides depression and personality changes, frontal tumors are associated with bowel and bladder incontinence. Temporal lobe tumors are especially likely to cause seizures, often with ictal or interictal psychosis. Poor memory, Korsakoff syndrome, aphasia, depression, and personality changes are also seen with temporal lobe tumors. Akinetic mutism, an alert but immobile state, occurs with upper-brainstem tumors. Delirium is a sign of rapidly growing, large, or metastatic tumors.

Paraneoplastic Syndromes Paraneoplastic syndromes are most often seen with small-cell carcinoma of the lung. They produce neuropsychiatric symptoms that can precede by many

months the detection of the causative, non-CNS tumor. Tumors of the breast, stomach, uterus, kidney, testicle, thyroid, and colon can also cause paraneoplastic syndromes. These syndromes can arise from tumor production of hormones, with clinical manifestations of inappropriate antidiuretic hormone secretion (SIADH), hypercortisolism, hypercalcemia, or hyperparathyroidism. Less well understood are the mechanisms responsible for encephalitic paraneoplastic syndromes, which involve non-reversible, often selective, inflammatory and/or neurodegenerative destruction. Paraneoplastic limbic encephalitis has an insidious onset over weeks to months, with confusion and agitation. Depressed mood, anxiety, personality change, hallucinations, and catatonia are also reported, and can lead to psychiatric hospitalization. Initial memory loss progresses to dementia. Pathologically, there is neuronal loss in the medial temporal lobe and other limbic areas, along with meningeal and perivascular lymphocytic infiltration.

Pancreatic Cancer Pancreatic cancer is associated with a higher-than-expected incidence of depression, which may be its initial presentation.

Colloid Cysts Colloid cysts , non-malignant, space-occupying lesions of the third ventricle, exert pressure on diencephalic structures and can increase intracranial pressure by ventricular obstruction. They have been associated with depression, mood lability, psychosis, personality change, and position-dependent, intermittent headache.

Degenerative Disorders Degenerative disorders , especially of the basal ganglia, produce not only motor and sensory dysfunction, but a spectrum of neuropsychiatric symptoms that include depression, psychosis, and dementia. In fact, the severity of the movement symptoms can vary with the level of emotional stress. This association between movement and emotion can be mediated by the largely limbic and cortical inputs to the basal ganglia, and the shared neurotransmitter systems (dopamine, γ -aminobutyric acid [GABA], serotonin, norepinephrine).

Parkinson’s Disease Parkinson’s disease affects 1% of the population over the age of 65 years and is known for its classic features of bradykinesia, rigidity, and tremor, as well as

characteristic disturbances of gait and posture. The major degenerative loss is in the pars compacta of the substantia nigra, although other structures are also involved. Dopamine, and to some extent norepinephrine and possibly other neurotransmitters, are depleted, which can contribute to the depression experienced by more than half of patients. Dementia with Parkinson’s disease is also more common than it is in age-matched controls. Psychosis can develop, and is complicated by the dopaminergic and anticholinergic medications used to treat the disease.

Huntington’s Chorea Huntington’s chorea is an autosomal dominant disorder of primarily striatal destruction and GABA depletion. Besides atrophy of the caudate and putamen, there is mild frontal and temporal wasting. Most common in the age range of 30 to 40 years, onset is extremely variable, and juvenile disease has a more rapidly progressive course (average duration of 8, as opposed to 15, years). The prevalence is 10 per 100,000 population. The classic choreiform movement disorder can present before, with, or after prominent psychiatric symptoms. Early on, memory might be intact, but serious defects in attention, judgment, and executive function are evident. This can be followed by depression, apathy, social withdrawal, and a lack of attention to personal grooming. Irritability and impulsivity are common. The initial presentation can also mimic obsessivecompulsive disorder or schizophrenia. The depression is responsive to antidepressants and should be treated. The cognitive decline, like the movement disorder, is progressive, and leads to dementia.

Wilson’s Disease Wilson’s disease is an autosomal recessive defect in copper excretion that causes deposition of copper in the liver, brain, cornea, and kidney. This genetic deficiency of ceruloplasmin has a prevalence of 3.3 per 100,000 population. One person in 90 might be a heterozygous carrier. Symptoms are rare before the age of 6 years, and they commonly present in the teens. However, some patients remain asymptomatic well into adulthood. About half of patients present with liver manifestations: acute hepatitis, parenchymal liver disease, cirrhosis, or fulminant hepatitis. The vast majority of remaining patients present with neuropsychiatric symptoms, virtually always accompanied by gold or greenbrown copper deposits around the cornea—the pathognomonic Kayser-Fleischer rings. Copper toxicity in the brain affects the lenticular nuclei and, to a lesser degree,

the pons, medulla, thalamus, cerebellum, and cerebral cortex. Neurologic features include tremor, spasticity, rigidity, chorea, dysphagia, and dysarthria. Cognition is generally intact, although the dysarthria can be mistaken for intellectual disability. About 10% to 25% of patients present with psychiatric symptoms, although those who present with neurologic findings also have psychiatric symptoms. Schizophreniform, bipolar, and more typical depressive symptoms might be seen, but bizarre, possibly frontal, behavior is more common. Psychiatric symptoms that respond incompletely to excess copper removal require more specific treatment and psychopharmacotherapy.

Immune Diseases AIDS is caused by HIV infection, and is discussed earlier in this chapter and elsewhere in this book.

Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE ) is an autoimmune, inflammatory disease of unknown etiology that affects women more often than men (9:1), usually in the third to fifth decades. Tissue damage occurs in multiple systems, which gives the disorder an extremely variable presentation and course. Laboratory tests might be confirmatory, but are not totally specific or reliable. When patients present with depression, sleep disturbance, mood lability, mild cognitive dysfunction, or psychosis (which up to one-half of patients do), the non-specific nature of their complaints can lead to the erroneous diagnosis of a primary mental disorder, such as major depression or a somatic symptom disorder. Correct diagnosis can lead to steroid therapy, which can worsen psychiatric symptoms.

Head Trauma Trauma to the head is extremely common in the United States, with roughly a million severe traumatic brain injuries per year. Young males are at highest risk. Motor vehicle accidents are responsible for about half of all closed head injuries, with falls, violence, and sports causing most of the rest. Penetrating head injury, such as that received from a gunshot wound, is often dramatic; it tends to cause focal symptoms related to the size and location of directly involved brain tissue.

Closed-Head Injury This type of injury is far more common, and complicated, causing more diffuse symptoms and prolonged sequelae that do not correlate with the severity of the

injury. Returning veterans of the wars in the Middle East have raised awareness of the prolonged and varied symptoms suffered following one or more closedhead blast injuries from roadside explosive devices. The neurobehavioral dysfunction, including cognitive, somatic, and emotional symptoms, might clear in 3–6 months, or can persist for years after the injury. The mechanisms of injury in blunt trauma to the head might account for this variable course. Direct impact, acceleration/deceleration, and shearing forces, parenchymal stretching, and microscopic tears cause brain contusion and neuronal damage that can be followed by edema and bleeding. Limbic areas of the brain, the anterior temporal lobes, and the inferior surface of the frontal lobes, are the major sites of damage. Cognitive slowing can occur with poor attention, increased distractibility, memory difficulties, perseveration, and poor planning. Personality changes, irritability, impulsivity, depression, anxiety, and mood lability are also common. Among the many somatic symptoms are headache, dizziness, fatigue, and sleep disturbance, which can be attributed to depression. Photophobia, noise sensitivity, tinnitus, and blurred vision also occur. Multiple head injuries, advanced age, drug or alcohol use, increase the risk of prolonged impairment. Patients with head injuries are often very sensitive to psychotropic medications and might require “geriatric” doses.

Post-Concussive Syndrome Post-concussive syndrome (PCS ) is the prolonged duration of cognitive, somatic, and emotional symptoms following “head trauma that caused significant cerebral concussion.” A careful history for distant head trauma is necessary to recognize the syndrome.

Evaluation of the Problem Because mental disorders DTAMC should be a part of the differential diagnosis for any psychiatric syndrome, the evaluation is the same as for any careful psychiatric evaluation. A high level of “medical suspicion” is required to gather the necessary information to make the diagnosis. History should be gathered from records, the patient, other caregivers, and, when possible and appropriate (e.g., when the patient is a poor, or limited historian, or for medical or mental reasons), from family members or others close to the patient. The psychiatric history should pay close attention to onset, course, treatment response, and past episodes, for typical and atypical features of primary mental disorders. The medical history should include a careful review of past and present illnesses, treatments, procedures, all medications, exposures,

travel, head injuries, seizures, habits (caffeine, tobacco), and recreational drug use. When possible, communication with the patient’s primary care provider can corroborate or add to the medical history (e.g., date of last physical exam and patterns of care). A focused time-line between medical events and psychiatric symptoms is important to determine a possible correlation. The family history might reveal the presence of similar symptoms, other psychiatric disorders, or medical illnesses that “run” in the family. Early or unexplained deaths can also provide clues. The social history (ethnic or religious background, education, occupation, living situation, interpersonal relationships, recreational activities) can provide clues to unusual exposures, travel, patterns of violence or substance use. Examination of the patient begins with a mental status exam (MSE ). This is not specific for general medical conditions, but is comparable to the MSE in similar, primary mental disorders. Certain medical conditions, however, can present patterns of behavior or cognitive deficits that might be found on the MSE. Laboratory examination should be focused to support or rule out a suspected diagnosis. Imaging should also be used to confirm a diagnosis, not to discover unsuspected pathology. Sudden onset, focal signs, rapid progression, infectious disease, or trauma are indications for appropriate brain imaging. Other tests can be specific to a given medical condition (e.g., a sleep-deprived EEG for suspected complex partial seizures).

Treatment Considerations/Strategies Some general medical conditions are chronic, stable, or unremitting, and little can be done to change or treat them or to alter their course (e.g., previous stroke or toxic exposures and degenerative or demyelinating diseases). The mental disorder or psychiatric symptoms should be treated to the fullest extent possible, regardless of their medical etiology. Whenever possible, underlying medical conditions should be treated, controlled, and/or stabilized. For example, infections should be treated with appropriate agents, metabolic perturbations should be normalized, and diabetic control and renal function optimized. Some mental disorders will clear when the underlying condition is treated, and thus long-term treatment of the mental disorder is unnecessary. Short-term comfort measures, however, might be necessary as the mental symptoms can lag behind the course of the medical

condition. An example of this would be the judicious use of benzodiazepines in a patient being treated for hyperthyroidism. Often, the medical condition and the psychiatric symptoms require ongoing treatment. Maximal seizure control, for instance, might not be perfect, leaving the patient with interictal symptoms, such as depression, that also should be treated. The psychosocial stresses of chronic or acute medical conditions, as well as other, primary mental or personality disorders, can exacerbate the psychiatric symptoms, interfere with treatment, and generally complicate the clinical picture.

Conclusions Neuropsychiatric symptoms can precede, accompany, or follow the onset of a variety of general medical conditions. The psychiatrist must maintain a high level of suspicion as well as a current knowledge of the broad categories and common features of these more prevalent conditions to consider mental disorders DTAMC in the differential diagnosis of every patient. Few, if any, general laboratory or imaging examinations are necessary, but the judicious use of specific examinations to support or confirm the suspected diagnosis is recommended. Although the underlying condition should be treated, when possible, psychiatric symptoms might also require specific treatment.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing, 2013. 2. Beck BJ, Tompkins KJ: Mental disorders due to another medical condition. In: Stern TA, Fava M, Wilens TE, et al, eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016: 205–227. 3. Berry N, Sagar R, Tripathi BM: Catatonia and other psychiatric symptoms with vitamin B12 deficiency. Acta Psychiatr Scand . 2003; 108: 156–159. 4. Black DN, Taber KH, Hurley RA: Metachromatic leukodystrophy: a model for the study of psychosis. J Neuropsychiatry Clin Neurosci . 2003; 15: 289–293.

5. Boylan LS, Flint LA, Labovitz DL, et al: Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology . 2004; 62: 258–261. 6. Coker LH, Rorie K, Cantley L, et al: Primary hyperparathyroidism, cognition, and health-related quality of life. Ann Surg . 2005; 242: 642–650. 7. Darnell RB, Posner JB: Paraneoplastic syndromes involving the nervous system. N Engl J Med . 2003; 349: 1543–1554. 8. Dubovsky A, Arvikar S, Stern TA, et al: The neuropsychiatric complications of glucocorticoid use: Steroid psychosis revisited. Psychosomatics . 2012; 53(2): 103–115. 9. Ecevit IZ, Clancy CJ, Schmalfuss IM, et al: The poor prognosis of central nervous system cryptococcosis among non-immunosuppressed patients: A call for better disease recognition and evaluation of adjuncts to antifungal therapy. Clin Infect Dis . 2006; 42: 1443–1447. 10. Fallon BA, Vaccaro BJ, Romano M, et al: Lyme Borreliosis: neuropsychiatric aspects and neuropathology. Psychiatric Ann . 2006; 36: 120–128. 11. Fermo SL, Barone R, Patti F, et al: Outcome of psychiatric symptoms presenting at onset of multiple sclerosis: a retrospective study. Mult Scler . 2010; 16: 742–748. 12. Golden MR, Marra CM, Holmes KK: Update on syphilis: Resurgence of an old problem. JAMA . 2003; 290: 1510–1514. 13. Hemachudha T, Laothamatas J, Rupprecht CE: Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol . 2002; 1: 101–109. 14. Hurley RA, Fisher R, Taber KH: Sudden onset panic: Epileptic aura or panic disorder? J Neuropsychiatry Clin Neuro . 2006; 18: 436–443. 15. Koponen S, Taiminen T, Portin R, et al: Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study. Am J Psychiatry . 2002; 159: 1315–1321. 16. Stojanovich L, Zandman-Goddard G, Pavlovich S, et al: Psychiatric manifestations in systemic lupus erythematosus. Autoimmun Rev . 2007; 6:

421–426.

CHAPTER Alcoholism and Alcohol Use 12 Disorders PETER R. JACKSON, MD; JOHN A. RENNER, MD; AND KARSTEN KUEPPENBENDER, MD

KEY POINTS Overview Alcohol consumption and its consequences represent a leading risk factor for premature death and contribute to the overall global burden of disease including that of both physical and mental health problems. The impact spans all age groups and crosses generations. In addition, there are significant societal and economic consequences of heavy alcohol use in communities. Epidemiology Prevalence studies show that approximately 7% of the adult population in the United States meets criteria for an alcohol use disorder (AUD). Lifetime prevalence has been estimated at almost 30% and is higher in men than women. The average age of first intoxication in the United States is 15 years old and the highest prevalence of binge drinking is during adolescence and early adulthood, a critical period of brain development. Clinical Features Problematic alcohol use ranges from brief episodes of excessive drinking to chronic patterns impairing function, to physiological dependence often represented by severe and dangerous symptoms of withdrawal. An AUD is present when there is a problematic pattern of use, which leads to clinically significant impairment as measured and graded in severity by assessing specified symptom criteria. Biological, psychological, and social impairments are all common. The majority of those diagnosed with an AUD have at least one other co-occurring

psychiatric disorder. Etiology Alcoholism represents a chronic disease of the brain’s memory, motivation, and reward circuitry. Neurobiologic changes are related to the increased activity of GABA, the main inhibitory neurotransmitter in the brain, and a secondary increase in release of endogenous opioid peptides and dopamine in reward centers of the brain. Twin and adoption studies have shown that genetic factors, independent of environment, have a major influence in the development of AUDs. The heritability of AUDs is estimated to be around 45% and risk is increased with higher severity of the disorder in family members. Proposed typologies have contributed to the important understanding of the heterogeneity of these disorders. Other psychiatric disorders are independent risk factors of the development of an AUD. Among the most closely associated are bipolar disorder, schizophrenia, and antisocial personality disorder. Environmental risk factors are also contributory and include family and peer influence, availability of alcohol, and cultural attitudes. Differential Diagnosis Given significant overlap between symptoms of alcohol withdrawal or intoxication and other cognitive or psychiatric diagnoses, providers are cautioned against attributing all presenting symptoms to alcohol use. Even if there is objective data of alcohol use, other acute and chronic conditions should be considered. Approaches to Evaluation Screening for alcohol-related problems should be routine for all mental health patients and should begin in early adolescence. Well-validated, age-specific, non-proprietary screening tools have been developed for practical use in the clinic. Evaluation should include thorough screening for other substance misuse and a full assessment for other psychiatric conditions. The general interview approach should be non-confrontational with a goal of understanding a patient’s level of readiness for treatment and evoking the patient’s desire for change.

Treatment Psychosocial treatments for AUDs include mutual help groups such as AA or Smart Recovery, cognitive-behavioral therapy, and motivational enhancement therapy. Strong family support, which can be bolstered through couples or family therapy, increases the likelihood of successful treatment. Large studies have shown that therapeutic treatment combined with medication is more effective than therapeutic treatment alone. FDA-approved pharmacologic treatments include naltrexone, acamprosate, and disulfiram. Treatment of co-morbid psychiatric disorders is imperative and should generally not be delayed until a patient has achieved sobriety.

Introduction In 2012, 5.9% of all deaths worldwide were attributable to alcohol consumption. Among those aged 20 to 39, approximately 25% of all deaths were alcohol related. Globally, alcohol misuse is the leading risk factor for premature death and disability among those aged 15 to 49 years. When factoring all age groups, alcohol use is the fifth leading cause for premature death and disability worldwide. Moreover, roughly 5% of the global burden of disease and injury can be attributed to alcohol. Alcohol use is implicated in more than 200 diseases and conditions. Accompanying alcohol-associated disease and mortality is a marked economic impact. According to the Centers for Disease Control and Prevention (CDC), excessive drinking cost the United States $249 billion in 2010, a significant increase from the cost of $223.5 billion in 2006. Most of this cost was due to crime, treatment of health problems caused by excessive drinking, and reduced workplace productivity. In addition, approximately 10% of children in the United States live with a parent who has an alcohol use disorder (AUD). Despite these consequences, heavy alcohol use remains commonplace.

Epidemiology According to the 2014 National Survey on Drug Use and Health (NSDUH), 16.3 million adults in the Unites States, accounting for approximately 7% of the adult population, met criteria for an AUD. One-fourth of adults reported

engaging in binge drinking (i.e., five or more drinks on one occasion) in the past month and 7% reported heavy drinking (i.e., binge drinking on five or more days in the past 30 days). The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) found the 12-month and lifetime prevalence of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) AUDs to be 14% and 29%, respectively, among United States adults. The prevalence is higher in men than in women and is higher in Caucasians and Native Americans than it is in other racial groups. Alarmingly, only 20% of respondents with life-time AUDs ever received treatment for their condition. Particular attention is warranted regarding alcohol use in young people. The average age of first intoxication in the United States is 15 years old. According to the 2015 data from the Monitoring the Future survey, 17% of 12th grade students, 11% of 10th graders, and 5% of 8th grade students reported binge drinking in the past two weeks. Across the life span, the highest prevalence of binge drinking is during late adolescence and early adulthood, with college students drinking even more heavily than non-college-enrolled peers. Evidence clearly shows that the earlier the onset of regular heavy drinking, the more likely it is for an individual to develop an AUD.

Diagnosis Problematic alcohol use spans the continuum from brief episodes of binge drinking, to chronic patterns that produce significant problems, to either psychological or physiological dependence. A DSM-5 AUD is present when there is a problematic pattern of use, which leads to clinically significant impairment as measured by 11 criteria. Diagnostic criteria include tolerance and withdrawal symptoms. Although these signs of physical dependence are not required for the diagnosis, they are associated with more severe forms of the disorder. AUDs are classified based on severity. Mild severity includes the presence of two to three symptoms; moderate severity has four to five symptoms, and a severe AUD diagnosis requires the presence of at least six symptoms. Other specifiers can be added to the diagnostic criteria: in early remission (with none of the criteria, except for craving, have been met for at least 3 months, but less than 12 months); in sustained remission (none of the criteria, apart from craving, have been met for 12 months or longer); and, in a controlled environment (the individual is in an environment in which access to alcohol is restricted).

Co-Occurring Disorders In 1994, the National Co-Morbidity Survey (NCS) reported that the majority of patients in the United States with serious psychiatric disorders also used alcohol or other drugs to excess. Individuals in this group accounted for more than half of all lifetime psychiatric disorders in the United States; they typically had at least three disorders, one of which was a substance use disorder (SUD). Most individuals with an AUD have at least one other psychiatric disorder. Cooccurring conditions (in rank order) associated with a SUD diagnosis are: anxiety disorders, another SUD, affective disorders, conduct disorder, and antisocial personality disorder. This list represents influence of the natural prevalence of these disorders. When looking at the risk of an AUD when another condition is primary, 60% of those with bipolar I disorder have a co-occurring SUD and 40% of those with major depressive disorder (MDD) have a cooccurring AUD. Anxiety disorders and affective disorders co-occur more frequently with alcohol disorders in women. Other SUDs, conduct disorder, and antisocial personality disorder co-occur more frequently with alcohol disorders in men. Roughly 25% to 50% of suicides involve alcohol.

Neurobiology of Alcohol The positive reinforcement of alcohol appears to be mediated by a combination of neurobiological changes. Alcohol use leads to increased activity of γ -amino butyric acid (GABA), the main inhibitory neurotransmitter in the brain, via action at pre-synaptic neurons that leads to an increase in GABA release as well as action on post-synaptic neurons where it binds to GABAA receptors, facilitating the opening of chloride channels for a primary central nervous system (CNS) depressant effect. Alcohol also leads to an increase in release of endogenous opioid peptides and dopamine in the nucleus accumbens, inhibition of glutamate N -methyl-D-aspartate (NMDA) receptors, and interaction with serotonin systems. Chronic alcohol use causes: up-regulation of excitatory glutamate NMDA receptors; down-regulation of inhibitory neuronal GABA receptors; and increased central norepinephrine activity. The CNS hyperactivity following termination of persistent alcohol consumption results from a lack of opposition to a higher baseline excitatory state.

Alcohol Metabolism The primary metabolism of alcohol occurs through oxidation in the liver. Ethanol is metabolized via alcohol dehydrogenase to acetaldehyde, which is converted to acetate via aldehyde dehydrogenase; thereafter, carbon dioxide and water are produced. Disulfiram (Antabuse) inhibits the action of aldehyde dehydrogenase and produces toxic blood levels of acetaldehyde. A healthy liver oxidizes 0.75 ounces of 80-proof alcohol in 1 hour; in regular drinkers, the metabolic rate is even faster. Approximately 90% of alcohol is oxidized by the liver and 10% is excreted unchanged by the lungs and kidneys. Asians have lower levels of both alcohol dehydrogenase and aldehyde dehydrogenase. Therefore, they metabolize alcohol more slowly and become intoxicated on less alcohol than do members of other ethnic groups. The blood alcohol concentration (BAC ) helps determine alcohol intoxication (Table 12-1). (Note: A 160-lb. man who drinks 5 ounces of whiskey in 1 hour develops a BAC of 0.10%.) A BAC of more than 150 mg% in an individual who does not appear intoxicated, or more than 300 mg% in any awake person, is suggestive of physiological dependence upon alcohol (tolerance). The decreased gastric and esophageal metabolism of alcohol in women contributes to a higher BAC per drink in women than in men. On average, in a healthy adult, the blood alcohol content decreases at a rate of 15 to 20 mg/dL per hour. Table 12-1: Blood Alcohol Concentration and Associated Clinical Findings BAC Clinical Findings 0.05% Exhilaration, loss of inhibitions, slowed reaction time 0.10% Slurred speech, staggering gait 0.20% Euphoria, marked motor impairment, nausea and vomiting, double vision 0.30% Confusion 0.40% Stupor 0.50% Coma 0.60% Respiratory paralysis → death

Physiologic Effects of Alcohol The cardiovascular effects of alcohol include: increased cardiac output (in alcoholics); elevated blood pressure; increased heart rate and cardiac oxygen

consumption (in non-alcoholics); and an increased risk of atrial fibrillation and ventricular tachycardia as well as myocardial infarction. Long-term effects of chronic heavy drinking also include alcoholic cardiomyopathy. Gastrointestinal (GI) effects are well known and include fatty liver and alcoholic hepatitis early on, and fibrosis and cirrhosis after long-term heavy alcohol use. Acute and chronic pancreatitis are also well documented sequelae of heavy or chronic alcohol use. In addition, there is an increased incidence of cancer (of the mouth, pharynx, larynx, esophagus, head, neck, liver, and breast) among individuals with AUDs. Both the innate and adaptive immune systems are impaired by alcohol use via disrupted production of cytokines and suppressed development of T cells, among other effects. Miscellaneous physiological effects of heavy alcohol use include: hypoglycemia (with acute intoxication); increased blood estradiol levels in women; alcoholic neuropathy; and dysregulation of triglycerides and lipoproteins.

Withdrawal and Related Syndromes Alcohol Withdrawal The earliest withdrawal symptoms can begin within a few hours of cessation or reduction in prolonged, heavy drinking. Symptoms include: sweating and tachycardia; tremor; insomnia; nausea or vomiting; transient hallucination or illusions psychomotor agitation; anxiety; and, seizures. Two of these symptoms are required to make a diagnosis of alcohol withdrawal.

Alcoholic Hallucinosis (Alcohol-Induced Psychotic Disorder, with Hallucinations) (See Table 12-2) This condition usually occurs 12 to 24 hours after cessation of drinking in an alcohol-dependent person and resolves within 24 to 48 hours after cessation. Hallucinations are typically visual but auditory and tactile phenomena can also occur. Alcoholic hallucinosis can also occur without a drop in the BAC (with an onset during intoxication); no delirium, tremor, or autonomic hyperactivity develops. Symptoms can become chronic and are not due to schizophrenia (it has a late-onset, and there is no typical pre-morbid personality).

Alcohol Withdrawal Delirium (Formerly Delirium Tremens) (See

Table 12-2) Symptoms usually begin 48 to 96 hours after the last drink and include: tremor ; an increase in psychomotor activity; vivid hallucinations; profound disorientation; tachycardia; hypertension; sweating; and, fever. There are some reports of alcohol withdrawal delirium starting as late as seven days after the last drink. Risk factors for withdrawal delirium include: age > 30 years; the presence of concurrent illness; withdrawal symptoms occurring in the presence of an elevated alcohol level; and, a history of withdrawal delirium. When using the Clinical Institute Withdrawal Assessment for Alcohol-Revised scale (CIWA-r ), a score of ≥ 15 is a predictor of complicated withdrawal (Shu, 2015). Patients with severe withdrawal delirium often require ICU level of care. First-line treatment includes use of benzodiazepines . Shorter-acting medications and those available for intravenous (IV) administration (e.g., lorazepam) are commonly used to enable monitoring and more rapid dosing adjustments, if needed. Additional treatments, especially for cases refractory to high-dose benzodiazepines, include phenobarbital or propofol . In contrast to treatment of other delirium, antipsychotics are not indicated. Table 12-2: DTs versus Acute Alcohol Hallucinosis Condition

Sensorium Tremor Hallucinations Pupils

Vital Signs

Onset Duration

Delirium tremens

Confused

Yes

Visual

Dilated, slow to react

↑

Gradual 3–10 days

Alcohol hallucinosis

Clear

Rare

Auditory

Normal

±

Rapid

5–30 days

Alcohol Withdrawal Seizures Alcohol withdrawal seizures usually involve generalized tonic-clonic seizures with an absence of focal findings. They occur within 6 to 48 hours after the last drink and are typically treated with benzodiazepines. Rarely is more than one seizure involved, but a second seizure can occur within 3 to 6 hours of the first seizure. Status epilepticus occurs in less than 3% of patients. Hypoglycemia, hyponatremia, and hypomagnesemia often arise in chronic alcoholics.

Other Alcohol-Related Syndromes Fetal Alcohol Spectrum Disorders

Fetal alcohol spectrum disorders (FASDs) are the leading cause of preventable intellectual disability in the Western hemisphere. The CDC has reported that 1 in 10 pregnant women continue to use alcohol after they learn of their pregnancy. Signs of FASD can include intellectual disability (44% have an IQ ≤ 79) or an early stage of liver disease, and a delayed weight and height curve. Congenital heart disease and other defects can be noted, including: wide-set eyes; a short palpebral fissure; a short and broad-bridged nose; a hypoplastic philtrum; a thinned upper lip; and, a flattened mid-face. The incidence of FASD increased 6fold between 1979 and 1993, to 6.7 per 10,000 births (CDC, 1995). Roughly 17% are stillborn or die shortly after birth, and 20% have birth defects (32% show full “fetal alcohol syndrome”). Moreover, maternal alcohol use while breast-feeding impairs a child’s motor development but not his/her mental development. The long-term effects of FASD include poor educational and social function (< 6% can function in school and most never hold a job). The average IQ in those meeting criteria for fetal alcohol syndrome has been scored as 68 (Streissguth, 1991); 72% have a major psychiatric disorder (Famy, 1998).

Wernicke-Korsakoff Syndrome (Alcohol-Induced Major Neurocognitive Disorder) Both Wernicke encephalopathy and Korsakoff syndrome are caused by a deficiency of thiamine (vitamin B1 ), a common deficiency seen in alcoholics. This is conceptualized as two distinct syndromes. Wernicke encephalopathy is the more acute/subacute and reversible of the two conditions and includes a classic triad of confusion, ataxia, and nystagmus. Korsakoff syndrome develops secondarily, is persistent, and is typically irreversible, with anterograde amnesia (the inability to form new memories), general memory loss, and confabulation. It can also include chronic visual and auditory hallucinations. If untreated, 85% of those with Wernicke encephalopathy will go on to develop the more permanent symptoms of Korsakoff syndrome. Treatment consists of IV thiamine supplementation (3–7 days) and then oral supplementation. Although treatment often can reverse the acute effects of Wernicke encephalopathy, it can generally only prevent further deterioration when Korsakoff syndrome is present, and strategies for secondary harm prevention should be pursued.

Other Alcohol-Induced Disorders The DSM-5 includes categories for many other alcohol-induced disorders, including alcohol-induced depressive disorder , alcohol-induced bipolar

disorders , alcohol-induced anxiety disorders , alcohol-induced sexual dysfunction , and alcohol-induced sleep disorder . Because there is much overlap between symptoms of alcohol intoxication or withdrawal and symptoms of many primary psychiatric conditions, diagnoses of alcohol-induced disorders should be considered judiciously to ensure that other primary conditions are not overlooked or left untreated. In general, criteria involve symptoms that develop during or shortly after alcohol intoxication or withdrawal, did not precede the AUD, and do not persist for a substantial period (e.g., about a month for depression) after withdrawal or intoxication.

Genetics and the Biologic Correlates of Alcoholism The heritability of AUDs is estimated to be 35% to 55% and it is suspected that the heritability is higher in males than in females. In general, the most severe symptoms and phenotypic characteristics of alcohol and other SUDs will develop in about 10% of the population exposed to these substances (Warner, 1995). Genome-wide association studies (GWAS) support a polygenic model for AUDs (Yan, 2014). Although a detailed review of candidate genes implying risk is beyond the scope of this review the value of such research (Levey, 2014) can be appreciated for its potential to lead to more targeted screening, pharmacotherapy, and prevention among those at highest risk. The Virginia Twin Registry Study supports the current research findings of genetic factors having a major influence on the development of AUDs. The specific biologic mechanisms affected by these genetic factors are less clearly understood. This large population-based study also demonstrated that environmental factors shared by family members had little influence on the development of alcoholism in males (Prescott and Kendler, 1999). The social use of alcohol, however, is primarily influenced by environmental factors (such as peer pressure, cultural attitudes, price, and availability). Non-familial AUD accounts for half of all alcoholism and is characterized by less severe alcoholism, later onset, better school and work histories, smaller families, higher socioeconomic status, and less psychopathologic or antisocial behavior (Frances, 1980). Risk data analysis reveals that any drinker has a 5% to 10% risk of becoming an alcoholic; if one parent is an alcoholic, the risk doubles to 20%; if both parents are alcoholic, the risk is between 20% and 50%; the risk for fathers, sons, and brothers of male alcoholics approaches 50%; the risk for male and female twins is 28% for fraternal twins and 54% for identical twins; and, if the father is severely alcoholic and criminal, the son’s risk is 90%.

The Stockholm adoption study (of 862 males and 913 females, adopted and raised by non-relatives) found two types of alcoholism (Cloninger et al, 1981): Type I , or “milieu-limited” alcoholism (that affects both men and women, reflects a congenital susceptibility [both parents can have mild, adult-onset AUD], has a severity that is determined by post-natal stress, is associated with a risk in sons that is twice that of the normal incidence, and is associated with a risk in daughters with an alcoholic mother that is three times the normal incidence), and Type II, or “male-limited” alcoholism (that is passed only from fathers to sons, involves fathers who are both severely alcoholic and criminal, affects sons of affected individuals [nine times more than the normal incidence], has an early-onset of alcohol misuse [before the age of 25 years]). There is no relationship with the post-natal environment, and daughters of such fathers have no increased incidence. Prospective personality “trait” studies (e.g., involving the Minnesota Multiphasic Personality Inventory [MMPI]) have failed to document a typical pre-alcoholic personality. However, certain constellations of personality traits and biological findings might be associated with specific alcoholic sub-types (Cloninger, 1987; Buydens-Branchey et al, 1989). Type II males are three times as likely to be depressed and four times as likely to have attempted suicide as Type I males.

Sub-Types of Alcoholics The overall goal of identifying typologies, including the earliest work of Jellinek, is to identify more targeted treatment approaches for sub-types of individuals with AUDs. Other early research by Cloninger (on type I and type II, 1981) and Babor (on type A and type B, 1992) using empirical clustering techniques identified binary classifications of sub-types among both male and female alcoholics who differed during their illness and their response to treatment. Type A alcoholics show a later onset and have fewer childhood risk factors, less severe dependence, fewer alcohol-related problems, and less psychopathological dysfunction. Type B alcoholics have early-onset alcoholrelated problems, familial alcoholism, childhood risk factors, greater severity of dependence, use of other substances, more chronic treatment history (despite younger age) and greater psychopathological dysfunction. Several additional typologies, including three, four, and five type classifications have been proposed and studied, including that from Del Boca

and Hesselbrock (1996) identifying low- and high-risk groups as well as separating those with more internalizing symptoms (i.e., anxiety) and those with more externalizing symptoms (i.e., antisocial behavior). More recently, research from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) (see Table 12-3) identified five sub-types of alcoholism with unique family histories, age of alcohol dependence onset, endorsement of the DSM-IV AUD criteria, and the presence of co-occurring psychiatric and SUDs. This typology was unique compared to others in that the sample was of the general population rather than an exclusively clinical population. This is particularly relevant because only one-fourth of those with an AUD have ever received treatment. Table 12-3: Alcohol Sub-Types

Characteristics

Cluster Cluster 1 2 Cluster 3 31.5% 19.4% 18.8%

Cluster 4 21.1%

Cluster 5 9.2%

Working name

Young Adult Sub-type

Functional Intermediate Familial Sub-type Sub-type

Young Antisocial Sub-type

Chronic Severe Sub-type

Age group

Young adults

Middleaged

Young adults

Middle-aged

Onset of AD from drinking initiation

2.8 years

18.4 years 15.0 years

2.9 years

13.2 years

Middle-aged

✓

✓

Antisocial personality disorder

✓ ✓

✓ ✓

DSM-IV Alcohol abuse criteria

✓ ✓

✓

Multi-generational familial alcoholism

✓

Mood disorders

✓

✓

✓

Anxiety disorders

✓

✓

✓

Regular smoking

✓

✓

✓

Other substance abuse disorders

✓

✓

✓

Cluster 1, “Young Adult Sub-type,” was the largest sub-group (~31%); it comprised binge-drinking young adults with relatively low rates of co-occurring

psychiatric disorders, and multi-generational alcohol dependence. Cluster 2, “Functional Sub-type,” and cluster 3, “Intermediate and Familial Sub-type,” (~19% each) had the latest onset, higher psychosocial functioning, the lowest rates of periodic heavy drinking, and medium/low levels of co-occurring psychiatric disorders. Cluster 4, “Young Antisocial Sub-type,” and cluster 5, “Chronic Severe Sub-type,” (~21% and 9%, respectively) had the most severe alcohol dependence, substantial rates of multi-generational alcohol dependence (53% and 77%, respectively), and were associated with both co-occurring psychiatric and other SUDs. (Moss, Chen, & Hsiao-ye, 2007). Although further research is required before the broad adoption of any one subtyping scheme into major psychiatric classification systems, typologies have contributed to the important understanding of the heterogeneity of AUDs and thus the possibility for more targeted psychopharmacologic and psychosocial treatments.

Evaluation of the Patient General Recommendations Screening for alcohol-related problems should be routine for all mental-health patients regardless of setting, and is a mandatory part of history-taking for clinical skills verification exams and interviews. Individuals with alcohol problems are also at high risk for problematic use of other drugs; they should therefore be screened for use of other legal and illegal substances.

Psychiatric and Social Problems Associated with Alcoholism Mental disorders that very commonly co-occur with alcoholism include other SUDs, antisocial personality disorder, conduct disorder, bipolar I disorder, and schizophrenia. Other mental disorders that often co-occur with alcoholism include: MDD (especially in females); anxiety disorders; attention deficit hyperactivity disorder (ADHD); and post-traumatic stress disorder (PTSD); as well as an erratic school or employment history, domestic violence, and marital problems (especially multiple divorces).

Screening Instruments for Problematic Alcohol Use Since 2003, the Substance Abuse and Mental Health Services Administration (SAMHSA ) has advocated the SBIRT (screening, brief intervention, and referral to treatment ) model as an evidence-based public health approach for the reduction of problematic alcohol use. This approach has been tested in a broad

range of medical settings (Madras et al, 2009) and replaces the CAGE questions (discussed shortly) with a single alcohol screening question: “How many times in the past year have you had more than five drinks (more than four drinks for women) in one day?” Any positive response for drinking within the past year warrants assessment for problem drinking with an additional screening tool (Canagasby & Vinson, 2005). For details on the SAMHSA recommended screening process, see “Helping Patients Who Drink Too Much. A Clinician’s Guide,” updated January 2007. The National Institute on Alcohol Abuse and Alcoholism (NIAAA ) suggests asking the following three questions (NIAAA, 2007) (see Table 12-4): “How many days per week do you drink? How many drinks do you have on a typical drinking day? What is the maximum number of drinks you had on any given occasion during the past month?” For healthy men up to age 65 years, no more than four (and for women and men over the age of 65, no more than three) drinks per day and no more than 14 (for women, and for men over the age of 65 years, seven) drinks per week are considered low risk. Approximately 30% of patients consume unhealthy amounts of alcohol, and 10% exceed both daily and weekly limits. Table 12-4: Standard Drinks Beer

Wine 80-proof Liquor

12 ounces 5 ounces 1.5 ounces

Several other reliable screening instruments are available. The CAGE questionnaire has four simple questions (Table 12-5) that can be easily inserted into the psychiatric interview. Two or more positive responses correlate with significant alcohol-related problems. This is a quick and reliable screening tool, even for those patients with less overt alcohol use problems; it is a more reliable indicator than elevated liver function tests. The Alcohol Use Disorders Identification Test (AUDIT) is a ten-question screen created by the World Health Organization that can be clinician or self-administered. The AUDIT-C is a shorter, three-question version that has also been validated. The Michigan Alcoholism Screening Test (MAST) is a 25-question instrument (Table 12-6) that takes longer to administer, but is a more accurate screening tool than the CAGE, especially for women and the elderly. Regarding screening tools specifically created for adolescents, the CRAFFT screening tool, which screens

for alcohol as well as other misused substances, is the most commonly used. All of the aforementioned screening tools are easy to use and are available at no charge. Table 12-5: The CAGE Questionnaire “ C ”

Have you ever felt you should C ut down on your drinking?

“ A ”

Have people A nnoyed you by criticizing your drinking?

“ G ” Have you ever felt bad or G uilty about your drinking? “ E ”

Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (E ye opener)?

Scoring: Item responses on the CAGE are scored 0 or 1, with a higher score indicative of alcohol problems. A score of 2 or more is considered clinically significant. Source: Published in the American Journal of Psychiatry , 1974, the American Psychiatric Association.

Table 12-6: Michigan Alcoholism Screening Test (MAST ) Clinical utility of instrument

To screen for alcoholism with a variety of populations

Research applicability

Useful in assessing extent of lifetime alcohol-related consequences

Copyright, cost, and source issues

No copyright Cost: $5 for copy, no fee for use Source Melvin L. Selzer, M.D. 6967 Paseo Laredo La Jolla, CA 92037

Points

YES

NO

( )

0. Do you enjoy a drink now and then?

—

—

(2)

1. Do you feel you are a normal drinker? (By normal, we mean you drink less than — or as much as most other people.a

—

(2)

2. Have you ever awakened the morning after some drinking the night before and found that you could not remember a part of the evening?

—

—

(1)

3. Does your wife, husband, a parent, or another near relative ever worry or complain about your drinking?

—

—

(2)

4. Can you stop drinking without a struggle after one or two drinks?a

—

—

(1)

5. Do you ever feel guilty about your drinking?

—

—

(2)

6. Do friends or relatives think you are a normal drinker?a

—

—

(2)

7. Are you able to stop drinking when you want to?a

—

—

(5)

8. Have you ever attended a meeting of Alcoholics Anonymous (AA)?

—

—

(1)

9. Have you gotten into physical fights when drinking?

—

—

(2)

10. Has your drinking ever created problems between you and your wife, husband, — parent, or other relative?

—

(2)

11. Has your wife, husband (or other family members) ever gone to anyone for help about your drinking?

—

—

(2)

12. Have you ever lost friends because of your drinking?

—

—

(2)

13. Have you ever gotten into trouble at work or school because of drinking?

—

—

(2)

14. Have you ever lost a job because of drinking?

—

—

(2)

15. Have you ever neglected your obligations, your family, or your work for two or — more days in a row because you were drinking?

—

(1)

16. Do you drink before noon fairly often?

—

—

(2)

17. Have you ever been told you have liver trouble? Cirrhosis?

—

—

(2)

18. After heavy drinking have you ever had delirium tremens (DTs) or severe shaking, or heard voices or seen things that really weren’t there?b

—

—

(5)

19. Have you ever gone to anyone for help about your drinking?

—

—

(5)

20. Have you ever been in a hospital because of drinking?

—

—

(2)

21. Have you ever been a patient in a psychiatric hospital or on a psychiatric ward of a general hospital where drinking was part of the problem that resulted in hospitalization?

—

—

(2)

22. Have you ever been seen at a psychiatric or mental health clinic or gone to any doctor, social worker, or clergyperson for help with any emotional problem where drinking was part of the problem?

—

—

(2)

23. Have you ever been arrested for drunk driving, driving while intoxicated, or driving under the influence of alcoholic beverages?c

—

—

(2)

24. Have you ever been arrested, taken into custody, even for a few hours, because of — other drunk behavior? (IF YES, how many times? —)

—

a Alcoholic response is negative b 5 points for each delirium tremens c 2 points for each arrest

Scoring System: In general, five points or more would place the subject in an “alcoholic” category. Four points would be suggestive of alcoholism, and three points or less would indicate the subject was not alcoholic. Programs using the above scoring system find it very sensitive at the five-point level, and it tends to find more people alcoholic than anticipated. However, it is a screening test and should be sensitive at its lower levels. Source: Selzer ML: The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am J Psychiatry 1971; 127: 1653–1658. Supporting References: Zung BJ, Charalampous KD: Item analysis of the Michigan Alcoholism Screening Test. J Stud Alcohol . 1975; 36: 127– 132.

Skinner HA: A multi-variate evaluation of the MAST. J Stud Alcohol . 1979; 40: 831–844. Zung BJ: Factor structure of the Michigan Alcoholism Screening Test in a psychiatric outpatient population. J Clin Psychol. 1980; 36: 1024–1030. Skinner HA, Sheu WJ: Reliability of alcohol use indices: the Lifetime Drinking History and the MAST. J Stud Alcohol . 1982; 43: 1157–1170. Hedlund JL, Vieweg RW: The Michigan Alcoholism Screening Test (MAST): a comprehensive review. J Operational Psychiatry . 1984; 15: 55–64.

Interviewing the Patient Patients with a suspected SUD should be approached in a respectful and nonjudgmental manner. A confrontational approach by the clinician does not facilitate the interview process and has been shown to decrease the rate of successful referral to alcohol treatment. A moralistic approach is never helpful and is also likely to alienate and to demoralize patients; it can also increase denial and diminish motivation for treatment.

Abnormal Blood Chemistries Commonly Seen in Individuals with an AUD No one test is considered diagnostic for alcohol dependence. Carbohydratedeficient transferrin (CDT ) is the most specific indicator of alcoholism, and levels rise sooner than other biomarkers in the presence of heavy drinking, often as early as one week. The GGTP (or GGT, γ-glutamyltranspeptidase) is a liver enzyme; a blood level of more than 30 units/L of this enzyme is induced by more than four drinks per day for 2 weeks. It is an early indicator of an alcoholism relapse and remains one of the most commonly used biomarkers. Levels will return to normal levels (< 30 units/L) after four or five weeks of sobriety. A mean corpuscular volume (MCV) > 95 μ m3 in males and > 100 in females is typically seen in chronic alcoholism. Other markers of alcoholism are elevated liver function tests (LFTs), e.g., an elevated aspartate transaminase (AST), serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT), serum glutamic-pyruvic transaminase (SGPT) or alkaline phosphatase. Cyclic adenosine monophosphate (cAMP) levels in white blood cells (WBC) of alcoholics are three times normal. Other than alcohol itself, the only other direct biomarker for alcohol use is ethyl glucuronide (EtG), a metabolite of ethyl alcohol that is detectable in the urine for up to 5 days after drinking. It is a highly sensitive measure of consumption or contact with alcohol and it might not be possible to distinguish between drinking and use of an alcohol hand wash or contact with similar alcohol-based liquids.

Differential Diagnosis Medical Problems Mild alcohol intoxication is marked by disinhibition; more severe intoxication results in delirium, ataxia, or even coma. The clinician needs to rule-out lifethreatening conditions (e.g., head injuries) and other neurologic and metabolic problems (e.g., hypoglycemia). AUDs can mimic insomnia and can cause a variety of medical problems, including GI bleeding, pancreatitis, cirrhosis, hepatitis, cardiomyopathy, labile hypertension, intracranial hemorrhage, sexual dysfunction, and peripheral neuropathy.

Psychiatric Problems The presence of a non-alcohol-induced psychiatric disorder is suggested by psychiatric symptoms that precede alcohol use, are greater than what would be expected given the amount and duration of the drinking, and that last more than 4 weeks following cessation of use. Appropriate diagnostic assessment is difficult while an individual is actively drinking; diagnosis requires accurate reports about the mood of the patient prior to the onset of drinking, ideally corroborated by family or friends.

Persistent Depressive Disorders Persistent depressive disorders, with or without suicidality, can be difficult to distinguish from the depression induced by chronic alcohol consumption. More than 60% of individuals with an AUD are clinically depressed when admitted for alcohol withdrawal treatment, and many complain of dysthymia during the early months of sobriety. Any individual with an AUD or one who is intoxicated who expresses suicidal ideation should be considered a serious suicide risk, regardless of the presence or absence of MDD. In most cases, depressive symptoms should clear after 2 weeks of sobriety. If the patient remains depressed beyond 2 weeks, he or she should be reassessed for a co-morbid MDD or bipolar disorder.

Anxiety Anxiety is a common symptom during alcohol withdrawal, but it usually resolves within a few days. Some individuals with an AUD also complain of generalized anxiety and/or panic attacks lasting up to 12 months following alcohol withdrawal treatment. These symptoms are difficult to distinguish from a co-occurring anxiety disorder and require a comprehensive psychiatric

evaluation after the patient has achieved sobriety. Although anxiety has long been known as a risk factor for developing an alcohol and drug use disorder, recent evidence suggests that an AUD increases the risk for new-onset social phobia (Robinson et al, 2011).

Schizophrenia Schizophrenia or other psychotic disorders can be confused with the hallucinations associated with delirium tremens or with alcoholic hallucinosis, particularly in the presence of other long-term cognitive sequelae of chronic alcohol use.

Treatment Strategies Effective treatment of problematic alcohol use requires more than management of the medical aspects of alcohol withdrawal treatment. Psychiatrists must also understand: the distinction between detoxification/alcohol withdrawal treatment (the gradual elimination of alcohol from the body) and definitive treatment for AUDs; the stages of the recovery process and the way ambivalence impedes progress toward sobriety; and the types of psychiatric problems that complicate the management of these patients.

Chronic Disease Model Although a brief office intervention might be sufficient for people with minor problems, long-term treatment is usually required for individuals with severe AUDs. Successful management of such patients can be a process of many years, during which treatment interventions must be matched to the needs of each patient. Psychiatrists must understand the stages that individuals with an AUD usually pass through during the recovery process, the importance of using correct intervention skills, and the need to identify and treat co-occurring psychiatric conditions. The Project Match study showed that “matching” patients to a specific type of AUD treatment did not improve outcome except in cases of psychiatric severity. Alcoholics Anonymous (AA ), cognitive-behavioral therapy (CBT ), and motivational enhancement are equally effective for other patients. Research also shows that strong family support, which can be bolstered through couples or family counseling, increases the likelihood of maintaining abstinence compared to those who receive only individual counseling. The critical treatment question is: “Which treatment for which patient at which time?”

The Stages of Behavioral Change The work of Prochaska and DiClemente has provided a paradigm for the process of behavioral change, including change in the addictive disorders. Individuals commonly move through a series of specific stages on the road from uncontrollable drinking to stable sobriety. Successful treatment involves helping the alcoholic move from one stage to the next, using those intervention techniques that are most effective for each stage. Typically, patients cycle through this process several times before achieving stable sobriety. This approach works best when the clinician understands the importance of a gradual step-wise progression through the stages of change, rather than demanding instant recovery (Table 12-7). Table 12-7: The Stages of Behavioral Change Precontemplation Drinker is unaware that alcohol use is a problem or has no interest in changing drinking pattern. Contemplation

Drinker becomes aware of problems but is still drinking and is usually ambivalent about stopping.

Preparation

Previous pattern continues, but drinker now makes decision to change. Can initiate small changes.

Action

Behavioral change begins; typically a trial-and-error process with several initial relapses.

Maintenance

New behavior pattern is consolidated; relapse prevention techniques help to maintain change.

Relapse

Efforts to change are abandoned. Cycle might be repeated until permanent sobriety is established.

Source: Adapted from Prochaska, DiClemente, and Norcross, 1992.

Motivational Interviewing Techniques Based on the Stages of Change Model, Miller and Rollnick elaborated a counseling style designed to avoid patient resistance, to resolve ambivalence about drinking, and to induce change. The basic concepts of this approach are: therapist style is a powerful determinant of patient resistance and change; confrontation of the problem is a goal, not an intervention style; argumentation is a poor tool to induce change; when resistance is evoked, patients tend not to change; motivation can be increased by specific treatment techniques; motivation emerges from the interaction between patient and therapist; ambivalence is normal, not pathological; and, helping patients resolve ambivalence is the key to change. This interviewing technique suggests the following approaches for use during each stage in the recovery process.

Moving Patients from Pre-Contemplation to Contemplation

Many patients are unaware that their drinking is problematic. Therefore, you should provide feedback, explore the patient’s perspective on alcohol and its effects (but not confront or argue), obtain a physical examination and laboratory data (e.g., LFTs, BAC, MCV), administer an assessment instrument (e.g., CAGE, AUDIT, MAST), and review the quantity and frequency of a patient’s drinking; summarize your findings and connect drinking to identified problems; involve family in this process whenever possible (and if the patient refuses to accept your conclusions, maintain medical follow-up, listen empathically to the patient’s complaints, and encourage the patient to agree to an “evaluation” of his or her problems; and help patients connect their problems to their drinking.

Moving Patients from Contemplation to Preparation Moving from contemplation to preparation involves exploring the patient’s ambivalence about drinking; start with the positives (e.g., Positive: “What do you like about your drinking?” Negative: “What problems does the drinking create?”); helping the patient internalize this conflict; helping the patient discuss their anger, humiliation, guilt, and resentment; evoking their own motivation to control and/or stop their drinking; and helping the patient resolve his or her ambivalence (action is not recommended until the patient has made the decision to stop).

Moving Patients from Preparation to Action In this phase, the plan is to clarify the patient’s goal (to stop, to control drinking, or to explore problems); recommend treatment options (if the patient wants to stop drinking); recommend substance-use counseling (if the patient wants to “control” use or remains highly ambivalent about his or her drinking); support the patient’s self-efficacy; and develop an action plan (letting the patient choose from a menu of treatment options).

Action: Active Quitting Begins Here the focus is on directive behavior-based therapy and other specific prescriptions for gaining and maintaining sobriety (e.g., going to AA, stopping socializing with other drinkers, seeing a counselor); avoidance of passive, nondirective, forms of psychotherapy; anticipation of a trial-and-error process to refine treatment needs; provision of ongoing optimism and support; and work with mutual-support programs (AA, Rational Recovery , Smart Recovery ). AA is the primary treatment resource for most alcoholics. It relies on group support to guide the alcoholic through a process of spiritual renewal and

characterological change. The emphasis on “one day at a time,” reliance on one’s “higher power” and spirituality are central to the AA philosophy. Psychiatrists rely on AA to complement other types of interventions. The immediate and almost ubiquitous accessibility, connection to a network of sober individuals, and the provision of free unlimited 24-hours-a-day support make AA an invaluable resource. Schizoid individuals and persons with more severe psychopathology can be uncomfortable in any type of mutual-support group. Professionally run groups or individual counseling are the preferred options for such patients. Non-religious persons might find Rational Recovery or similar mutual-support programs an effective alternative to traditional AA. Psychiatrists might need to reassure patients that AA does not discourage psychotherapy or the use of appropriately prescribed medication for the treatment of AUDs and other psychiatric conditions. Successful referral to mutual-support programs requires familiarity with the resources available in the local community. You should try to: match the program to the patient’s age, race, social or professional status, and religious or sexual orientation, if the patient so desires; insist that the patient initially attend four or five different groups, to “shop around”; and realize that most programs will provide a volunteer to escort a newcomer to his or her first meetings. This will greatly facilitate referral.

Maintenance Relapse Prevention is a specialized form of CBT developed by Marlatt to help maintain sobriety. Individuals with an AUD are taught to identify high-risk situations and predictors of relapse. Feelings, thoughts, and behaviors that trigger craving and relapse are explored and the patient is taught to modify them. Making the distinction between lapses (brief slips) and full relapses helps patients terminate drinking episodes promptly before they experience a complete loss of control. Re-defining such events as opportunities for learning reduces guilt and demoralization and enhances the likelihood of successful outcome. These techniques are most helpful after patients have achieved an initial period of sobriety.

Medications in the Treatment of AUDs In addition to the drugs used to treat alcohol withdrawal, medications are now available that significantly enhance the long-term management of AUDs.

“Medical management” (Petinatti, 2004)—20-minute visits with a clinician who reviews side effects and other adverse events, discusses drinking, and encourages medication adherence—and the placebo effect contribute to the success of the intervention. In COMBINE, a large prospective trial that compared naltrexone, acamprosate, placebo, and behavior therapy (and combinations thereof) in the treatment of AUD, all interventions that included medication or placebo were more effective than behavior therapy alone (Weiss et al, 2008).

Alcohol Withdrawal Treatment Benzodiazepines are the preferred medications for alcohol withdrawal treatment because of their excellent side-effect profile. Long-acting benzodiazepines, such as chlordiazepoxide and diazepam, are the standards for uncomplicated alcohol withdrawal treatment. When high enough initial doses (> 60 mg diazepam over 24–36 hours) are used, these drugs are self-tapering. The short-acting benzodiazepine, lorazepam, is recommended only for patients with significant liver disease, for those who are cognitively impaired, for patients over 65 years, and for any patient with unstable medical problems. This medication needs to be tapered over 4 to 8 days, but it is metabolized to the glucuronide form and is rapidly excreted by the kidney, giving the clinician more flexibility when managing unstable patients. Symptom-triggered dosing based on withdrawal scales, such as the Clinical Institute Withdrawal Assessment (CIWA-Ar ) can work best, but it requires frequent patient monitoring. This approach provides for adequate control of symptoms, avoids over-medication, and shortens the period of detoxification treatment.

FDA-Approved Medications for Long-Term Treatment Naltrexone , an opiate antagonist, is thought to reduce feelings of reward or excitement associated with drinking or being cued to drink alcohol. It has been extensively studied and found to reduce alcohol consumption, particularly heavy drinking days in those with AUDs (Jonas et al, 2014). Given in doses of 50 mg orally per day, it is well tolerated and seems to work best in motivated patients who describe intense craving, early-onset drinking, and a strong family history of alcohol dependence. It is contraindicated for patients taking opiates because

its antagonism of the mu receptor will render opioid analgesia ineffective. It should not be given to any patient who has taken or is suspected of misusing opioids because it can precipitate withdrawal. It is also contraindicated for those patients with acute hepatitis or liver failure. A positive response in terms of reduced craving and/or drinking is usually apparent within 7 to 10 days. If there is no response at 50 mg, increasing the dose to 100 mg is recommended. Treatment adherence can be improved with 30-day, 380 mg depot injections of intramuscular naltrexone, which are typically well tolerated (Garbutt et al, 2005). Acamprosate modulates NMDA-glutamate receptors and can reduce the experience of cravings. It is not metabolized in the liver and is excreted through the kidneys. Other than flatulence or diarrhea, there are no common side effects. The usual dose is 333 to 666 mg three times daily. Numerous placebo-controlled European clinical trials, where it has been used for 25 years, have shown shortterm and long-term effects in decreasing relapse rates in patients with AUDs who are committed to abstinence (Bouza et al, 2004). These findings have not been replicated in the United States (Anton et al, 2006). Disulfiram inhibits the enzyme aldehyde dehydrogenase, leading to elevated levels of acetaldehyde. Doses of 250 mg orally per day can produce tachycardia, dyspnea, hypotension, facial flushing, nausea, and vomiting, if the patient drinks. Disulfiram works as a self-imposed deterrent from drinking, and is best understood as a behavioral tool (with potentially serious medical side effects) rather than a traditional medication. In controlled trials, disulfiram and placebo were equally effective in producing continuous abstinence. Compared to placebo, disulfiram reduced the number of days drinking and the severity of concurrent medical problems. Disulfiram works best in motivated patients who are engaged in behavioral couples or family counseling (Fals-Stewart et al, 2004), and who are followed closely by their psychiatrist. Disulfiram can cause sudden-onset fulminant hepatitis, which causes death in 1 in 10,000 to 20,000 patient years. The risk is highest in the first few months. LFTs need to be monitored periodically for signs of disulfiram-induced hepatitis. Patients need to be educated about clinical signs of hepatitis because changes in LFTs can precede severe hepatitis only by days; thus, they need to understand that prompt medical attention is required when they experience fatigue, diarrhea, whitening of stool, darkening of urine, nausea, or vomiting, which often precede the hallmark jaundice.

Non-FDA-Approved Medications for Long-Term Treatment Topiramate can be particularly helpful for early-onset heavy drinkers. Common, reversible side effects include word-finding difficulties, paresthesias, and, rarely, metabolic acidosis. Clinicians should begin with 25 mg daily and increase to 25 mg twice daily after one week. The dose can be gradually titrated up to 300 mg daily (Johnson et al, 2007; Johnson, 2010). Serotonergic agents have been shown to reduce craving and improve outcomes in specific sub-types of AUD. Ondansetron (a selective 5-HT3 antagonist) reduced alcohol consumption in early-onset Type B alcoholics but not in Type A alcoholics (Johnson, 2000), and this might be related to a variation in the gene for a serotonin transporter (Johnson et al, 2011). Sertraline ( a selective serotonin re-uptake inhibitor [SSRI]) increased abstinence and reduced days drinking in Type A but not Type B Alcoholics (Pettinati, 2000). Citalopram had a similar effect, but only in male alcoholics (Naranjo, 2000). Fluoxetine did not improve drinking outcomes in either sub-type (Kranzler, 1996). Baclofen , an agonist at pre-synaptic GABAB receptors that is primarily excreted through the kidneys, has shown promise in the treatment of patients with liver impairment, at doses of 10 to 20 mg three times per day (Addolorato et al, 2007; Pastor et al, 2012). Gabapentin , structurally related to GABA, can potentiate CNS GABA activity, inhibit glutamate activity and reduce the release of dopamine and norepinephrine. The potential balancing of the excitatory and inhibitory dysregulation that is present in early abstinence can make this particularly useful in decreasing the likelihood of early relapse. Doses studied were between 600 and 1800 mg per day, most commonly in three divided doses (Mason et al, 2013).

Treating Associated Symptoms Following alcohol withdrawal treatment, individuals with AUD might experience various distressing symptoms and might pressure their psychiatrist to provide medication for these complaints. After a careful evaluation to rule-out co-occurring psychiatric disorders, patients should be reassured that these symptoms are a normal part of early recovery and will usually resolve with extended sobriety. Avoiding prescribed medications helps patients learn that they are moving beyond a dependency on exogenous chemicals.

Anxiety Relaxation techniques and cognitive-behavioral interventions can be utilized. You should avoid the prescription of benzodiazepines because of their potential for misuse in this population.

Depression Most individuals with an AUD entering alcohol withdrawal treatment programs are clinically depressed. Following withdrawal treatment, approximately 3% of men and 12% of women meet criteria for a depressive disorder. These individuals should be considered for antidepressant therapy. Fluoxetine has been demonstrated to reduce both drinking and depression in severely depressed individuals with AUDs. Paroxetine and nefazodone are also well tolerated by this population, although efficacy data is less clear-cut. For individuals with less severe depressive symptoms, psychotherapy is often helpful in managing guilt and discouragement.

Insomnia If appropriate sleep hygiene does not resolve the problem, use of the sedating antidepressant, trazodone, or the anticonvulsant, gabapentin , might help. Trazodone has no significant misuse potential and is effective for long-term use. Gabapentin has sedative properties and some patients misuse it. Careful monitoring is indicated (Arnedt et al, 2007). Sedative-hypnotic drugs have not been studied in the treatment of insomnia in patients with an AUD, and most psychiatrists recommend avoidance of these agents because of the potential for misuse. Formal CBT for insomnia (CBT-I) is the most effective treatment where available. Self-help books are a good alternative (e.g., Jacobs, 2009).

Managing Dual Diagnosis Patients Failure to adequately diagnose and treat co-occurring psychiatric disorders is the most common cause for the failure of AUD treatment. Assessment of cooccurring disorders can be challenging and new psychiatric diagnoses made during periods of active drinking are often unreliable. The patient should be observed following a minimum of 2 weeks of sobriety to confirm any diagnosis. After it is clear that the symptoms are not secondary to the patient’s AUD, any co-occurring psychiatric disorder must be treated.

Anxiety Disorders

If anxiety complaints are associated with alcohol craving or preoccupation, an initial response should be a 2-week trial of naltrexone. If there is no response or if anxiety symptoms persist despite reduced craving, the patient should be evaluated for an independent anxiety disorder. Specific treatment options for anxiety disorders co-occurring with the substance use disorders are outlined in Table 12-8. Most data for efficacy and tolerability of medication treatment for anxiety disorders in the context of AUDs is for SSRIs . Judicious use of the benzodiazepines with lower misuse liability, such as oxazepam or chlordiazepoxide , can be considered for patients with panic disorder or generalized anxiety disorder (GAD) who have failed to respond to more conservative therapies. These patients should be monitored carefully for signs of misuse of these medications and/or relapse to drinking. Table 12-8: Treatment of Specific Conditions in the Presence of an AlcoholRelated Disorder Condition

Primary Treatment

If No Response

Panic disorder

CBT + SSRI or nefazodone

Alternative SSRI or venlafaxine

Social phobia Specific type

CBT + beta-blocker

Generalized + depression

CBT + SSRI

Generalized, no depression

SSRI or nefazodone

Post-traumatic stress disorder (PTSD)

Psychotherapy

Medications as needed

Plus depression

SSRI or nefazodone

Alternative SSRI

With related psychosis

New generation antipsychotics

Alternative antipsychotic

With severe insomnia

Trazodone

Sedating TCA

Obsessive-compulsive disorder (OCD)

SSRI

Clomipramine, if no seizures or suicidal ideation

Generalized anxiety disorder (GAD) 90% are co-morbid for panic disorder, PTSD, social phobia, or OCD

Treat any co-morbid anxiety disorders, as above

GAD + depression

SSRI or nefazodone

GAD, not depressed

CBT/relaxation therapy

Buspirone, up to 60 mg QD

Panic disorder can precede the development of an AUD and usually becomes more severe following extended drinking. Behavioral psychotherapy and antidepressants , such as imipramine and paroxetine , have proved to be effective treatments. PTSD and co-morbid AUDs are very difficult to treat. Such patients should be referred to specialized treatment programs. Improvement has been demonstrated in outpatient treatment utilizing the “seeking safety” CBT protocol (Najavits, 1998).

MDD Various tricyclic antidepressants (TCAs ) and the SSRIs have been used with some success in depressed individuals with an AUD, though there are few adequately controlled clinical trials. Nefazodone appears to have value in those individuals with a combination of anxiety and depressive symptoms, but it must be used with caution because of the risk of hepatotoxicity. It is well tolerated and rapidly normalizes sleep patterns. An excellent study showed the superiority of a combination of sertraline and naltrexone over each medication alone or placebo in the treatment of co-occurring AUD and MDD when used as an adjunct to CBT (Pettinati et al, 2010).

Bipolar Disorder Mood-stabilizing drugs can have dramatic benefits in these cases. Adequate control of manic episodes often eliminates excessive drinking. Adding valproic acid to treatment-as-usual (including lithium therapy ) reduced heavy drinking in one randomized prospective clinical trial (Salloum et al, 2005).

Schizophrenia Patients with schizophrenia do poorly in most AA groups and can be highly ambivalent about sobriety because they often use alcohol to moderate psychotic symptoms or to reduce the side effects of their antipsychotic medications. Intensive long-term substance use counseling must be provided in conjunction with comprehensive psychiatric management. There is evidence that clozapine and some other atypical anti-psychotics might reduce alcohol craving and consumption.

ADHD

The mainstay of treatment for ADHD remains pharmacotherapy, including in the presence of co-occurring AUDs. Stimulants are generally more effective at reducing symptoms of ADHD. Because of the potential for misuse, if stimulants are used, close monitoring is necessary and extended-release versions are preferable because of their lower potential for misuse (Doyle, 2006). A conservative approach might include beginning with a trial of a non-stimulant, such as atomoxetine, or high-dose bupropion (450 mg daily).

Criteria for Referral for Inpatient Alcohol Withdrawal Treatment and for Specialized LongTerm AUD Treatment Criteria for referral for inpatient alcohol withdrawal treatment include: a history of failure in outpatient withdrawal treatment, or multiple relapses; suicidal ideation or acute psychosis; a history of complicated withdrawal, including delirium tremens; and co-occurring medical problems that require frequent daily monitoring during withdrawal treatment. Criteria for referral for specialized long-term AUD treatment include: a history of multiple treatment failures; serious co-occurring psychiatric conditions (especially if they have failed to respond to initial efforts at psychiatric management); another or multiple other substance use disorders (formerly referred to as polysubstance abuse); and living in very unstable environments (e.g., being homeless).

Selected Readings 1. Addolorato G, Leggio L, Ferrulli A, et al: Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet . 2007 Dec 8; 370(9603): 1915–1922. 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition . Washington: American Psychiatric Association; 1994. 3. Anton RF, O’Malley SS, Ciraulo DA, et al: COMBINE Study Research Group: Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial.

4. 5.

6. 7. 8.

9.

10. 11.

12. 13.

14.

15. 16.

JAMA . 2006 May 3; 295(17): 2003–2017. Arnedt JT, Conroy DA, Brower KJ: Treatment options for sleep disturbances during alcohol recovery. J Addict Dis . 2007; 26(4): 41–54. Babor TF, Hofmann M, DelBoca FK, et al: Types of alcoholics, I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Arch Gen Psychiatry . 1992; 49(8): 599–608. Bein TH, Miller WR, Tonigan JS: Brief intervention for alcohol problems: a review. Addiction . 1993; 88: 315–335. Blum K, Noble EP, Sheridan PJ, et al: Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA . 1990; 263: 2055–2060. Bouza C, Magro A, Muñoz A, et al: Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: A systematic review. Addiction . 2004; 99: 811–828. Brown GL, Linnoila MI: CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin Psychiatry . 1990; 51(4, suppl): 31–41. Buydens-Branchey L, Branchy M, Noumair D, et al: Age of alcoholism onset, I & II. Arch Gen Psychiatry . 1989; 46: 225–236. Canagasby A, Vinson DC: Screening for hazardous or harmful drinking using one or two quantity-frequency questions. Alcohol & Alcoholism . 2005; 40(3): 208–213. Center for Disease Control and Prevention, reported in The Boston Globe , More babies are found to suffer fetal alcohol syndrome, April 7, 1995. Ciraulo DA, Renner, JA: Alcoholism. In Ciraulo DA, Shader RI (eds): Clinical Manual of Chemical Dependence . Washington DC: American Psychiatric Press; 1991. Cloninger CR, Bohman M, Sigvardsson S: Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch Gen Psychiatry . 1981; 38: 861–868. Cloninger CR: Neurogenic adaptive mechanisms in alcoholism. Science . 1987; 236: 410–416. Comings DE, Comings BG, Muhleman D, et al: The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA . 1991; 266: 1793–1800.

17. Doyle BB: Understanding and Treating Adults with Attention Deficit Disorder . Arlington, VA: American Psychiatric Publishing, Inc.; 2006. 18. Fals-Stewart W, O’Farrell TJ, Birchler GR: Behavioral couples therapy for substance abuse: rationale, methods, and findings. Sci Pract Perspect . 2004 Aug; 2(2): 30–41. 19. Famy C, Streissguth AP, Unis AS: Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. Am J Psychiatry . 1998; 155: 552–554. 20. Frances RJ, Timm S, Bucky S: Studies of familial and non-familial alcoholism. Arch Gen Psychiatry . 1980; 37: 564–566. 21. Friedman L, Fleming NF, Roberts DH, et al, eds.: Source Book of Substance Abuse and Addiction . Baltimore, MD: Williams and Wilkins, 1996. 22. Garbutt JC, Kranzler HR, O’Malley SS, et al: Vivitrex Study Group: Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA . 2005 Apr 6; 293(13): 1617–1625. 23. Grant BF, Dawson DA, Stinson FS, et al: The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991– 1992 and 2001–2002. Drug Alcohol Depend . 2004 Jun 11; 74(3): 223–234. 24. Grant BF, Goldstein RB, Saha TD et al: Epidemiology of DSM-5 alcohol use disorder: results from the National Epidemiologic Survey on alcohol and Related Conditions III. JAMA Psychiatry . 2015 Aug; 72(8): 757–766. 25. Jacobs GD: Say Goodnight to Insomnia . New York: Macmillan; 2009. 26. Johnson BA, Ait-Daoud N, Seneviratne C, et al: Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry . 2011 Mar; 168(3): 265–275. 27. Johnson BA: Medication treatment of different types of alcoholism. Am J Psychiatry . 2010 Jun; 167(6): 630–639. 28. Johnson BA, Roache JD, Javors MA, et al: Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial. JAMA . 2000; 284(8): 963–971. 29. Johnson BA, Rosenthal N, Capece JA, et al: Topiramate for Alcoholism Advisory Board; Topiramate for Alcoholism Study Group: Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA . 2007

Oct 10; 298(14): 1641–1651 30. Jonas DE, Amick HR, Feltner C, et al: Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and metaanalysis. JAMA . 2014; 311: 1889 31. Kessler RC, Crum RM, Warner LA, et al: Lifetime co-occurrence of DSMIII-R alcohol abuse and dependence with other psychiatric disorders in the National Co-morbidity Survey. Arch Gen Psychiatry . 1997; 54: 313–321. 32. Kessler RC, McGonagle KA, Zhao S, et al: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry . 1994; 51: 8–19. 33. Koob GF, Roberts AJ: Brain reward circuits in alcoholism. CNS Spectrums . 1999; 4: 23–33. 34. Kranzler HR, Burleson JA, Brown J, et al: Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics. Alcohol Clin Exp Res . 1996; 20(9): 1534–1541. 35. Levey D, Le-Niculescu H, Frank J, et al: Genetic risk prediction and neurobiological understanding of alcoholism. Transl Psychiatry . 2014; 4: e391. 36. Linnoila MI, Virkhunen M: Aggression, suicidality, and serotonin. J Clin Psychiatry . 1992; 53: 46–51. 37. Madras BK, Compton WM, Avula D, et al: Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: Comparison at intake and 6 month later. Drug Alc Dependence . 2009; 99(1-3): 280–295. 38. Mason BJ, Quello S, Goodell V, et al: Gabapentin treatment for alcohol dependence: a randomized clinical trial [published online November 4, 2013]. JAMA Intern Med . doi: 10.1001/jamainternmed.2013.11950. 39. Mayfield D, McLeod G, Hall P: The CAGE questionnaire: validation of a new alcoholism instrument. Am J Psychiatry . 1974; 131: 1121–1123. 40. Miller WR, Rollnick S: Motivational Interviewing: Preparing People for Changer, Second Edition . New York: The Guilford Press; 2002. 41. Moss HB, Chen CM, Hsiao-ye Y: Sub-types of alcohol dependence in a nationally representative sample. Drug Alc Dependence . 2007, 91(2-3): 149–158.

42. Moss HB, Guthrie S, Linnoila M: Enhanced thyrotropin releasing hormone in boys at risk for development of alcoholism: preliminary findings. Arch Gen Psychiatry . 1986; 43: 1137–1142. 43. Najavits LM, Weiss RD, Shaw SR, et al: “Seeking safety”: outcome of a new cognitive-behavioral psychotherapy for women with post-traumatic stress disorder and substance dependence. J Trauma Stress . 1998; 11(3): 437–456. 44. Naranjo CA, Knoke DM, Bremner KE: Variations in response to citalopram in men and women with alcohol dependence. J Psych Neurosci . 2000; 25(3): 269–275. 45. National Epidemiologic Survey on Alcohol and Related Conditions: Selected Findings, 2006; 29(2). http://pubs.niaaa.nih.gov/publications/arh29-2/toc29-2.htm . 46. National Institute of Alcohol Abuse and Alcoholism: Helping Patients Who Drink Too Much: A Clinician’s Guide . 2007. http://www.niaaa.nih.gov/ Publications/EducationTrainingMaterials/guide.htm . 47. Noble EP, Blum K, Ritchie T, et al: Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry . 1991; 48: 648–654. 48. O’Malley SS, Jaffe AJ, Chang G, et al: Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch Gen Psychiatry . 1992; 49: 881–887. 49. Osser DN, Renner JA, Bayog R: Algorithms for the pharmacotherapy of anxiety disorders in patients with chemical abuse and dependence. Psychiatr Ann . 1999; 29: 285–301. 50. Pastor A, Jones DM, Currie J: High-dose baclofen for treatment-resistant alcohol dependence. J Clin Psychopharmacol . 2012 Apr; 32(2): 266–268. 51. Pettinati HM, Oslin DW, Kampman KM, et al: A double-blind, placebocontrolled trial combining sertraline and naltrexone for treating cooccurring depression and alcohol dependence. Am J Psychiatry . 2010 Jun; 167(6): 668–675 52. Pettinati HM, Volpicelli JR, Kranzler HR, et al: Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res . 2000; 24(7): 1041–1049.

53. Pettinati HM, Weiss RD, Miller WR, et al, eds.: Medical Management Treatment Manual: A Clinical Research Guide for Medically Trained Clinicians Providing Pharmacotherapy as Part of the Treatment for Alcohol Dependence . NIAAA COMBINE Monograph Series, Vol. 2, DHHS Publication No. (NIH) 04-5289, Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism; 2004. 54. Prescott CA, Kendler KS: Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry . 1999; 156: 34–40. 55. Prochaska J, DiClemente C, Norcross J: In search of how people change. Applications to addictive behaviors. Am Psychol . 1992; 47: 1102–1114. 56. Robinson J, Sareen J, Cox BJ, et al: Role of self-medication in the development of co-morbid anxiety and substance use disorders: a longitudinal investigation. Arch Gen Psychiatry . 2011 Aug; 68(8): 800– 807. PubMed PMID: 21810645 57. Rollnick N, Heather N, Bell A: Negotiating behavior change in medical settings: the development of brief motivational interviewing. J Ment Health . 1992; 1: 25. 58. Sacks J, Gonzales K, Bouchery E, et al: 2010 National and State Costs of Excessive Alcohol Consumption. Am J Prev Med . 2015 Nov; 49(5): 73–79 59. Saitz R, Mayo-Smith MF, Roberts MS, et al: Individualized treatment for alcohol withdrawal. JAMA . 1994; 272: 519–523. 60. Salloum IM, Cornelius JR, Daley DC, et al: Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a doubleblind placebo-controlled study. Arch Gen Psychiatry . 2005 Jan; 62(1): 37– 45. 61. Sandberg GG, Marlatt GA: Relapse prevention. In: Ciraulo DA, Shader RI (eds.): Clinical Manual of Chemical Dependence . Washington DC: American Psychiatric Press; 1991. 62. Schuckit MA: Low level of response to alcohol as a predictor of future alcoholism. Am J Psychiatry . 1994; 151: 184–189. 63. Selzer ML: The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am J Psychiatry . 1971; 127: 1653–1655. 64. Shu JE, Lin A, Chang G: Alcohol withdrawal treatment in the medically

hospitalized patient: A pilot study assessing predictors for medical or psychiatric complications. Psychosomatics . 2015; 56(5): 547–555 65. Streissguth AP, Aase JM, Clarren SK, et al: Fetal alcohol syndrome in adolescents and adults. JAMA . 1991; 265: 1961–1967. 66. Sullivan JT, Syhora K, Schneiderman J, et al: Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar). Br J Addict . 1989; 84: 1353–1357. 67. Swift RM: Drug therapy for alcohol dependence. N Engl J Med . 1999; 340: 1482–1490. 68. Tarter RE, Alterman AI, Edwards K.: Vulnerability to alcoholism in men: a behavioral-genetic perspective. J Stud Alcohol . 1985; 46: 329–356. 69. Tarter RE, Hegedus AM, Goldstein G, et al: Adolescent sons of alcoholics: neuropsychological personality characteristics. Alcohol Clin Exp Res. 1984; 8: 216–222. 70. Warner LA, Kessler RC, Hughes M, et al: Prevalence and correlates of drug use and dependence in the United States: results from the National CoMorbidity Study. Arch Gen Psychiatry . 1995; 52: 219–229. 71. Weiss RD, O’Malley SS, Hosking JD, et al: COMBINE Study Research Group. Do patients with alcohol dependence respond to placebo? Results from the COMBINE Study. J Stud Alcohol Drugs . 2008 Nov; 69(6): 878– 884. PubMed PMID: 18925346 72. Whiteford H, Degenhardt L, Rehm J, et al: Global burden of disease attributable to mental health and substance use disorders: findings from the Global Burden of Disease Study. Lancet . 2013 Nov 9; 382(9904): 1575– 1586. 73. Yan J, Aliev F, Webb B, et al: Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence. Addict Biol . 2014 Jul;19(4): 708–721

CHAPTER Substance-Related Disorders: 13 Cocaine and Opioids JOHN MATTHEWS MD, MSC

KEY POINTS COCAINE Overview The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition categorizes cocaine-related disorders as: cocaine use disorder; cocaine intoxication; cocaine withdrawal; other cocaine-induced disorders; and unspecified cocaine-related disorders. Epidemiology Recent data estimates that the prevalence rate is 0.2% for 12- to 17-year-olds, and 0.3% for 18-year-olds and greater; rates are highest among those18 to 29 years old and lowest among those 45 to 64 years old. Clinical Features Signs and symptoms of cocaine intoxication include tachycardia or bradycardia; pupillary dilation; elevated or lowered blood pressure; diaphoresis or chills; nausea or vomiting; weight loss; psychomotor agitation or retardation; muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias; confusion, seizures, dyskinesias, or coma. Signs and symptoms of cocaine withdrawal include: dysphoric mood; fatigue; vivid and unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. ETIOLOGY Co-morbid psychiatric disorders contribute to the development of cocaine use disorder: patients with major depressive disorder (MDD) use cocaine to elevate their mood; patients with bipolar disorder use to sustain their highs; patients with attention deficit disorder use to help their distractibility and mood;

patients with schizophrenia use to help relieve their negative symptoms; and patients with narcissistic personality disorder use to further increase feelings of grandiosity. Differential Diagnosis Psychiatric disorders include MDD, generalized anxiety disorder, panic disorder, schizophrenia, and bipolar disorder. Other substance use disorders include amphetamines, phencyclidine, and mephedrone (bath salts). Treatment For cocaine intoxication, there are no FDA-approved antidotes; treatment is generally supportive. Use of antipsychotic medications should be avoided due to the risk of inducing seizures. There are no specific treatments for cocaine withdrawal symptoms; the symptoms begin within a few hours of discontinuation and can persist for several days. CBT and contingency management therapies have been shown to be effective in relapse prevention in randomized controlled studies (RCTs). OPIOIDS Overview The DSM-5 categorizes opioid-related disorders as opioid intoxication, opioid withdrawal, other opioid-induced disorders, and unspecified opioid-related disorders. Epidemiology In a recent study, 0.06% of the population in the United States, 12 years and older, used heroin. The same study reported that 2.1% of that same population used opioid medications in the past month for non-medical purposes. For those who seek treatment, the average period between being dependent and obtaining treatment is 2 to 3 years. Clinical Features Signs and symptoms of opioid intoxication include: initial euphoria followed by apathy; dysphoria; psychomotor agitation or retardation; impaired

judgment; pupillary constriction (or pupillary dilation due to anoxia from severe overdose); drowsiness or coma; slurred speech; and impairment in attention or memory. Signs and symptoms of opioid withdrawal include: dysphoric mood; nausea or vomiting; muscle aches; lacrimation or rhinorrhea; pupillary dilation, piloerection, or sweating; diarrhea; yawning; fever; or insomnia. Etiology There are genetic, biological, and psychosocial factors that contribute to opioid-use disorder. Twin studies have shown that monozygotic twins are more likely than dizygotic twins to be concordant for opioid dependence. It is believed by some researchers that cravings are trigged by increased activity of the HPA-axis. This is supported by evidence for glucocorticoid receptors on the VTA dopamine neurons; VTA is believed to be the reward system for all drugs of abuse. Environmental factors that increase cravings include availability of the drug; alienation from social institutions; social deviancy; high unemployment; and impulsivity. Conditioned cues include: people; neighborhoods; paraphernalia; and situations. Differential Diagnosis Alcohol and sedative-hypnotic intoxication and opioid-induced disorders (e.g., depressive disorder) resemble opioid intoxication. Treatment Acute intoxication of an opioid does not generally require any treatment. However, with ingestion of a large amount, resulting in respiratory depression and coma, naloxone 0.4 mg IV should be administered; if there is no response in 2 minutes, naloxone 0.8 mg IV can be repeated twice more, 5 minutes apart. There are three strategies used for opioid detoxification: methadone, buprenorphine/naloxone, and clonidine. Methadone and buprenorphine/naloxone are used for opioid substitution maintenance treatment. A methadone dose between 70 and 80 mg/d is needed to block opioid cravings and drug use. Buprenorphine/naloxone is typically dosed in a range from 12 mg/3 mg to 16 mg/4 mg per day.

During pregnancy, buprenorphine (without naloxone) has been shown to exhibit fewer complications of neonatal abstinence syndrome compared with methadone. Extended-release naltrexone was recently FDA-approved for opioid-use disorder; it is given monthly in an injectable formulation. RCTs have demonstrated that cognitive-behavioral therapy and contingency management behavioral approaches are effective in relapse prevention for opioid-use disorder.

Cocaine-Related Disorders The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) categorizes cocaine-related disorders as: cocaine use disorder; cocaine intoxication; cocaine withdrawal; other cocaine-induced disorders; and unspecified cocaine-related disorder.

Cocaine Use Disorder Cocaine use disorder involves at least two areas: use was in larger amounts or for longer periods than was intended; a persistent desire (or failure) to cut down or control use; extended periods obtaining, using, and overcoming the effects cocaine; presence of cravings to use cocaine; use results in failure to fulfill role obligations at work, school, and home; continued use in spite of social or interpersonal problems created or exacerbated by use; reduction in social, occupational, or recreational activities due to use; continued use in hazardous situations; continued use despite an awareness that it is the cause of persistent physical or psychological problems; development of tolerance, i.e., the need to increase the amount of use to attain intoxication or the desired effect; and cocaine withdrawal symptoms or the need to take cocaine to avoid withdrawal symptoms.

Cocaine Intoxication Criteria for cocaine intoxication involves: problematic behavioral or psychological manifestations (e.g., euphoria or affective blunting, changes in sociability, hypervigilance, interpersonal sensitivity, anxiety, tension or anger, stereotyped behaviors, impaired judgment) that occur during or shortly after use. It is also accompanied by two or more of the following during or shortly following use: tachycardia or bradycardia; pupillary dilation; elevated or

lowered blood pressure; diaphoresis or chills; nausea or vomiting; weight loss; psychomotor agitation or retardation; muscular weakness, respiratory depression, chest, pain, or cardiac arrhythmias; confusion, seizures, dyskinesias, or coma.

Cocaine Withdrawal Cocaine withdrawal occurs within hours or days after cessation of heavy and prolonged use. It is manifest by dysphoria along with at least two of the following: fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.

Other Cocaine-Induced Disorders Cocaine-induced disorders include cocaine-induced psychotic disorder; cocaine-induced bipolar disorder; cocaine-induced depressive disorder; cocaineinduced anxiety disorder; cocaine-induced obsessive -compulsive disorder (OCD); cocaine-induced sexual dysfunction; and cocaine-induced sleep disorder.

Unspecified Cocaine-Related Disorder This refers to a clinical presentation that does not meet the full criteria for a cocaine-related disorder but causes significant distress or impairment in social, occupational, or other important areas of functioning.

Pharmacology of Cocaine Cocaine comes in different forms and can be administered by different routes of administration. Cocaine hydrochloride (oral) is a powder with a wide range of purity (20%– 80%); its bioavailability is 20% to 30%. When taken orally, the average dose is 100 to 200 mg, with an onset of action in 10 to 30 minutes, and its duration of action is 45 to 90 minutes. When cocaine hydrochloride is taken intranasally, it has a bioavailability of 20% to 30%; the average dose is 30 mg, and its onset of action is 2 to 3 minutes, whereas its duration of action is 30 to 45 minutes. Cocaine hydrochloride can be dissolved in water to produce an intravenous (IV) form. This form is particularly potent because it’s bioavailability is 100%. The average dose is 25 to 50 mg and its onset of action is 30 to 45 seconds, whereas its duration of action is 10 to 20 minutes. When combined with heroin, it forms a mixture known as a “speedball.”

Cocaine alkaloid is separated from its hydrochloride base by heating it with ether, ammonia, or some other solvent that produces a smokable form called “freebase.” The purity of this form is 90% to 100%. The average dose is 60 to 250 mg, whereas its onset of action is 10 seconds, and its duration of action is 5 to 10 minutes. A mass-produced and low-cost form of freebase is “crack”—the name comes from the cracking sound it makes when heated.

Metabolism of Cocaine Cocaine has a half-life of less than 60 minutes. It is metabolized in the liver to benzoylecgonine, which can be detected in the urine for up to 36 hours after acute use and more than a week after heavy daily use.

Impact on Neurotransmitters Cocaine blocks the uptake of dopamine (DA ), serotonin (5-HT ), and norepinephrine (NE ) from each of their neuron terminals by binding to the presynaptic transporter complexes. The reinforcing properties of cocaine are believed to be mediated by enhanced neurotransmission through the mesolimbic DA pathway. In animal studies: the reinforcing effects of cocaine correlate with its affinity to DA transporters, but not NE or 5-HT transporters; there is a dosedependent correlation between DA concentrations in the nucleus accumbens and self-administration of cocaine. In human studies using positron emission tomography (PET), the intensity of self-reported euphoria correlates with the occupancy of the DA transporter by cocaine. (Haney, 2008) With prolonged use of cocaine, there is a depletion of DA in the terminals of the DA neurons, which is thought to contribute to the presence of low mood.

Physical and Psychological Effects of Cocaine Use The acute physical and psychological effects of cocaine include: vasoconstriction; increased heart rate; increased blood pressure; euphoria; increased energy; heightened alertness and sensory awareness; increased anxiety; increased self-confidence; decreased appetite; increased sexual excitement and spontaneous ejaculation; and increased risk for psychosis. With chronic use of cocaine, many individuals develop depression, irritability, agitation, lack of motivation, insomnia, panic attacks, hypervigilance, paranoia, and hallucinations. The long-term effects of cocaine might be due to neurotransmitter depletion.

Co-Morbid Substance Use

Sedating substances, such as alcohol, are frequently used to combat the stimulating effects of cocaine and to prolong cocaine’s euphoria. Alcohol combines with cocaine to produce cocaethylene which has similar neurochemical, pharmacological, and behavioral properties as cocaine. However, cocaethylene is believed to have more cardiac toxicity.

Epidemiology of Cocaine Use Historical Trends In the 1970s, cocaine was considered to be a safe and non-addictive drug. Cocaine use peaked in 1978 at 25% in the general population; however, use has dropped since then. Reasons provided for the reduction in use included education about the detrimental effects of cocaine, promotion of better health, and the need to be competitive in today’s society. Data from the National Institute of Drug Abuse (1997) demonstrated that 55% of drug-abusing patients, mostly in outpatient treatment programs, were dependent on cocaine. Since then, admissions to substance-abuse treatment centers have declined (DASIS Report, 2007). More recent data reveals that the prevalence rate is 0.2% for 12- to 17-year-olds, and 0.3% for 18-year-olds and greater; rates are highest among 18- to 29-year-olds, and lowest among 45- to 64-year-olds.

Social Impact Cocaine use continues to be a serious problem among the disadvantaged who have easy access to the drug. Crack has become very affordable; vials cost as little as $10. Cocaine use is more prevalent among African-Americans and is associated with violence and the transmission of AIDS. When compared to other drugs of abuse, cocaine accounted for more frequent emergency room visits nationwide, with 76 visits per 100,000 of the population. In addition, cocaine is associated with reckless driving, suicide, homicide, violence, and premature deaths (Gold and Jacobs, 2005).

Patterns of Cocaine Use There are two primary patterns of use: episodic and daily use. Binges are a type of episodic use during which large amounts of cocaine are consumed within a few hours or a few days. Binges end when cocaine supplies are depleted or it is no longer tolerated.

Daily use of cocaine generally progresses from small amounts to large amounts due to the development of tolerance to the euphoric effects of cocaine. Intranasal use tends to lead to more gradual progression from use to abuse or dependence over months to years, whereas IV administration and smoking the drug tends to show a progression to dependence over weeks to months.

Co-Morbid Psychiatric Disorders The rate for any psychiatric disorder (excluding other substance abuse) in cocaine-abusers who seek treatment is 50%; the lifetime prevalence is 80%. Among cocaine abusers, the rates for a life-time diagnoses of major depressive disorder (MDD), dysthymic disorder, or bipolar disorders are 50%, 25% to 50%, and 25%, respectively (Gold and Jacobs, 2005).

Cocaine Use in Co-Morbid Psychiatric Disorders Many cocaine-dependent patients with co-morbid psychiatric disorders use cocaine to self-medicate their psychiatric symptoms—depressed patients use to elevate their mood; bipolar patients use to sustain their highs; patients with attention deficit disorder use to reduce their distractibility and enhance their mood; patients with schizophrenia use to help relieve their negative symptoms; and patients with narcissistic personality disorder use to increase feelings of grandiosity. Patients with anxiety disorders, especially panic disorder, tend to avoid cocaine because it heightens anxiety and can trigger panic attacks.

Use of Other Substances Other substances of abuse , such as alcohol, marijuana, benzodiazepines, and opiates, are associated with cocaine abuse and dependence. Alcohol, marijuana, and benzodiazepines are often used to treat the stimulatory effects of cocaine, whereas opiates are used to enhance the euphoric effect of cocaine.

Medical Complications Associated with Cocaine Use Cardiovascular Cocaine causes adrenergic stimulation that can elevate blood pressure and induce tachycardia, arrhythmias (supraventricular and ventricular), atrioventricular nodal conduction block, and corrected QT interval (QTc) prolongation. It also can cause vasospasm in coronary arteries. Adrenergic stimulation, and an increase in the oxygen demand of the heart, in combination with coronary artery vasospasms, can lead to myocardial infarction.

Central Nervous System Cocaine causes vasospasm in cerebral vasculature and can lead to cerebral vascular accidents acutely as well as multi-focal infarcts (with prolonged use). Single-photon emission computed tomography (SPECT) has demonstrated significant hypoperfusion in frontal and temporal-parietal areas among chronic cocaine users. These findings correlate with cognitive impairment (e.g., diminished concentration, attention, and memory, as measured by neuropsychological testing). These cognitive deficits can persist after abstinence is achieved in chronic cocaine abusers. Cocaine also can induce seizures, either after single or repeated use by a phenomenon called kindling .

Respiratory System Cocaine-induced respiratory features include hemoptysis, fever, productive cough, and chest pain due to the buildup of carbon monoxide. Respiratory disorders secondary to cocaine use include asthma, pneumonia, pneumothorax, pneumomediastinum, pneumopericardium, pulmonary edema, and respiratory depression and sudden death. “Crack lung” is a potentially fatal eosinophilic pneumonitis manifest by fever, shortness of breath, chest pain, and pneumonia. It is treated with anti-inflammatory medications and corticosteroids.

Other Systems Chronic intranasal use of cocaine can cause necrosis of the nasal septum due to its vasoconstricting effects. Cocaine binges can result in dehydration, malnutrition, and weight loss. IV cocaine use can lead to vasculitis, endocarditis, granulomas, hepatitis B and C, HIV infection, pulmonary emboli, and septicemia due to contaminants in the injection solution.

Use During Pregnancy Due to its vasoconstriction properties, cocaine increases the risk of fetal hypoxia and placental abruption. Cocaine readily crosses the placenta and can induce toxic effects on the fetus; echocardiograms reveal left ventricular hypertrophy in the fetus. Cocaine can cause fetal growth retardation, reduced head circumference, decreased birth weight, congenital anomalies, malformations of the urogenital system, central nervous system (CNS) irritability (“jittery baby”), attentional problems, cerebral vascular accidents, and death. Cerebral vasoconstriction and hypoxia can interfere with brain development. Cocaine is found in breast milk up to 60 hours after use.

Symptoms observed in babies who ingest cocaine from breast milk include rapid heart rate, increased blood pressure, apnea, diaphoresis, and mydriasis.

Treatment of Cocaine Use Treatment Settings Treatment in the least restrictive environment should be arranged so that family, social, and occupational responsibilities are disrupted as little as possible. Most patients can be effectively treated in an outpatient setting; however, patients with complicated psychosocial, psychiatric, or medical problems might require a more structured environment. Criteria for inpatient treatment (Washton, 1986) include: lack of motivation to participate in an intensive outpatient program; significant psychological, cognitive, or neurological deficits; serious co-morbid psychiatric or medical problems; several failed attempts at outpatient and partial hospital treatments; lack of a support network; use of highly addictive crack, freebase, or IV cocaine; significant dependence on alcohol and/or other substances of abuse; or the risk for aggressive behaviors towards self, others, or property.

Intoxication There is no specific antidote for cocaine intoxication. Treatment is generally supportive. Benzodiazepines can be helpful to treat aggressive or agitated behavior. Patients with a paranoid psychosis should not be treated initially with an antipsychotic medication because of the risk of seizures. Their psychosis generally resolves within hours to days (3 to 5). If the psychosis continues, the diagnosis should be reconsidered and an antipsychotic started. Although cocaine increases the risk for seizures, prophylactic use of anticonvulsants has not been shown to be beneficial.

Withdrawal There is no specific treatment for cocaine-associated withdrawal symptoms. The symptoms begin within several hours of discontinuing cocaine use and may persist for several days. Dopamine agonists, bromocriptine and amantadine, were initially used to treat cocaine withdrawal and cravings, but recent studies have failed to support their use.

Relapse Prevention

Cognitive-behavioral therapy (CBT ) helps patients identify their internal (e.g., emotions) and external (e.g., situations, people, places, things) cues that activate addictive beliefs (“The only way I can have fun is to get high”), which trigger cravings to use. After cravings and urges are activated, permissive beliefs (“I can stop after one smoke”) and rationalizations to use are realized; permissive beliefs lead to strategies (“I’ll drive to Bill’s to buy crack”) to use. The therapist helps the patient to challenge the validity of his or her addictive and permissive beliefs. A behavioral approach using contingent vouchers has been particularly effective in keeping patients in treatment and maintaining abstinence. In this approach, patients earn vouchers to purchase predetermined items (e.g., books, social events with their family) provided that they maintain clean urines (Higgins and Silverman, 2008).

Self-Help Groups Cocaine Anonymous (CA ) is a twelve-step program modeled after Alcoholics Anonymous. A recent study of day hospital cocaine-abusing patients showed that ongoing participation in self-help groups at 3 months predicted less cocaine use at 6 months post-treatment.

Pharmacological Treatments Pharmacological treatment is not indicated for cocaine dependence; there are no FDA-approved medications for the treatment of cocaine dependence. Pharmacological treatments that target the subjective effects of cocaine and the reduction of the symptoms from cocaine abstinence have been mixed. Multiple methodological problems (e.g., differences in patient populations, absence of controls, differences in psychosocial interventions, differences in routes of cocaine administration, and inconsistent outcome measures) have plagued clinical studies. Dopamine agonists (e.g., amantadine, bromocriptine) and tricyclic antidepressants (e.g., desipramine) initially showed promise in treating cocaine dependence, but more recent studies have failed to confirm earlier findings. However, use of antidepressants in depressed cocaine-dependent patients leads to reduced cocaine use if their depressive symptoms improved (Kosten and Ciraulo, 2005). Some of the ongoing problems in the development of the cocaine vaccine include determining the contributing factors for the large variability in antibody response across individuals, improving on vaccine booster schedules, finding the most effective immunogenic carrier protein, and determining the optimal place of attachment of the carrier protein on the cocaine molecule (Kinsey et al, 2010).

DSM-5 Opioid Use Disorders The DSM-5 categorizes opioid-related disorders as: opioid use disorder; opioid intoxication; opioid withdrawal; other opioid-induced disorders; and unspecified opioid-related disorders.

Opioid Use Disorder This involves impairment or distress in at least two areas within a 12-month period: use in larger amounts or for longer periods than was intended; a persistent desire or failure to cut down or control use; extended periods obtaining, using, and overcoming the effects opioids; presence of cravings to use opioids; use results in failure to fulfill role obligations (at work, school, and home); continued use in spite of social or interpersonal problems created or exacerbated by use; reduced engagement in significant social, occupational, or recreational activities due to use; continued use in hazardous situations; continued use despite awareness that use causes persistent physical or psychological problems; development of tolerance; and withdrawal or the need to take opioids to avoid withdrawal symptoms. In addition, there are four specifiers: early remission, late remission, in a controlled environment, and current severity.

Opioid Intoxication Criteria for opioid intoxication include: recent use of an opioid; problematic behavioral or psychological changes (e.g., initial euphoria followed by apathy; dysphoria; psychomotor agitation or retardation; impaired judgment) during or shortly after use; pupillary constriction with drowsiness, slurred speech, impairment in attention or memory, or coma.

Opioid Withdrawal Withdrawal occurs in the context of either cessation (or reduction) of the opioid or the administration of an opioid antagonist in the presence of heavy and prolonged opioid use (several weeks or longer), manifest by the development of more than three of the following: dysphoric mood; nausea or vomiting; muscle aches; lacrimation or rhinorrhea; pupillary dilation, piloerection, or sweating; diarrhea; yawning; fever; or insomnia.

Other Opioid-Induced Disorders

Other opioid-induced disorders include: opioid–induced depressive disorder; opioid–induced anxiety disorder; opioid–induced sleep disorder; and opioid– induced sexual dysfunction. These disorders are diagnosed instead of opioid intoxication or opioid withdrawal only when the symptoms are in excess of those usually associated with the opioid intoxication or withdrawal syndrome and when the symptoms are sufficiently severe to warrant independent clinical attention.

Unspecified Opioid-Related Disorder This refers to a clinical presentation that does not meet the full criteria for one of the opioid-related disorders or any of the disorders in the substance-related and addictive disorders diagnostic class but causes significant distress or impairment in social, occupational, or other important areas of functioning.

Opioid Pharmacology Opioid Receptors Opioids bind to three types of receptors in the brain, which are referred to as mu , delta , and kappa . When activated, mu and delta receptors influence mood, reinforcement, analgesia, respiration, blood pressure, gastrointestinal function, and endocrine functions; whereas, kappa receptors, produce dysphoria and analgesia. Receptor sub-types (mu1 , mu2 , kappa1 , and kappa2 ) have been identified, but their specific functions have yet to be determined. Opioids are categorized by how they can bind and activate receptor types: agonists readily bind to and activate receptors; antagonists readily bind to but do not activate receptors; and partial agonists bind to receptors but only activate them to a limited extent and they might also block receptors from occupation by other agonists or antagonists. Morphine, methadone , fentanyl, and sufentanil are primarily pure mu receptor agonists; buprenorphine and pentazocine are partial agonists; and naloxone and naltrexone are pure antagonists. Opioid receptors are located throughout the CNS, parts of the autonomic nervous system, and the gastrointestinal (GI) system. When CNS receptors are activated, individuals experience tranquillity, analgesia, cough suppression, respiratory depression, pupillary constriction, changes in temperature, and reduced apprehension. Activation of GI receptors results in nausea, constipation, and vomiting. Opioids can also effect bladder function by increasing sphincter tone and interfering with voiding reflexes, thus resulting in urinary retention.

Some opioids, methadone in particular, can cause QTc prolongation, which puts patients at risk for torsades de pointes. The positive reinforcing effects of opioids are mediated through the ventral tegmental area (VTA) DA projections to the nucleus accumbens and through direct effects of mu and delta agonists on neurons in the nucleus accumbens. Mu and delta agonists also inhibit g -aminobutyric acidA (GABAA ) interneurons that normally tonically inhibit VTA DA cells. The net effect of mu and delta agonists is to increase VTA DA cells firing rates, which results in an increased release of DA in the nucleus accumbens.

Urine Testing Opioids are measured in blood, urine, saliva, and hair. Heroin is measured as morphine in urine. Most short-acting opioids are detected in the urine 12 to 36 hours after they are administered. Routine urine screens do not detect meperidine, fentanyl, and oxycodone. Poppy seeds contain small amounts of morphine and codeine, which can result in false-positive urine tests for opioid abuse.

Epidemiology of Opiate Abuse In a recent survey ( Substance Abuse and Mental Health Services Administration [SAMHSA], 2008), heroin was used by 153,000 or 0.06% of the population in the United States, age 12 years and older. The same survey reported by SAMHSA (2008) noted that 5.2 million individuals, or 2.1% of the same population, again 12 years and older, had used pain medications in the past month for non-medical purposes. Most opioid-dependent individuals do not receive treatment. For those who seek treatment, the average time between becoming dependent and obtaining treatment is 2 to 3 years. A relatively new controlled-release formulation of oxycodone , Oxy-Contin, has received much attention among addiction and pain specialists. It was introduced to the market in the early 1990s and it has been particularly popular among adolescence and young adults addicted to opioids. When it is chewed, a large dose of oxycodone is released that provides a marked but potentially lethal high. Pain patients treated with Oxy-Contin report having difficulty tapering off the drug and some have developed an opiate addiction. Abuse of prescription opioids has been on the rise since 1999; there has been a 300% increase in the sales of opioid pain medications in the United States. Death rates from opioid pain medications quadrupled from 1999 to 2010. This surge in

deaths was more than for heroin and cocaine combined. In 2011, the Centers for Disease Control and Prevention (CDC) reported that half of the prescription opioid-related deaths occurred in combination with other drugs (including heroin, cocaine, alcohol, and benzodiazepines). The recent opioid epidemic has lead to a national prevention program aimed at educating physicians on safe prescribing practices of opioids. Access to naloxone by law enforcement has been initiated in some states to reverse the potential lethal consequences of opioid overdoses.

Course of Opiate Use Studies examining patterns of use in adolescents and young adults have discovered a progression of drug use beginning with cigarettes, alcohol, marijuana, and eventually opioids. The onset of opioid abuse tends to be in the teens and early twenties. After opioid dependence develops, the course is generally longstanding with frequent lapses and relapses. Even after long periods of incarceration, relapse rates are high. According to some experts, the average duration of active opioid addiction is 9 years. However, in a 33-year follow-up study of 581 opioid addicts (Hser et al, 2001), only 25% were able to achieve abstinence, and less than 6% were in any treatment during most of that time.

Etiological Factors Associated with Opiate Use Not everyone who experiments with opioids develops abuse or dependence. According to the National Co-Morbidity Survey (1994), 7.5% of individuals who used any opioids for non-medical purposes and 23% of individuals who used heroin eventually developed opioid dependence. There are genetic, biological, and psychosocial factors that contribute to opioid dependence.

Genetic and Biological Factors Animal studies demonstrate that various strains of rodents exhibit differences with regard to their ability to learn opioid self-administration behavior and to their sensitivity to the effects of opioids. In humans, family members of opioid addicts exhibit higher rates of addictive disorders and psychiatric disorders. Twin studies have shown that monozygotic twins are more likely than dizygotic twins to be concordant for opioid dependence. Environmental stress can sensitize animals to self-administer opioids. Corticotropin-releasing factor (CRF), a peptide important in the brain’s response to environmental stress, can stimulate opioid-seeking behavior in opioid-

dependent animals, whereas CRF antagonists can reduce stress-related opioid self-administration. There is evidence that corticosteroids can sensitize animals to self-administer opioids and that they also increase the sensitivity of the VTA DA neurons to excitatory input. In addition, those who are physically dependent on heroin have high serum levels of glucocorticoids during withdrawal, and they have increases in adrenocorticotropic hormone (ACTH) prior to their withdrawal symptoms. This increase of hypothalamic-pituitary-adrenal (HPA) axis activity is thought by some researchers to trigger cravings for opioids in opioiddependent individuals via the VTA DA system; to support this hypothesis, glucocorticoid receptors have been found on VTA DA neurons. Perceived environmental stressors might be influencing drug-seeking behavior through increases in corticosteroids and through increases in VTA activity via excitatory input from prefrontal cortical areas. The development of tolerance and withdrawal symptoms are additional biological factors that maintain opioid addiction. This applies particularly to heroin and to other short-acting opioids. With heroin, addicts can experience withdrawal several times a day due to its short half-life; thus, repeated heroin use to diminish or stop withdrawal symptoms becomes a powerful positive reinforcer for continued use.

Psychosocial Factors The self-medication hypothesis proposed by Khantzian argued that there is a strong relationship between the type of dysphoric state and one’s drug preference. Khantzian emphasized the “anti-rage” properties of opioids. In adolescents, risk factors for the development of opioid dependence include: marijuana abuse; symptoms of depression; lack of a close relationship with parents; single parent families; poor schools and leaving school. Other risk factors include availability of opioids, alienation from social institutions, social deviancy, high unemployment, and impulsivity. Opioid addicts tend to score low on sensation-seeking, and they tend to avoid excessive internal and external stimulation. Conditioned cues (which include people, neighborhoods, paraphernalia, and situations) can increase cravings. Studies suggest that the cues associated with use tend to create more intense urges to use than cues associated with opiate withdrawal (Epstein et al, 2005).

Co-Morbid Psychiatric Disorders

Studies show that 80 to 90% of opioid-addicted individuals carry a life-time diagnosis of a psychiatric disorder. MDD (25% current and 50% lifetime) and antisocial personality disorder (25%–40%) are the two most common co-morbid psychiatric disorders in opioid-dependent individuals. There is also an increased risk of post -traumatic stress disorder (PTSD) in both women and men addicted to opioids; the life-time prevalence for women is 20%, and 11% for men (Villagomez et al, 1995). Children and adolescents with conduct disorder are also at greater risk of developing substance abuse problems, especially opioid dependence. Addicted individuals who seek treatment have more depression and anxiety, lower levels of social functioning, and more drug-related legal problems than those who are untreated and addicted to opioids. Biopsychosocial complications of opioid abuse appear to encourage addicted individuals to seek out treatment earlier. It can be difficult to distinguish the difference between a primary mood disorders from an opioid-induced mood disorder. Chronic use of opioids can cause symptoms consistent with the diagnosis of MDD. Finally, addicted individuals also experience severe psychosocial complications from chronic opioid use, hence, the need for psychosocial interventions. The diagnosis of antisocial personality disorder is questionable in the context of opioid addiction unless antisocial behaviors predated the onset of the addiction; addictive disorders in general tend to promote antisocial behaviors.

Medical Complications of Opiate Use Intravenous Complications The most common injectable opioids are heroin, hydromorphone, and meperidine. Heroin is sold on the streets in “bags” and there is a wide variability of purity and potency. Contamination, both chemical and microbial, of the injectable opioid contributes to multiple medical complications. Chemical contaminants include talc, starch, and quinine (used as adulterants) and cotton (used as a filter), whereas the primary microbial contaminants include Staphylococcus aureus , Beta-hemolytic streptococci, and anaerobes. Some of the most common medical complications include cellulitis; skin abscesses; endocarditis; septic arthritis; hepatitis A, B, C, and D; osteomyelitis; nephropathy; rhabdomyolysis; pulmonary emboli, pulmonary hypertension; pneumonia; meningitis; brain abscess; tuberculosis; and HIV infection.

Liver Disease

Studies using serological testing show that two-thirds of IV drug users have been exposed to hepatitis B and C. According to the CDC (1998), 79% of IV drug users in the United States are infected by hepatitis C; between 75% and 85% of these cases will become chronic, 20% will develop cirrhosis, and 1% to 5% will die annually from chronic liver disease. In many states, hepatitis C has surpassed AIDS as being the most common cause of death in methadone clinic patients (Epstein et al, 2005).

Pulmonary Disease Talc and cotton can cause granulomatous pulmonary reactions. Heroin is known to cause pulmonary edema but the mechanism is unclear. The common causes of pneumonia include Hemophilus influenzae and Streptococcus pneumoniae . Tuberculosis (TB) is on the increase in IV drug users, thus TB must be considered in the presence of pulmonary infiltrates. One study showed that one-fourth of IV drug users had latent TB. The antitussive property of opioids contributes to respiratory infection and to pneumonia.

Cardiac Disease Endocarditis occurs in 0.2% of addicted individuals in a 12-month period. Contaminated needles and opioids cause endothelial damage on heart valves followed by platelet fibrin deposition and bacterial infection. S. aureus is the most common infectious agent followed by Streptococcus. Right-sided endocarditis can result in pulmonary emboli, which are generally not fatal, whereas left-sided endocarditis can result in systemic emboli, which can lead to death.

Renal Disease IV heroin use can lead to focal or diffuse glomerulosclerosis, which can progress to nephrotic syndrome and end-stage renal failure. Hematuria and proteinuria are found on urinalysis. Frequently occurring skin abscesses and ulcerations can result in renal amyloidosis.

HIV Infection Studies of individuals receiving treatment in methadone clinics found that between 29 and 57% of IV drug users were HIV-positive (Brown et al, 1993; Des Jarlais et al, 1998). Twenty-eight per cent of individuals with new-onset HIV infections use IV drugs, including opiates (Cooper et al, 2003). Infants born HIV-positive can have clinical features similar to fetal alcohol syndrome.

Pregnancy and Opioid Use For the past 30 years, it has been common practice to place pregnant opioiddependent women on methadone maintenance. The dose of methadone needs to be high enough to block cravings and illicit opioid use yet low enough to decrease the risk for neonatal abstinence syndrome (NAS ) at the time of delivery. The appropriate dosing of methadone is complicated because of the impact of pregnancy on the metabolism and distribution of methadone in the mother. During the course of pregnancy, there is an increase in methadone plasma elimination rate and decreased half-life due to a combination of an increased volume of distribution and increased maternal liver metabolism; there is also increased placental and fetal metabolism (Schottenfeld, 2008). These observations are even more important in the third trimester with increasing blood volumes (Saxon and Miotto, 2011). Thus, it might be necessary to increase the dose of methadone and to give it in divided daily doses. Trough methadone blood levels between 0.2 and 0.4 mg/L should reduce the risk of illicit opioid use and prevent withdrawal; withdrawal puts the fetus at serious risk of being aborted (Schottenfeld, 2008). Upon delivery, the associated withdrawal symptoms of NAS include hyperactivity, hyperactive reflexes, increased muscle tone, diaphoresis, a high-pitched cry, yawning, insomnia, decreased eating, tremor, and mottling. A few neonates experience more severe withdrawal symptoms, including seizures, vomiting, diarrhea, and fever. Perinatal mortality rates are about 7% for neonatal deaths and 4% for stillbirths. Methadone is secreted in breast milk; a study by (Begg et al, 2001) found that 2% to 3% of the maternal methadone dose is found in the infant’s blood. There is controversy regarding whether mothers should breast feed while on methadone, but some experts support breast-feeding provided that the mother is not taking illicit drugs.

Treatment of Opiate Use Intoxication Acute intoxication does not generally require treatment. With ingestion of large amounts of opioids resulting in respiratory depression and coma, hospital treatment is required. Life supports including a ventilator are essential. The respiratory depression can be reversed by naloxone 0.4 mg IV; if there is no response within 2 minutes, naloxone 0.8 mg IV can be repeated twice more, 5 minutes apart. Signs of a response to naloxone include: increased respirations, increased blood pressure, and reversal of constricted pupils. Depending on the

half-life of the opioid used, naloxone needs to be continued until the effects of the opiate abate. For short-acting opioids like heroin, the crisis resolves in about 4 hours; however, for long-acting opioids, such as methadone or L-alphaacetlymethadol (LAAM), hospitalization might be required for up to 48 hours.

Approaches to Detoxification There are three commonly used strategies for opioid detoxification : methadone, buprenorphine/naloxone, and clonidine.

Methadone Methadone has a long half-life (24–36 hours) which provides for a smoother withdrawal off opioids. Some clinicians believe that it should be used only for detoxification off more-addictive substances (such as heroin, morphine, meperidine, or hydromorphone). For less-addictive opioids (such as codeine, oxycodone, propoxyphene or pentazocine), simply tapering the dose or using clonidine is the best strategy. The starting dose of methadone can vary between 10 and 20 mg/d. Doses of methadone of 30 mg/d and above in a patient who is not opioid-dependent can be lethal; thus, the initial dose should not exceed 20 mg daily and the total 24-hour dose in the subsequent few days should not exceed 30 mg. For inpatient settings, it is ideal to split the dose for better monitoring for potential dangerous dosing. Signs of a dangerous dose include sedation, impaired motor function, hypothermia, nausea, and miosis; these symptoms might not surface for 1 to 3 days because of methadone’s long halflife. It might take a few days to determine the stabilizing dose of methadone (based on signs and symptoms of withdrawal) before starting the taper. Patients who are being detoxified off opioids for medical purposes and for whom there is accurate documentation of narcotic doses, equivalent dose tables for methadone and the narcotic being used are available. (Polydorou and Kleber, 2008). However, according to Epstein et al. (2005), caution should be used when relying on equivalency tables because equivalent doses of oral methadone vary markedly across studies. For example, the equivalent dose of morphine for methadone 1 mg ranged from 2.5 mg to 14 mg depending on the study. Adjusting methadone dose should be based on objective signs of withdrawal. Poldorou and Kleber (2008) recommend two approaches to detoxification; either decreasing by 5 mg daily until 0 mg is reached or decreasing by 10 mg daily until 10 mg/d is reached and then reduced by 2 mg daily. The former approach might be best for individuals with a severe addiction and who are starting at a methadone dose

greater than 50 mg/d. For outpatients, the dose should be tapered at a rate of 10% per week until a dose of 20 mg/d is achieved, and then proceed at a rate of 3% per week for the remainder of the detoxification. Outpatients are more likely to relapse during the detoxification due to the availability of opioids; thus, it is important to provide a more comfortable taper. Patients tend to tolerate the taper to 20 mg/d, but below 20 mg/d, they express more sensitivity to withdrawal symptoms and significant fears of being off opioids. For the long-acting opioids (methadone and LAAM) that have been used for long periods in a methadone program, a gradual detoxification over a period up to 180 days (in a licensed facility) has been shown to put the patient at less risk for relapse.

Buprenorphine Buprenorphine is a partial mu receptor agonist and a kappa receptor antagonist. It has a high affinity for the mu receptor and a slow dissociation constant; thus, it readily displaces other opiates from the mu receptor. For this reason, care must be taken when initiating detoxification or maintenance treatment in order to avoid precipitating opiate withdrawal. Although it is less likely to precipitate withdrawal compared with an opiate antagonist (e.g., naloxone), there are conditions for which buprenorphine-related precipitated withdrawal have been reported. Thus, buprenorphine induction should not be initiated without the presence of withdrawal symptoms and without a delay of more than 12 hours after the last dose for short-acting opiate and more than 24 hours after the last dose of methadone. In 2002, sublingual formulations of buprenorphine (Subutex) and buprenorphine/naloxone (Suboxone) were approved by the US Food and Drug Administration (FDA) for detoxification and for maintenance treatment of opioid dependence. The combination formulation of buprenorphine/naloxone is in a 4:1 ratio; it comes in two doses, 2 mg/0.5 mg and 8 mg/2 mg. In 2010 a new film strip formulation of buprenorphine/naloxone was introduced. Naloxone was added to help prevent diversion of buprenorphine by injection. When buprenorphine/naloxone combination is injected, the naloxone can precipitate withdrawal in individuals who are dependent on opioids. However, because naloxone has minimal absorption via the sublingual route of administration, there is no risk of it precipitating withdrawal for patients who are being detoxified off opioids or who are engaged in maintenance therapy. The advantages of buprenorphine for opioid detoxification and opioid substitution

therapy are its long half-life (24–36 hours), no known effect on the QTc interval, and safety due to being a partial mu receptor agonist; this latter property provides a “ceiling effect” on respiratory depression. Buprenorphine is metabolized in the liver by CYP450 3A/4 enzyme system; thus, the coadministration of it with inducers, substrates, or inhibitors of CYP450 3A/4 should be avoided. Buprenorphine/naloxone detoxification for short-acting opioids is started after objective signs of withdrawal are observed, which occurs 12 to 24 hours after last use. The initial dose of buprenorphine/naloxone is 2 mg/0.5 mg to 4 mg/1 mg with a repeat dose in 1 to 2 hours if withdrawal continues; for Day 1, the maximum dose is 8 mg/2 mg. If the patient is still in withdrawal on Day 2, one should give the Day 1 dose plus 2 mg/0.5 mg to 4 mg/mg every 1 to 2 hours, for a maximum total Day 2 dose of 12 mg/3 mg. (Epstein et al, 2005) Patients are generally stabilized on 8 mg/2 mg–12 mg/3 mg daily before tapering off buprenorphine/naloxone. After the patient is stabilized, buprenorphine is often tapered over 1 to 2 weeks. For patients who are dependent on methadone, buprenorphine/naloxone is not initiated until the dose of methadone is reduced to ≤ 30 mg daily and the patient is showing mild to moderate signs of withdrawal, and a ≥ 36 hours has lapsed after the last dose of methadone. The initial dose of buprenorphine/naloxone is 2 mg/0.5 mg with repeat doses every 1 to 2 hours, based on symptoms of withdrawal, to a total dose of 8 mg/2 mg on Day 1. On Day 2, if the patient continues to show signs of withdrawal, one should repeat the Day 1 dose and add 2 mg/0.5 mg to 4 mg/1 mg, as needed, for a maximum total dose of 12 mg/3 mg; monitor for over-sedation and give a lower dose. (Epstein et al, 2005) Buprenorphine is favored over methadone for detoxification by most individuals with opioid addiction.

Clonidine Clonidine is an alpha2 adrenergic agonist that reduces symptoms of opioid withdrawal by inhibiting noradrenergic hyperactivity in the locus coeruleus. There has been no FDA approval for clonidine in the treatment of opioid detoxification. Clonidine suppresses many symptoms of withdrawal, including rapid heart rate, increased blood pressure, sweating, nausea, vomiting, diarrhea, and cramps. However, clonidine has no effect on craving, muscle aches, or insomnia; thus, adjunctive medications (such as non-steroidal anti-inflammatory drugs for muscle aches and possibly benzodiazepines for insomnia) need to be

added; however, benzodiazepines need to be used cautiously and for a brief period of time. The most common side effects of clonidine are sedation and hypotension. Exclusions for the use of clonidine include use of tricyclic antidepressants in the previous 3- to 4-week period (cause alpha2 receptor hyposensitivity), hypotension, cardiac arrhythmias, treatment with antihypertensives, pregnancy, psychosis, and medical disorders for which the use of clonidine is contraindicated (Vaughan and Kleber, 2015). Patients should be cautioned regarding the sedative effects of clonidine. Clonidine detoxification should be performed in an inpatient setting. For shortacting opioids, the usual dose of opioid is stopped and the starting dose of clonidine on Day 1 is 0.1 to 0.2 mg every 4 to 6 hours up to a maximum of 1.0 mg in 24 hours. During Days 2 to 4, clonidine doses are gradually increased by 0.2 to 0.4 mg every 4 to 6 hours to a maximum of 1.2 mg in 24 hours based on the need to control withdrawal symptoms. Beginning Day 5, the dose of clonidine is reduced by 0.2 mg/d and continued in two or three divided doses, with the bedtime dose reduced last. (Vaughan and Kleber, 2015) Orthostatic blood pressures need to be monitored before each dose for inpatients. Doses should be held if the blood pressure is ≤ 90/60 mm Hg and subsequent doses initiated after blood pressure stabilizes. Fluids should be encouraged. For long-acting opioids, the starting dose is 0.1 mg three time per day on Day 1; for methadone, begin as soon as the dose is less than 30 mg/d. On Days 2 through 4 the dose of clonidine is gradually increased, not to exceed 0.4 mg three time per day by Day 4, based on the need to control withdrawal symptoms. The Day 4 dose is maintained until Day 11 at which time the dose of clonidine is reduced by 0.2 mg/d but not to exceed 0.4 mg/d; divided dosing is maintained throughout the detoxification protocol. (Vaughan and Kleber, 2015) As with detoxification of short-acting opioids, orthostatic blood pressure and pulse need to be monitored before each dose of clonidine with long-acting opioids, as well. Clonidine doses should be held if blood pressure is ≤ 90/60 mm Hg. Fluids should be encouraged and subsequent doses can be initiated after blood pressure stabilizes.

Lofexidine Lofexidine is an alpha2 agonist currently used in England for opioid detoxification. Its advantages over clonidine include reduced risks for sedation and hypotension. Lofexidine is now being studied for possible FDA approval.

Opioid Substitution Methadone Maintenance Only a facility licensed by a state and certified by SAMHSA (i.e., a federal agency) can dispense methadone maintenance for the treatment of opioid dependence. The criteria for initiating methadone maintenance include age at least 18 with at least a 1-year history of opioid-dependence, current signs and symptoms of withdrawal, needle tracks, and positive urines. For previously treated patients, reinstatement into a methadone maintenance program can occur within 2 years of discontinuation of methadone without current physical dependence and with documentation from a physician that relapse to opioid dependence is imminent. Individuals who are released from a penal institution and who met the criteria for methadone maintenance prior to incarceration can be admitted to a methadone program without the presence of physical dependence. Women who are pregnant are eligible for methadone maintenance if they are physically dependent on opioids or if they were dependent on opioids in the past and are now at imminent risk of relapse. Patients younger than 18 years must have failed at least 2 opioid detoxifications and have the consent of a parent, legal guardian, or an adult designated by state authority to enter a methadone maintenance program. Patient characteristics that predict a successful outcome in a methadone program include: brief history of drug abuse; age younger than 25 years; psychological stability; good social support system; good work history; minimal legal problems; and low severity of opioid abuse. Methadone’s slow-onset of subjective effects and its long half-life result in a reduction in the euphoric peaks and distressing withdrawal symptoms, both of which, account for the positive reinforcing properties of opioids. It is these properties that make methadone well suited for maintenance therapy. Methadone is well tolerated, and its main side effects include sedation, constipation, excessive sweating, ankle edema, decreased libido, and mild euphoria. The starting dose of methadone maintenance is determined by the intensity of the withdrawal signs and symptoms. For mild withdrawal, the initial dose is about 10 mg/d of methadone, whereas for severe withdrawal, the initial dose is 20 to 30 mg/d, but not to exceed 30 mg according to federal regulations. Patients should be monitored for a period of 2 hours after the first dose in order to determine the effectiveness of the starting doses in reversing withdrawal signs and symptoms. It might take 2 to 4 weeks to achieve the maintenance dose. (Saxon and Miotto, 2011) The maintenance dose is determined by the reduction

or the elimination of opioid abuse as determined by negative urine screens; elimination of the reinforcing properties (such as euphoria); elimination of cravings and urges to use; elimination of withdrawal symptoms; and minimization or elimination of potential side effects. Dosage adjustments are made every 5 to 7 days by 5 to 10 mg increments (Saxon and Miotto, 2011). Although there is a broad range of effective maintenance doses across patients (10–100 mg/d), recent studies have shown that doses averaging 70 to 80 mg/d are needed to block opioid cravings and drug use. Methadone blood levels are helpful, and the goal is to achieve trough blood levels of 150 to 600 ng/mL with a target blood level of 400 ng/ml for most patients. The maximum allowable dose according to federal regulations is 120 mg/d. It is important to avoid rapid increases in doses because methadone has a half-life of up to 36 hours; it’s necessary to keep in mind that it takes five half-lives to achieve 90% of steady state blood levels. Methadone is metabolized by CYP450 3A/4; thus, inhibitors of this enzyme can cause toxicity, and there might be additional contributions by CYP450 2B6 and CYP450 2D6. In 2006, the FDA issued a black box warning because methadone might induce QTc prolongation. Thus, EKG monitoring before starting methadone and at high doses is recommended. It is important to screen patients who might be at risk for QTc prolongation by asking about family history, cardiac disease, history of syncopal episodes, and current treatment with other drugs that can prolong the QTc interval. About one-third of methadone maintenance patients do well and about onethird show no benefit. With doses of methadone > 60 mg/d, retention rates in methadone programs reach 60% at 6 months and up to a 90% reduction in opioid abuse. Unfortunately, the treatment reaches only 20%–25% of opioid addicts. The benefits from methadone maintenance include decreased opioid use, reduced criminal behavior, decreased unemployment, and decreased risk for contracting AIDS.

LAAM LAAM is long-acting congener of methadone that had been approved for the use as an opioid substitute in methadone programs. However, high-dose therapy was linked to QTc prolongation and fatal torsades de pointes; thus, its manufacturer, Roxanne, stopped its production in 2004. It was pulled from the European market in 2001.

Buprenorphine/naloxone Since 2000, buprenorphine /naloxone has been available as an alternative to

methadone for maintenance opioid substitution in an office-based setting. This new option has increased and broadened access to opioid substitution therapy. There are many patients who refuse treatment at methadone clinics due to stigma and their desire for greater flexibility in how medication is prescribed and dispensed (Fiellin et al, 2001). The requirements for office-based treatment with buprenorphine include being a licensed physician with DEA certification and having one of the following: certification in Addiction Psychiatry from the American Board of Medical Specialties; certification from the American Society of Addiction Medicine; certification in Addiction Medicine from the American Osteopathic Association; completion of an 8-hour course on opioid addiction and treatment; or participation in the investigation of buprenorphine in clinical trials or other opioid medications in the field of addiction medicine (Tompkins and Strain, 2011). Clinicians are also required to have access to psychotherapists and counselors as needed. Ling et al. (1998) established the efficacy of buprenorphine maintenance treatment in a large multi-center randomized clinical trial. In another maintenance study, buprenorphine (16–24 mg/d) showed equal efficacy to high-dose methadone (60–100 mg/d) and LAAM (75–115 mg/d) for program retention and illicit use of opioids (urine samples); all three were superior to low-dose methadone (20 mg/d) (Johnson et al, 2000). For patients to receive maintenance treatment, they must be dependent on opioids and show objective signs of withdrawal at the time of induction. In addition, induction of buprenorphine/naloxone is delayed more than16 hours for short-acting opioids, 24 hours for sustained-release opioids, and 36 hours for methadone, from the time of the last dose. For patients being switched from methadone maintenance to buprenorphine/naloxone, their methadone dose needs to be reduced to 30 to 40 mg/d. The initial dose of buprenorphine/naloxone is 4 mg/1 mg; patients are instructed to wait in the office for 2 hours to determine if withdrawal symptoms persist. A second dose of 4 mg/1 mg of buprenorphine/naloxone is given if needed with a maximum dose of 8 mg/2 mg for Day 1 of induction. On subsequent days, buprenorphine/naloxone is increased, based on withdrawal and/or cravings, by no more than 8 mg/2 mg daily to a target dose in the range of 12 mg/3 mg to 16 mg/4 mg per day by Day 2, which is a maintenance dose for most patients. If higher doses are required, patients can be increased to a maximum of 32 mg/8 mg per day over days 3 and 4 (Tompkins and Strain, 2011). The frequency of office visits and urine testing

varies depending on the status of the patient. Early in treatment, visits might be 1 to 3 times weekly, but time between visits is usually lengthened due to family and work commitments.

Buprenorphine and Pregnancy For pregnant opiate-dependent women , methadone has been the standard treatment . However, buprenorphine is a vital alternative. In pregnancy, burprenorphine is given without naloxone. In a recent study by Jones et al. (2010), 175 pregnant opiate-dependent women at eight international sites participated in a double-blind, double-dummy, flexible-dosing, randomized, controlled study comparing buprenorphine and methadone. Both drugs were effective and safe; treatment retention rates for methadone and buprenorphine were 72% and 67%, respectively. Most of the buprenorphine drop-outs occurred in the first few days or after the first dose. Assessment for NAS (i.e., autonomic, respiratory, and gastrointestinal distress) in 131 neonates showed that the dose of morphine to treat NAS was 1.1 mg for buprenorphine versus 10.4 mg for methadone; in addition, the duration of NAS was 4.1 days versus 10.4 days for buprenorphine and methadone, respectively. Hospital length of stay also favored buprenorphine over methadone: 10.0 days versus 17.5 days, respectively.

Buprenorphine and Pain Management The management of pain while patients are on buprenorphine maintenance treatment can be complicated and it is preferred to keep them on buprenorphine while managing their pain with non-steroidal analgesics and/or acetaminophen. However, this approach might not be sufficient. Strain and Lofwall (2008) suggest three approaches for the treatment of acute pain: give buprenorphine in divided doses (four times daily is preferred) or continue buprenorphine and titrate a short-acting full mu agonist or discontinue buprenorphine and start a short-acting full mu agonist with careful titration to avoid withdrawal while achieving the desired analgesic effect. If the latter approach is used, it is recommended to re-start buprenorphine with the resolution of the acute pain. For chronic pain, one should give methadone in multiple daily doses or for patients not receiving enough benefit from multiple daily doses of buprenorphine, switch them to multiple daily doses of methadone (Strain and Lofwall, 2008).

New Pharmacological Treatment Developments Buprenorphine Implants for Maintenance Therapy A buprenorphine implant (Probuphine) consists of a small implantable subdermal rod of buprenorphine (mono-formulation) that provides 6 months of continuous dosing. Ling et al. (2012) reported on a 24-week randomized, placebo-controlled study of opioid-dependent adults (ages 18–65). One hundred eight were randomized to receive buprenorphine implants and 55 to receive placebo implants. The buprenorphine group had significantly more mean urine samples negative for opioids than the placebo group (40.4% versus 28.3%). Seventy-one of 108 (65.7%) buprenorphine patients completed the study versus 17 of 55 (30.9%) (p < .001) in the placebo group. Also, patients on buprenorphine had significantly lower scores on withdrawal symptoms and cravings than the placebo group. The advantages of the implant formulation over the sub-lingual formulation include: elimination of the problem with diversion and treatment non-adherence. As of May 26, 2016, the FDA approved the use of the buprenorphine implant (Probuphine) for maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of transmucosal buprenorphine.

Opioid Antagonist Therapy In October 2010, extended-release (ER) naltrexone (Vivitrol) was FDA approved for opioid dependence. ER naltrexone is given monthly in an injectable formulation. A recent double-blind, placebo-controlled, randomized 24-week study of 250 opioid-dependent patients showed superior efficacy of ER naltrexone (n = 126) versus placebo (n = 124) (Krupitsky et al, 2011). Patients were at least 18 years old and had completed 30-day or less inpatient detoxifications and at least 7 days off all opioids post-detoxification. The median proportion of weeks of confirmed abstinence (urine samples) was 90% for ER naltrexone and 35% for placebo (p = 0.0002). Also, the ER naltrexone group had significantly longer median days of program retention (168 days) versus the placebo group (96 days; p = 0.0042) and greater reductions on craving scores. Relapse to confirmed opioid-dependence was found in 17 patients in the placebo group versus one patient in the ER naltrexone group (p < 0.0001). There were no significant differences in safety or tolerability between the two groups. Opioid antagonist therapy might be indicated for individuals who are young or have short dependency histories or who live in an area where opioid substitution

therapy is not readily available or who choose not to be exposed to long-term physical dependence on long-acting opioids.

Psychological Treatments Psychosocial treatment modalities include individual, group, and family psychotherapy; therapeutic communities; and self-help groups like Narcotics Anonymous.

Psychotherapy The greater the degree of psychopathology in opioid addicts, the poorer the treatment outcome. However, for those addicted to opioids with psychiatric disorders, psychotherapy can significantly improve treatment outcome compared to treatment without psychotherapy. Antisocial personality predicts poor response to psychotherapy. Positive predictors of psychotherapy outcome include: establishing a good alliance between therapist and patient; treating psychiatric symptoms (such as depression) early; assessing and addressing psychosocial problems; and monitoring treatment compliance.

CBT Studies in community-based methadone clinics showed that CBT plus drug counseling or supportive-expressive therapy plus drug counseling, are each more effective than drug counseling alone at 7 and 12 months in methadone patients with high levels of psychiatric symptoms. All three treatment conditions were equally effective in methadone patients with low levels of psychiatric symptoms.

Behavioral Therapy Cue extinction and contingency management are two effective behavioral approaches. There is good evidence that cravings can be classically conditioned; thus, through repeated exposures to internal or external cues, cravings are extinguished. With contingency management, the therapist and the patient establish a set of rewards for maintaining abstinence and a set of aversive consequences for opioid use; urine toxicology screens are randomly used to determine treatment compliance. In a study of patients in a methadone maintenance program, adding psychosocial services (on-site medical and psychiatric services, family therapy, and employment services) to contingency management and methadone substitution significantly improved outcome. Patients in the methadone substitution alone condition had to be terminated from

the study by week 12 due to a high percent of opiate-positive urine samples (Higgins and Silverman, 2008).

Family Therapy Family members can be helpful in assisting the treatment team in initiating and monitoring contingency management protocols and to help with compliance issues.

Group Therapy Relapse-prevention groups combined with self-help groups are more effective in reducing opioid use, legal problems, and unemployment than no treatment in detoxified opioid-dependent patients.

Therapeutic Communities Patients reside in these facilities from 6 to 18 months. The environment is structured and consists of a hierarchy of privileges and responsibilities. The community confronts denial and emphasizes personal responsibility for achieving abstinence. Only highly motivated individuals are successful; 50% drop out by 6 months, and only 15% to 25% graduate.

Narcotic Anonymous There are essentially no differences between Narcotic Anonymous (NA ) and Alcoholics Anonymous (AA ). NA assists patients with an addiction to any illicit drug. The main purpose of NA is to provide a support network, confront denial, and help prevent relapse by addressing thinking and behaviors that often lead to use.

Suggested Readings 1. American Psychiatric Association: Cocaine-Related Disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Press, Inc.; 2000: 241– 250. 2. American Psychiatric Association: Opioid-Related Disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Press, Inc.; 2000: 269– 277.

3. American Psychiatric Association: Substance-Related disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Press, Inc.; 2000: 191– 212. 4. Begg EJ, Malpas TJ, Hackett LP, et al: Distribution of R- and S- methadone into human milk during multiple, medium to high oral dosing. Br J Clin Pharmacol. 2001; 52: 681–685. 5. Brown LS, Hickson MJ, Ajuluchukwu DC, et al: Medical disorders in a cohort of New York City drug abusers: much more than HIV disease. J Addict Dis . 1993; 12: 11–27. 6. Carroll K: Cognitive-Behavioral Therapies. In: Galanter M, Kleber HD, eds. Textbook of Substance Abuse Treatment . 4th ed. Washington, DC: American Psychiatric Press, Inc.; 2008: 349–360. 7. Centers for Disease Control and Prevention: Recommendations for prevention and control of hepatitis (virus HCV) infection and HCV-related chronic disease. MMWR Recommendations and Reports 1998; 47(RR19): 1–39 8. Cooper OB, Brown TT, Dobs AS: Opiate drug use: a potential contributor to the endocrine and metabolic complications in human immunodeficiency virus disease. Clin Infect Dis . 2003; 37(suppl 2): S132–S136. 9. DASIS Report: Cocaine route of administration trends: 1995-2005 . Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Rockville, MD: Sep 13,2007 [online]. Available http://www.oas.samhsa.gov/2k7/crackTX.htm . 10. Des Jarlais DC, Perlis T, Friedman SR, et al: Declining seroprevalence in a very large HIV epidemic: injecting drug users in New York City. Am J Public Health . 1998; 88: 1801–1806. 11. Epstein S, Renner JA, Ciraulo DA, et al: Opioids. In: Clinical Manual of Addiction Psychopharmacology. Washington, DC: American Psychiatric Press, Inc.; 2005: 55–110. 12. Fiellin DA, O’Connor PG, Chawarski M, et al: Methadone maintenance in primary care: a randomized controlled trial. JAMA . 2001; 286: 1724–1731. 13. Franklin JE, Frances RJ: Alcohol and other psychoactive substance use disorders. In: Hales RE, Yudofsky SC, Talbott JA, eds.: The American Psychiatric Press Textbook of Psychiatry . 3rd ed. Washington, DC:

American Psychiatric Press, Inc.; 1999: 363–423. 14. Fudala PJ, O’Brien CP: Buprenorphine for the treatment of opioid addiction. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds.: Substance Abuse: A Comprehensive Textbook . 4th ed.: Baltimore, MD: Lippincott Williams & Wilkins; 2005: 634–640. 15. Gold M, Jacobs W: Cocaine and crack: Clinical aspects. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds.: Substance Abuse: A Comprehensive Textbook . 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: 218–251. 16. Haney M: Neurobiology of stimulants. In: Textbook of Substance Abuse Treatment . 4th ed. Washington, DC: American Psychiatric Press, Inc.; 2008: 143–154. 17. Higgins ST, Silverman K: Contingency Management. In: Galanter M, Kleber HD, eds.: Textbook of Substance Abuse Treatment . 4th ed. Washington, DC: American Psychiatric Press, Inc.; 2008: 387–400. 18. Hser YI, Grella V, et al: A 33-year follow-up of narcotic addicts. Arch Gen Psychiatry . 2001; 58: 503–508. 19. Johnson RE, Chutuape MA, Strain EC, et al: A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med . 2000; 343: 1290–1297. 20. Jones HE, Kaltenbach K, Heil SH, et al: Neonatal Abstinence Syndrome after methadone or buprenorphine exposure. N Engl J Med . 2010; 363: 2320–2331. 21. Kinsey BM, Kosten TR, Orson FM: Anti-cocaine vaccine development. Expert Rev Vaccines . 2010; 9(9): 1109–1114. 22. Knapp CM, Ciraulo DA, Jaffe J: Opiates: clinical aspects. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds.: Substance Abuse: A Comprehensive Textbook . 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: 180–194. 23. Kosten TR, Ciraulo DA: Cocaine and psychostimulants. In: Clinical Manual of Addiction Psychopharmacology. Washington, DC: American Psychiatric Press, Inc.; 2005: 183–209. 24. Kosten TR, Sofuoglu M, Gardner TJ: Clinical Management: cocaine. In: Textbook of Substance Abuse Treatment . 4th ed. Washington, DC:

American Psychiatric Press, Inc.; 2008: 157–168. 25. Kreek MJ: Neurobiology of opiates and opioids. In: Galanter M, Kleber HD, eds.: Textbook of Substance Abuse Treatment , 4th ed. Washington, DC: American Psychiatric Press, Inc.; 2008: 247–264. 26. Krupitsky E, Nunes EV, Ling W, et al: Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multi-centre randomized trial. Lancet . 2011; 377: 1506–1513. 27. Ling W, Casadonte P, Bigelow G, et al: Buprenorphine implants for treatment of opioid dependence. JAMA . 2010; 304(14): 1576–1583. 28. Ling W, Charuvastra C, Collins JF, et al: Buprenorphine maintenance treatment of opiate dependence: a multi-center, randomized clinical trial. Addiction . 1998; 93: 475–486. 29. Mirin SM, Weiss RD, Michael J: Psychopathology in substance abusers: diagnosis and treatment. Am J Drug Alcohol Abuse . 1988; 14: 139–157. 30. Nunes EV, Kinlock TW, Hanlon TE, et al: Imipramine treatment of opiatedependent patients with depressive disorders: a placebo-controlled trial. Arch Gen Psychiatry . 1998; 55: 153–160. 31. Paczynski RP, Gold MS: Cocaine and crack. In: Ruiz and Strain eds. Lowinson and Ruiz’s Substance Abuse A Comprehensive Textbook . 5th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2011: 199–213. 32. Repetto M, Gold M: Cocaine and crack: neurobiology. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds.: Substance Abuse: A Comprehensive Textbook . 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: 195–217. 33. Ruiz P, Strain EC, Langrod JG: Cocaine. In: The Substance Abuse Handbook. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2007: 45–52. 34. Ruiz P, Strain EC, Langrod JG: Opiates. In: The Substance Abuse Handbook. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2007: 31–41. 35. SAMSHA. Results from the 2007 National Survey on Drug Use and Health: National Findings (NSDUH Series H-34, DHHS Publication No. SMA 08-4343). Rockville, MD: Department of Health and Human

Services; 2008. 36. Saxon AJ, Miotto K: Methadone maintenance. In: Ruiz and Strain, eds.: Lowinson and Ruiz’s Substance Abuse A Comprehensive Textbook . 5th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2011: 419–436. 37. Schottenfeld RS: Opioid Maintenance Treatment. In: Galanter M, Kleber HD, eds.: Textbook of Substance Abuse Treatment . 4th ed. Washington, DC: American Psychiatric Press, Inc.; 2008: 289–308. 38. Simon EJ: Opiates: neurobiology. In: Substance Abuse: A Comprehensive Textbook . 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 164–179. 39. Strain EC, Lofwall MR: Buprenorphine maintenance. In: Galanter M, Kleber HD, eds.: Textbook of Substance Abuse Treatment . 4th ed. Washington, DC: American Psychiatric Press, Inc.; 2008: 309–324. 40. Substance Abuse and Mental Health Administration: Overview of Findings from the 2003 National Survey on Drug Use and Health (DHHS Publ No SMA-04-3963. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2004. 41. Tompkins DA, Strain EC: Buprenorphine in the treatment of opioid dependence. In: Ruiz and Strain, eds.: Lowinson and Ruiz’s Substance Abuse: A Comprehensive Textbook . 5th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2011: 437–446. 42. Vaughan BR, Kleber HD: Opioid Detoxification. In: Galanter M, Kleber HD, Brady, KT eds. Textbook of Substance Abuse Treatment . 5th ed. Washington, DC: American Psychiatric Press, Inc.; 2015: 295–309. 43. Villagomez RE, Meyer TJ, Lin MM, et al: Post-traumatic stress disorder among inner city methadone maintenance patients. Subst Abuse Treat . 1995; 12: 253–257. 44. Washton AM: Non-pharmacologic treatment of cocaine abuse. Psychiatr Clin of North Am . 1986; 9: 563–571. 45. Woody GE, O’Brien CR, Rickels K: Depression and anxiety in heroin addicts: a placebo-controlled study of doxepin in combination with methadone. Am J Psychiatry . 1975; 132: 447–450.

CHAPTER 14 Psychosis and Schizophrenia HANNAH E. BROWN, MD AND DAPHNE J. HOLT, MD, PHD

KEY POINTS Overview Psychosis consists of symptoms (delusions, hallucinations) related to an impairment of reality testing caused by a variety of different psychiatric and medical illnesses. Schizophrenia is a heterogeneous illness with psychotic symptoms as a core feature. In addition to psychotic symptoms, negative symptoms and cognitive deficits might be present in schizophrenia and contribute to significant functional impairment. Epidemiology Schizophrenia affects individuals worldwide, with a life-time risk of 1%. There is a higher prevalence of disease in immigrants compared to those native-born to the United States, and a higher prevalence in urban versus rural settings. Males tend to manifest the illness at an earlier age than females (on average age 18 to 25 in males versus age 26 to 45 in females). Clinical Features The active psychotic phase of schizophrenia can include delusions, hallucinations, disorganized or catatonic behavior, a thought disorder, and negative symptoms. Mood symptoms, substance abuse, and cognitive impairment might also be prominent features of the illness. Longitudinally, most patients experience relapses after an initial psychotic episode, and a decline in multiple domains of functioning frequently occurs. Pathophysiology Schizophrenia is a highly heritable, polygenic disease. The illness manifests in individuals who carry multiple susceptibility genes and experience the effects

of a variety of environmental insults. Genome-wide association studies have identified over 100 loci that are associated with increased risk for schizophrenia. Abnormal dopamine function (a hyperdopaminergic state) has long been hypothesized to contribute to the underlying causes of schizophrenia. More recent research reveals that glutamate hypofunction also might play a role in schizophrenia pathophysiology. Neuroimaging studies reveal that a loss of brain volume and disruption of communication among distributed networks of regions might be characteristic of individuals with schizophrenia.

Differential Diagnosis A diagnosis of schizophrenia is made based on clinical evaluation and thorough history taking. Schizophrenia is a diagnosis of exclusion, and an underlying medical condition as the cause of the psychosis must be ruled out. There is no standard, agreed-upon workup to exclude all medical causes; a physical exam and a thorough history should guide the workup. Conditions that can present with psychosis include delirium, infectious diseases, endocrinopathies, nutritional deficiencies, neoplasms, and neurologic disorders. Many illicit substances can cause psychotic symptoms including alcohol, cannabis, and stimulants. Schizophrenia can be differentiated from schizoaffective disorder; in the latter disorder, mood symptoms predominate for most of the total duration of active and residual psychotic symptoms, and psychotic symptoms persist beyond the remission of mood episodes. In major depressive disorder and bipolar disorder, psychosis is present solely during mood episodes. Treatment Antipsychotic medications are the mainstay of treatment for individuals with schizophrenia, both during acute and maintenance phases. In addition to treatment with antipsychotic medication, psychosocial treatment also should be an ongoing part of treatment. This treatment modality includes cognitivebehavioral therapy, individual psychotherapy, family psychoeducation, and supportive employment.

Introduction

Psychosis is a cluster of symptoms typically associated with an individual’s impaired perception of reality, which can result from a variety of psychiatric and medical illnesses. Psychotic symptoms generally include hallucinations, delusions, and manifestations of a thought disorder (e.g., abnormal speech), behavioral disorganization, and catatonia. Hallucinations are sensory perceptions in the absence of external stimuli that can occur in any sensory modality (e.g., auditory, visual, olfactory, tactile, gustatory). Delusions are firmly held false beliefs that can take the form of several common themes (e.g., persecutory, somatic, grandiose, erotomanic, religious) or have idiosyncratic (not easily classified) content. A thought disorder refers to a disruption in the form, or organization of thinking that is manifested by disorganized speech (e.g., a patient might be incoherent and have difficulty communicating his or her thoughts to others, have a loosening of associations, be over-inclusive or concrete, produce neologisms, or have thought-blocking, clanging, echolalia, or poverty of speech). Behavioral disorganization refers to odd behaviors including mannerisms, stereotyped movements, agitation, or behaviors that do not conform to social norms. Catatonia is an extreme decrease in responsiveness to the surrounding environment and can be characterized by signs or symptoms such as negativism (resisting engagement with interviewer), mutism, stupor (minimal to no speech output and immobility), and abnormal posturing. Catatonic excitement includes purposeless and excessive movements.

History of the Diagnostic Classification of Schizophrenia In 1896, Kraepelin distinguished “dementia praecox” from “manic depressive psychosis” and emphasized the chronic, deteriorating course of dementia praecox. Consequently, the term “Kraepelinian schizophrenia” has been used by some investigators to refer to a condition in which a patient fails to achieve remission and to live independently for a 5-year period. In 1911, Bleuler described “schizophrenia” as a splitting of psychic functions. He described specific fundamental symptoms of schizophrenia as the “Four As”: autism, ambivalence, loosening of associations, and inappropriate affect. He emphasized these “negative symptoms” but also described accessory symptoms that included delusions and hallucinations. In the 1970s, Schneider described eleven “first-rank symptoms” of schizophrenia (including hallucinations, delusions, thought withdrawal, thought

insertion, as well as imposed feelings and impulses). He emphasized the “positive symptoms” of schizophrenia and believed that the diagnosis of schizophrenia also could be made with “second-rank symptoms,” which include other disorders of perception (not first-rank), sudden delusional ideas, perplexity, emotional impoverishment, as well as depressive and euphoric mood changes.

DSM-5 Diagnosis of Schizophrenia Clinical Features Schizophrenia is a heterogeneous illness: the clinical presentation varies among individuals. Core symptoms can include psychotic, cognitive, behavioral, and/or emotional changes. A formal diagnosis includes: active psychotic symptoms for at least 1 month (less if adequately treated); functioning below the highest expected level for that person in one or more areas; duration of illness lasting at least 6 months (including the prodromal or residual phases); and other illnesses that could account for the symptoms (including other medical conditions or a drug-induced psychosis) must be ruled out. The active psychotic phase requires at least two of the following symptoms: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms. At least one of the two symptoms must be delusions, hallucinations, or disorganized speech. The onset of symptoms can be acute or subacute, and often a prodromal period beginning months to years before onset of frank psychotic symptoms is diagnosed retrospectively. Prodromal and residual phase symptoms include social isolation or withdrawal, negative symptoms, impairment of functioning, peculiar behavior, impaired personal hygiene, blunted or inappropriate affect, abnormal speech (e.g., digressive, vague, overly elaborate), odd beliefs (e.g., superstitions, extrasensory perception), unusual perceptual experiences, and apathy. Mood symptoms can also occur during the active phase; however, in schizophrenia, psychotic symptoms persist in the absence of mood changes, and mood symptoms are present only for a small amount of the total duration of the illness. Individuals with schizophrenia also frequently lack insight about the nature of their illness (anosognosia). Negative symptoms and cognitive impairment can be prominent features of the illness and contribute to significant psychosocial difficulties. Negative symptoms of schizophrenia include anhedonia, asociality, avolition, affective flattening, and alogia (poverty of speech and thought). In general, negative symptoms are

not treatable with antipsychotic medications. Changes in negative symptoms can occur independently of improvements or relapses in psychotic symptoms, and follow a different time course. Schizophrenia is a diagnosis of exclusion in the sense that an underlying medical condition as the cause of the psychosis must be ruled-out prior to diagnosis (see the following sections).

Differential Diagnosis of Psychotic Symptoms Several clinical and historical features can help to distinguish between psychiatric causes of psychotic symptoms. In schizoaffective disorder, either a major depressive or manic episode occurs concurrently with active psychotic symptoms; also, the mood symptoms persist for most of the total duration of the active and residual psychotic symptoms, and delusions or hallucinations are present for at least 2 weeks during euthymia. However, in major depressive disorder (MDD) or bipolar disorder with psychotic features, the psychosis is present solely during the manic or depressive episodes. Schizophreniform disorder is of shorter duration than schizophrenia; it consists of a prodromal phase, an active phase, and a residual phase of less than 6 months. Brief psychotic disorder includes acute (no prodromal period) onset of psychotic symptoms (delusions, hallucinations, disorganized speech or behavior) lasting for at least 1 day but less than 1 month. In schizotypal personality disorder there is an acute discomfort with, and reduced capacity for, close relationships as well as cognitive or perceptual distortions and behavioral eccentricities. Delusional disorder is characterized by the presence of one or more delusional beliefs persisting for at least one month. It differs from schizophrenia in that there are no other characteristic symptoms such as prominent hallucinations, disorganized speech, behavior or negative symptoms. Sub-types of delusions observed in delusional disorder include erotomanic, grandiose, jealous, persecutory, somatic, mixed, and unspecified. Overall functioning is usually better in individuals with delusional disorder than in those with schizophrenia.

Psychosis Due to Another Condition Substance or Medication-Induced Psychotic Disorder This disorder is characterized by delusions or psychotic symptoms that are due to the direct physiologic effects of a substance or prescribed medication. Substance-induced psychosis is differentiated from a primary psychotic illness by taking a careful history, including collecting information about the nature and

age of onset of symptoms, presence or absence of a prodromal period, the timing in relation to drug ingestion, and obtaining a urine drug screen. Often, prolonged periods of sobriety can clarify the diagnosis. Many different types of substances can cause psychotic symptoms, including alcohol, cannabis, stimulants, and anxiolytics. Phencyclidine (PCP), used at high doses, can cause illusions and hallucinations as well as the full range of the symptoms of schizophrenia (such as delusions, paranoia, disordered thinking, a sensation of distance from one’s environment, and catatonia). Speech is often sparse and garbled. Those who use PCP for long periods report memory loss, difficulty with speech and thinking, depression, and weight loss. These symptoms can persist for up to one year after cessation of PCP use. Ketamine, a dissociative anesthetic with a chemical structure and mechanism of action similar to that of PCP, is a non-competitive antagonist of the N methyl-D-aspartate (NMDA) receptor that produces perceptual alterations, disordered thought, and mood changes. Its effects are similar to those of PCP but are of shorter duration. Patients report sensations ranging from a pleasant feeling of floating to being separated from their bodies. Some experience a terrifying feeling of almost complete sensory detachment. The effects of lysergic acid diethylamide (LSD) depend on the amount taken, the patient’s personality and expectations, and the surroundings in which the drug is used. The LSD user might feel several different emotions at once or swing rapidly from one emotion to another. If taken in a large enough dose, the drug produces delusions and visual hallucinations. The person’s sense of time and self-changes; synesthesias (hearing colors and seeing sounds) are experienced that can lead to panic. Ecstasy, MDMA (3,4-methylene dioxymethamphetamine), has properties similar to both amphetamines and hallucinogens. Psychological effects can occur either during or weeks after use; symptoms include confusion, depression, sleep problems, drug craving, severe anxiety, and paranoia. Cannabis is one of the most commonly abused drugs in the United States; its main psychoactive ingredient is delta-9-tetrahydrocannabinol (THC). Symptoms of intoxication include a relaxed or elevated mood, alteration in the perception of time, tachycardia, and conjunctival injection. Cannabis users might report paranoia or hallucinations, although in these cases it is important to assess for other drugs of abuse and for underlying psychiatric disorders.

Psychosis Due to a Medical Condition These disorders present with psychotic symptoms that are the direct physiologic consequences of an underlying medical condition. Medical conditions that can cause psychosis include but are not limited to delirium, infectious diseases, endocrinopathies, nutritional deficiencies, neoplasms, heavymetal exposures, and neurologic disorders (see Table 14-1). There is no standard, agreed-upon workup to rule out medical causes of psychosis. A comprehensive medical history and a physical and neurological examination should be performed; the history and exam then can guide the extent of the workup (i.e., clinicians should screen for rare disorders only if clinically indicated). Basic screening laboratory studies should be obtained, including HIV screening and syphilis screening (see Table 14-2). Magnetic resonance imaging (MRI) can definitively exclude the presence of a brain tumor; however, in the absence of an abnormal neurological exam, the clinical yield of MRI is low, and incidental findings occur at the same rate in patients with new-onset schizophrenia as in the healthy population. Table 14-1: Selected Drugs and Medical/Neurological Conditions Associated with Psychosis Drugs of Abuse

Infectious Diseases

Alcohol

Brain abscess

Amphetamines

Hepatic encephalopathy

Barbiturates

Infectious mononucleosis

Caffeine

Malaria

Cannabis (THC)

Meningitis

Cocaine

Syphilis

Hallucinogens (e.g., LSD, PCP, MDMA)

Endocrine Disorders

Inhalants

Addison’s disease

Opioids

Cushing’s syndrome

Sedative-hypnotics

Hypo/hyperthyroidism Hypo/hyperparathyroidism

Neurological Disorders

Nutritional Deficiencies

Alzheimer’s disease

Niacin deficiency

Complex partial seizures

Thiamine deficiency

Huntington’s disease (pellagra)

Vitamin B12 (pernicious anemia)

Hydrocephalus

Other

Lupus cerebritis (Korsakoff’s psychosis, beriberi) Neoplasms Parkinson’s disease

Heavy-metal exposures

Pick’s disease

Prescription medications-steroids

Wilson’s disease

Table 14-2: Evaluation of Psychosis Perform a complete physical and neurological exam Conduct a mental status exam (ordering neuropsychological testing as indicated) Obtain a full laboratory screen: electrolytes, blood urea nitrogen, creatinine, calcium, glucose, complete blood count, thyroid panel, liver enzymes, syphilis screen, vitamin B12 , folate, HIV Obtain a toxicological screen Order brain imaging Obtain an EEG (order brain imaging if clinically indicated)

To distinguish medical causes of psychosis from psychiatric ones, and to make the differential diagnosis among psychiatric causes of psychosis, several key questions must be answered by the evaluating clinician: Has a reversible, organic cause been ruled out? Are cognitive deficits, (e.g., memory impairment) prominent? (If so, consider delirium or dementia.) Is the psychiatric illness episodic or continuous? Have psychotic symptoms been present for at least 4 weeks? Are negative symptoms present? Has evidence of the illness been present for at least 6 months? Are mood episodes prominent? Have there been episodes of major depression or mania? Do psychotic features occur only during affective episodes? In addition, neuropsychological testing can frequently uncover underlying psychotic symptoms and cognitive impairments. Although brain imaging often yields little information in the absence of focal neurologic impairment, a brain

MRI is generally recommended for a patient with an atypical psychosis or with treatment-refractory psychotic symptoms. An electroencephalogram (EEG) can help to detect an underlying seizure disorder.

Epidemiology of Schizophrenia Schizophrenia is present worldwide. A recent systematic review of general population-based studies found that the median life-time prevalence risk is 4.0 per 1,000. The prevalence is higher in immigrants compared to those native-born to the United States, and higher in urban versus rural settings. The prevalence also differs based on socioeconomic status: developed countries have a higher median life-time prevalence compared with less-developed countries. The median incidence rate is 15.2 per 100,000 individuals, and the life-time morbidity risk is 1%. The standardized mortality rate (SMR) for all-cause mortality is 2.6 (i.e., individuals with schizophrenia are 2.6 times more likely to die from any cause compared to the average rate) and has been increasing over the past four decades. Substance abuse is seen in roughly 50% of individuals with schizophrenia. Psychotic symptoms associated with schizophrenia most often begin in adolescence or young adulthood. The life-time risk of schizophrenia is approximately equal for men and women. Males manifest the illness earlier (on average between 18 and 25 years) than do females (on average between 26 and 45 years). Roughly 20% of cases occur after the age of 40 years; most of these cases are women (there is a second, smaller peak of occurrence in women around menopause, at ages 40–45 years). Gender differences have been reported for pre-morbid functioning (better in women), clinical course, and response to antipsychotic drugs. Children at risk for the development of schizophrenia later in life have lower scholastic test scores and social involvement than typically developing children. Some evidence also suggests that children at risk for schizophrenia experience a thought disorder and delayed developmental milestones as early as infancy. Stress appears to be a significant factor that affects the age of onset of schizophrenia. When onset occurs in college, 44% of cases develop during the first semester. Among army draftees, there is an eight-fold higher incidence of first-break psychosis during the first few months of service as compared with the incidence during the second year. Child abuse victims have an earlier age of onset and a more problematic course of schizophrenia.

There is a modest increase in the prevalence of schizophrenia among those born in the winter and spring. An increased incidence of schizophrenia exists among individuals exposed to influenza or to other viruses during the late second trimester (around 6 months’ gestation). However, direct evidence of viral causation or contribution to disease development is lacking. The local incidence of schizophrenia doubled two decades after two famines, the Dutch Hunger Winter of 1944–1945 and the Chinese famine in the 1950s, suggesting nutritional deficiency might contribute to the etiology of schizophrenia. Further, among those conceived during the peak of the Dutch famine, there was also an increase in neural tube defects; it is hypothesized that pre-natal folate deficiency or perturbation in folate metabolism contributes to the development of schizophrenia.

Genetics of Schizophrenia Schizophrenia is highly heritable. Both earlier and more recent studies involving twins consistently show higher rates of monozygotic concordance (45%–50%) compared with rates of dizygotic concordance (10%–15%). Compared with a life-time risk for schizophrenia in the general population, the risk for a sibling or child of a patient with schizophrenia is 10-fold higher. The risk increases further with the number of affected relatives. For example, an individual has a 16% risk of developing schizophrenia when both a parent and a sibling are affected and a 46% risk when both parents are affected. Increased risk, although still present, decreases sharply for second- and third-degree relatives (5% and 2%, respectively). Estimates for the overall heritability (i.e., the proportion of variance in disease incidence due to genetic factors) of the disease range from 63% to 85%. There is also a linear relationship between paternal age and risk for schizophrenia: this increase in risk is hypothesized to be due in part to de novo mutations in the germ-line cells. Genome-wide association studies (GWAS) have identified 108 loci that contain single nucleotide polymorphisms (SNPs) that are significantly associated with an increased risk of schizophrenia. These associations include genes involved in glutamatergic transmission and the major histocompatibility complex (MHC). Recent discoveries revealed that the association of schizophrenia with the MHC locus involves common alleles of the complement C4 gene; higher expression of the C4A allele is associated with schizophrenia. Because it was also found that the C4 protein plays a role in brain development and synaptic pruning, excess C4A might result in abnormal pruning of connections of the brain during

adolescence, increasing the risk for schizophrenia. Also, individuals with velocardio-facial syndrome, a disorder associated with a chromosome 22q 11 microdeletion, have high rates of schizophrenia, suggesting that the genes lost via this deletion are in some way protective against the development of the disorder.

Biological Abnormalities The first and most replicated abnormality of the brain observed in schizophrenia is a small (~10%) increase in ventricular size. Subsequent studies using advanced MRI techniques have found reduced volumes of the prefrontal cortex, thalamus, hippocampus, and superior temporal gyri in individuals with schizophrenia compared to age and gender-matched healthy subjects. Also, an increase in volume of the basal ganglia has been observed in treated patients with schizophrenia that is secondary to the use of antipsychotic medications. A wide range of subtle abnormalities in the function of the brain have also been detected in schizophrenia, by using functional neuroimaging methods (e.g., functional MRI) and experimental paradigms developed by cognitive neuroscientists. For example, abnormal activation of the lateral and medial prefrontal and parietal cortices, hippocampus, amygdala, and thalamus have been observed during cognitive and affective tasks. Many of these abnormalities have been linked to abnormalities in cognition or social cognition in individuals with schizophrenia, which include deficits in attention, verbal memory, facial affect recognition, processing speed, and set shifting. Problems with verbal memory and vigilance can be particularly predictive of poor functional outcomes. In addition, smooth pursuit eye movements (SPEM ) are abnormal in 50% to 85% of patients with schizophrenia as well as in 45% of their first-degree family members. Also, many of these deficits precede the onset of the illness in an attenuated form, worsening around the time of the first psychotic episode, suggesting that they represent “risk phenotypes” of the illness and manifestations of the underlying pathophysiology. Functional neuroimaging studies also have led to a consensus that schizophrenia represents a “disconnection syndrome,” characterized by abnormal communication between and within distributed brain networks involved in cognitive, affective, and sensory processes. This “disconnection” might result from altered synaptic pruning and other aspects of neurodevelopment that normally occur during adolescence and early adulthood.

Histopathological changes observed in the brains of patients with schizophrenia in post-mortem samples include a decreased size of the anteromedial temporal lobe (along with cytoarchitectural abnormalities of the parahippocampal gyrus), a widespread reduction in the density of neurons without neuronal cell loss and an absence of gliosis (suggestive of a developmental rather than a neurodegenerative abnormality), and evidence of abnormal cell migration in the hippocampus and frontal cortex.

Theories of Etiology The “dopamine hypothesis” of schizophrenia is based on the fact that dopamine receptor agonists (such as amphetamines) produce psychosis in healthy individuals and that all conventional antipsychotic agents are dopamine antagonists. Acute psychosis in schizophrenia and in other illnesses is associated with increased mesolimbic dopamine activity (in the striatum) that can be mediated, in part, by mesocortical hypoactivity (loss of dopamine function in the prefrontal cortex). Further, there is increased dopamine synthesis and presynaptic release in individuals with schizophrenia and in those at risk for the disorder. Thus, the most proximal “cause” of psychotic symptoms is dopamine overactivity; whether this abnormality is an early or late manifestation of the underlying pathophysiology of the illness is not yet known. Dopamine is not the only neurotransmitter system thought to be involved in the pathophysiology of schizophrenia. The “glutamate hypothesis” of schizophrenia arose from evidence that glutamate antagonists such as PCP and ketamine also produce symptoms resembling psychosis in healthy individuals. Based on this hypothesis, targets for the development of new treatments for schizophrenia have included the glycine modulatory site of the NMDA receptor, and AMPA glutamate receptors. Abnormalities in the density or expression of glutamate and GABA receptor sub-types, as well as abnormalities in the expression of GABA-related proteins and density of GABA-ergic interneurons also have been observed in postmortem studies of schizophrenia. This overall constellation of findings has led to the proposal that schizophrenia might result from hypofunctioning or loss (due to excessive pruning) of glutamatergic synapses and decreased glutamate receptor (particularly the NMDA receptor) functioning. This hypofunction of glutamatergic projections might, in turn, lead to loss of GABA-ergic interneuron function (particularly of the fast-spiking parvalbumin-containing ones), with resulting disinhibition of pyramidal cells and other neuronal types in select

areas of the brain (such as the CA1 sub-field of the hippocampus and the dopaminergic cells of the ventral tegmental area). This disinhibition of pyramidal cells is hypothesized to result in overactivity of brain regions, such as the hippocampus, as well as elevations in extra-cellular glutamate, leading to oxidative damage and progressive atrophy of nearby neurons and the affected regions. Although the causal chain of events proposed by this model is supported mainly by indirect evidence, it is being systematically tested using animal models and neuroimaging techniques in humans. Other important unresolved questions about the etiology of schizophrenia are related to the timing of the cellular events involved in the pathophysiology of the illness and the nature of what triggers those events. The diathesis and stress model (two-hit model) of schizophrenia posits that the first factor (or hit) is an inherited vulnerability to schizophrenia, which can be manifested by early neuropsychological deficits (e.g., impaired auditory gating). The second factor is an environmental insult that can occur early and/or late in development (e.g., an obstetrical injury, infection, or hypoxia in utero , or childhood trauma or adversity, cannabis abuse, urban living, social stress in childhood or adolescence). Thus, genetic and/or environmental factors disrupt early brain development, producing long-term vulnerability to a “second hit” that then leads to the onset of psychotic symptoms.

Predictors of Outcome There are several clinical factors that predict poor outcomes , including longer duration of untreated psychosis (DUP), non-adherence to antipsychotic medication, initial poor response to antipsychotic medication, insidious onset, younger age of onset, predominant negative symptoms, poor pre-morbid function, substance abuse or another co-morbid disorder, minority status, and the absence of remissions. Longer DUP influences response to antipsychotic medication, rates of remission and relapse, and overall long-term functioning. Conversely, better outcomes are associated with the presence of affective symptoms and being female.

Course of Illness Morbidity and Mortality On average , the overall functional outcome for schizophrenia is poor. Approximately 14% of patients achieve a full functional recovery from a first

episode with no relapses and a return to a normal level of social and occupational role functioning. However, only 22 to 40% of individuals with schizophrenia are employed, and many patients experience repeated exacerbations of psychotic symptoms. Individuals who begin treatment with antipsychotic medications after a first psychotic episode typically have a good symptomatic response. But, poor medication adherence is common and associated with a poor illness course (i.e., relapses followed by partial remissions and treatment resistance). Those who discontinue antipsychotic medication have a 77% recurrence rate after one year and a greater than 90% recurrence rate after 5 years. The completed suicide rate for patients with schizophrenia is 5%, and 18% to 55% of patients with schizophrenia attempt suicide, most frequently during the first few years of illness. However, the incidence of suicide and attempts has decreased with the introduction of the second-generation antipsychotic medication, clozapine. In addition to suicide, cardiovascular death also contributes to premature mortality: 40% of individuals with schizophrenia develop metabolic syndrome. Individuals with schizophrenia also have an elevated rate of violence compared to those in the general population, particularly if they experience paranoia and disorganization. Individuals with schizophrenia who experience paranoid delusions, other delusions that promote violence, or command auditory hallucinations are at greatest risk for violence.

Awareness of Illness More than half of patients with schizophrenia have impaired insight regarding the nature of their illness (i.e., that they have schizophrenia, which means that they most likely need to take medication to treat their symptoms). This impairment might reflect frontal-cortical dysfunction. Lack of insight is a core symptom of the illness, which often results in refusal of treatment, and notably, medication non-adherence.

Negative Symptoms Negative symptoms of schizophrenia include anhedonia, asociality, avolition, affective flattening, and alogia (poverty of speech and thought). In general, negative symptoms are not treatable with antipsychotic medication and contribute to the significant psychosocial difficulties that patients experience. The evaluation of a patient with negative symptoms should include consideration of other disorders or conditions with similar symptoms (e.g., neuroleptic-induced akinesia, depression, frontal lobe injury, idiopathic or

neuroleptic-induced parkinsonism, substance abuse hypothyroidism, trauma, and post-traumatic stress disorder).

Pharmacologic Treatment Antipsychotic medication is the mainstay of treatment during both acute and maintenance phases of the illness. Aside from clozapine, no one first- or secondgeneration antipsychotic medication has proven to have greater efficacy than any others. Thus, choice of antipsychotic medication should be based on side effect profiles and tolerability for the patient. In general, second-generation antipsychotic medications cause more metabolic side effects (e.g., weight gain, elevated blood glucose and lipids) than first-generation agents, whereas firstgeneration antipsychotic medications cause more movement-related abnormalities (e.g., extrapyramidal symptoms [EPS ]) than second-generation agents. Goals of treatment include minimizing the duration of untreated psychosis, decreasing the intensity of psychotic symptoms, and preventing negative outcomes, including suicide and violent behavior. Up to 30% of patients do not respond to initial trials of antipsychotic medications. These individuals are labeled “treatment resistant” and a trial of clozapine is indicated in this population. Clozapine also should be offered to suicidal or violent patients. Long-acting injectable (LAI) antipsychotic medications should be offered early during the illness to ensure adherence.

Psychosocial Treatment Between 25% and 50% of individuals with schizophrenia will continue to have disabling residual symptoms and impaired social functioning, and most will experience a relapse. Thus, psychosocial treatment is an important component of both early and maintenance treatment. Implementing a multi-disciplinary teambased treatment approach that includes tailored medication management, family psychoeducation, individual therapy, and supported employment and education during the first-episode improves both functional and clinical outcomes. Those with a shorter DUP derive the most benefit from this multi-disciplinary approach.

Cognitive-Behavioral Therapy (CBT) Cognitive-behavioral therapy (CBT) results in the reduction of delusions and hallucinations in patients receiving optimal pharmacological treatment. These interventions focus on rationally exploring the subjective nature of the psychotic

symptoms, challenging the evidence for these, and subjecting such beliefs and experiences to reality testing.

Individual Psychotherapy This type of therapy can assist patients with managing life stressors, enhancing medication adherence, and improving self-esteem.

Group Psychotherapy Group therapy provides a supportive social network and a good setting for teaching coping and interpersonal skills. Other advantages include increased social interaction and peer support.

Assertive Community Treatment Assertive community treatment (ACT ) provides comprehensive integrated community services. Patients are assigned to one multi-disciplinary team (with a case manager, a nurse, and a physician). The team has a fixed case-load and a high staff-to-patient ratio; it delivers all services needed by the patient 24 hours per day, 7 days per week. ACT has been shown to reduce time spent in the hospital, but it is less effective for improving social adjustment or employment. High-quality case management with adequate service availability might be equally effective.

Family Therapy Family therapy is effective in the prevention of psychotic relapse and rehospitalization. Expressed emotion (EE) is a measure of the family environment that is based on an index of criticism, hostility, and over involvement with a psychiatric patient. High EE has been demonstrated to be a predictor of relapse in schizophrenia, particularly in chronically ill patients.

Social Skills Training This training uses principles of learning theory to improve social function by working with patients to remediate problems in activities of daily living, employment, leisure, and relationships. There are three forms: the basic model, the social problem-solving model, and the cognitive remediation model.

Supportive Employment Programs These programs, which use the place-and-train model, can significantly improve the ability to obtain competitive employment (e.g., a regular community

job as opposed to being employed in a program overseen by a rehabilitation agency).

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing, 2013. 2. Bustillo JR, Laurriello J, Horwan WP, et al: The psychosocial treatment of schizophrenia: An update. Am J Psychiatry , 2001; 158: 163–175. 3. Freudenreich O, Brown HE, Holt DJ: Psychosis and Schizophrenia. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier Inc, 2016; 307–323. 4. Freudenreich O, Schulz CS, Goff DC: Initial medical work-up of firstepisode psychosis: a conceptual review. Early Interv Psychiatry . 2009; 3: 10–18. 5. Friston KJ, Frith CD: Schizophrenia: a disconnection syndrome? Clin Neurosci . 1995; 3(2): 89–97. 6. Goff DC, Cather C, Evins AE, et al: Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry . 2005; 66: 183–194. 7. Ho NF, Iglesias JE, Sum MY, et al: Progression from selective to general involvement of hippocampal subfields in schizophrenia. Mol Psychiatry . 2016. 8. Howes OD, Kambeitz J, Kim E, et al: The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry . 2012; 69(8): 776–786. 9. Johnstone EC, Crow TJ, Frith CD, et al: Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet . 1976: 2(7992): 924–926. 10. Kane JM, Robinson DG, Schooler NR, et al: Comprehensive versus usual community care or first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program. Am J Psychiatry . 2016: 173(4):

11. 12.

13.

14.

15. 16.

362–372. McGrath J, Saha S, Chant D, Welham J: Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev . 2008; 30: 67–76. Rotaru DC, Lewis DA, Gonzalez-Burgos G: The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia. Rev Neurosci . 2012; 23(1): 97–109. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature . 2014; 511(7510): 421–427. Schobel SA, Chaudhry NH, Khan UA, et al: Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron . 2014; 78(1): 81–93. Sekar A, Bialas AR, de Rivera H, et al: Schizophrenia risk from complex variation of complement component 4. Nature . 2016; 530(7589): 177–183. Zipursky RB, Menezes NM, Streiner DL: Risk of symptom recurrence with medication discontinuation in first-episode psychosis: A systematic review. Schizophr Res . 2014; 152: 408–414.

CHAPTER Depressive Disorders 15 JOHN D. MATTHEWS, MD, MSC AND CHRISTOPHER M. CELANO, MD

KEY POINTS DSM-5 Depressive Disorder Diagnoses The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes eight categories of depressive disorders: major depressive disorder (MDD), persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, pre-menstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. Epidemiology of MDD MDD is characterized by discrete depressive episodes, which (when recurrent) are interspersed with periods of euthymia. Twelve-month prevalence rates range from 6% to 7% in healthy adults and are significantly higher in patients with medical illness. MDD has been linked to high rates of disability and impaired functioning, highlighting the importance of prompt diagnosis and treatment. Causes of MDD Genetic, physiologic, and environmental factors have been linked to the development and maintenance of depression. Genetic and twin studies suggest that there is a significant genetic basis for depression, though this likely involves multiple genes that interact with the environment. Multiple neurotransmitters, including serotonin, norepinephrine, and dopamine, have been implicated in MDD. Furthermore, depression has been associated with inflammation, alterations in neurohormonal regulation, and structural and functional brain changes.

Treatment of MDD Pharmacologic, psychotherapeutic, and neurostimulation interventions might be indicated for the management of MDD. Antidepressant medications (e.g., selective serotonin re-uptake inhibitors) and psychotherapy, alone or in combination, tend to be first-line treatments for the management of MDD. For treatment-refractory patients, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and other neurostimulation techniques can be employed.

Overview The DSM-5 denotes eight categories of unipolar depressive disorders: Major depressive disorder Persistent depressive disorder (dysthymia) Disruptive mood dysregulation disorder Pre-menstrual dysphoric disorder Substance/medication-induced depressive disorder Depressive disorder due to another medical condition Other specified depressive disorder Unspecified depressive disorder In contrast to Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision (DSM-IV-TR), DSM-5 separates out depressive disorders from bipolar-related disorders. Disruptive mood dysregulation disorder is limited to children up to age 12; children with this diagnosis are at increased risk of developing unipolar depressive disorders and anxiety disorders, rather than bipolar disorder. The common features of depressive disorders include sad, empty, and irritable mood in combination with somatic and cognitive impairments that interfere with an individual’s ability to function. Features that distinguish the depressive disorders include duration, timing, and etiology of the specific disorder.

Major Depressive Disorder DSM-5 Criteria To diagnose major depressive disorder (MDD), at least five of the following symptoms must be present during the same two-week period; they must not be the direct result of a medical disorder; and at least one of the symptoms must be either depressed mood or a loss of interest or pleasure: depressed mood most of the day and nearly every day as expressed by either subjective account or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day, as expressed by either subjective account or observation made by others; significant unintentional weight loss or weight gain (e.g., more than 5% of body weight in a month), or a decrease or increase in appetite nearly every day; insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt (which can be delusional) nearly every day (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate , or indecisiveness, nearly every day (either by subjective account or as observed by others); and recurrent thoughts of death (not just a fear of dying), recurrent suicidal ideation without a specific plan, a suicide attempt , or a specific plan for committing suicide. The symptoms must cause disruption in social, occupational, or other important areas of functioning; they might not be secondary to a medical condition (e.g., Cushing’s Disease) or to the physical effects of a substance (e.g., alcohol, recreational drugs, or medications); and they might not occur in the context of schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder NOS. The criteria require the absence of episodes of hypomania or mania; however, this does not apply if symptoms of hypomania or mania occur only in the context of being substance-induced or due to the physiological effects of a medical condition. Finally, although bereavement might also represent an exclusionary criterion for MDD, bereavement can be complicated by MDD if the symptoms persist for 2 months or longer, or are characterized by marked functional impairment, by preoccupation with worthlessness, by suicidal ideations or behavior, or by psychotic symptoms.

Specifiers for MDD

Several specifiers can be used to describe MDD: mild; moderate; severe without psychotic features; severe with psychotic features; in partial remission; in full remission; chronic; with catatonic features; with melancholic features; with atypical features; with post-partum onset; with or without full inter-episode recovery; and with a seasonal pattern.

MDD with Psychotic Features In this condition, delusions and hallucinations are present in addition to the symptoms of major depression. The psychotic symptoms can be mood-congruent (i.e., the content is consistent with depressive themes, such as guilt, poor selfworth, death, hopelessness, punishment), or mood-incongruent (i.e., where the content is not consistent with typical depressive themes, such as delusions of control, thought broadcasting, thought insertion, persecutory delusions). Both mood-congruent and mood-incongruent psychotic symptoms can be present concurrently. Delusions occur without hallucinations in about one-half to twothirds of adults, whereas hallucinations occur without delusions in one-fourth or less of adults. After psychotic symptoms appear, they tend to be present in each subsequent depressive episode.

MDD with Melancholic Features During the most severe period of the episode, there is either loss of pleasure in all, or almost all, activities, or there is lack of reactivity to usually pleasurable stimuli. In addition, three or more of the following must be present. A depressed mood that is experienced as qualitatively different from the feeling experienced after a loss Depression that is worse in the morning Awakening at least two hours before the usual time Marked psychomotor retardation or agitation Significant anorexia or weight loss Excessive or inappropriate guilt

MDD with Atypical Features In this condition, mood reactivity occurs in response to actual or potential positive events. Two of the following features must be present:

Significant weight gain or an increase in appetite Hypersomnia Leaden paralysis or a heavy feeling in the arms and legs A longstanding pattern of sensitivity to interpersonal rejection that results in social and occupational dysfunction

MDD with Post-Partum Onset The onset of episodes in this condition must occur within 4 weeks of delivery.

MDD with a Seasonal Pattern A temporal relationship exists between the onset of episodes and the season of the year. Episodes of depression generally occur in the fall or winter.

MDD with Catatonic Features At least two of the following must be present: Motor immobility (including waxy flexibility or stupor) Excessive motor activity that is purposeless and not influenced by external stimuli Extreme negativism (manifested by maintenance of a rigid posture or resistance to commands) Unusual voluntary movements (manifested by posturing, stereotyped movements, mannerisms, or grimacing) Echolalia or echopraxia

Differential Diagnosis When considering a diagnosis of MDD, several other diagnoses must be ruledout, which we define in the subsections that follow.

Mood Disorder Due to a General Medical Condition The diagnosis is based on history, physical examination, and laboratory results. A temporal relationship must exist between the onset of depressive symptoms and the development of the abnormal physiological condition.

Substance-Induced Mood Disorder with Depressive Features

The diagnosis is based on history, physical examination, and laboratory results. The symptoms of depression must develop during or within a month of substance intoxication or withdrawal.

Dysthymic Disorder This diagnosis differs from MDD based on its severity, chronicity, and persistence. In dysthymic disorder, the depressed mood needs to be present more days than not for a period of 2 years.

Dementia In dementia , there is a pre-morbid period of cognitive decline, whereas in depression, the cognitive decline is associated with onset of depression.

Manic Episodes with Irritable Mood or Mixed States in the Setting of Bipolar Disorder A manic episode with mixed features requires the presence of symptoms that meet criteria for a manic or hypomanic episode and at least three symptoms of depression. In contrast, a depressive episode with mixed features is characterized by the presence of symptoms that meet criteria for a depressive episode, along with at least three symptoms of mania. If an individual meets full criteria for both mania and depression simultaneously, the diagnosis should be manic episode with mixed features.

Attention-Deficit/Hyperactivity Disorder Distractibility and low frustration tolerance are common in both attentiondeficit/hyperactivity disorder (ADHD) and MDD. The disturbance in mood in ADHD is one of irritability rather than sadness or loss of interest.

Adjustment Disorder with Depressed Mood This diagnosis is made if the depressive episode occurs in the context of a psychosocial stressor; it is not due to bereavement, and it does not meet criteria for MDD.

Epidemiology of MDD MDD is very common, with cross-sectional prevalence rates ranging from 2% to 5%. Life-time and 12-month prevalence rates are 13% to 17% and 6% to 7%, respectively, in American adults over the age of 18 years. For adults under age 50, it is twice as likely to affect women when compared to men; however, this

disparity dissipates in older adults. In patients with co-morbid medical illnesses, rates of depression can be significantly greater than those seen in the general population. MDD has been associated with high rates of psychiatric and medical morbidity, disability, and impaired social and work functioning. In otherwise healthy individuals, MDD can carry an increased risk of mortality related to suicide attempts, which are much more common in depressed patients (~20% life-time prevalence) compared to those in the general population (~0.9%). In patients with significant medical illness, the effects of MDD can be even greater. In patients with cardiovascular disease, depression has been associated with increased rates of post-surgical complications, recurrent cardiac events, and allcause mortality. In patients with diabetes, MDD has been associated with poorer adherence to medications, greater functional impairment, and greater rates of diabetes-related complications. These elevated rates highlight the importance of adequately identifying and treating MDD in these populations. Despite the prevalence of MDD and the impact it has on psychiatric and medical outcomes, MDD is poorly recognized and generally under-treated. One recent review estimated that approximately half of depressed patients are recognized as such, and only 18% to 25% are adequately treated.

Course of MDD MDD typically has a relapsing and remitting course. The onset of MDD can be sudden or gradual and develop over several weeks or months. Early signs can include sub-threshold level insomnia, poor appetite, decreased concentration, loss of interest, or other symptoms of depression. Other prodromal symptoms include anxiety and panic attacks. MDD with a sudden onset often occurs in the context of a severe psychosocial stressor, especially divorce or loss of a loved one. Eighty percent of acute episodes of MDD are associated with a significant stressor in the previous 6-month period. The natural course of MDD is to have eventual resolution of the depressive episode. This occurs within 6 months in 50% of cases but can take significantly longer for other individuals, with 40% still meeting criteria for MDD at 1 year, 20% at 2 years, and 12% at 5 years. Following a depressive episode, patients have a significantly elevated risk of relapse to depression; the risk of relapse depends on the number of life-time depressive episodes. The risk of relapse after one episode is about 50%, whereas after three episodes, this number climbs to more than 80%. Factors that contribute to relapse include: a high number of previous episodes; inadequate

antidepressant treatment; partial response to treatment; discontinuation of effective treatment; rapid discontinuation of antidepressants; a highly emotional environment; and co-morbid medical or non-affective psychiatric disorders. The average life-time number of episodes is four. The inter-episode interval shortens with increasing numbers of episodes from 6 years after 2 episodes to 2 years after 3 episodes. The rates of recurrence after a full recovery from an episode of MDD, in patients with recurring illness, ranges from 50% within 2 years to approximately 90% within 6 years.

Etiology Family Studies MDD is common in families . It is found 2 to 3 times more frequently in the first-degree biological relatives of individuals with the disorder than in the general population. Family studies of depressed patients demonstrate significantly higher rates of depression in first-degree relatives, who share 50% of the genome, than in second-degree relatives, who share 25% of the genome. These findings suggest a genetic contribution.

Twin Studies and Adoption Studies Studies conducted in Europe and in the United States have demonstrated that the concordance rate for MDD is about 50% in monozygotic twins (compared to 20% in dizygotic twins); the heritability of MDD has been estimated at 40% to 50%. These results argue for a genetic factor in the development of MDD. However, most of the twins in these studies were raised together, and it has been hypothesized that twins’ behavior can influence each other and that identical twins tend to be treated more alike by their environment than are fraternal twins or siblings. Adoption studies attempt to differentiate the influence of genetic and environmental factors on the expression of an illness. A common strategy is to examine differences in rates of the illness among biological relatives as opposed to adoptive relatives. Studies of adoptees with MDD have shown that the rates for depression are higher in their biological parents as compared to the rates in their adoptive parents. Studies of identical twins raised apart have shown a concordance rate of about 70% for unipolar and bipolar disorder, which is similar to that of identical twins raised together. These results provide further support for a genetic contribution to the development of MDD. However, in both twin and adoption studies, 20% to 30% of identical twin pairs are not concordant

for depression, thus arguing for an interaction of the environment with a genetic vulnerability for MDD to be expressed. Reviews of recent twin studies have shown that 20% to 45% of the variance in the risk for depressive disorders is attributed to genetic factors and the remainder to environmental factors.

Genetic Studies Given the evidence in family and adoption studies, there appears to be a genetic component to MDD. However, the genetic contribution to MDD likely involves multiple genes interacting with the environment; this makes the identification of single causal genes exceedingly difficult (and likely impossible). Gene association studies that focus on potential pathways involved in the pathogenesis of MDD have found the disorder to be associated with certain glucocorticoid receptor genes, monoamine oxidaseA genes, and glutamate receptor genes. Aside from those studies linking depression itself with genetic variants, several genes (including polymorphisms in the serotonin transporter gene, catechol-o-methyltransferase [COMT] gene, and brain-derived neurotrophic factor [BDNF] gene) have been associated with an increased likelihood of antidepressant response or decreased likelihood of side effects. Further studies might enable clinicians to more readily identify which patients are at highest risk for depression and to what medications these patients will be most likely to respond.

Biochemical Theories: Biogenic Amine Hypothesis The biogenic amine hypothesis was the first biochemical theory to explain the biological basis of both depression and mania. The theory evolved from clinicians’ observations that certain medications had either a negative or positive effect on mood. Reserpine (which depletes the brain of norepinephrine, serotonin, and dopamine) had a tendency to make patients feel depressed, whereas iproniazid (which inhibits the metabolism of norepinephrine, serotonin, and dopamine), had a tendency to improve the mood in some patients with tuberculosis. The hypothesis argued that depression is the result of too little catecholamine or indoleamine neurotransmitter and that mania is the result of too much catecholamine or indoleamine transmitter. Further support for the theory emerged with the finding from animal studies that the tricyclic antidepressants (TCAs) block the uptake of norepinephrine and serotonin from pre-synaptic terminals. Problems with the theory became evident with the observation that the uptake blocking mechanism occurs within minutes, whereas the therapeutic effect of

TCAs takes several weeks. Other explanations for the effectiveness of antidepressants were pursued with the new technological advances in receptor biology. Subsequent animal research demonstrated that TCAs, monoamine oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT) down-regulate beta-adrenergic receptors over a period consistent with the time course to achieve a therapeutic effect. The down-regulation of beta-adrenergic receptors did not fully explain the biochemical basis of depression because most of the new antidepressants have no effect on these receptors. Recent studies have demonstrated that norepinephrine and serotonin are important for the therapeutic effect of TCAs and selective serotonin re-uptake inhibitors (SSRIs), respectively. In one study, dietary depletion of L-tryptophan (which decreases the synthesis of serotonin) resulted in a relapse of depression in SSRI-responders. In another study, subjects given alpha-methyl-paratyrosine (AMPT) (which inhibits the synthesis of norepinephrine) resulted in a relapse of depression in TCA (primarily norepinephrine uptake blockers)-responders. The SSRIs and atypical antidepressants, except bupropion, increase serotonin neurotransmission non-selectively. However, two atypical antidepressants, mirtazapine and nefazodone, selectively increase serotonin neurotransmission through the 5-HT1A receptor sub-type by blocking the 5-HT2 receptor. An increase in 5-HT1A receptor activity might be important for the therapeutic effect of many of the newer antidepressants.

Sleep Dysregulation Electroencephalographic studies in patients with MDD have identified several architectural abnormalities during sleep, including shortened rapid eye movement (REM) latency (decreased time from sleep onset to the onset of the first REM cycle); decreased non-REM sleep; increased REM density (increased number of REMs per unit of time during REM sleep); reduced total sleep time; and decreased sleep continuity. Sleep architecture abnormalities are most commonly associated with the melancholic sub-type in unipolar depression. Any single sleep architecture abnormality is not closely associated with MDD. However, the combination of decreased REM latency, increased REM density, and decreased sleep efficiency discriminates patients with MDD from controls. These measures, however, are not specific to MDD; thus, they are not appropriate for use as a diagnostic test.

Hypothalamic-Pituitary-Adrenal Axis Dysregulation Hypersecretion of cortisol over the 24-hour circadian cycle has been repeatedly

observed in patients with MDD. The dexamethasone suppression test (DST) has been used to assess the finding of hypersecretion of cortisol in depressed patients. The test consists of giving a 1 mg dose of dexamethasone at 11:00 p.m. and measuring serum cortisol the following day at 8:00 a.m. and 4:00 p.m. Normally, cortisol is suppressed to levels below 5 micrograms/dL for 24 hours. Decreased suppression or non-suppression of serum cortisol in response to a 1mg dexamethasone challenge occurs in about 41% of patients who have MDD with melancholia and in about 64% of patients who have MDD with psychotic features (Nelson and Davis, 1997). According to Nelson and Davis (1997), the DST has a sensitivity of 64% and a specificity of 59%, which limits its value as a diagnostic test for MDD. The hypothesized mechanism for the dysregulation of the hypothalamicpituitary-adrenal (HPA)-axis is based on studies demonstrating glucocorticoidmediated feedback impairment at the levels of the pituitary and hypothalamus (de Kloet et al, 1998; Young et al, 1991). The glucocorticoid receptors are in the cytoplasm of cells. Normally, when cortisol binds to the glucocorticoid receptor, the cortisol-glucocorticoid receptor complex translocates into the cell nucleus to complete the feedback loop and enhance gene expression. However, in depressed patients, it has been hypothesized that the translocation of the cortisolglucocorticoid receptor complex into the nucleus is impaired, thus interfering with feedback and resulting in hypercortisolemia. Pre-clinical studies support this hypothesis, given that antidepressants enhance the translocation of the cortisol-glucocorticoid receptor complex from the cytoplasm into the nucleus. This dysregulation is believed to be a state-dependent phenomenon because HPA axis hyperactivity resolves after depression is effectively treated. Thus, treatment of depression with antidepressants might mediate the normalization of the HPAaxis (Pariante and Miller, 2001).

Hypothalamic-Pituitary-Thyroid Axis Dysregulation Thyroid abnormalities have been associated with mood disorders: About 10% of hospitalized depressed patients have a diagnosis of hypothyroidism. Thyroiditis is more common in patients with mood disorders. Patients with rapid-cycling bipolar disorder are more likely to exhibit hypothyroidism. Triiodothyronine (T3) is used to augment antidepressants for treatment-

resistant depression. The thyrotropin-releasing hormone (TRH) stimulation test can be used to challenge the hypothalamic-pituitary axis. Protirelin (55 international units [IU]), is given intravenously as the standard dose, and thyroid stimulating hormone (TSH) serum levels are measured at 30 minutes and 90 minutes after the infusion. An increase in serum TSH less than 5 IU/ml after TRH infusion is considered a blunted response. One-third of euthyroid patients with melancholia have blunted responses. Some studies show the blunted response is a trait marker, whereas others identify it as a state marker. The underlying mechanism for this abnormal response has not been determined.

Inflammation In recent years, depression has been associated with several pro-inflammatory markers , including C-reactive protein, interleukin-1, interleukin-6, and tumor necrosis factor. These markers might be present in the setting of significant stress and can normalize with treatment of depression. As pro-inflammatory cytokines are present in elevated levels in a number of other medical illnesses (e.g., cardiovascular disease, cancer, diabetes mellitus), abnormalities in the inflammatory cascade can in part mediate the relationship between depression and other medical illnesses.

Brain-Derived Neurotrophic Factor Brain-derived neurotrophic factor (BDNF) is a substance in the brain that promotes neuronal growth and is a critical component allowing for neuroplasticity in the developing brain. In addition to its role in development, BDNF might play a significant role in the development and improvement of depressive symptoms in patients with MDD. As noted later in the chapter, MDD has been associated with decreases in the size of the amygdala, anterior cingulate, and prefrontal cortex, all of which are areas implicated in the pathogenesis of MDD. Decreased serum BDNF levels have been found in patients with MDD and might play a role the atrophy of these brain areas. Other evidence implicating BDNF in the pathophysiology of depression include the findings that mutations in the BDNF gene have been associated with MDD and that antidepressant medications can increase levels of BDNF.

Neuroimaging

Several imaging abnormalities are associated with MDD. Structural imaging studies suggest that depression is associated with reductions in size in the amygdala, anterior cingulate cortex, and prefrontal cortex. Although results have been mixed, some researchers also have found reductions in the size of the hippocampus in depressed patients and have suggested that longer periods of depression are associated with greater reductions in hippocampal volume. Studies utilizing positron emission tomography (PET) have shown decreased metabolic activity in the frontal cortex of unipolar depressed patients, and those utilizing single photon emission computed tomography (SPECT) to assess cerebral blood flow have found global reductions in cerebral blood flow in unipolar depressed patients compared to controls. Functional imaging studies have identified two areas of abnormality in patients with MDD when compared to non-depressed individuals: increased activity in the amygdala, ventral striatum, dorsal anterior cingulate cortex, insula, and medial prefrontal cortex in response to negative stimuli, and, decreased activity in the ventral striatum in response to positive stimuli. These findings provide evidence for negative biases in emotional processing that are often seen in patients with depression (Kupfer, 2012).

Pharmacological Treatment of MDD Antidepressants are classified into several categories: TCAs and tetracyclic antidepressants MAOIs SSRIs Serotonin-norepinephrine re-uptake inhibitors (SNRIs) Atypical antidepressants (including dopamine-norepinephrine re-uptake inhibitors [DNRIs], trazodone, mirtazapine, nefazodone, and others)

Efficacy Randomized, double-blind, placebo-controlled studies have demonstrated that all classes of antidepressants are equally effective in treating MDD. Response rates (≥ 50% reduction in symptoms on standardized depression rating scales) range from 50% to 75% for medications and from 30% to 40% for placebo. Remission rates range from 30% to 40% for antidepressants.

To determine the effectiveness of pharmacologic and psychotherapy treatments for MDD, the National Institute of Mental Health (NIMH) sponsored the S equenced Treatment Alternatives to Relieve Depression (STAR*D) Trial , which was a multi-center, open-label, prospective study (n = 2,876) attempting to determine response and remission rates to a systematic approach for the treatment of depression. In this study, patients underwent up to 4 levels of treatment characterized by treatment switches or augmentation until they experienced remission of their symptoms. There were no significant differences in effectiveness between any treatments at any treatment level. The cumulative Q uick Inventory of Depression Symptomatology-Self Rated (QIDS-SR ) remission rates for Levels 1 to 4 were 37%, 56%, 62%, and 67%, respectively, suggesting that aggressive treatment of MDD can lead to high rates of remission. Patients who achieved remission rather than response were less likely to relapse at 12-month naturalistic follow-up (Rush et al, 2004; Sinyor et al, 2010). In view of the absence of a difference in response rates or remission rates among the antidepressants, decisions concerning which antidepressant to use are based on side-effect profile, history of response, family history of response, potential for drug interactions, risk of aggravating an existing medical condition (e.g., cardiac conduction defect), risk in overdose, depression sub-types (e.g., atypical depression), patient preference, and cost. After an antidepressant has been chosen, the dose must be titrated slowly in view of the risk of inducing side effects. The SSRIs have a flat dose-response curve that enables clinicians to achieve the therapeutic dose more quickly. With elderly and medically ill patients on multiple medications, the dose should be increased more slowly, and the final maintenance dose may be one-half or onethird of the usual average dose. An adequate trial for antidepressants is 4 to 6 weeks at the optimal therapeutic dose. None of the available antidepressants appears to have a more rapid onset of action. Blood levels can be obtained for all antidepressants, but only three of the TCAs —desipramine, nortriptyline, and imipramine—show a correlation between blood level and therapeutic effect. Other reasons to obtain blood levels include monitoring compliance, risk of toxicity, and potential drug interactions.

Treatment Phases Treatment is divided into three phases to assist in treatment decision-making: the acute phase , the continuation phase , and the maintenance phase . The acute phase has an average duration of about 12 weeks, which is the time it often takes

to achieve full remission after there is evidence of a response to an antidepressant. The continuation phase begins when full remission is achieved. This phase lasts from 4 to 9 months and is considered a high-risk period for relapse. It is highly recommended that antidepressant medication be continued at the same dose as in the acute phase throughout this period. When the antidepressant is discontinued, it should be tapered gradually over several weeks or months to prevent withdrawal (from SSRIs), anticholinergic rebound (from TCAs), or increased risk for relapse. Psychotherapeutic approaches (there is the most evidence for c ognitive-behavioral therapy [CBT]) which focus on reducing stress and maintaining adherence are often helpful in preventing relapse during the continuation phase. The maintenance phase represents the long-term commitment to prophylactic treatment with an antidepressant. Research has demonstrated that all classes of antidepressants not only treat the acute symptoms of depression, but also prevent recurrence of episodes. Longitudinal studies demonstrate that a history of three or more episodes conveys a greater than 80% risk for recurrence. Therefore, in general it is recommended that patients with three or more depressive episodes continue to receive treatment (at the same dose as in the acute phase) indefinitely. Patients with other risk factors for relapse (co-morbid psychiatric disorders [e.g., panic disorder], co-morbid substance abuse, dysthymic disorder, ongoing psychosocial stressors, family history of MDD, and chronic medical illnesses) should also consider maintenance treatment.

Side Effects The side-effect profile of antidepressants depends on their unwanted receptorblocking properties and their effect on increasing certain neurotransmitter transmission. Side-effects related to receptor-blocking properties include: muscarinic blockade (manifest by dry mouth, constipation, blurred vision, difficulty initiating urination); alpha 1 -adrenergic blockade (orthostatic hypotension); and, histaminic blockade (weight gain and sedation). Side-effects related to receptor activation include effects of norepinephrine (rapid heart rate, increased anxiety, insomnia, tremor, and diaphoresis); serotonin (insomnia, sexual dysfunction, gastrointestinal disturbances [e.g., nausea, vomiting, diarrhea], restlessness [akathisia], headaches, and appetite loss); and, dopamine (psychosis, agitation, and elevated blood pressure) (see Tables 15-1, 15-2, 15-3, 15-4, and 15-5).

Table 15-1: TCAs

Name

Mechanism Uptake Blockade

Alpha1 Adrenergic Blockade

Histamine Muscarinic H1 Blockade Blockade

Amitriptyline (Elavil)

NE/5-HT

+++

+++

+++

Amoxapine (Asendin)

NE

+++

+

++

Clomipramine (Anafranil)

NE / 5-HT

+++

+++

+

Desipramine(Norpramin) NE

++

+

+

Doxepin (Sinequan)

NE

+++

++

+++

Imipramine (Tofranil)

NE / 5-HT

+++

++

++

Nortriptyline (Pamelor)

NE

+++

+

+

Protriptyline (Vivactil)

NE

++

+++

++

Trimipramine (Surmontil)

None

+++

++

+++

NE

+++

+

+++

Tetracyclic Antidepressant Maprotiline (Ludiomil)

+ = weak; ++ = moderate; +++ = strong; NE (norepinephrine); 5-HT (serotonin)

Table 15-2: SSRIs Name

Alpha1 Histamine H1 ACh Adrenergic Blockade Blockade Blockade

Citalopram (Celexa)

+/0

+/0

+/0

Escitalopram (Lexapro) +/0

+/0

+/0

Fluoxetine (Prozac)

+/0

+/0

+/0

Fluvoxamine (Luvox)

++

+/0

+/0

Paroxetine (Paxil)

+/0

+

+/0

Sertraline (Zoloft)

+/0

+/0

+/0

0 = none; + = weak; ++ = moderate

Table 15-3: SNRIs Name

Alpha1 Muscarinic Histamine H1 Adrenergic Blockade Blockade Blockade

Desvenlafaxine (Pristiq)

+/0

+/0

+/0

Duloxetine (Cymbalta)

+/0

+/0

+/0

Levomilnacipran (Fetzima) +/0

+/0

+/0

Venlafaxine (Effexor)

+/0

+/0

+/0

0 = none; + = weak

Table 15-4: Atypical Antidepressants

Name

Alpha1 Histamine Adrenergic Muscarinic H1 Blockade Blockade Blockade

Mechanism of Action

Bupropion Blocks NE and DA uptake (Wellbutrin)

+/0

+/0

+/0

Mirtazapine Release NE and 5-HT; blocks 5-HT2 and 5-HT3 (Remeron) receptors

+

+

+++

Nefazodone Blocks 5-HT2 receptor; blocks NE and 5-HT uptake (Serzone)

+

+/0

+/0

Trazodone (Desyrel)

+++

+/0

+

0

0

+/0

Vortioxetine Inhibits 5-HT re-uptake. Blocks 5-HT1D , 5-HT3 , and 5- 0 (Brintellix) HT7 ; agonist at 5-HT1A ; partial agonist at 5-HT1B .

0

0

Blocks 5-HT2 receptors and 5-HT uptake

Vilazodone Inhibits 5-HT re-uptake; partial agonist at 5-HT1A (Viibryd) receptors

0 = none; + = weak; ++ = moderate; +++ = strong

Table 15-5: Monoamine Oxidase Inhibitors (MAOIs ) Name

Rev./Irrev.

Inhibits MAOA

Inhibits MAOB

L-Deprenyl (Eldepryl)

Irreversible

–*

+

Moclobemide

Reversible

+

–

Phenelzine (Nardil)

Irreversible

+

+

Selegiline (Emsam)

Irreversible

±**

+

Tranylcypromine (Parnate)

Irreversible

+

+

* L-Deprenyl at doses above 10 mg/d inhibits both MAOA and MAOB ** In oral form at lower doses, selegiline is a specific inhibitor of MAOB . However, when given orally at higher doses, it inhibits both MAOA and MAOB . In transdermal form, selegiline inhibits both MAOA and MAOB in the brain, but at lower doses does not affect MAOA in the GI tract (since it is absorbed transdermally).

Finally, there can be a slightly increased risk of suicidal thoughts or behaviors when beginning a new antidepressant medication, especially in children, adolescents, and young adults (under the age of 25 years). This can be related to side effects (such as agitation or restlessness) that might increase prior to improvements in mood associated with the medication. Therefore, close monitoring should occur in patients who are just starting one of these medications. That being said, the risks of untreated depression likely outweigh these risks associated with antidepressant medication treatment; therefore, treatment should not be withheld based on this risk alone. It also has been shown that suicidal thoughts or behaviors are decreased in adults over the age of 65 with antidepressant treatment.

ECT Overview and Indications ECT is a procedure whereby an electrical current is applied to an anesthetized patient in order to generate a generalized seizure for the purpose of treatment for MDD or another disorder. Although it is most often utilized when a patient has failed trials with several antidepressant medications, it can be used as a first-line treatment for patients with severe depression with psychotic features, a high risk of suicide, a medical emergency due to severe weight loss (related to poor appetite), depression with catatonic features, or a previous good response.

Efficacy With remission rates of 70% to 90%, ECT is the most effective treatment for MDD. It has been shown to be more effective than antidepressant medication therapy and still has high levels of efficacy in patients who are considered treatment-resistant from a pharmacologic standpoint.

Procedure ECT is given three times per week with the average number of treatments between 8 and 12. Unilateral ECT is the preferred procedure because it is less likely to cause confusion and/or memory disturbances. Bilateral ECT is used when there is no response to at least 6 unilateral treatments or when there is a need for rapid response (e.g., in patients with catatonic symptoms or severe, imminently life-threatening depressive episodes). Patients who are at high risk for cognitive impairments from ECT (or those who develop significant cognitive impairment when undergoing brief-pulse, unilateral ECT) might benefit from

ultra-brief pulse unilateral ECT, which is associated with fewer cognitive side effects.

Side Effects The primary side-effect is memory loss for events close to the time of the treatment (retrograde) and for events 3 to 6 months after completing ECT (anterograde). Post-ECT confusion is also common and can take up to 7 days to clear. Factors that contribute to memory loss and confusion include: long seizures; older age; a high intensity-stimulus; bilateral electrode placement; inadequate oxygenation; many treatments; and a short interval between treatments. Recent advancements that have reduced memory loss and confusion include ultra-brief pulse stimulus, unilateral electrode placement, and hyperventilation with 100% oxygen prior to applying the stimulus.

Contraindications There are no absolute contraindications to ECT; however, certain high-risk medical conditions must be reviewed with an appropriate consultant. Some of the high-risk conditions include: hypertension; cardiac arrhythmias; congestive heart failure; presence of a cardiac pacemaker; myocardial infarction; intracardiac thrombi; anticoagulant therapy; pregnancy; dementia; vascular aneurysms; respiratory disorders (e.g., chronic obstructive pulmonary disease [COPD], asthma, emphysema); a brain tumor or mass; epilepsy; orthopedic problems; and a history or family history of problems with anesthesia (e.g., malignant hyperthermia).

Repetitive Transcranial Magnetic Stimulation Repetitive transcranial magnetic stimulation (rTMS ) obtained FDA-approval for the treatment of MDD in 2008. In the pivotal multi-site, 6-week trial involving 301 medication-free depressed patients randomized to either rTMS or sham rTMS, O’Readon and associates (2007) demonstrated response rates of 24% versus 12% and remission rates of 14% versus 5% with rTMS versus sham rTMS, respectively. Standard rTMS uses a figure-8 coil placed over the left dorsolateral prefrontal cortex area of the head to produce a powerful magnetic field that results in an electrical current in the superficial cortical neurons. Its advantages over ECT include absence of a generalized seizure; fewer cardiovascular and neurologic side effects; fewer cognitive side effects; and no requirement for generalized anesthesia. However, in head-to-head studies, rTMS

is not as effective as ECT, particularly in severe MDD. Furthermore, rTMS must be administered daily (typically 5 days per week), for four to six weeks, thus making it an inconvenient option for some patients. rTMS is most useful for patients with a poor response or intolerance to antidepressant trials; for those who meet criteria for ECT but are unwilling to undergo that treatment; for those who are medically unstable for ECT (e.g., congestive heart failure; COPD); or for those who are at high risk for cognitive impairment from ECT. rTMS is generally safe and well tolerated. Although infrequent, the most common side effects are headache and dizziness. There are rare reports of seizure induction with high frequency rTMS, but the seizures are brief and without significant sequelae (Wassermann, 1998). Because of this, a history of seizures is a relative contraindication to rTMS, and seizure risk should be included in the informed consent process. Absolute contraindications for rTMS include: metal in the head (outside the mouth); metal particles in the eye; implanted neurostimulators; medical pumps; cochlear implants; or ironcontaining surgical clips (Rosenberg and Dannon, 2009). A new development to improve the efficacy of rTMS is deep rTMS, which allows stimulation of the deep structures of the brain important to reward and motivation. These structures include ventral prefrontal cortex and its connections to the nucleus accumbens and ventral striatum. The new H-coil induces an effective magnetic field at 3 cm below the skull compared to less than 1 cm with the existing figure-8 coil. Early Phase II studies show evidence of feasibility and safety. Deep rTMS might be especially applicable for elderly depressed patients who do poorly with routine rTMS. Their poor response is believed to be due to progressive brain shrinkage with age, thus increasing the distance from the coil to the prefrontal cortex (Levkovitz et al, 2007).

Vagal Nerve Stimulation Vagal nerve stimulation (VNS ) is now FDA-approved for treatment-resistant MDD . It involves a minor surgical procedure to implant a pulse generator under the skin of the chest and to attach an electrode to the vagus nerve. The generator is turned on after a 2-week recovery period from the surgery. The presumed mechanism of action is through the vagus nerve’s afferent projections to the nucleus tractus solitarius, which has connections to brain regions important in MDD. PET imaging has shown that stimulation of the vagus nerve produces changes in the brainstem and limbic system similar to antidepressant medications. Further, studies have shown that VNS changes the concentration of

serotonin, norepinephrine, glutamate, and GABA (McClintock et al, 2009). In the pivotal trial to obtain FDA-approval for treatment-resistant depression, a total of 235 patients with MDD or bipolar disorder I and II were randomized to VNS plus medications or medications alone. At 3 months, there was no difference between the two groups; however, at 12 months, the response rates were 29.8% versus 12.5%, and the remission rates were 17% versus 7% for VNS plus medications versus medication monotherapy, respectively. This suggests that the antidepressant effect from VNS is realized 6 to 12 months after initiating treatment (Rush et al, 2005; George et al, 2005). The most common side effects are incision pain, hoarse voice, and cough; less common side effects are dyspnea, neck pain, dysphagia, laryngismus, and paresthesia (McClintock et al, 2009). VNS is indicated for MDD and bipolar disorder I and II.

Deep Brain Stimulations Deep brain stimulations (DBS ) is not FDA-approved for the treatment of MDD ; however, there is a multi-site, Phase III study in progress to obtain an FDA indication for treatment-resistant MDD. Mayberg (2005) and others (Holtzheimer et al, 2012) have demonstrated that the subcallosal cingulate area (SCG) is hyperactive in treatment-resistant depression (TRD) (i.e., multiple failed trials of antidepressants, ECT, CBT) and that stimulation of the SCG, at a given frequency, reduces neuronal activity in that region. In addition, Mayberg has demonstrated that there is a corresponding clinical response with the reduction of activity in the SCG. Other evidence that hyperactivity of the SCG is important in the pathogenesis of depression is found from studies showing reductions in blood flow and metabolic activity in this region with other treatment modalities for depression. In a multi-site open study of 21 patients with TRD, response rates (50% reduction on HAM-17-D) were 57%, 48%, and 29% at 1, 6, and 12 months (Lozano et al, 2012), respectively. The results of the Phase III study are much anticipated.

Treatment of Sub-Types of MDD MDD with Psychotic Features The standard treatment of psychotic depression includes use of an antidepressant and an antipsychotic medication. The response rate for an antidepressant alone is 40% and for an antipsychotic alone is 20%, whereas the response rate for the combination of an antidepressant and an antipsychotic

medication is 70%. Recent studies have suggested that SSRIs are as effective as TCAs in combination with an antipsychotic medication.

MDD with Catatonic Features In addition to treating depressive symptoms with antidepressant medications, patients with prominent catatonic symptoms should receive intravenous (IV) benzodiazepines as a first-line treatment. If these are not effective, ECT should be strongly considered. Untreated catatonia can quickly progress to malignant catatonia, which is characterized by catatonic symptoms as well as by autonomic instability, which has been associated with high rates of morbidity and mortality.

MDD with Melancholic Features There is some evidence that SNRIs and TCAs might be more effective than SSRIs in treating MDD with melancholic features. In addition, patients with MDD with melancholic features have higher rates of recurrent depressive episodes; therefore, maintenance treatment should be strongly considered for these patients.

MDD with Atypical Feature The MAOIs and SSRIs are more effective than TCAs in treating atypical depression; they are considered first-line treatment for these patients.

MDD with Seasonal Features Artificial light with an intensity of 2,500 lux placed 1 meter from the patient is very effective in treating seasonal affective disorder (SAD ). The response rate is as high as 75%, a rate comparable to antidepressant medications. Light therapy is more effective in treating patients with SAD than patients with non-seasonal MDD. Patients can be exposed to the light at any time of the day; however, some patients require the exposure in the morning. Response to light occurs within a week, and relapse can occur as soon as 3 to 4 days after discontinuation. Light therapy should begin in the fall and be continued through the spring. Given the rapidity of response and the effectiveness of light therapy, a 1- to 2-week trial is often recommended prior to the addition of an antidepressant. Although bupropion is FDA-approved for treating SAD, other antidepressants also are efficacious.

Psychotherapy

CBT and interpersonal psychotherapy (IPT) have been shown to be effective in the treatment of mild to moderate depression. Brief forms of psychodynamic psychotherapies and supportive psychotherapy are considered helpful by many clinicians and are now being studied using RCTs.

CBT The cognitive-behavioral approach to treating depression focuses on the impact of maladaptive belief systems on patients’ views of themselves, their environment, and their future. Patients who are depressed tend to see themselves as defective, their environment as unsupportive and too demanding, and their future as unchanging and hopeless. The primary tasks are to identify distorted beliefs and then to challenge their validity by using a variety of cognitivebehavioral techniques. CBT is focused and time-limited (16 to 20 sessions) for Axis I disorders and acute crises; however, for significant co-morbid Axis II disorders, therapy can have a duration of 1 to 2 years. For the acute treatment of depression, meta-analyses have shown that CBT has a medium effect size of 0.67 compared to controlled conditions, including absence of treatment and non-specific controls (Driessen and Hollon, 2010). This effect size corresponds to a number-needed-to-treat (NNT) of 2.75. In the outpatient setting, early studies and a recent meta-analysis have shown that CBT and antidepressant treatment are equally effective at treating an acute depressive episode. For severely depressed patients, results from studies comparing CBT and antidepressant treatment are mixed. One consideration when referring a patient for CBT is the level of training of the CBT therapist; this has been shown to be an important factor in demonstrating equal efficacy of CBT with antidepressants (Driessen and Hollon, 2010). CBT also has demonstrated durability after treatment is discontinued. When comparing CBT to antidepressants for patients who had initially responded to acute treatment followed by treatment discontinuation, CBT monotherapy showed lower relapse rates than antidepressants. Two recent studies showed that acute treatment with CBT exhibited long-term benefits that were equal to maintenance treatment with antidepressants (Hollon et al, 2005; Dobson et al, 2008).

IPT IPT emphasizes the status of individuals as social beings and the impact of environment and current life events on psychopathology. Specifically, IPT focuses on interpersonal losses, role disputes and transitions, social isolation,

and deficits in social skills as contributing factors for precipitating depression. Techniques such as role-playing are used to develop social skills, and role expectations are clarified in conjoint sessions for role disputes. IPT is focused on the present, and it is conducted using a manual. It is time-limited and typically lasts 16 weeks. It makes use of psychoeducation and teaches patients that depression is a medical illness. In a 16-week randomized trial of the acute treatment of depression comparing IPT alone, amitriptyline alone, combined IPT and amitriptyline, and a nonscheduled control treatment, amitriptyline reduced symptoms faster than IPT, but there was no difference in symptom severity at week 16; combined amitriptyline and IPT was significantly better than either monotherapy alone. IPT was superior to amitriptyline with regard to social functioning at one-year follow-up (DiMascio et al, 1979; Weissman et al, 1979; Weissman et al, 1981). In a landmark multi-site trial referred to as the National Institute of Mental Health Treatment of Depression Collaborative Research Program (TDCRP) (Elakin et al, 1989), 250 acutely depressed outpatients were randomized to receive 16 weeks of IPT, CBT, imipramine plus clinical management, or placebo plus clinical management. Patients with mild depression (HAM-D-17 < 20) responded equally well regardless of treatment approach. For severely depressed patients (HAM-D-17 > 20), imipramine worked faster and imipramine and IPT showed equal responses on the HAM-D-17; CBT was not superior to placebo for severely depressed patients. In an 18-month follow-up of the NIMH TDCRP, relapse rates among acute phase remitters for CBT, IPT, imipramine (stopped at 16 weeks), and placebo were 36%, 33%, 50%, and 33%, respectively (Shea et al, 1992). Other studies evaluating the efficacy of IPT in the acute treatment of depression have concluded that IPT is more effective than antidepressants in treating mood, suicidal ideation, and lack of interest, whereas antidepressants are more effective for disturbances of appetite and sleep. Studies evaluating the efficacy of IPT in the maintenance treatment of depression have shown that IPT relapse-free survival rates are 30% to 40%, whereas supportive care relapse-free survival rates are 10% at 3-year follow-up. Also, patients receiving high-quality IPT had 2-year survival rates similar to those with antidepressants. The lack of adequate dosing of IPT may account for some of the differences between survival rates for IPT and antidepressants (Frank et al, 1990, 1991). In a maintenance study of elderly depressed patients, Reynolds and associates (1999) found that IPT was significantly better than placebo and that the combination of IPT and nortriptyline provided the best outcome. Frank and colleagues (2007)

did not find a dose relationship of IPT maintenance treatment and outcome. There is a lack of studies comparing IPT and serotonin re-uptake inhibitors and atypical antidepressants.

Brief Psychodynamic Psychotherapy There are two primary approaches for the treatment of depression with psychodynamic psychotherapy: short-term (STPP ) and long-term (LTPP ). STPP is generally focused and time-limited to 20 to 24 sessions, whereas LTPP is open-ended and has no predetermined duration. The common themes associated with depression that are identified and targeted in psychodynamic psychotherapy include anger turned inward, concerns about harming others because of one’s destructiveness or greed, perfectionistic expectations, a persistent superego, hopelessness due to losses from the past or present, selfsacrifice at the expense of one’s desires, and feelings of helplessness, weakness, and loneliness (Gabbard and Bennett, 2006). There is also a focus on the defense mechanisms that the patient uses to cope with his/her emotional distress (e.g., anger over feeling unjustly treated is turned toward oneself by making selfdeprecating statements). The therapist will make use of transference, countertransference, and resistance in the sessions to gain insight into what occurs in the patient’s relationships outside of therapy. The therapist’s formulations will consist of common patterns of interactions with significant individuals over the course of the patient’s development. The unconscious relationships among early and current conflicts, both in and outside of therapy, are interpreted in order for the patient to gain insight. There are relatively few controlled studies of psychodynamic psychotherapy. Most of the studies assessing the efficacy of psychodynamic therapy have been with STPP. LTPP does not lend itself to RCTs (Leichsenring, 2009); thus, LTPP studies are generally naturalistic or effectiveness studies, which are performed in clinical practice settings. In a meta-analysis comparing four STPP studies with CBT, Leichsenring (2001) showed that both approaches were equally effective in reducing depressive symptoms and general psychiatric symptoms as well as improving social functioning; in addition, these results had durability. Maina and co-workers (2005) showed that STPP and brief supportive therapy were significantly better than a waiting-list for patients with dysthymic disorder, depressive disorder not otherwise specified, or adjustment disorder with depressed mood. They also found that STPP was superior to supportive therapy at 6-month follow-up.

Combination Psychotherapy and Antidepressant Treatment Despite an array of psychotherapy approaches, the data suggests that the combination of pharmacologic and psychotherapeutic treatment is more effective than either treatment alone. The benefits are mild in patients with less-severe disease and more pronounced in patients with severe illness (e.g., those in the hospital and those with severe depression). Combined therapy should be used in the following situations: Treatment with one modality is insufficient to produce a complete response The depression is chronic The clinical presentation includes multiple symptoms, some of which might be more responsive to one modality over the other For example, problems with assertiveness would be more amenable to psychotherapy, whereas an appetite disturbance would likely respond best to an antidepressant.

Persistent Depressive Disorder (Dysthymia) DSM-5 Criteria In contrast to MDD (which is characterized by episodic, severe alterations in mood accompanied by neurovegetative symptoms), dysthymic disorder is characterized by a milder but more chronic depressed mood. This depressed mood (or potentially an irritable mood in children and adolescents) must be present for most of the day, more days than not, for at least two years (one year in children or adolescents). Patients exhibit at least two neurovegetative symptoms—poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions, or feelings of hopelessness—and are never symptom-free for more than 2 months during the 2-year period (one year in children or adolescents). Patients might not meet criteria for a major depressive episode during the first 2 years of dysthymia. Furthermore, as in MDD, patients must have no history of mania, hypomania, or cyclothymia; symptoms cannot be caused by a medical condition, drug of abuse, or a medication; symptoms cannot occur exclusively during the course of psychotic disorders; and symptoms must cause clinically significant distress or impairment in psychosocial function. Persistent depressive disorder is

essentially an amalgam of DSM-IV dysthymic disorder and chronic major depressive episode.

Epidemiology and Course Dysthymic disorder is less common than MDD, with a life-time prevalence rate of 6% and point prevalence of 3%. Dysthymic disorder generally exhibits a slow and insidious onset beginning in childhood, adolescence, or early adulthood. When dysthymic disorder is co-morbid with MDD, the condition is referred to as a “double depression.” The presence of dysthymic disorder increases the risk for an episode of MDD in vulnerable individuals.

Treatment The treatment of dysthymic disorder parallels that of MDD. Antidepressant medications have similar efficacy in patients with dysthymic disorder as in patients with MDD. The addition of psychotherapy to antidepressant treatment often yields a better response than if either were used individually.

Pre-Menstrual Dysphoric Disorder Pre-menstrual dysphoric disorder (PDD ) presents with dysphoria, mood lability, irritability, and anxiety. The quality and intensity of the symptoms are the same as experienced in MDD, but for a shorter duration. The symptoms have their onset in the pre-menstrual phase of the cycle and remit at the onset of menses. The diagnostic criteria include five or more of the following symptoms during the period between onset and termination of menses: Mood swings, sudden sadness or tearfulness, or sensitivity to rejection Marked irritability or anger or increased interpersonal conflict Marked depressed mood, hopelessness, or self-deprecating thoughts Marked anxiety, feeling tense, or on edge In addition, one of the following symptoms must be present to add up to a total of five symptoms to meet criteria: Decreased interest in usual activities Decreased ability to concentration Marked fatigue or low energy

Marked change in appetite including food cravings and overeating Insomnia or hypersomnia Feeling of being out of control or overwhelmed Physical symptoms including breast tenderness or swelling, joint or muscle pain, or a sensation of bloating or weight gain. The five or more symptoms must be met for most menstrual cycles over the prior 12-month period. The severity of symptoms must cause significant distress that interferes with function in work, school, or relationships. Finally, the symptoms do not represent an exacerbation of another depressive or anxiety disorder.

Epidemiology and Course The most conservative estimate of PDD prevalence for women that meet full symptom criteria with functional impairment and without co-morbid psychiatric disorders is 1.3%. The onset of PDD can occur any time after menarche up to menopause; PDD can worsen as a woman approaches menopause.

Treatment The treatment approach for PDD is multi-factorial that includes medications, lifestyle changes, nutritional supplements, and CBT. SSRIs have been shown to be very effective in the treatment of PDD; sertraline was the first SSRI to show significant efficacy. The SSRIs are initiated one week before the onset of menses or prescribed on a regular basis; they often show a response within 24 hours. Other medications to consider include contraception medications, diuretics, and pain-relievers. Recommended lifestyle changes include relaxation, stress management, exercise, and the reduction in the use of caffeine, alcohol, and tobacco. CBT has been shown to be effective in the context of cognitive, emotional, or physical changes consistently occurring with the onset of menses.

Substance/Medication-Induced Depressive Disorder The diagnostic criteria include persistent depressed mood or significant decrease in interest or pleasure in all, or almost all activities. In addition, there is evidence based on history, physical examination, or laboratory findings that the persistent depressed mood or loss of interest developed during or soon after intoxication, withdrawal, or exposure to a substance/medication that is known to produce these symptoms. The disturbed mood is not better explained by a depressive disorder that is not substance/medication-induced. The disturbance in

mood is independent of delirium and it interferes with social, occupational, or other areas of important functioning.

Depressive Disorder Due to Another Medical Condition The predominant clinical picture consists of a persistent depressed mood or significant decreased interest or pleasure in all or almost all activities. History, physical examination, or laboratory findings demonstrate that the disturbed mood is a direct pathophysiological consequence of another medical disorder. In addition, the disturbed mood is not due to another psychiatric disorder including delirium. Also, there is significant distress to the degree that social, occupational, or other important areas of functioning are impaired.

Other Specified Depressive Disorder This diagnosis applies to clinical presentations that include symptoms of depression that do not meet the criteria for any of the depressive disorders diagnostic class, while severe enough to impair social and occupational functioning. The clinician chooses this diagnosis to communicate the reason that the diagnosis does not meet criteria for one of the specific depressive disorders. Examples could include recurrent brief depression, short-duration depressive episode, or depressive episode with insufficient symptoms.

Unspecified Depressive Disorder This diagnosis applies for presentations with depression that do not meet the criteria for any of the depression-related disorders and causes significant social and occupational impairment. This diagnosis is used when the clinician chooses not to indicate the reason that the clinical presentation does not meet the criteria for any of the other depression-related disorders. This choice might occur within the context in which there is insufficient information.

Suggested Readings 1. American Psychiatric Association: Mood disorders. In: Diagnostic and Statistical Manual of Mental Disorders . 4th Text Revision ed. Washington, DC: American Psychiatric Press, Inc.; 2000: 345–428.

2. American Psychiatric Association: Practice guideline for major depressive disorder in adults . Washington, DC: American Psychiatric Press, Inc.; 2010. 3. Bernstein JG: Drug Therapy in Psychiatry . 3rd ed. St. Louis, MO: Mosby; 1995: 112–194. 4. Blackburn I, Bishop S, Glen A, et al: The efficacy of cognitive therapy in depression: A treatment trial using cognitive therapy and pharmacotherapy, each alone and in combination. Br J Psychiatry . 1981; 139: 181–189. 5. Castren E, Rantamaki T: The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Develop Neurobiol . 2010; 70: 289–297. 6. De Kloet ER Vreugdenhil E, Oitzl MS, et al: Brain corticosteroid receptor balance in health and disease. Endocrine Reviews . 1998; 19(3): 269–301. 7. DiMascio A, Weissman MM, Prusoff BA, et al: Differential symptom reduction by drugs and psychotherapy in acute depression. Arch Gen Psychiatry . 1979; 36: 1450–1456. 8. Dobson KS, Hollon SD, Dimidjian S, et al: Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression. J Consult Clin Psychol . 2008; 76(3): 468–477. 9. Driessen E, Hollon SD: Cognitive Behavioral Therapy for Mood Disorders: Efficacy, moderators, and mediators. In: Olatunji BO, ed.: Psychiatric Clin North America . Philadelphia, PA: W.B. Saunders Company; 2010; 33(3): 537–556. 10. Dubzovsky SL, Buzan R: Mood disorders. In: Hales RE, Yudofsky SC, Talbott JA, eds.: The American Psychiatric Press Textbook of Psychiatry . 3rd ed. Washington, DC: American Psychiatric Press, Inc.; 1999: 479–565. 11. Ebmeier KP, Donaghey C, Steele JD: Recent developments and current controversies in depression. Lancet . 2006; 367: 153–167. 12. Elkin I, Shea MT, Watkins JT, et al: National Institute of Mental Health Treatment of depression collaborative research program: general effectiveness of treatments. Arch Gen Psychiatry . 1989; 46: 971–982. 13. Fava M, Ostergaard SD, Cassano P: Depressive disorders (Major depressive disorder). In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts

General Hospital Comprehensive Clinical Psychiatry, 2nd. Philadelphia, PA: Mosby/Elsevier; 2016: 324–329. 14. Fava M, Papakostas GI: Antidepressants. In: Stern TA, Fava M, Wilens TE, et al, ed. Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby/Elsevier; 2016: 489–505. 15. Frank E, Kupfer DJ, Buysse DJ, et al: Randomized trial of weekly, twicemonthly, and monthly interpersonal psychotherapy as maintenance treatment for women with recurrent depression. Am J Psychiatry . 2007; 164: 761–767. 16. Frank E, Kupfer DJ, Perel JM, et al: Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry . 1990; 47: 1093– 1099. 17. Frank I, Kupfer DJ, Wagner ER, et al: Efficacy of interpersonal therapy as a maintenance treatment of recurrent depression: contributing factors. Arch Gen Psychiatry . 1991; 48: 1053–1059. 18. Frazer A: Antidepressants. J Clin Psychiatry . 1997; 58(suppl 6): 9–23. 19. George MS, Rush AJ, Maragell, LB, et al: A one-year comparison of VNS with treatment as usual for treatment resistant depression. Biol Psychiatry . 2005; 58: 364–373. 20. Hollon SD, DeRubeis RJ, Shelton R, et al: Prevention of relapse following cognitive therapy vs. medications in moderate to severe depression. Arch Gen Psychiatry . 2005; 62(4): 417–422. 21. Holtzheimer PE, Kelley ME, Gross RE, et al: Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry . 2012; 69(2): 150–158. 22. Klerman G, Weissman M, Rounsaville B, et al: Interpersonal Psychotherapy of Depression . New York: Basic Books; 1984. 23. Kupfer DJ, Frank E, Phillips ML: Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet . 2012; 379: 1045– 1055. 24. Leichsenring F: Applications of psychodynamic psychotherapy to specific disorders: efficacy and indications. In: Gabbard GO, ed.: Textbook of Psychotherapeutic Treatments. Washington, DC: American Psychiatric Publishing, Inc.; 2009: 97–132.

25. Leichsenring F: Comparative effects of short-term psychodynamic psychotherapy and cognitive-behavioral therapy in depression: a metaanalytic approach. Clin Psychol Rev . 2001; 21: 401–419. 26. Levkovitz Y, Roth Y, Harel EV, et al: A randomized controlled feasibility and safety study of deep transcranial magnetic stimulation. Clin Neurophysiol . 2007; 118: 2730–2744. 27. Lohoff FW: Overview of the genetics of major depressive disorder. Curr Psychiatry Rep . 2010; 12(6): 539–546. 28. Lozano AM, Giacobbe P, Hamani C, et al: A multi-center pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg . 2012; 116(2): 315–322. 29. Maina G, Forner F, Bogetto F: Randomized controlled trial comparing brief dynamic and supportive therapy with waiting list condition in minor depressive disorders. Psychother Psychosom . 2005; 74: 3–50. 30. Mayberg HS, Lozano AM, Voon V, et al: Deep brain stimulation for treatment-resistant depression. Neuron . 2005; 45(5): 651–660. 31. McLintock SM, Trevino K, Husain MM: Vagus nerve stimulation: indications, efficacy, and methods. In: Swartz CM, ed.: Electroconvulsive and Neuromodulation Therapies . Cambridge: Cambridge University Press; 2009: 543–555. 32. Nelson JC, Davis JM: DST studies in psychotic depression: a metaanalysis. Am J Psychiatry . 1997; 154: 1497–1503. 33. O’Reardon JP, Solvason HB, Janicakc PG, et al: Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multi-site randomized control trial. Biol Psychiatry . 2007; 62(11): 1208–1216. 34. Pariante CM, Miller AH: Glucocorticoid Receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry . 2001; 49(5): 391–404. 35. Parker G, Hadzi-Pavlovic D, Pedic F: Psychotic (delusional) depression: a meta-analysis of physical treatments. J Affect Dis. 1992; 24: 17–24. 36. Quitkin FM, Harrison W, Stewart JW, et al: Response to phenelzine and imipramine in placebo non-responders with atypical depression. Arch Gen

Psychiatry . 1991; 48: 319–323. 37. Reynolds CF, III, Dew MA, Pollock BG, et al: Maintenance treatment of major depression in older age. N Engl J Med . 2006; 354: 1130–1138. 38. Reynolds CF, III, Frank E, Perel JM, et al: Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA . 1999; 281: 39–45. 39. Rosenbaum JF, Fava M: Approach to the patient with depression. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Psychiatry in Primary Care . New York: McGraw-Hill Companies, Inc.; 1998: 1–14. 40. Rosenbaum JF, Fava M, Nierenberg AA, et al: Treatment-resistant mood disorders. In: Gabbard GO, ed.: Treatments of Psychiatric Disorders . 2nd ed. Washington, DC: American Psychiatric Press, Inc.; 1995: 1275–1328. 41. Rosenberg O, Dannon PN: Transcranial magnetic stimulation. In: Swartz CM, ed.: Electroconvulsive and Neuromodulation Therapies . Cambridge: Cambridge University Press; 2009: 527–542. 42. Rothschild AJ: Management of Psychotic, treatment-resistant depression. In: Hornig-Rohan M, Amsterdam JD, eds.: Psychiatric Clin North Am . 1996; 19(2): 237–252. 43. Rush AJ, Fava M, Wisniewski SR, et al: Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials . 2004; 25(1): 119–142. 44. Rush AJ, Marangell LB, Sackeim HA, et al: Vagus nerve stimulation for treatment-resistant depression: A randomized controlled acute phase trial. Biol Psychiatry . 2005; 58: 347–354. 45. Shea MT, Elkin I, Imber SD, et al: Course of depressive symptoms over follow-up: findings from the National Institute of Mental Health Treatment of Depression collaborative Research Program. Arch Gen Psychiatry . 1992; 49: 782–787. 46. Sinyor M, Schaffer A, Levitt A: The sequenced treatment alternatives to relieve depression (STAR*D) Trial: A review. Can J Psychiatry . 2010; 55(3): 126–135. 47. Wassermann EM: Risk and safety of repetitive transcranial magnetic stimulation: Report and suggested guidelines from the International

Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation. Electroencephalogr Clin Neurophysiol . 1998; 108: 1–16. 48. Weissman MM, Klerman GL, Prusoff BA, et al: Depressed outpatients: results one year after treatment with drugs and/or interpersonal psychotherapy. Arch Gen Psychiatry . 1981; 38: 51–55. 49. Weissman MM, Prusoff BA, Dimascio A, et al: The efficacy of drugs and psychotherapy in the treatment of acute depressive episodes. Am J Psychiatry . 1979; 136: 555–558. 50. Welch CA: Electroconvulsive therapy. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia PA: Mosby/Elsevier, 2016: 510–517. 51. Wright J, Thase M, Sensky T: Cognitive and biological therapies: A combined approach. In: Wright J, Thase M, Beck A, et al, eds.: Cognitive Therapy with Inpatients. New York: Guilford Press, 1992; 193–218. 52. Young EA, Haskett RF, Murphy-Weinberg V, et al: Loss of glucocorticoid fast feedback in depression. Arch Gen Psychiatry . 1991; 48(8): 693–699.

CHAPTER Bipolar Disorder 16 SHARMIN GHAZNAVI, MD, PHD AND FRANKLIN KING, IV, MD

KEY POINTS Epidemiology Bipolar disorder affects between 1% to 2.5% of the general population, with estimates as high as 4.5% when including the full spectrum of bipolar disorders. The prevalence of bipolar disorder is similar across racial groups and affects men and women equally. There is a high co-morbidity of anxiety and substance use disorders among patients with bipolar disorder. Etiology Studies show about a 5% increased risk of bipolar disorder in individuals who have a first-degree relative who has bipolar disorder, suggesting genetic contributions to the illness. Lack of complete concordance among monozygotic twins suggests that environmental factors (e.g., birth-related complications, exposure to substances) also influence development of the illness. Clinical Features Most individuals with bipolar disorder present in a depressed state. A history of hypomania/mania is defined as at least 4 days (hypomania) to 1 week of euphoric or irritable mood and a minimum number of symptoms characterized by the DIGFAST mnemonic, distractibility, indiscretions, grandiosity, flight of ideas, activities (increase in), sleeplessness (decreased need for sleep) and talkativeness. In the case of euphoric mood, only three of these symptoms need to be concurrent, whereas for irritable mood, four of these symptoms need to be concurrent.

Bipolar disorder is chronic, highly recurrent, and progressive. Individual with bipolar disorder generally have more depressive episodes than mania/hypomanic episodes and the depressive episodes are usually longer than the manic or hypomanic episodes. Differential Diagnosis Patients presenting with a major depressive episode might meet criteria for major depressive disorder (MDD) or bipolar disorder. Anger and irritability may be consistent with bipolar disorder or the anger subtype of MDD, intermittent explosive disorder, or cluster B personality disorder. Mood swings may indicate a bipolar disorder or a Cluster B personality disorder. Distractibility might suggest attention-deficit hyperactivity disorder. Patients with mood symptoms and psychotic symptoms might have a primary psychotic disorder.

Diagnosis and Approach to Evaluation A single episode of mania is diagnostic; this makes a thorough history for mania essential. Additionally, because many patients present with depression, assessing for a history of mania/hypomania in all patients who present with depression is critical. Hypomania must be distinguished from normal levels of activity. Mania secondary to medical or substance use must be ruled-out, especially if the first episode is later in life. Management Acute mania is treated with a mood stabilizer, including either lithium or atypical antipsychotics. Severe cases may be treated with both, and/or electroconvulsive therapy. Acute depressive episodes may be more severe and refractory than unipolar depressive episodes. Common treatments include mood stabilizing agents and mood stabilizing atypical antipsychotics approved for bipolar depression. The mainstay of maintenance therapy is with lithium, with atypical antipsychotics and neuroleptics used in conjunction or as second-line agents. Behavioral therapies and family involvement are also effective as adjunctive treatments.

Introduction Bipolar disorder is characterized by episodes of mania or hypomania, with or without one or more episode(s) of depression. By recent estimates, it affects between 1% to 2.5% of the general population. Bipolar disorder is associated with significant morbidity and mortality. According to recent studies, more than 30% of individuals with bipolar disorder attempt suicide during their life-time. Bipolar disorder can vary widely in its presentation, making the diagnosis a challenge. An individual patient might look very different than their counterparts when manic or depressed. In addition, the disorder shares features with both major depressive disorder (MDD) and schizophrenia. Complicating things further, substance abuse and certain medical conditions can have a similar presentation to bipolar states. With appropriate diagnosis, effective treatment can result in remission for many patients.

Epidemiology The life-time prevalence of type I bipolar disorder (with manic episodes) is approximately 1% while for type II bipolar disorder (with hypomanic episodes) it is also 1%; by including the full spectrum of bipolar disorders, the prevalence can be as high as 4.5%. Prevalence estimates for both type I and II bipolar disorder are similar for males and females; this differs from those for MDD, which affects females more than males. Previously, it was thought that rapid cycling bipolar disorder is commonly associated with females, but recent studies have not confirmed this. According to recent studies, the average age of onset of any bipolar disorder is around 20 years, with the mean age of onset for type I bipolar disorder around 18 years, and for type II closer to 20 years. Up to 65% of bipolar patients will have their first mood episodes before the age of 25 years. The reported age of onset of affective disorders has decreased in the past few decades, which can either reflect earlier diagnosis or a cohort effect. The diagnosis of bipolar disorder in children is a subject of active research; in this age group accurate diagnosis can be complicated by developmental issues and co-morbidities, such as attentiondeficit hyperactivity disorder (ADHD). New-onset bipolar disorder is rare after the fourth decade of life; when it occurs, it is usually secondary to a medical or neurological condition, or to the effects of medications, particularly antidepressants and steroids. An exception would be for those patients with

recurrent depression who experience their first manic episode after the age of 40 years. The prevalence of bipolar disorder is similar across racial groups. Individuals with bipolar disorder from some racial groups (African-Americans and Hispanics) might be more likely to be misdiagnosed with schizophrenia, particularly if they present with psychotic symptoms. Unlike primary psychotic disorders, bipolar disorder is not necessarily associated with as marked a downward drift in socioeconomic class. However, the incidence of bipolar disorder is elevated among the unemployed-disabled compared to the employed; rates of disability for bipolar patients can be quite high. Patients with bipolar disorder often have co-morbid substance use and anxiety disorders, and, to a lesser extent, eating disorders and ADHD . The prevalence of co-morbid substance use disorders is estimated to be as high as 60%, with rates for alcohol abuse or dependence higher than for abuse or dependence with other drugs. The prevalence of any life-time anxiety disorder in patients with bipolar disorder is estimated to be slightly more than 50%. Previously it was thought that there is a greater co-morbidity with anxiety disorders in patients with bipolar I disorder relative to bipolar II disorder; however, a recent meta-analysis found no significant differences in co-morbid anxiety disorders between the two subtypes. The prevalence of eating disorders in bipolar disorder has been reported to be as high as 15%, and it seems to be more prevalent in type II bipolar disorder, with binge-type figuring more prominently. Finally, ADHD is estimated to be co-morbid in 60% to 90% of pediatric patients with bipolar disorder.

Differential Diagnosis Differentiation from Other Psychiatric Disorders Many symptoms of bipolar disorder are also found in other psychiatric disorders, making knowledge of the distinguishing characteristics and differential diagnosis of suspected bipolar disorder critical. Following are common presenting complaints and symptoms, reviewed and presented along with a strategy for differentiating bipolar disorder from other disorders. Importantly, a single episode of primary mania or hypomania is always diagnostic for bipolar disorder, with the exception of schizoaffective disorder, bipolar type.

A patient who presents with an episode of major depression might meet criteria for either MDD or bipolar disorder. It is critical that the clinician remember that a major depressive episode does not necessarily mean the patient meets criteria for MDD. If the patient’s history reveals a past episode of mania or hypomania, the patient meets criteria for bipolar disorder. Patients who present with anger or irritability might meet criteria for bipolar disorder, MDD (anger sub-type variant), i ntermittent explosive disorder (IED ), or cluster B personality disorder (antisocial, borderline, oppositional defiant). Again, here it will be critical to discern whether there is a history of a hypomanic or manic episodes, precipitating factors leading to the anger, and the nature of the anger (e.g., are they anger attacks—discrete sudden episodes of intense anger or do they exhibit frequent constant irritability or anger). Some research suggests that anger attacks are more common in depressed patients with bipolar disorder; however, it also can be suggestive of a sub-type of MDD. If the patient has a history of irritability and anger in the context of other characterological traits and it is fueled by interpersonal slights, the anger or irritability might be due to a cluster B personality disorder. Finally, if the anger is characterized by extreme expressions of anger, disproportionate to the situation, in the absence of mood symptoms or other personality disorder criteria, the patient might meet criteria for IED. A patient who presents with a complaint of “mood swings ” might meet criteria for bipolar disorder, MDD or a cluster B personality disorder. Mood swings are common in all mood disorders, so a careful history to distinguish a depressive disorder from bipolar disorder is critical. If the “mood swings” seem to be in response to interpersonal factors or other external factors with little persistence of the mood, the clinician should consider a personality disorder, particularly cluster B personality disorders. Patients who present with psychosis might meet criteria for a primary psychotic disorder, such as schizophrenia or schizoaffective disorder, MDD with psychotic features, or bipolar disorder. If the patient presents with psychosis in the absence of mood features and does not have a history of mood episodes, this is suggestive of a primary psychotic disorder. If the patient has a history of mood episodes, but does not currently have any mood symptoms, the patient might meet criteria for schizoaffective disorder. Schizoaffective disorder is distinguished from bipolar disorder by the persistence of psychotic symptoms for at least 2 weeks in the absence of a manic, mixed, or depressive episode. If the patient currently meets criteria for a depressive episode and does not have a

history of hypomania or mania, the patient might meet criteria for either MDD with psychotic features or schizoaffective disorder, depressed type. Finally, if a patient also meets criteria for a current manic episode, the patient meets criteria for schizoaffective disorder, bipolar type. When a patient presents with distractibility, especially in pediatric populations, the patient might meet criteria for either bipolar disorder or ADHD /attention deficit disorder (ADD). The key feature that distinguishes bipolar disorder from these other conditions is the history of a manic or hypomanic episode; distractibility or impulsivity alone is insufficient to make a diagnosis of a bipolar disorder. Unlike bipolar patients, those with ADD will continue to experience these symptoms in the absence of other mood symptoms. However, as the two diagnoses can co-exist, patients must often be re-evaluated for symptoms of ADD after their mood episodes are adequately treated. Patients who present with impulsivity might meet criteria for ADHD, an impulse control disorder, or bipolar disorder. If the impulsivity is in the absence of mood symptoms, the clinician should consider ADHD or an impulse control disorder. If the impulsive behaviors or actions include violent behavior, gambling, fire-starting, stealing, and body-focused behaviors (e.g., skin-picking, hair-pulling, nail-biting), clinicians should consider an impulse control disorder.

Sub-Types of Bipolar Disorder A diagnosis of type I bipolar disorder requires one life-time manic episode, with or without major depressive episodes. Type II bipolar disorder requires that the patient has had one life-time hypomanic episode and at least one life-time major depressive episode. Mania is distinguished from hypomania largely by the severity of symptoms, including significant impairment in functioning, requirement for hospitalization, and/or presence of psychotic symptoms and duration of symptoms. The criteria for rapid-cycling bipolar includes one lifetime manic or hypomanic episode as well as a history of four episodes of depression, mania, or hypomania within a single year.

The Impact of Genetics and Environment Family studies of bipolar disorder reveal that the risk of developing bipolar disorder in individuals with a first-degree relative who has bipolar disorder is elevated compared to the controls, with most studies reporting about 5% risk for both type I and type II bipolar disorder. Notably, the risk of unipolar depression or MDD in family members with first-degree relatives who have bipolar disorder

is elevated and it is even higher than the risk of having bipolar disorder. However, the risk for bipolar disorder is not elevated in family members with a first-degree relative having MDD. Family studies also suggest that early-onset disorder might represent a more severe sub-type with a stronger genetic loading. Twin studies find that the concordance rate for monozygotic twins (genetically identical) is between 60% and 70%, and between 20% and 30% for dizygotic twins, suggesting that its heritability is greater than 60%. Studies to identify genes that might be associated with bipolar disorder are currently underway. Given the complexity and heterogeneity of bipolar disorder it is likely that multiple genes/loci of susceptibility will be associated with the risk for developing bipolar disorder. Although there is a high concordance in monozygotic twins, the fact that it is not 100% suggests that there are environmental factors, as well. Obstetric complications, intrauterine viral infections, neurodevelopmental abnormalities in childhood, parenting/attachment styles, psychosocial trauma, and exposure to substances have all been proposed as possible environmental influences. It is likely that the most potent environmental influences on the etiology of the illness occur early in life, before the illness’s typical onset in adolescence and early adulthood. Psychosocial stressors later in adulthood (such as the death of family and friends, the end of romantic relationships, and occupational stress) often serve as environmental triggers for mood episodes, thus affecting the course of the illness rather than giving rise to it.

Course of the Illness Bipolar disorder has a chronic course with a natural history that is both highly recurrent and progressive. A single manic episode heralds the near certainty of future manic or depressive episodes, with the majority of episodes being depressive episodes. Studies also suggest that vulnerability to episodes increases as the numbers of episodes experienced increases. Untreated, bipolar patients are likely to relapse and to have more frequent mood episodes. Additionally, incomplete remission is the rule, with many patients struggling with residual hypomanic or manic and depressive symptoms. Adults with early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment. There appears to be seasonal variation in bipolar disorder, but the data is far from conclusive. Some studies show an increase in hospital admissions for depressive episodes in the autumn and for mania in the spring and summer. Of

note, this refers to the seasonal variation in symptoms and is distinct from seasonal affective disorder, in which individuals experience mood symptoms, usually depression, only during a particular season, usually autumn and/or winter. Depressive episodes (with a mean untreated duration of 6 to 12 months) tend to last longer than manic episodes (with a mean untreated duration of 3 to 6 months). There is also evidence to suggest that mixed states last longer than pure states.

Evaluation The Depressed Patient Over their life-time, patients with bipolar disorder experience many more depressive episodes than manic or hypomanic episodes and spend more time depressed than manic or hypomanic. They are also more likely to consult a psychiatrist (or another physician) for depression than for mania. Because of this, patients who meet the criteria for MDD need to be screened for life-time manic or hypomanic symptoms to rule-out bipolar disorder. Importantly, having a history of, or current symptoms of, mania or hypomania is the only way to make a diagnosis of bipolar disorder when a patient presents with a depressive episode. Whereas previous thinking was that atypical depressive symptoms might be more suggestive of bipolar disorder, atypical depressive symptoms are also common among those with MDD. Also, as reviewed earlier, having a firstdegree relative with bipolar disorder carries a greater risk for MDD than bipolar disorder, so a positive family history cannot be used to discern whether the patient presenting with a depressive episode has bipolar disorder.

The Manic Patient A diagnosis of mania requires that a patient has experienced abnormally and persistently elevated (euphoric), expansive, or irritable mood, as well three (if euphoric) or four (if irritable) of the seven cardinal symptoms of mania, for at least 1 week. The cardinal symptoms of mania are easily remembered by the mnemonic “DIGFAST ” (Table 16-1). A manic episode is diagnosed when symptoms are present for 7 days or more and result in significant impairment in social or occupational functioning, or if they result in hospitalization after any duration of time (including less than a week). In addition, the existence of psychotic symptoms necessitates a diagnosis of mania and rules out hypomania. A hypomanic episode might be diagnosed by the presence of the same requisite

number of cardinal “DIGFAST” symptoms (3 if euphoric, 4 if irritable) after a period of 4 consecutive days. In addition to the criteria shown in Table 16-1, as with all Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I disorders, the patient must experience significant social or occupational dysfunction (that can include hospitalization) as a result of the symptoms cited. If there is no social or occupational dysfunction, a hypomanic episode is diagnosed. Also, to make a diagnosis of a manic episode, the symptoms must last at least 1 week or require hospitalization. If symptoms last less than 1 week, but at least 4 days, a diagnosis of a hypomanic episode is made. Table 16-1. Mnemonic for the Recollection of Symptoms of Mania/Hypomania: DIGFAST D Distractibility as demonstrated by an inability to maintain one’s focus on tasks for any extended duration; for instance, attention is easily drawn to irrelevant external stimuli. I Indiscretions suggesting impulsivity and poor judgment (e.g., promiscuity or sexual indiscretions, fast or reckless driving, spending sprees, sudden travel). G Grandiosity or inflated self-esteem that can range from increased self-confidence out of proportion to one’s abilities or circumstances to delusional (e.g., believing one is all-powerful). F Flight of ideas in which thoughts switch quickly from one unrelated idea to another, or based on understandable associations, distracting stimuli, or plays on words. Note that the pace of thought does not define flight of ideas, i.e., “my thoughts are racing” is not sufficient. A Activities, namely an increase in functional goal-directed activities (e.g., increased productivity at school or work and increased socializing). S Sleeplessness or more specifically decreased need for sleep. Note that this refers to maintaining energy despite low sleep. Many patients with mood disorders struggle with sleep but what distinguishes mania is that the need for sleep to maintain normal or higher than normal levels of activity is decreased. T Talkativeness, which refers to being overly talkative or having pressured speech, defined as speech that is rapid and difficult to interrupt. This can be observed on the mental status exam or obtained through history. Note that patients in drug-induced states or severe anxiety states may also have pressured speech.

Ruling-Out Secondary Mood Disorders A secondary mood disorder is one that results from another medical or psychiatric condition (e.g., anemia, hypothyroidism, substance abuse). Secondary mania/hypomania is especially important to rule-out when there is a first episode of mania or hypomania, and when there is a later onset. The medical causes of secondary mood disorders fall into several broad categories; these are discussed later in the chapter, in order of descending importance.

Medications used to treat a variety of medical and psychiatric conditions can precipitate mania or hypomania. The most common ones are antidepressants , steroids (anabolic as well as corticosteroids), and amphetamines. In patients with a history of substance abuse, a number of drugs of abuse can precipitate mania or hypomania, most notably stimulants . Neurological disorders are the most common non-psychiatric illnesses that cause mood disorders, especially among patients with later-onset mania. Cognitive dysfunction or focal neurologic signs are often present. Mania or hypomania can result from the effects of a number of conditions resulting in injury to the brain (including cerebrovascular incidents, neoplasms, demyelinating and degenerative disorders, infections, seizures, trauma, and autoimmune disorders). When regions of the frontal lobe are affected in particular, patients might appear manic because they are disinhibited and manifest indiscretions (such as hypersexuality and reckless behaviors). When limbic areas are involved, individuals may also be more likely to display manic/hypomanic symptoms. Additionally, the use of steroids in the treatment of a number of neurologic illnesses can precipitate mania/hypomania. Endocrine disorders are less common and unusual in the absence of other more characteristic physical symptoms associated with endocrine disorders. Hyperthyroidism and Cushing’s syndrome have both been associated with mania. Infectious diseases, metabolic states, and immunologic diseases also can produce symptoms of mania or hypomania. In the treatment of secondary mood disorders, whenever possible the offending agent should be removed or the underlying medical condition treated. In most cases of secondary mania, caused by medications or metabolic disturbance, the manic symptoms are reversible; however, symptoms can persist in patients with mania secondary to diseases in which there is damage to the central nervous system. In those cases, long-term treatment with mood stabilizers might be required to minimize mood symptoms.

Approach to the Patient with Bipolar Disorder General Strategies Non-adherence with medications is a major problem in bipolar disorder. Medications used to treat bipolar disorder carry substantial side-effects as well as other burdens such as the need for blood-draws, leading many patients to discontinue their medication. Additionally, many patients lack insight into their

illness, especially when hypomanic or manic. As a result, they might be reluctant to take medications that they perceive as preventing or eliminating mood elevation. A therapeutic alliance can be helpful to achieve better adherence. Whenever possible, the treatment of bipolar disorder should be a collaboration between the patient and physician. Depression and psychosis are symptoms not diagnoses. Given that patients with bipolar disorder are more likely to present in a depressive episode, it is important not to assume that they have MDD based on their presentation alone. Screening for manic or hypomanic symptoms is essential. Furthermore, mania can present with psychotic symptoms. As such, an individual presenting with psychosis might not have a primary psychotic disorder. Like “fever,” depressive and psychotic symptoms need further analysis to determine the underlying diseases. Patients in depressive or manic or hypomanic episodes cannot always accurately recall their episodes and might even fail to recognize that they were ill, especially during hypomanic episodes, so obtaining collateral from family, friends, or other caregivers is essential. It is important to assess for the possibility of suicide and violence in all patients with bipolar disorder. Acutely manic patients, especially if they are engaged in dangerous behaviors (e.g., reckless driving, excessive spending) usually require hospitalization. Depressed patients with an acute risk of suicide, or those whose depression is so severe that it impairs their ability to care for themselves, will also require hospitalization. Not surprisingly, suicide risk is greatest during depressive episodes.

Specific Elements of History The essential component in an assessment for bipolar disorder is to determine if the patient has had at least one manic or hypomanic episode at any point in their life-time. A single episode is nearly diagnostic for bipolar disorder. A careful medical and substance abuse history is critical to rule-out secondary causes of bipolar disorder and to guide the need for additional medical workup, including blood-work and imaging. In obtaining a substance use history the goal is to determine whether the current mood episode is secondary to substance abuse. In particular, a careful history will ascertain whether the current or previous mood episodes were precipitated by substance use and whether the individual experiences mood episodes outside of periods when he is using or withdrawing from substances. The clinician should remember that the presence

of substances in a urine or serum toxicology screen does not establish a secondary mood disorder; there is a greater than 60% co-morbidity of substance abuse with bipolar disorder. A diagnosis of substance-induced bipolar disorder requires that episodes of abnormal mood invariably occur during periods of substance abuse and not outside of those periods, or (in those without a history of abstinence) a history of consistent substance abuse preceding the onset of a mood disorder. It is important to assess for manic symptoms using the DIGFAST criteria, both screening for past as well as recent historical symptoms. It is helpful to establish time frames in which to use the mnemonic. At least two time frames are considered: past history and current (the past 1 to 2 weeks). When assessing for past manic symptoms, the clinician should begin by assessing for mania, requiring that patients recall time frames of 1 week or longer when they might have experienced elevated or irritable mood, decreased need for sleep, or other manic symptoms. If not volunteered, the stereotypic impulsive behaviors of mania (sexual indiscretions, reckless driving, spending sprees, impulsive traveling) should be assessed. If mania is not identified, hypomania at any point must be assessed. Special attention should be given to establishing a patient’s “normal” baseline in mood and energy. Additionally, it is important to determine whether there was any substance abuse during periods of manic or hypomanic symptoms. Hypomania represents any deviation above this baseline for 4 days or longer, associated with some manic symptoms but without significant social or occupational dysfunction. If significant dysfunction exists, mania should be diagnosed, even in the absence of the aforementioned stereotypic behaviors. Conversely, because hypomania might not be experienced as illness, identifying these symptoms can require careful probing. Many, but certainly not all, patients with bipolar disorder have a family history of a psychiatric illness. This history can include mood disorders (MDD and bipolar disorder), substance use disorders, or a primary psychotic disorder. In part, this variability can be the result of prior misdiagnosis of family members; however, family members of patients with bipolar disorder do not necessarily present with identical diagnoses. Prior psychiatric treatment must also be assessed. In particular it is helpful to focus on medication trials that might have precipitated mania or hypomania, or increased the frequency of mood episodes. The presence of co-morbid psychiatric conditions should also be determined. As described earlier, common co-morbid conditions include substance abuse disorders, anxiety disorders,

ADHD, eating disorders, and cluster B personality disorders (especially borderline personality disorder). These co-morbid conditions can influence treatment decisions. If current or past symptoms of mania or hypomania are identified, the following features of the history should be determined: Age of onset of first mania or hypomania Age of onset of first major depression Number of life-time manic or hypomanic episodes Number of life-time major depressive episodes Typical cycle of episodes (mania followed by depression followed by well interval, or depression followed by mania followed by well interval, or continuous cycling) Last and longest periods of euthymia Age of first psychiatric treatment; age of first bipolar diagnosis and previous psychiatric diagnoses (if present, presence of psychotic symptoms during any episode) Sleep pattern Intentions to become pregnant (which may influence choice of pharmacotherapy) Effect of illness on social and occupational functioning Last period of best occupational functioning Note that including an informant in the evaluation to verify the patient’s history can be enormously helpful.

Specific Elements of Mental Status Examination The general appearance of patients in both depressive and manic episodes can be unremarkable; however, with more severe mood episodes, appearance can become affected. Depressed patients might show decreased attention to self-care. In contrast, patients with mania might be dressed provocatively (consistent with hypersexuality) or flamboyantly. During manic episodes, patients can sometimes be overly familiar or provocative. Patients can also be irritable and uncooperative when manic. Signs of psychomotor pressure such as physical agitation, pressure of speech, pacing, or having difficulty sitting still in the chair

can be observed in the manic patient, whereas psychomotor slowing is more characteristic of a depressive episode. Patients might express their mood as “down” or “sad” when depressed, but, when manic, mood might be reported as “fine,” “good,” or even “irritable” or “angry a lot.” In some cases, euphoric mood might be described as “giddy,” “high,” or “up.” If a patient is currently manic, her affect will be euphoric, irritable, or labile. If a patient is currently in a mixed state or depressed, the affect is usually depressed. Anxiety might or might not be present. Speech is often, but not always, characterized by an increased pressure; patients might be overly talkative and difficult to interrupt or re-direct, and conversations might be unduly prolonged. Thought content can be notable for grandiosity and ideas of reference. Patients might also exhibit paranoid ideation. When depressed, patients might have suicidal ideation. When manic, and in particular irritable, there can be homicidal ideation. It is critical to assess for suicidal ideation and homicidal ideation. In many cases of mania, the thought process is characterized by flight of ideas and looseness of associations. In milder cases, thought process can be circumstantial, tangential, or even linear and goal-directed. Usually, cognition is generally intact, with normal orientation to person, place, and time, and unimpaired immediate, short-term, and long-term recall. There can be some disturbance in all of these with more severe mood episodes. Concentration is often impaired in depression and mania; manic patients are often easily distractible and have difficulty with maintaining focus, often jumping from topic to topic.

Management of the Patient with Bipolar Disorder Acute Mania In acute mania, the first step is to remove agents that might exacerbate mania. Antidepressants, stimulants, and, if possible, steroids, should be tapered or discontinued (note that abrupt discontinuation of antidepressants has itself also been associated with mania, so a taper might be advisable). Next, an anti-manic agent must be selected. The next step in treatment is to choose a mood stabilizer. Lithium remains the “gold standard” for the treatment of acute mania. However, there have been some recent meta-analyses that support the use of antipsychotics as more effective in the treatment of acute manic episodes; of the antipsychotic agents, risperidone, olanzapine, and haloperidol were most favorable in terms of both efficacy and tolerability. However, other first-line agents include valproate,

olanzapine, aripiprazole, quetiapine, risperidone, and ziprasidone. Asenapine and lurasidone are also approved for mania. Additionally, patients often require symptomatic treatment, and benzodiazepines are the mainstay of adjunctive short-term treatment for acute mania. In the presence of psychotic symptoms, short-term use of antipsychotics has proven to be helpful. For cases of severe or refractory mania, adjunctive treatments should be considered; research suggests that lithium or valproate combined with short-term administration of an atypical antipsychotic is superior to either alone. Because lithium can require more time to achieve efficacy, atypical antipsychotics, or a combination of an atypical agent plus lithium might be preferable in treating acute mania, particularly if associated with psychotic features. If symptoms persist or are severe, electroconvulsive therapy (ECT) should be considered. Finally, behavioral measures can prove very helpful. Distractions and stimulation should be reduced, activity decreased, and major decisions delayed.

Acute Depression As with acute mania, when a patient presents with an acute depressive episode, the first step should be to remove agents that might exacerbate depression. Clinicians should consider tapering, ceasing, or replacing medications (such as steroids, beta-blockers, varenicline, statins, oral contraceptive pills, hormone replacement therapy), which might be contributing to the depression. First-line therapy in a depressive episode is also a mood stabilizer; agents include lithium, valproate, quetiapine, lamotrigine, and olanzapine. Of note, there is evidence to suggest that lithium can significantly decrease the risk of suicide, which is increased during the depressed phase of bipolar disorder. Adjunctive treatment (with the olanzapine/fluoxetine combination, quetiapine, or lurasidone, the only FDA-approved treatments for bipolar depression) should be considered first. Although one study showed that lamotrigine plus lithium is better than placebo plus lithium, lamotrigine monotherapy might just have a modest effect size for bipolar depression. Currently, the predominance of evidence shows that antidepressants are, at best, of questionable efficacy compared to placebo when added to a mood stabilizer. Antidepressants should not be considered in rapid-cycling bipolar disorder, because tricyclic antidepressants (TCAs) and venlafaxine are associated with a higher risk of switching patients into mania. If psychotic symptoms are present, augmentation with atypical antipsychotics (provided the patient is not already on an antipsychotic as a mood-stabilizer) should be considered.

If the patient’s symptoms are severe or persist, or there is high risk of selfharm, or psychotic features are present, electroconvulsive therapy (ECT) should be considered. For mixed states, the first-line options for treatment are quetiapine, olanzapine, or valproate as monotherapy, or a combination of olanzapine and fluoxetine or olanzapine and valproate. Lithium might be less effective in mixed states. If symptoms are severe or protracted ECT should be considered.

Maintenance Treatment In maintenance therapy, the goal is to minimize potential for relapse, and mood-stabilizers are the mainstay of treatment, with lithium being the gold standard. Other first-line agents include valproate, lamotrigine, olanzapine, aripiprazole, and quetiapine. The efficacy of antidepressants in the maintenance of bipolar disorder has not been established. Individual psychotherapy, including cognitive-behavioral therapy (especially around insight and psychoeducation about the illness and recognition of early warning signs) is especially effective. Family-focused therapy can be especially helpful for family members who work in collaboration with the treatment team.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC, American Psychiatric Publishing; 2013. 2. Cipriani A, Barbui C, Salanti G, et al: Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet . 2011; 378: 1306–1315. 3. Geddes JR, Miklowitz DJ: Treatment of bipolar disorder. Lancet . 2013; 381: 1672–1682. 4. Goodwin EK, Ghaemi SN: Understanding manic-depressive illness. Arch Gen Psychiatry . 1998; 55: 23–25. 5. Goodwin EK, Jamison KR: Manic depressive illness. New York: Oxford University Press; 1990. 6. Harrow M, Goldberg JE, Grossman LS, et al: Outcome in manic disorders. Arch Gen Psychiatry . 1990; 47:665–671.

7. Judd LL, Akiskal HS, Schettler PJ, et al: The long-term natural history of the weekly symptomatic status of Bipolar I disorder. Arch Gen Psychiatry . 2002; 59:530–537. 8. Judd LL, Akiskal HS, Schettler PJ, et al: The long-term natural history of the weekly symptomatic status of Bipolar II disorder. Arch Gen Psychiatry . 2003; 60:261–269. 9. Malhi GS, Adams D, Lampe L, et al: Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand . 2009; 119(Suppl. 439): 27–46. 10. Merikangas KR, Akiskal HS, Angst J, et al: Life-time and 12-month prevalence of bipolar spectrum disorder in the National Co-Morbidity Survey Replication. Arch Gen Psychiatry . 2007; 64(5): 543–552. 11. Pavlova B, Perlis RH, Alda M, et al: Lifetime prevalence of anxiety disorders in people with bipolar disorder: a systematic review and metaanalysis. Lancet Psychiatry . 2015; 2:710–717. 12. Pope HG, Jr, Lipinski JF: Diagnosis in schizophrenia and manic-depressive illness. Arch Gen Psychiatry . 1978; 35: 811–828. 13. Sachs GS, Dupuy JM, Wittmann CW: The pharmacologic treatment of bipolar disorder. J Clin Psychiatry . 2011; 72: 1–478. 14. Simon NM, Otto MW, Wisniewski SR, et al: Anxiety disorder co-morbidity in bipolar disorder patients: Data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEPBD). Am J Psychiatry . 2004; 161(12): 2222–2229. 15. Smoller JW, Finn, CT: Family, twin and adoption studies of bipolar disorder. Am J Med Genetics . 2003; 123c: 48–58.

CHAPTER Anxiety Disorders 17 ERIC BUI, MD, PHD; BRIAN J. SCHULMAN, MD; DAN V. IOSIFESCU, MD, MSC; AND MARK H. POLLACK, MD

KEY POINTS Overview Anxiety is an emotional response similar to fear, consisting of a sense of dread and foreboding. Although anxiety is an expected, normal, and transient response to stress, it can be pathological when it becomes unrelated to the circumstances, intense, persisting, and alters behaviors. Anxiety is manifested in physical, affective, cognitive, and behavioral domains. Etiology Psychodynamic theories posit that anxiety disorders derive from developmental experience. Cognitive behavioral models suggest that anxiety disorders stem from distorted cognitions and avoidance behaviors. Neurobiological models emphasize the role of a hyperactive limbic system (e.g., amygdala, locus coeruleus), and a hypoactive prefrontal cortex, as well as specific neurotransmitters (e.g., GABA, monoamines). Epidemiology More than 25% of the United States population experiences pathologic anxiety in their lifetime. The heritability of anxiety disorders is about 30% to 67%. Anxiety disorders are associated with marked impairments in physical and psychosocial function as well as poorer quality of life. Anxiety disorders are frequently co-morbid with major depression, other anxiety disorders, and alcohol and drug abuse.

Differential Diagnosis Anxiety can stem from organic causes, including respiratory, cardiac, endocrine, metabolic, neurological diseases, as well as drug-related intoxication or withdrawal. Anxiety can complicate medical illnesses. The medical work-up of an anxious patient relies on the medical and psychiatric history, medication and drug history, and on an appropriate physical and neurological examination. Anxiety can be present in other psychiatric disorders including depression, personality disorders (cluster C), or more rarely, schizophrenia.

Psychiatric Disorders Panic disorder is a syndrome characterized by recurrent unexpected panic attacks with at least one of these attacks followed by 1 month or more of persistent concern about additional attacks, or their consequences, and a significant change in behavior related to the attacks. Agoraphobia involves marked fear or anxiety (lasting 6 months or more), in two or more agoraphobic situations (outside home alone, public transportation, open spaces, enclosed spaces, and standing in line or in a crowd) that are usually avoided. Generalized anxiety disorder involves excessive anxiety or worry that is out of proportion to situational factors, and that occurs more days than not for longer than 6 months, associated with three or more somatic symptoms including muscle tension, restlessness, insomnia, difficulty concentrating, fatigability, and irritability. Specific phobia involves a marked fear (lasting 6 months or more) of circumscribed situations or objects (e.g., heights, closed spaces, animals, the sight of blood) that are usually avoided. Social anxiety disorder involves a marked fear (lasting 6 months or more) of being humiliated or embarrassed in social situations (i.e., under public scrutiny) that are usually avoided. Adult separation anxiety disorder involves a marked fear or anxiety (lasting 6 months or more) concerning separation from home or attached persons, associated with separation-related symptoms (e.g., recurrent distress or worry about a separation, fear or reluctance to be alone). Post-traumatic stress disorder involves directly or indirectly experiencing a life-threatening event that is followed by 1 month of re-experiencing symptoms, avoidance, alterations in moods and cognitions, and hyperarousal.

Introduction Anxiety is an expected, normal, and transient response to stress; it can be a necessary cue for adaptation and coping. Pathologic anxiety is distinguished from a normal emotional response by four criteria: autonomy (i.e., it has no, or a minimal, recognizable environmental trigger); intensity (i.e., it exceeds the person’s capacity to bear discomfort); duration (i.e., the symptoms are persistent rather than transient); and, behavior (i.e., anxiety impairs coping and results in disabling behavioral strategies, such as avoidance or withdrawal). Anxiety is an emotional response similar to fear, consisting of a sense of dread and foreboding. However, unlike fear, which occurs in response to an external threatening event, anxiety results either from an unknown internal stimulus or is inappropriate or excessive to the reality of the current situation. Anxiety is manifested in physical, affective, cognitive, and behavioral domains. Physical symptoms of anxiety are related to autonomic arousal (e.g., tachycardia, tachypnea, diaphoresis, diarrhea, lightheadedness). Anxiety-related affective symptoms range in severity from mild (e.g., edginess) to severe (experienced as terror, the feeling that one is “going to die” or “lose control”). Cognitively, the experience is one of worry, apprehension, obsessions, and thoughts about emotional or bodily damage. Behaviorally, anxiety is characterized by avoidance (e.g., non-compliance with medical procedures) or compulsions.

Etiological Models Psychodynamic Model Psychodynamic formulations of anxiety emphasize the meanings, memories, and internal mental representations derived from developmental experience. In Freud’s later writing, anxiety was described as a signal of threat to the ego; signals are elicited because current events have similarities (symbolic or actual) to threatening developmental experiences (traumatic anxiety).

Cognitive-Behavioral Model Cognitive-behavioral formulations of anxiety focus on the informationprocessing and behavioral reactions that characterize the anxiety experience. The emphasis is placed on the role of thoughts and beliefs (cognitions) in activating

anxiety, as well as on the role of avoidance or other escape responses in the maintenance of both fear and dysfunctional patterns of thinking. Faulty cognitions are often characterized by over-prediction of the likelihood, or impact, of negative events. Attempts to neutralize anxiety with avoidance or compulsive behavior serve to “lock in” anxiety reactions and contribute to the chronic arousal and anticipatory anxiety that mark anxiety disorders.

Neurobiological Model A burgeoning body of research points to the critical importance of several central nervous system (CNS) structures in the genesis of anxiety, as well as the involvement of several central neurotransmitter systems that generate and modulate anxiety symptoms. The limbic system, including the amygdala, is involved in the bottom-up processing of anxiety, whereas the prefrontal cortex is involved in its top-down regulation. In addition, specific brainstem nuclei that release neurotransmitters, such as the locus coeruleus (LC) and raphe nucleus, are interconnected with these regions. Acute panic or alarm states have been tied to central noradrenergic activity. Particular importance has been placed on the LC, the major source of the brain’s norepinephrine. For example, it has been shown that stimulation of the LC generates panic attacks, whereas its blockade (e.g., by tricyclic antidepressants [TCAs], by benzodiazepines [e.g., alprazolam]) decreases panic attacks. Chronic states of generalized anxiety, worry, and vigilance are mediated in part by the γ-amino butyric acid (GABA ) neurons from the limbic system, especially the septo-hippocampal areas. The highly concentrated GABA receptors in those structures bind benzodiazepines to reduce this heightened state of vigilance. Monoamines (such as serotonin and dopamine), neuropeptides (such as corticotropin-releasing hormone [CRH] and vasopressin), and stress hormones (such as cortisol) are important modulators of anxiety. For example, there is evidence that serotonergic agents increase synaptic plasticity in the amygdala and thereby facilitate fear extinction, whereas cortisol promotes the stress response. The interconnections of these neuronal systems both anatomically and neurochemically might explain the efficacy of clinical interventions with diverse mechanisms of action (serotonergic and noradrenergic antidepressants, benzodiazepines, and cognitive-behavioral therapy [CBT]) on pathologic anxiety.

Epidemiology Anxiety disorders are among the most prevalent psychiatric disorders in the general population. More than one-fourth of the United States population experiences pathologic anxiety over the course of their lifetime (see Table 17-1). First-degree relatives of patients with anxiety disorders have a significantly increased risk for anxiety disorders compared with those in the general population. For first-degree relatives of patients with panic disorder, the risk is increased four- to eight-fold. Clinical genetic studies propose a strong genetic contribution to the pathogenesis of anxiety disorders with a heritability of about 30% to 67%. Table 17-1. Lifetime and 12-Month Prevalence of Anxiety Disorders in the United States Disorder

Life-Time Prevalence (%) 12-Month Prevalence (%)

Any anxiety disorder

28.8

18.1

Specific phobia

12.5

8.7

Social phobia

12.1

6.8

Post-traumatic stress disorder

6.8

3.5

Generalized anxiety disorder

5.7

3.1

Panic disorder

4.7

2.7

Obsessive-compulsive disorder 1.6

1.0

Course of Anxiety Disorders Anxiety disorders are associated with marked impairments in physical and psychosocial function as well as in quality of life. For example, panic disorder is associated with increased rates of alcohol abuse, marital and vocational problems, and suicide attempts (in individuals with co-morbid depression and personality disorders). Panic disorder is also associated with increased rates of cardiovascular mortality in men. Patients with panic disorder lose workdays twice as often as those in the general population, with 25% of patients with panic disorder becoming chronically unemployed, and up to 30% receiving public assistance or disability. Patients with panic disorder are five to seven times more likely to be high utilizers of medical services than are individuals without panic disorder.

Although most patients with anxiety disorders improve with treatment, most them do not achieve full and sustained remission with current therapies. High rates of relapse after discontinuation of pharmacotherapy support the need for maintenance treatment for many individuals.

Differential Diagnosis Anxiety disorders should be differentiated from medical and psychiatric conditions that are associated with anxiety. It is also important to recognize when anxiety symptoms mimic the symptoms of medical illness.

Organic Causes of Anxiety In a patient with a known medical illness, the condition, its complications, and its treatment should be suspected as potential causes of anxiety. For example, in a patient with chronic obstructive pulmonary disease (COPD), hypoxia, respiratory distress, and sympathomimetic bronchodilators can all cause symptoms of anxiety. There are certain clinical clues that can help differentiate an organic anxiety syndrome from a primary anxiety disorder. The following six factors are associated with medical causes of anxiety: Onset of symptoms after the age of 35 years Lack of personal or family history of an anxiety disorder Lack of a childhood history of significant anxiety, phobias, or separation anxiety Absence of significant life events generating or exacerbating the anxiety symptoms Lack of avoidance behavior A poor response to anti-panic agents. A patient with an organic cause of anxiety might not otherwise meet criteria for panic disorder or generalized anxiety disorder (GAD); there is often a significant lack of psychological symptoms in the context of severe physical symptoms. Common medical conditions associated with anxiety include endocrine dysfunction (e.g., hyperadrenalism, pheochromocytoma, hypothyroidism, hyperparathyroidism), drug-related intoxication (e.g., use of caffeine, cocaine, sympathomimetics, theophylline, corticosteroids, thyroid hormones), drug-

withdrawal reactions (e.g., from alcohol, narcotics, or sedative-hypnotics), causes of cerebral hypoxia including cardiovascular (e.g., arrhythmias, angina, congestive heart failure [CHF], anemia) and respiratory (e.g., COPD, pulmonary embolism), metabolic disarray (e.g., acidosis, hyperthermia, electrolyte abnormalities [such as hypercalcemia]), or neurological abnormalities (e.g., vestibular dysfunction, seizures, temporal lobe epilepsy).

Anxiety That Complicates Medical Illness Anxiety disorders are particularly common in the general medical setting, affecting about 10% of patients. Patients can sometimes specifically complain about anxiety symptoms, however, they often present primarily with somatic complaints. They therefore seldom seek psychiatric care; typically, they first seek help in primary-care settings or emergency rooms. They tend to be frequent health-care service users; for example, most heavy users of primary-care services (including patients with chronic illness) have significantly higher rates of mood and anxiety disorders than do less-frequent visitors to primary-care physicians. High rates of anxiety disorders are thus found in patients who present with chest pain, dizziness, dyspnea, and symptoms of irritable bowel syndrome. The medical work-up of the anxious patient relies primarily on the medical and psychiatric history, the medication and drug history, and on an appropriate physical and neurological examination. Clinicians should consider the anxiogenic effects of existing medications and medical conditions as well as the aforementioned effects of substance use and withdrawal. A targeted physical examination as well as laboratory and clinical tests are employed based on the clinical assessment, patient characteristics, and the focus of the patient’s somatic complaints (e.g., cardiac, pulmonary, gastrointestinal, neurologic).

Psychiatric Disorders, Other Than Anxiety Disorders Anxiety is also present in psychiatric disorders other than anxiety disorders. In delusional disorders , there are persecutory fears that can mimic anxiety or phobias. Anxiety symptoms occur in the prodromal phase and during the course of schizophrenia. The presence of hallucinations, delusions, or disorganized speech associated with a marked decrease of social functioning for a long period differentiates schizophrenia from anxiety disorders. More than half of all anxious patients also experience significant depression. Symptoms such as dysphoria, hopelessness, anhedonia, early-morning awakening, psychomotor retardation, and suicidal thoughts are typically more

indicative of depression than anxiety. Patients with anxiety disorders usually maintain their interest in their activities but find it difficult to negotiate them comfortably. Cluster C personality disorders (avoidant, obsessive-compulsive, and dependent) should be considered when disruptions in interpersonal functioning and inflexible behavioral patterns date back to childhood and are pervasive across a broad range of personal and social situations. If anxiety develops in reaction to a stressful situation, and within three months of a stressor, but lasts less than 6 months after cessation of the stressor, a diagnosis of adjustment disorder with anxiety can be made. Treatment of this condition is typically aimed at reducing the impact of the known stressor. However, symptomatic relief with an anxiolytic or antidepressant treatment can markedly improve the patient’s quality of life and prevent complications.

Co-Morbidities Anxiety disorders are frequently co-morbid with major depression, other anxiety disorders, and alcohol and drug abuse. When anxiety and depression coexist, monotherapy with an antidepressant or the combination of an antidepressant and a benzodiazepine is indicated; treatment with a benzodiazepine alone is best avoided.

Primary Psychiatric Disorders Panic Disorder Panic disorder is a syndrome characterized by recurrent unexpected panic attacks about which there is persistent concern. Panic attacks are discrete episodes of intense anxiety that develop abruptly and peak within minutes ; they can occur from a calm state but also from an anxious state and are associated with at least four other symptoms of autonomic arousal. Associated symptoms are in the following domains: cardiac (e.g., palpitations, tachycardia, chest pain, discomfort), pulmonary (e.g., shortness of breath, a feeling of choking), gastrointestinal (e.g., nausea, abdominal distress), neurological (e.g., trembling and shaking, dizziness, lightheadedness, faintness, paresthesias), autonomic arousal (e.g., sweating, chills hot flashes), or psychological (e.g., derealization, depersonalization, a fear of losing control or going crazy, a fear of dying). Panic attacks have been associated with specific impairment and distress, and can be

used as a specifier across all the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) disorders. Whereas the initial panic attack is usually spontaneous, subsequently, apprehension frequently develops about future attacks (anticipatory anxiety). Panic disorder has a life-time prevalence of 4.7%; it is more commonly diagnosed in women (2:1). This difference might reflect a true gender difference or the fact that men tend to self-medicate with alcohol and are less likely to seek treatment. Many affected individuals recall a significant life event in the year before onset of the disease. The age of onset is typically between late adolescence and the third decade of life, but many affected individuals experience anxiety dating back to childhood, in the form of inhibited, anxious temperament or childhood anxiety disorders. Panic disorder tends to run in families; studies indicate that genetic factors explain about half of the variance. Based on the DSM-5, the diagnosis requires four criteria that assess the frequency, impact, characteristics, and cause of the panic attacks. First, there must be recurrent, unexpected panic attacks. Second, at least one of the attacks is followed by more than a month of persistent concern about additional attacks (“anticipatory anxiety”), or their consequences, and a significant change in behavior related to the attacks. Third, there is no organic factor (e.g., general medical condition, substance use) that generates these symptoms. Fourth, panic attacks are not accounted for by any other mental disorder. Many patients have limited-symptom attacks , in which only one or two of the panic symptoms are experienced. Limited-symptom panic attacks are also associated with significant morbidity. In terms of disease course, panic disorder is often a chronic disease, with high rates of relapse after discontinuation of treatment. Untreated panic disorder is often complicated by persistent anxiety and avoidant behavior, social dysfunction, marital problems, alcohol and drug abuse, as well as by increased utilization of medical services and an increased mortality rate (from cardiovascular complications and suicide). Avoidant behavior can lead to a progressive constriction of a patient’s social interactions, and it prevents the individual from going to places where panic attacks have occurred or places where easy escape might be difficult or where assistance is unavailable. Affected patients can experience chronic distress and demoralization, which can trigger depression. Although alcohol can temporarily alleviate symptoms of anxiety, patients who abuse it might experience rebound anxiety, tolerance, and withdrawal, which can all exacerbate anxiety.

The established treatments of panic disorder include use of antidepressants, high-potency benzodiazepines, CBT, and a manualized form of psychodynamic therapy called “panic-focused psychodynamic psychotherapy” (see Chapter 47 ).

Agoraphobia Agoraphobia , involves marked fear or anxiety in at least two of the following situations: outside home alone; public transportation; open spaces (e.g., large parking lots, markets); enclosed spaces (stores, theaters, cinemas); and standing in a line or in a crowd. The diagnosis also requires that the individual avoid these situations because of a difficulty to escape or a lack of help in the event of developing panic attacks, or fears of embarrassing (e.g., incontinence) or incapacitating symptoms (e.g., falling). In addition, the agoraphobic situations should almost always provoke fear or anxiety, and be actively avoided (or endured with intense fear or anxiety), and the fear and anxiety must be out of proportion, persistent (usually at least 6 months), and cause significant distress or impairment. Additional stipulations are that the symptoms are not better accounted by another disorder, and that if the fear is due to the presence of a medical condition, the symptoms must be excessive. Although agoraphobia is often co-morbid with panic disorder, and has been previously “attached” to the diagnosis of panic disorder, it is now a condition that can be diagnosed independently of panic disorder in the DSM-5. Agoraphobia can significantly restrict a patient’s daily activities, to the point where he or she becomes dependent on companions to face situations outside of the home; some individuals can become home-bound.

Generalized Anxiety Disorder Patients with generalized anxiety disorder (GAD) suffer from excessive anxiety or worry that is out of proportion to situational factors ; it occurs more days than not for longer than 6 months. These patients are often considered “worriers” or “nervous” by their families and friends. The anxiety is usually associated with muscle tension, restlessness, insomnia, difficulty concentrating, easy fatigability, and irritability. Affected patients typically experience persistent anxiety rather than discrete panic attacks, as in panic disorder. The prevalence of GAD is about 5.7% in community samples; it is more typically diagnosed in women (2:1). The age of onset ranges from adolescence to early adulthood, though symptoms are often detected in childhood. GAD is frequently co-morbid with other anxiety disorders (e.g., panic disorder, social

phobia), depression, as well as alcohol and drug abuse. The course of the disease is chronic but it fluctuates in severity; it is frequently worsened by stress. According to the DSM-5, the diagnosis requires the presence of excessive anxiety and worry regarding a number of events or activities, which occurs more days than not for at least 6 months, and which the individual finds difficult to control. Moreover, the individual must exhibit three out of the following six symptoms: restlessness, easy fatigability, difficulty concentrating, irritability, muscle tension, or insomnia. The anxiety must cause significant distress or impairment in function. Finally, the worry must not be related to features of other disorders, and the anxiety is not attributed to an organic cause (e.g., substance use, medical condition). The treatment of GAD includes pharmacotherapy (e.g., antidepressants, benzodiazepines, buspirone, pregabalin) and CBT (see Chapter 47 ).

Specific Phobia Patients with specific phobias have marked and persistent fears of circumscribed situations or objects (e.g., heights, closed spaces, animals, the sight of blood). Exposure to the phobic stimulus results in intense anxiety and avoidance that interferes with the patient’s life. The life-time prevalence of phobias is about 12.5% in the general population. The age of onset varies depending on the sub-type. Phobias to animals, natural environments (e.g., heights, storms, water), blood, and injections each have an onset in childhood. Situational phobias (e.g., those triggered by airplanes, elevators, enclosed places) have a bimodal distribution with one peak in childhood and another peak in the mid-20s. To meet diagnostic criteria (per DSM-5) for a specific phobia, an individual must demonstrate: persistent and excessive (out of proportion) fear or anxiety of an object or situation; a duration 6 months or more; and an invariable provocation of anxiety, including panic, upon exposure to the feared stimulus. As a result, the phobic stimulus is either avoided or endured with dread. Finally, the fear and the avoidant behavior must interfere with the person’s normal routine or cause marked distress. An additional stipulation is that the symptoms are not better accounted by another disorder (e.g., obsessive-compulsive disorder [OCD], panic disorder). Specifiers include animal, natural environment, bloodinjection-injury, situational, and other. To treat specific phobias, benzodiazepines are useful acutely to decrease phobic anxiety and to facilitate exposure (e.g., to take an airplane flight). However,

CBT, involving exposure and desensitization to the feared stimulus, offers more comprehensive and persistent benefits (see Chapter 47 ).

Social Anxiety Disorder or Social Phobia Patients with a social anxiety disorder (SAD ) fear being exposed to public scrutiny; they fear that they will behave in a way that will be humiliating or embarrassing. Although discomfort related to public speaking is a relatively frequent occurrence in the general population, a significant degree of distress or the presence of impairment is necessary to warrant the diagnosis of SAD. The anxiety can be limited to circumscribed performance situations; that is, “performance anxiety” (e.g., speaking, eating, using a public bathroom, writing in public) or can affect more general social interactions. The life-time prevalence of social phobia varies between 5% and 12% in different studies, depending on the threshold. In epidemiological and community studies, the prevalence is greater in women than in men; however, the prevalence is greater for men in clinical samples. This might be the result of males experiencing more pressure for social performance and thus becoming aware of existing pathology. The onset of social phobia is usually in adolescence, although most affected individuals have a history of anxiety that dates to childhood. The symptoms of social phobia can overlap with those of panic disorder, avoidant personality, and shyness. The course of the disease is chronic but it fluctuates; it is frequently worsened by stress. Diagnostic criteria (per the DSM-5) for SAD require a fear or anxiety of being exposed to public scrutiny, behaving in a humiliating or embarrassing way that is persistent (invariable) and excessive (out of proportion), and last at least 6 months. Because of the fear or anxiety, social situations are either avoided or endured with fear or anxiety. The fear and the avoidant behavior must interfere with the person’s normal routine or cause marked distress to warrant the diagnosis. Additional stipulations are that the fear or anxiety are not due to a medical condition, or to the use of a psychoactive substance, and are not better accounted by another disorder (e.g., panic disorder). In addition, if a medical condition is present (e.g., Parkinson’s disease), the symptoms must be unrelated or excessive. Finally, if the symptoms are restricted to performance situations, a “performance only” specifier can be indicated. The treatment of social phobia includes use of pharmacotherapy (e.g., antidepressants, benzodiazepines, beta-blockers) and CBT (see Chapter 47 ).

Adult Separation Anxiety Disorder

Adult separation anxiety disorder (ASAD ) has been recently included into the anxiety disorder section of the DSM-5. It consists of a persistent and excessive fear or anxiety of being separated from home or an attachment figure. ASAD usually develops in childhood, with prevalence in the adult population estimated to be between 1% and 2%. The presence of ASAD can be impairing, with major limitations of activities that occur away from home or without the attachment figures. In the DSM-5, the diagnostic criteria include: the presence of excessive and inappropriate fear or anxiety concerning separation from home or attached persons, with at least three symptoms among recurrent distress related to separation that is excessive; worry about losing the attached person or about their safety; worry that an event will lead to separation; reluctance or refusal to go to certain places for fear of separation; fear or reluctance to be alone or without attachment figures; reluctance or refusal to go to sleep without an attachment figure; repeated nightmares about separation; and repeated complaints of physical symptoms when separation is anticipated or actually occurs. In addition, the symptoms must last 6 months or more, cause significant distress or impairment, and not be better explained by another disorder (e.g., agoraphobia).

Post-Traumatic Stress Disorder Patients with post-traumatic stress disorder (PTSD) have experienced a traumatic event that involved the threat of death, injury, or severe harm to themselves or others. Patients frequently re-experience the traumatic event in the form of nightmares, flashbacks, or by marked arousal when exposed to situations reminiscent of the event. These patients avoid situations that remind them of the trauma; they might become emotionally numb, irritable, hypervigilant, or have difficulties with sleep and concentration. (For a more detailed discussion on trauma and PTSD, see Chapter 19 .) The syndrome can occur in those who were injured in combat as well as civilians who suffered life-threatening accidents or assaults; estimates of the lifetime prevalence of PTSD in the general population range from 6.8% to 9.2%. The syndrome can occur at any age. Symptoms usually begin within the first 3 months after a trauma, although they can be delayed for months or years. The course is varied: complete recovery occurs within 3 months in roughly half of those affected. Many others experience symptoms for more than 1 year after the trauma.

The complications of PTSD include social withdrawal, depression, suicidality, as well as alcohol and drug abuse. Psychosocial risk factors for PTSD include limited education, a chaotic childhood, and previous personal or familial mental illness. Protective factors include high self-esteem, external control, and social support. To receive a diagnosis (DSM-5) of PTSD, an individual must have experienced a traumatic event. Traumatic events include direct exposure to a life-threatening situation (e.g., being a victim), or witnessing or learning that it occurred to someone close. Further, extreme and repeated exposure to trauma details (e.g., as experienced by first-responders) as well as exposure through the media that are work-related also qualify as traumatic events. The syndrome must also exhibit four distinct types of symptoms: persistent re-experiencing of the trauma in the form of intrusive recollections, nightmares, flashbacks, psychological distress and psychological reactivity occurs on cue exposure; persistent avoidance of stimuli (thoughts and activities) associated with the trauma; alterations in cognitions and mood, such as dissociative amnesia, exaggerated negative beliefs about the self, diminished interest, persistent negative emotional states, feelings of detachment, and inability to experience positive emotions; and symptoms of increased arousal (e.g., self-destructive behavior, sleep disturbance, irritability, anger, difficulty concentrating, hypervigilance, a startle response). The symptoms must last for more than 1 month and cause significant distress and impairment. Clinicians should specify the sub-type: with dissociative symptoms (e.g., depersonalization or derealization), or with delayed onset (onset > 6 months after the trauma). The differential diagnosis includes acute stress disorder, in which symptoms occur within 4 weeks of the traumat ic event and persist for less than 4 weeks. The treatment of PTSD consists of pharmacotherapy (e.g., antidepressants) and psychotherapy, often in combination. Evidence-based psychotherapies include versions of CBT incorporating elements of exposure therapy (prolonged exposure), or cognitive restructuring (cognitive processing therapy), and a specific therapy called Eye Movement Desensitization and Reprocessing (EMDR).

Conclusions Anxiety disorders are a group of psychiatric disorders associated with high morbidity and with significant mortality (through suicide, co-morbid substance abuse, and from cardiovascular problems). Given the similarities in presentations

between certain medical conditions and anxiety disorders, a comprehensive medical, psychiatric, and substance use history is very important to the diagnostic process. Because most of the anxiety disorders tend to be chronic, many patients will benefit from ongoing pharmacotherapy and/or psychosocial interventions to optimize and maintain improvement.

Suggested References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Kessler RC, Berglund P, Demler O, et al: Lifetime prevalence, and age-ofonset distributions of DSM-IV disorders in the National Co-Morbidity Survey Replication. Arch Gen Psychiatry . 2005; 62(6): 593–602. 3. Kessler RC, Chiu WT, Demler O, et al: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Co-Morbidity Survey Replication. Arch Gen Psychiatry . 2005; 62(6): 617–627. 4. Pine DS: Anxiety disorders: Introduction and Overview. In: Sadock BJ, Sadock VA, Ruiz P, eds.: Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009: 1839–1843. 5. Pollack MH, Otto MW, Wittmann CW, et al: Anxious patients. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010:133–152. 6. Pollack MH, Smoller JW, Lee DK: The anxious patient. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw-Hill; 2004: 137–152.

CHAPTER Obsessive-Compulsive and 18 Related Disorders NOAH CHASE BERMAN, PHD; ERIN CURLEY, BA; AND SABINE WILHELM, PHD

KEY POINTS Overview The new Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) obsessive-compulsive and related disorders (OCRD) category includes: obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), trichotillomania (TTM), excoriation disorder, and hoarding disorder. DSM-5 Diagnostic Criteria Criteria for OCD include the presence of time-consuming or functionally impairing obsessions, compulsions, or both. Criteria for BDD include a preoccupation with one or more perceived defects in appearance that cause significant distress or impairment in everyday functioning. Criteria for TTM and excoriation disorder include recurrent hair-pulling or skin-picking, resulting in significant hair loss or skin lesions, respectively. Individuals also must have made repeated attempts to stop or decrease the behavior, and the behavior must cause significant distress or impairment. Criteria for hoarding disorder include significant difficulty and distress associated with discarding possessions due to a perceived need of items. Qualifier to OCRD Diagnoses OCRDs cannot be accounted for by another psychiatric or medical condition or be the result of substance use. For OCD, BDD, and hoarding disorder, clinicians can specify the individual’s insight (from absent/delusional to excellent). The DSM-5 also includes disorder-specific qualifiers: a tic-related specifier for OCD, a muscle dysmorphia specifier for BDD, and an excessive acquisition

specifier for hoarding disorder. Differential Diagnosis Due to the similarities among OCRD symptoms and other anxiety, mood, or psychotic disorders, it is imperative that clinicians carefully assess the content of the thought and the function of the behavioral response. Prevalence, Onset, Course The prevalence rates for OCRDs range from 1% to 5%. OCRDs affect both males and females, although gender differences exist in the course, prevalence, and symptom presentation for some OCRDs. With the exception of hoarding disorder, which often begins in middle age, the majority of OCRDs begin during adolescence. OCD, BDD, TTM, and excoriation disorder have a chronic course, with waxing and waning symptoms, whereas hoarding disorder has a progressive course.

Treatment Selective serotonin re-uptake inhibitors are the first-line pharmacological treatment for many OCRDs. Cognitive-behavior therapy (CBT) with a significant exposure and response prevention component is considered the “gold standard” psychosocial treatment for OCD and BDD. CBT is efficacious in treating hoarding disorder, with much of the work focused on improving the individual’s ability to sort possessions and make disposition decisions. TTM and excoriation disorder are typically treated with habit-reversal training and can be augmented with acceptance and commitment therapy and dialectical-behavioral therapy.

Introduction The Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes a new super-ordinate category titled the obsessive-compulsive and related disorders (OCRD). Given similarities among several factors (e.g.,

phenomenology, neurochemistry, family history, patterns of co-morbidity), obsessive-compulsive disorder (OCD ) was removed from the anxiety disorders section in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and identified as the primary disorder in this category. Four other disorders were moved from their respective categories into the new OCRD group: body dysmorphic disorder ([BDD ]; moved from the somatoform disorders), trichotillomania ([TTM]; also referred to as hair-pulling disorder and previously considered an impulse-control disorder), excoriation disorder (also referred to as skin-picking disorder and previously diagnosed as impulse-control disorder not otherwise specified), and hoarding disorder (previously considered a symptom of OCD).

DSM-5 Diagnostic Criteria Diagnostic criteria for OCD include the presence of obsessions (i.e., unwanted intrusive thoughts, impulses, ideas or images; e.g., “I am contaminated by germs from the faucet”), compulsions (i.e., overt or covert behaviors in response to the obsessional content that reduce anxiety; e.g., excessive hand-washing), or both. Together, the obsessions and compulsions must be time-consuming (e.g., occupying more than one hour per day) or significantly interfere with functioning. For BDD, the diagnostic criteria require a preoccupation with one or more perceived defects in appearance (e.g., the size of one’s nose) that are not observable to others and cause significant distress or impairment in everyday functioning. In response to these appearance-related concerns, individuals with BDD engage in repetitive overt (e.g., mirror-checking) or covert (e.g., comparison to others) behaviors. TTM and excoriation disorder possess similar diagnostic criteria in DSM-5; however, the body-focused target of the repetitive behavior differs. Specifically, individuals’ recurrent hair-pulling or skin-picking must lead to significant hair loss or skin lesions, respectively. Moreover, individuals must have attempted to decrease or stop the pulling or picking behavior and continued engagement in the maladaptive behavior must cause significant distress or functional impairment. DSM-5 criteria for hoarding disorder include significant difficulty discarding possessions (irrespective of value) due to a perceived need of the item and the distress associated with discarding. As a result of the discarding difficulties, individuals with hoarding disorder have cluttered living areas. To meet diagnostic criteria, an individual’s difficulty discarding items and his or her accumulation of possessions must cause clinically significant distress or impairment in functioning.

In addition to the five primary diagnoses in this category, four other OCRDs with less research support include: substance/medication-induced OCRD (i.e., OCRD symptoms develop during or following exposure to, or intoxication or withdrawal from, a substance or medication); OCRD due to another medical condition (i.e., OCRD symptoms occur as a consequence of a medical condition); other specified OCRD (i.e., full criteria for an OCRD are not met and the clinician specifies the reason; e.g., body dysmorphic concerns are in response to actual flaws); and unspecified OCRD (i.e., full criteria for an OCRD are not met and the clinician does not specify the reasons or not enough information has been gathered). Although these four diagnoses are clinically meaningful, the remainder of the chapter will focus solely upon the five primary OCRDs.

Qualifiers to OCRD Diagnoses DSM-5 includes a number of qualifiers for the OCRDs. Importantly, the five primary OCRDs cannot be accounted for by another psychiatric or medical condition (e.g., eating disorder) or be the result of substance use (e.g., cocaine). Another important qualifier for OCD, BDD, and hoarding disorder is the individual’s insight (i.e., ability to recognize the psychological nature of the disorder), which occurs across a continuum from delusional/absent to excellent. Additional qualifiers are diagnosis-specific. For OCD, clinicians can indicate whether the individual currently or historically meets diagnostic criteria for a tic disorder (tic-related specifier). For BDD, clinicians can indicate whether appearance-related concerns are focused on inadequate musculature (muscle dysmorphia specifier). For hoarding disorder, clinicians can indicate whether the individual excessively acquires items that are not needed (excessive acquisition specifier).

Differential Diagnosis Given the similarities among OCRD symptoms and other anxiety, mood, or psychotic disorders, clinicians should carefully assess the content of the thought and the function of the behavioral response. In OCD, the intrusions tend to have odd or irrational content (e.g., thinking about the number “6” will make my house burn down) and are not rooted in real-life (generalized anxiety disorder) or appearance-related concerns (BDD). Moreover, the unwanted thoughts cannot be circumscribed to a specific stimulus (e.g., spiders) or situation (e.g., public speaking; specific phobia, social anxiety disorder, respectively). The presence of

rituals also differentiates OCD from other anxiety disorders, in which avoidance is the pervasive behavioral response. Significantly, the repetitive rituals in OCD must occur in response to an obsession, not a premonitory sensory urge (tic disorder) or increased tension (TTM, excoriation disorder). In BDD , the obsessions are focused upon one’s appearance. Unlike social anxiety disorder, individuals with BDD fear that they are being judged based upon perceived appearance flaws and thus engage in repetitive behaviors to try to fix, hide, or change their appearance (e.g., wearing excessive make-up, wearing sunglasses indoors). As compared to individuals with eating pathology, those with BDD often focus on multiple body areas (instead of, or in addition to, shape and weight) and do not typically engage in d isordered eating (e.g., restricting, purging). Hair-pulling and skin-picking occurs in approximately onethird of BDD patients; therefore, the function of these behaviors should be carefully assessed. If the repetitive behaviors serve to fix perceived skin or hair defects, consider a diagnosis of BDD. In addition to the aforementioned important diagnostic differentials for TTM and excoriation disorder, clinicians should also assess whether the hair-pulling or skin-picking occurs in response to delusions or hallucinations (psychotic disorder) or culturally-normative hair removal that is performed for cosmetic reasons (e.g., waxing). Lastly, in the assessment of collecting behaviors, clinicians should carefully differentiate hoarding disorder from a neurodevelopmental (autism spectrum) or neurocognitive (frontotemporal lobe degeneration) disorder. Other diagnoses also should be considered if the accumulation is a consequence of delusions (psychotic disorder); psychomotor retardation or fatigue (depression); or in response to fears of contamination, harm, or incompleteness (OCD).

Prevalence Prevalence estimates for the OCRDs range from 1% to 5%. Specifically, research estimates that approximately 1.5% to 3% of the global population will be diagnosed with OCD during their life-time. For BDD, survey-based prevalence research indicates that approximately 1.4% to 2.5% meet diagnostic criteria. Similarly, TTM and excoriation disorder affect approximately 1% to 3% and 2% to 4% of the general population, respectively. Hoarding disorder is considered the most prevalent OCRD, with estimates approaching 5% of the general population; however, no research has evaluated the prevalence rates of hoarding disorder using new DSM-5 criteria.

Gender Differences Research indicates that some OCRDs possess gender differences in their course, prevalence, or symptom presentation. In regard to OCD, there is a relatively equal gender distribution; however, males tend to have an earlier age of onset, more frequent forbidden or taboo obsessions (i.e., incest) and symmetry concerns (i.e., need for exactness), and co-morbid tic disorders. Females, on the other hand, more frequently report contamination and washing symptoms. For BDD, estimates suggest that women (1.5%–2.5%) meet diagnostic criteria at a slightly higher rate than men (1.4%–2.2%). Regarding gender differences in symptom presentation, research suggests that men and women engage in similar behavioral rituals, such as mirror-checking, in response to their concerns about appearance. Conversely, although men and women tend to be preoccupied with similar flaws in their appearance (e.g., of their nose or hips), males more frequently report preoccupation with their genital area and those who meet criteria for the muscle dysmorphia specifier (belief that their stature and muscles are too small) are almost exclusively male. In TTM, females are 10 times more likely to have the disorder than males. A similar trend occurs in excoriation disorder, in that more than 75% of individuals presenting with this psychiatric disorder are female. However, the observed gender distribution in TTM and excoriation disorder might reflect a difference in treatment-seeking or cultural standards regarding appearance (i.e., male pattern baldness). Scant epidemiological research suggests that hoarding disorder occurs more commonly in males than females. Paradoxically, the treatment-seeking population is predominantly female. The fundamental features of hoarding disorder (i.e., difficulties discarding possessions) do not differ between genders; however, females more frequently report excessive acquisition behaviors (a hoarding disorder specifier). Additional research exploring gender differences in hoarding disorder (using DSM-5 criteria) is needed.

Onset Research indicates that the majority of OCRDs begin during childhood or adolescence. The average age of onset for OCD is approximately 19.6; however, there is a bi-modal onset of the disorder at approximately 11 years and 22 years. BDD, on the other hand, has a uni-modal onset age in adolescence, with most individuals reporting symptom onset at approximately 16-years-old. Although TTM can develop at any age, this disorder parallels the uni-modal onset of BDD,

in that most individuals develop the disorder closely preceding or following the onset of puberty (approximately age 12). Research suggests that excoriation disorder has a tri-modal onset—with individuals developing the disorder before age 10, between the ages of 15 and 21, and between the ages of 30 and 45. Despite the trimodal onset, excoriation disorder, like TTM, most commonly emerges in the context of puberty. The development of hoarding disorder is unique from the other OCRDs. Although hoarding symptoms can begin during childhood or early adolescence, hoarding disorder typically does not interfere with function until middle age.

Course OCD, BDD, TTM, and excoriation disorder possess a chronic course, with symptoms that wax and wane. Despite the chronicity of these disorders, the associated symptoms tend to change over the course of the illness. Specifically, the obsessional content or pulling and picking sites (i.e., shifts from scalp to pubic area) tend to vary over time. Contrastingly, research on hoarding disorder suggests that this condition possesses a progressive course, such that the symptoms worsen with each decade that the disorder persists. Although suicidal ideation occurs in individuals with an OCRD, a diagnosis of BDD is associated with significantly greater risk for both suicidal ideation and attempts when compared to OCD, TTM, excoriation disorder, or hoarding disorder.

Treatment Pharmacological Interventions Selective serotonin re-uptake inhibitors (SSRIs ) are the first-line pharmacological treatment for many OCRDs. Neurochemical research suggests that individuals with OCD tend to have dysfunctional serotonergic and dopaminergic systems. Accordingly, SSRIs (e.g., fluoxetine) as well as augmenting dopamine antagonists (i.e., antipsychotics/neuroleptics; e.g., risperidone), have demonstrated efficacy in the treatment of OCD. Given research demonstrating that OCD and BDD share similar underlying pathophysiology in the dysregulation of the serotonergic and dopaminergic systems, SSRIs are considered the first-line treatment for BDD as well. Current SSRI guidelines for BDD approach the high-end of recommended dosage ranges (e.g., 80 mg/day of fluoxetine). Notably, initial studies have not found augmentation with dopamine antagonists to be efficacious for BDD. However,

these findings are preliminary and further research is needed to determine the efficacy of SSRI augmentation in the treatment of BDD. Little research has tested the effectiveness of pharmacological interventions for TTM and excoriation disorder. Research suggests that SSRIs might have some benefit; however, these findings are mixed. Importantly, N -acetylcysteine (NAC), an over-the-counter amino acid supplement, has demonstrated efficacy in a randomized, controlled trial among adults with TTM. Unfortunately, when compared to a placebo, no significant benefit of NAC was demonstrated in children with TTM. No studies have explored the effectiveness of NAC in treating excoriation disorder. Not surprisingly, there is a lack of research identifying the most effective pharmacologic interventions for hoarding disorder. One uncontrolled study provided preliminary evidence that SSRIs might be an efficacious treatment. Controlled studies are needed to adequately determine whether SSRIs can operate as a monotherapy or if neuroleptic augmentation would significantly improve outcome for this new DSM-5 condition.

Psychosocial Interventions For the majority of OCRDs, the most efficacious psychosocial treatment is cognitive-behavioral therapy (CBT). CBT is a goal-oriented and evidence-based approach to therapy. Broadly speaking, in CBT, patients are first administered empirically-based assessment procedures (i.e., standardized and validated selfreport and clinician-administered measures) and scores are interpreted with the patient. Next, the patient is provided with psychoeducation about the interplay between his or her thoughts, feelings, physiological sensations, and behavioral responses. Finally, clinicians teach the patient how to apply cognitive (e.g., evaluate the validity of dysfunctional interpretations and beliefs in a nonjudgmental manner) and behavioral (e.g., exposure) strategies to reduce the severity of psychological symptoms. Much research has tailored general CBT principles or the OCRDs. Below, we briefly outline the specifics of CBT for each of the OCRDs. For OCD, the “gold standard” CBT involves exposure with response prevention (ERP ) as the core treatment component. Importantly, CBT for adults with OCD has demonstrated efficacy when directly compared to pharmacological treatments. In CBT for OCD, the clinician first conducts a thorough diagnostic assessment to ensure that this treatment program is appropriate (e.g., a patient’s aggressive obsessions are not better explained by an

impulse-control disorder). Next, the clinician provides the patient with psychoeducation regarding the cognitive-behavioral model of OCD—unwanted intrusive thoughts escalate anxiety, which lead the individual to engage in compulsive rituals aimed at reducing distress. Next, the clinician and patient collaboratively develop a fear hierarchy that ranks the patient’s feared (e.g., doorknobs) or avoided (e.g., public bathrooms) situations. The patient then gradually and systematically confronts the identified situations by engaging in repeated “exposures” (e.g., touching a countertop at a hospital) while refraining from performing ritualistic behaviors (i.e., response prevention; e.g., washing hands for 10 minutes). At the onset of each exposure, the clinician identifies the patient’s feared outcome (e.g., “If I step on this crack, my house will burn down”) and accordingly, following the exposure, the clinician reassesses whether the outcome of the exposure supported or refuted the fearful prediction. This process assists the patient in developing alternative, non-distressing associations with stimuli. To supplement ERP, clinicians often instruct the patient how to modify maladaptive appraisals of obsessive intrusions (e.g., over-estimation of danger, need for certainty) through cognitive restructuring (e.g., identify the evidence for and against the misappraisal). Similar to OCD, ERP is the essential component of CBT for BDD . Indeed, CBT for BDD is an efficacious treatment for this debilitating psychiatric condition. In this treatment, patients are provided psychoeducation, engage in cognitive re-structuring and collaboratively construct a hierarchy of feared (e.g., large groups) or avoided (e.g., leaving the house without make-up) situations. Next, these situations are systematically approached through ERP (e.g., a patient attends a concert and does not attempt to fix, hide, or alter her appearance). There are also unique components to CBT for BDD, such as mirror retraining (i.e., modifies selective attention to perceived appearance flaws) and psychoeducation and motivational interviewing aimed at reducing surgeryseeking behavior. For TTM and excoriation disorder, the most efficacious form of CBT relies upon habit-reversal training (HRT ). HRT is a multi-component treatment package designed to target motor habits. Specifically, HRT includes awareness training (e.g., identify the patterned movement of the arm when picking or pulling), competing response training (e.g., engage in a behavior, such as making a fist, that is physically incompatible with the picking or pulling), stimuluscontrol strategies (e.g., decrease opportunities to, or prevent, picking or pulling, such as covering the mirror in the bathroom) and relaxation techniques (e.g.,

diaphragmatic breathing). For example, a patient who pulls from her scalp will be provided psychoeducation about TTM and will then learn to identify the situations (e.g., while watching TV) and motor patterns associated with pulling. Next, the patient will reduce her vulnerability for pulling in front of the TV by (a) employing stimulus-control strategies such as wearing gloves, and (b) utilizing relaxation skills. In instances when the patient engages in pulling, she is instructed to immediately employ a competing response and maintain the behavior for a minimum of 90 seconds. Unfortunately, HRT is not effective for all individuals with TTM and excoriation disorder. Researchers posit that HRT is most effective for individuals with habit-like picking and pulling. Thus, additional augmentation strategies have been incorporated into HRT to target negative affective states and sensations that might trigger picking or pulling behaviors. Recent trials have demonstrated the efficacy of augmenting traditional HRT for TTM or excoriation disorder with acceptance and commitment therapy (ACT ) and dialecticalbehavioral therapy (DBT). Although hoarding was previously considered a symptom of OCD until DSM5, treatment trials have demonstrated the efficacy of CBT for hoarding disorder. Treatment components integrate cognitive restructuring and exposure-based principles, along with executive functioning skills. Specifically, the “backbone” of the treatment is to improve the individual’s ability to sort possessions and make disposition decisions (e.g., keep, discard). Additionally, treatment aims to improve problem-solving and organization skills, reduce compulsive buying, and more broadly, teach the individual how to tolerate the distress associated with both reducing clutter and limiting the acquisition of new possessions.

References 1. Abramowitz JS, Deacon B, Olatunji B, et al: Assessment of obsessivecompulsive symptom dimensions: Development and validation of the Dimensional Obsessive-Compulsive Scale. Psychol Assessment . 2010; 22: 180–198. 2. Abramowitz JS, Franklin ME, Schwartz SA, et al: Symptom presentation and outcome of cognitive-behavioral therapy for obsessive-compulsive disorder. J Consult Clin Psychol . 2003; 71: 1049–1057. 3. Bloch MH, Landeros-Weisenberger A, Dombrowski P, et al: Systematic

review: Pharmacological and behavioral treatment for trichotillomania. Biol Psychiat . 2007; 62: 839–846. 4. Chamberlain SR, Odlaug BL, Boulougouris V, et al: Trichotillomania: Neurobiology and treatment. Neurosci Biobehav R . 2009; 33: 831–842. 5. Eisen JL, Phillips KA, Coles ME, et al: Insight in obsessive compulsive disorder and body dysmorphic disorder. Compr Psychiat . 2004; 45(1): 10– 15. 6. El Mansari M, Blier P: Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder. Prog NeuroPsychopha , 2006; 30(3): 362–373. 7. Fineberg NA, Brown A, Reghunandanan S, et al: Evidence-based pharmacotherapy of obsessive-compulsive disorder. Int J Neuropsychop . 2012; 15(8): 1–19. 8. Grant JE, Odlaug BL, Kim SW: N -acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: A double-blind, placebo-controlled study. Arch Gen Psychiatry . 2009; 66: 756–763. 9. Hollander E, Braun A, Simeon, D: Should OCD leave the anxiety disorders in DSM-V? The case for obsessive compulsive-related disorders. Depress Anxiety . 2008; 25(4): 317–329. 10. Ipser JC, Sander C, Stein DJ: Pharmacotherapy and psychotherapy for body dysmorphic disorder. Cochrane Database Syst Rev . 2009; 1:CD005332. 11. Koran LM, Hanna GL, Hollander E, et al: Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry . 2007; 164 (7 Suppl): 5–53. 12. Ruscio A, Stein D, Chiu W, et al: The epidemiology of obsessivecompulsive disorder in the National Co-Morbidity Survey Replication. Mol Psychiatr . 2010; 15(1): 53–63. 13. Saxena S: Neurobiology and treatment of compulsive hoarding. CNS Spectr . 2008; 13: 29–36. 14. Tolin DF, Stevens MC, Villavicencio AL, et al: Neural mechanisms of decision making in hoarding disorder. Arch Gen Psychiatry . 2012; 69: 832–841. 15. Wilhelm S, Phillips KA, Fama JM, et al: Modular cognitive-behavioral therapy for body dysmorphic disorder. Behav Ther . 2011; 42(4): 624–633.

CHAPTER Trauma and Post-Traumatic 19 Stress Disorder ERIC BUI, MD, PHD; BRIAN J. SCHULMAN, MD; RAFAEL D. ORNSTEIN, MD; AND ROGER K. PITMAN, MD

KEY POINTS Overview Most people are able to adapt following a traumatic event. When the symptoms following a trauma become maladaptive, they can be classified as acute stress disorder (ASD) or post-traumatic stress disorder (PTSD). Epidemiology The life-time prevalence of PTSD range from 7% to 9%. About 20% of those exposed to a significant trauma will develop PTSD during their life-time, with rates varying according to the nature of the trauma. Although the majority of people who develop PTSD will recover within the first year, one-third will present chronic and persistent symptoms. Main risk factors for PTSD include female gender, prior history of trauma and psychiatric history, peri-traumatic psychological reactions, low social support, and the interpersonal nature of the trauma. Clinical Features A traumatic event is defined as being exposed to a life-threatening event, witnessing it, or learning that it occurred to someone close. Extreme and repeated exposure to trauma details (e.g., as experienced by first-responders), as well as indirect exposure through the media if it is work-related, also qualify as traumatic events. The diagnosis of ASD requires a traumatic event and meeting a threshold of 9 symptoms out of 14 that last less than 1 month. The diagnosis of PTSD requires a traumatic event and meeting at least one symptom of re-experiencing, one symptom of avoidance, two symptoms of

negative alterations in mood and cognitions, and two symptoms of hyperarousal, that last more than 1 month. Etiology A persisting stress response involving an amygdala hyperactivity, the sympathetic system, and the hypothalamic–pituitary–adrenal (HPA) axis, is implicated in the pathophysiology of PTSD. Differential Diagnosis ASD occurs within the first month and PTSD is diagnosed thereafter. Adjustment disorders, psychotic disorders, mood disorders, and other anxiety disorders are potential differential diagnoses of PTSD, but the exposure to a traumatic event and re-experiencing symptoms are specific to PTSD.

Approaches to Evaluation Victims infrequently come to the attention of psychiatrists immediately following a traumatic event. Evaluation in the immediate aftermath of a trauma should focus on practical issues including establishing safety, obtaining information, responding to medical or legal concerns, securing food and shelter, and connecting with family and other social supports. Treatment Evidence-based psychotherapeutic approaches include prolonged exposure (PE) and cognitive processing therapy (CPT) as well as eye movement desensitization and re-processing (EMDR). Evidence-based pharmacological approaches include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine re-uptake inhibitors (SNRIs). Sertraline and paroxetine are FDA-approved. Prazosin can be used for PTSD-related nightmares. Benzodiazepines should be used with caution.

Overview

The puzzling and disturbing effects of psychological trauma on human functioning have been described for generations, going as far back as Homer’s Iliad . In more recent times, large numbers of American Civil War veterans complained of generalized weakness, heart palpitations, and chest pain, thought to result from the physical stress of war; it was referred to as “soldier’s heart.” In World War I, psychologically disabled veterans were thought to have suffered from blast-induced brain damage, or “shell shock.” Kardiner described a syndrome in World War II veterans that he labeled a “traumatic neurosis of war,” and he made the point that the syndrome was physiological in nature. The problem of psychopathology induced by psychological trauma was nearly ignored until after the Vietnam War, when veterans spoke out about “postVietnam syndrome” or “delayed stress,” and the feminist movement spoke out about “rape trauma syndrome.” Recognition of the common syndrome that resulted from these two different stressors led to a synthesis that in 1980 became “post-traumatic stress disorder” (PTSD) in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III). Acute and long-term responses to traumatic events are varied and multidetermined. Nearly every person can be expected to have some disruption in their mental functioning following a significantly traumatic event—a “normal” stress response. Most people are able to adapt following a traumatic event and return to their previous level of function with few if any lasting symptoms. When the symptoms following a trauma become maladaptive, they can be classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as acute stress disorder (ASD) or PTSD. Exposure to trauma that does not result in a formal psychiatric diagnosis (sometimes referred to as “sub-threshold” or “partial” PTSD) might still result in chronic symptoms that can have a significant impact on the individual, including depressed and anxious mood, and damage to the victim’s sense of self.

Post-Traumatic Stress Disorder Since its inclusion in the DSM-III, the diagnosis of PTSD has helped researchers and clinicians attend to the connection between psychological trauma and psychiatric morbidity. Initially, in DSM-III, PTSD was described as a normal, expectable response to a traumatic event that was “outside of the range of usual human experience.” DSM-III-R added that the traumatic event “would be markedly distressing to almost anyone,” and it gave the example of a “serious threat to one’s life or physical integrity,” although other stressors could qualify,

such as the sudden destruction of one’s home. The event could be either directly experienced or witnessed. Subsequently, DSM-IV re-defined a traumatic event from an incident outside the range of normal human experience to a situation involving “actual or threatened death or serious injury, or a threat to physical integrity of oneself or others,” which the person has “experienced, witnessed, or been confronted with,” and it added the requirement of a subjective response to the event of “intense fear, helplessness, or horror.” Examples of potential Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) traumatic events include military combat, violent assault, rape, robbery, domestic violence, automobile and industrial accidents, childhood physical or sexual abuse, natural disasters, and sudden catastrophic medical illness. Recently, the DSM-5, dropped the required subjective reaction to the trauma (APA, 2013). Qualifying traumatic events now include direct exposure (i.e., being a victim) to a life-threatening event, witnessing its occurrence, or learning that it occurred to a close relative or friend. Further, extreme and repeated exposure to trauma details (e.g., as experienced by first responders) as well as indirect exposure through the media, but only if this is work-related, also qualify as traumatic events. In all DSM conceptions, the development of PTSD following a trauma is the exception rather than the rule . Research suggests that individual vulnerabilities play a significant role in the development of the disorder. The DSM-5 criteria for PTSD further comprise four clusters of post-traumatic symptoms: intrusion/re-experiencing, avoidance, alterations in mood and cognitions, and hyperarousal. If there are sufficient symptoms in each of these clusters, accompanied by clinically significant distress and/or functional impairment, the threshold for a diagnosis will be reached. Common difficulties faced in integrating the traumatic experience include: fear of recurrence or repetition of the trauma; shame over helplessness; loss of a sense of invulnerability; feelings of personal failure; rage at the source of the trauma; guilt about actions either committed or omitted; and guilt over having survived while others perished. Re-experiencing symptoms are the hallmark of PTSD. As opposed to the other symptoms, which might be shared with other disorders (such as depression, or generalized anxiety disorder), re-experiencing symptoms are specific to PTSD, and their presence facilitates differential diagnosis. Traumatic memories are often disruptive; they can be vivid, sensory experiences, but they might also be recollections or emotions that can intrude unbidden. Nightmares are arguably the

most pathognomonic symptom in PTSD, although they are not required for the diagnosis. They are often repetitive and lifelike, but they do not necessarily involve an exact replay of the traumatic event; rather variations on the theme and introduction of related themes are common. Nightmares often disrupt sleep; patients with PTSD can dread falling asleep and fight it in order to avoid frightening nightmares. Flashbacks are distinguished from mere memories based upon their realistic quality and partial, or in rare cases, full loss of contact with reality. Traumatic hallucinations rarely occur. Intense emotional distress and physiological reactivity (such as palpitations, shortness of breath, chest tightening, excessive sweating), can occur in response to internal or external reminders of the trauma. Because remembering the traumatic event is so painful, patients with PTSD avoid things reminiscent of the trauma, including thoughts or feelings, activities, people, places that are associated with the event. Negative alterations in mood and cognitions that develop (or worsen) with exposure to the traumatic event can take various forms. Infrequently, there is amnesia for aspects of the event itself. An overall sense of detachment, a diminished ability to experience positive emotions, a loss of interest, exaggerated negative beliefs (about oneself of others), and persistent negative emotional states (such as fear, guilt, or shame) are reported frequently. Negative alterations in mood and cognitions can be the most disabling post-traumatic symptom cluster because of their damaging effects on personal relationships. Hyperarousal is the fourth major PTSD symptom cluster. Symptoms of increased arousal are broad and include disturbed sleep, irritability, angry outbursts, difficulty with concentration, hypervigilance, exaggerated startle response, and self-destructive behaviors. Although the DSM-5 specifies that symptoms of increased arousal not be present before the trauma, this is a difficult rule to apply because patients with preexisting mental disorders that also entail hyperarousal still can develop PTSD following a traumatic event; indeed, they are at greater risk for it. To meet DSM-5 criteria PTSD, the individual must have at least one symptom of re-experiencing, one symptom of avoidance, two symptoms of alterations in cognition and mood, and two symptoms of hyperarousal. In addition, the duration of the disturbance must be more than 1 month. (If the traumatic event occurred less than 1 month ago, the diagnosis of ASD should be considered. See the section that follows.) Moreover, the disturbance must cause clinically significant distress or impairment in social or occupational functioning. (Some authors incorrectly state that psychosocial impairment is required for the PTSD

diagnosis. Impairment is not required in the presence of clinically significant distress.) The evaluator has the option of specifying a PTSD sub-type when appropriate: with dissociative symptoms (e.g., depersonalization or derealization), or with delayed onset (more than 6 months after the event). Specific criteria that differ slightly from the adult ones are available for children under the age of 6 years.

ASD In the immediate aftermath of a traumatic event, because of the intensity of the feelings associated with the trauma, peri-traumatic reactions including distress and dissociation can occur. When peri-traumatic dissociation occurs, the perception of the event might be distorted, with the event’s being re-experienced as fragments of sensations, and time might be perceived as slowed or accelerated. Moreover, feelings can be dissociated from events as they are occurring, and there might be varying degrees of amnesia for all or part of the traumatic event. ASD is, by definition, an acute, shorter-lived condition that can follow the same kind of traumatic event that can cause PTSD . ASD involves symptoms similar to PTSD, although the diagnosis does not rely on a specific combination of symptoms, but on the number of symptoms present. In addition, ASD adds derealization (“altered sense of the reality”) as a dissociative symptom. Specifically, the ASD diagnosis requires at least nine symptoms that develop (or worsen) with exposure to the traumatic event out of 14: intrusive memories; nightmares; flashbacks; psychological distress or physiological reactions to reminders; difficulty experiencing positive emotions; derealization; dissociative amnesia; avoidance of internal reminders; avoidance of external reminders; sleep problems; anger or marked irritability; hypervigilance; concentration problems; and heightened startle reactions. Also differentiated from PTSD is the timeframe: in ASD, the disturbance lasts from 3 days to 4 weeks and occurs within 4 weeks of the traumatic event. Furthermore, as in all psychiatric diagnoses, clinically significant distress or impairment is required. If symptoms persist beyond 1 month, a substantial proportion of ASD patients can qualify for PTSD.

Epidemiology

Epidemiologic studies in the United States suggest that, over a life-time, more than half of the population will experience a traumatic event severe enough to be capable of causing PTSD. However, only a minority of those will go on to develop the disorder, because estimates of overall life-time prevalence of PTSD range from only 6.8% to 9.2%. The likelihood of developing PTSD is twice as high in women as in men. It is unclear whether this gender discrepancy is due to an increased vulnerability to the disorder or the fact that seemingly similar events are experienced differently by men and women. The most common causes of PTSD in men are combat and witnessing death or severe injury; the most common causes in women are rape and sexual molestation. Overall approximately 20% of those exposed to a qualifying event go on to develop PTSD, but rates vary significantly according to the nature of the trauma. Life-time rates of PTSD range from as low as 3.6% following natural disasters, to nearly 50% following rape, to as high as 90% among the most brutalized prisoners of war.

Longitudinal Course of PTSD The clinical course of PTSD varies. Symptoms of PTSD usually develop within three months after a trauma, although they can be delayed for years. According to the DSM-5, approximately half of people who develop PTSD will recover within the first year. However, other estimates in the literature are less optimistic. In about 30% of those initially diagnosed, PTSD can be a chronic and persistent illness. It has been reported that 17% of women who were sexually assaulted had PTSD 17 years later. Symptoms of PTSD can be intermittent or residual. It is not uncommon for PTSD to be reactivated years after it has apparently resolved. This might occur following another traumatic event or life stressor, a phenomenon known as “reinstatement.”

Risk Factors for Developing PTSD Studies have consistently detected certain personal vulnerabilities that predispose individuals to develop PTSD in the face of a severe trauma. Pretraumatic risk factors include: female gender; lower education and intelligence; prior personal or family psychiatric history; and a history of previous trauma, especially childhood abuse or neglect. In addition, panic, distress, and dissociative symptoms experienced during or shortly after the traumatic event (“peri-traumatic” risk factors) predict future PTSD. Poor social support is a post-

traumatic risk factor. Finally, as noted earlier, the nature of the traumatic stressor is an important risk factor for developing PTSD.

“Complex” PTSD Children exposed to physical or sexual abuse, or adults exposed to prolonged and repeated trauma, might develop long-standing problems with psychological and interpersonal functioning referred to in the literature as “complex PTSD ” or “ disorders of extreme stress not otherwise specified”. The syndrome can involve a range of debilitating symptoms, including difficulty with affect regulation (e.g., problems managing anger, self-destructive behavior, impulsive and risk-taking behavior), dissociation and amnesia, somatization, and a range of psychological difficulties (e.g., a damaged sense of self, chronic guilt and shame, a feeling of ineffectiveness, idealization of the perpetrator, difficulty in establishing and maintaining trusting relationships, a tendency to be revictimized or to victimize others, a chronic sense of despair and hopelessness). However, the validity of this condition is not universally accepted, and complex PTSD is not recognized as a diagnosis in the DSM-5.

Co-Morbidity Although studies continue to show that PTSD is a distinct syndrome, comorbidity is the rule rather than the exception. Co-morbid conditions typically include mood disorders (e.g., major depression, dysthymia, bipolar disorder), other anxiety disorders (notably specific phobias and generalized anxiety), and substance abuse. Moreover, even in the absence of provoking a full-blown PTSD syndrome, trauma itself can precipitate or aggravate other disorders (e.g., anxiety disorders, mood disorders, substance abuse). Major depressive disorder (MDD) is commonly co-morbid with PTSD. Although MDD is a risk factor for PTSD, the reciprocal is also true. A recent study reported that a reduction in PTSD symptoms was associated with improvement in substance abuse. The converse, however, was not true, suggesting that treating PTSD first might be more effective when co-morbid with substance abuse. However, this is not universally accepted; some maintain that patients with PTSD are less amenable to treatment when they are addicted to a substance. Regardless, given the frequent co-morbidity, if a patient presents with substance abuse, clinicians should screen for PTSD symptoms (and vice versa) and treat them if present. A dread complication, suicide, is a concern for

patients with PTSD; rates of suicide attempts are estimated to be as high as 19%. However, these typically occur in the presence of depressive co-morbidity or substance abuse.

Neurobiology of PTSD Neurobiological understanding of PTSD is rapidly advancing. Although there is no single model that completely explains the pathophysiology of the disorder, abundant data points to biological correlates. In the normative stress response, neurotransmitters and hormones are linked together in a web of feedback loops. The catecholamine epinephrine prepares the body for fight or flight. Its chemical cousin, norepinephrine (NE), which is found in the brain, whereas epinephrine is not, plays a role in orienting to new stimuli, in selective attention, and in autonomic arousal. The locus coeruleus (LC), located in the pons, contains a large number of the brain’s noradrenergic cell bodies that project throughout the brain as well as into the periphery. Serotonin plays a role in regulating the stress response. The hormone cortisol mobilizes short-term energy but can have adverse catabolic effects when chronically elevated. Cortisol also modulates the stress response by containing the actions of monoamines, such as NE and serotonin, and restoring homeostasis by providing negative feedback. During stress, corticotropin releasing hormone (CRH) increases the turnover of NE, and NE increases CRH concentrations in the LC. Neuropeptide Y, which is coreleased with NE, and the neurosteroids allopregnanolone and pregnanolone, promote adaptation to stressful circumstances and appear to confer resilience. Abnormalities in the sympathetic branch of the autonomic nervous system likely play a role in the PTSD symptoms of intrusion and arousal. Animal models have shown that severe stress can cause dysregulation of the LC, causing hypersensitivity to external stimuli. As human evidence of this, studies have demonstrated that combat veterans who suffer from PTSD have exaggerated heart rate responses during exposure to combat-related stimuli. Some studies have found that urinary excretion of NE is higher in patients with PTSD. Contrary to early expectations, cortisol is not elevated in PTSD. However, abnormalities of the hypothalamic–pituitary–adrenal (HPA) cortical axis are frequently reported, most notably increased glucocorticoid receptor sensitivity (which results in stronger negative feedback on the hippocampus, hypothalamus, and/or anterior pituitary gland), with a resultant decrement in cortisol release. Studies are conflicting as to whether increased negative feedback represents a pretrauma vulnerability factor or an acquired PTSD feature. In contrast, negative

feedback is often reduced in MDD. Insufficient cortisol levels immediately following a trauma might be a risk factor for developing PTSD at a later date, especially in a person who has had prior trauma exposure; for example, rape or assault. A recent preliminary study found that high-dose cortisol administration within hours of a traumatic event reduced the subsequent development of PTSD. Given that cortisol contains the effects of catecholamines, and the latter are known to play a role in selective attention and arousal as well as in enhancing memory consolidation, low levels of cortisol at the time of a trauma might predispose to enhanced encoding/consolidation of the traumatic memory and associated hyperarousal. Measurement of regional brain volumes by means of structural neuroimaging has revealed diminution most notably of hippocampus, but also of anterior cingulate cortex. Whether these reductions represent antecedent risk factors or acquired features of PTSD has not been resolved; both could be involved. Magnetic resonance spectroscopy is able to quantify the amount of the amino acid N -acetyl aspartate (NAA), which reflects the density or viability of neurons; diminished hippocampal NAA has also been found in PTSD. The most consistently replicated functional neuro-imaging abnormality in PTSD is under-activation of the rostral or pregenual portion of the anterior cingulate cortex, a component of ventromedial prefrontal cortex, which regulates emotion and promotes extinction of conditioned fear. This brain region exerts an inhibitory influence on the amygdala, which is a key structure in recognizing dangerous stimuli and coordinating the fear response, in part through the LC. In PTSD, the amygdala is hyper-reactive to stimuli linked to the traumatic event. Associated anterior paralimbic regions of the brain are also activated in response to symptom provocation. These findings support a model of PTSD in which the amygdala and related structures (the “hot” or “emotional” memory system) are overactive, whereas the hippocampus (the “cool” or “cognitive” memory system) and anterior cingulate cortex (emotion regulation) are underactive. Current research is exploring and refining these models. Twin and other epidemiological studies have demonstrated a substantial hereditary component to PTSD. However, identifying the contributing genes is an arduous task that to date has produced little payoff in informing new treatments. The greatest challenge appears to be that, as with most other mental disorders, the genetic contribution is polygenic, with numerous genes each making relatively small contributions to risk, and none (so far) explaining so much of the PTSD variance as to make it a very promising therapeutic target

(even if means were available to target it). Recent attention has focused on “epigenetics,” in which, although the DNA sequence is immutable, its expression might be modified by experience.

Evaluation and Treatment Immediately Following a Traumatic Event Victims infrequently come to the attention of psychiatrists immediately following a traumatic event. Rather, they focus on practical concerns (such as reestablishing safety, obtaining information, responding to medical or legal concerns, securing food and shelter, and connecting with family and other social supports). Most people adapt to traumatic events without professional help and often decline the offer. Requiring individuals to debrief in a group setting, known as critical incident debriefing , although previously popular, has not been found to be effective and might actually worsen outcome, perhaps by increasing hyperarousal associated with the expression of overwhelming feelings and further interfering with natural coping mechanisms. Whereas those in distress should be offered an opportunity to narrate their experience, requiring all trauma-exposed individuals to do so is inadvisable. Rather, guidelines recommend educating survivors about the usual course and reaction to trauma and increasing access to social supports and treatment when necessary. In the acute aftermath of a trauma, benzodiazepines are relatively contraindicated because they do not seem to prevent the development of PTSD and might actually increase risk. There is mixed evidence that the betaadrenergic antagonist, propranolol , might be efficacious in preventing the development of PTSD when administered soon after the traumatic event, by reducing the consolidation of the traumatic memory. Except in individuals with asthma or certain types of heart disease, propranolol is not harmful and offers an alternative to benzodiazepines for reducing acute post-trauma hyperarousal. As noted earlier, preliminary results suggest that acutely post-trauma, administration of high-dose hydrocortisone might be able to prevent PTSD. Retrospective data also suggest that opiates might have some protective effects. A recent influential Israeli study found that treatment of patients with full or partial ASD, with cognitive-behavioral therapy (CBT) but not a medication (escitalopram), had preventive value for the development of PTSD.

Differential Diagnosis

Important conditions to consider when evaluating for PTSD are ASD, adjustment disorder, dissociative disorders, psychosis, mood disorders, and other anxiety disorders. The time course since the trauma is the main factor in differentiating PTSD and ASD: ASD occurs within the first month and PTSD is diagnosed thereafter. As noted earlier, ASD also comprises a dissociative component that is not included in the criteria for PTSD. Psychotic disorders and PTSD each can present with hallucinations. However, hallucinations in patients with PTSD are both uncommon and limited, typically involving a fragment of the traumatic event, or a perpetrator’s voice. Patients with PTSD typically do not have delusions or formal thought disorder. Bipolar disorder and PTSD can both present with irritable and labile mood; angry outbursts; disturbed sleep; and impulsive, risk-taking behavior. However, patients with PTSD do not experience prolonged euphoria or expansive moods. MDD and PTSD share a number of symptoms including emotional withdrawal, detachment, social isolation, helplessness, agitation, and sleep disturbance. It is common for patients with PTSD to develop secondary depression. Weight loss or gain and generalized feelings of guilt are more typical of a primary depression, whereas reexperiencing symptoms is more typical of PTSD. Other anxiety disorders and PTSD share a number of characteristics; patients with panic and agoraphobia are also avoidant, panic attacks resemble the autonomic hyperarousal in patients with PTSD experience when they have an intrusive memory, and the obsessions in obsessive-compulsive disorder can resemble the fixation with the trauma seen in PTSD. However, other anxiety disorders lack the re-experiencing symptoms of PTSD.

Guidelines for the Treatment of PTSD As described earlier, PTSD varies in its severity and its time course. For most, the passage of time promotes recovery; for others, the trauma has made it virtually impossible to move forward in life. The symptoms of PTSD can create a cycle that traps some patients within a “black-hole” of the trauma. Traumatic memories, vivid and timeless, threaten to overwhelm the survivor. Efforts are made to cope with such powerful and disorganized memories. However, the threat from within is that any intense feeling might trigger a traumatic memory, and the threat from without is that many stimuli have become associated with the trauma. The person might withdraw into dissociative states or use alcohol or other substances in an attempt to reduce intrusive memories and hyperarousal. People with PTSD can feel helpless in coping with the past and helpless in

managing the present. The loss of control in the present stimulates traumatic memories and perpetuates the cycle. Most patients are able to use treatment to overcome overwhelming trauma, but others appear to make little progress. Psychiatric treatment for PTSD aims to address this cycle and is phase-oriented. The initial goal is to stabilize the patient and address acute symptoms, the second phase involves working through the trauma, and the last phase focuses on reestablishing social relationships and occupational functioning. The initial stabilization phase can be prolonged. Education about posttraumatic experiences is the cornerstone of therapy. If patients can anticipate expectable post-traumatic responses, they can feel less helpless. Identifying feelings and putting words to bodily experiences begins to organize a chaotic emotional world. As a patient learns to notice how symptoms come and go, he or she can discover how to exercise more control over his or her emotional life. Safety is facilitated by the connection to the therapist in a treatment that has clear and predictable boundaries. Stabilization involves addressing maladaptive behaviors such as substance abuse and self-destructive behavior. Ongoing exposure to trauma can undermine improvement and needs to be addressed, if present. Patients might need to be taught to distinguish safe from unsafe behavior. In the middle phase, patients can work through the trauma in several different ways. Patients can learn to tolerate the traumatic memories and environmental triggers and become desensitized, thereby diminishing avoidance. Patients also can begin to create a narrative of the traumatic event and understand its personal meaning. The reality of the trauma and its impact becomes integrated into the survivor’s sense of self. Ultimately, the patient must return to daily life in the community. Facilitating the (re)development of social relationships and occupational functioning is a necessary part of recovery from trauma. Families disrupted by PTSD in a member (e.g., a combat veteran), might require special attention. It is worth noting that treating a patient with PTSD can put the therapist under emotional strain. Hearing about the traumatic event and witnessing a patient’s distress can be stressful for the therapist. It can be difficult for the therapist to maintain the necessary balance between seeing the patient as a victim and as a survivor capable of taking responsibility. The therapist must balance the need for the patient to review the traumatic event with the danger that the patient will be traumatized by the retelling. Patients with a history of childhood sexual abuse or patients with complex PTSD are often challenging to treat. These patients often

have significant difficulties with affect regulation and trust. It can take years for such a patient to develop a relationship with the therapist sufficiently robust to manage the exploration of the trauma. For such a patient, learning impulse control, affect regulation, boundary management, and basic positive self-regard are prerequisites for exploration of the trauma itself.

Psychotherapeutic Modalities for PTSD CBT has been the most intensely studied in PTSD and has been found to be the most effective. Components of CBT for PTSD include exposure therapy, cognitive therapy, psychoeducation, and anxiety management. They are often used in combination. The goal of exposure is the disruption of the link between trauma-related cues and the resulting intense anxiety and avoidance that is typical in PTSD. The technique often stimulates the patient to re-experience a traumatic memory in a secure setting to modify the response to that memory. Patients are taught to distinguish traumatic memories and trauma-related emotions from current reality and thereby to feel more in control of their world. Repeated exposure helps patients learn to master their fear. An example of an evidence-based CBT approach for PTSD is prolonged exposure therapy . Prolonged exposure treatment involves imaginal exposure to the traumatic memory as well as repeated in vivo exposure to safe situations that have been avoided for fear of triggering post-traumatic symptoms. The repeated exposures in a controlled setting hopefully lead to response desensitization and resolution of symptoms. Cognitive therapy focuses on identifying underlying, distorted beliefs about the world following the trauma. For example, “I am a helpless person…The world is not a safe place...I am guilty about everything…If I could only get to do it again, I could change the outcome.” These distorted thoughts can be addressed and altered. An example of an evidence-based CBT approach for PTSD emphasizing cognitive therapy is cognitive processing therapy (CPT), which includes exposure via writing about the trauma, with a focus on challenging and modifying corresponding dysfunctional beliefs. Psychoeducation involves teaching the patient about the range of responses to traumatic events. By explaining to the patient the nature of his or her symptoms, how those symptoms might arise and what functions they might serve, helps to organize a frightening experience. By outlining common maladaptive responses to traumatic events, patients can focus on interventions to address the maladaptive behaviors. For example, by understanding that avoidance

commonly occurs following trauma, patients can begin to notice the behavior and try to alter it. Anxiety management teaches patients to handle anxiety. These techniques include relaxation training, breathing exercises, assertiveness training, and thought-stopping. Another psychotherapeutic technique with a proven research record in PTSD is eye movement desensitization and reprocessing (EMDR ). EMDR aims to attenuate negative responses to disturbing memories and thoughts via directed eye movements. An affect-laden image of the trauma is constructed along with a summary statement. Subjective distress is rated. An alternate, positive statement is formulated. Eye movements are initiated by the patient following an object moving across the visual field while the patient holds in mind the traumatic image. After 12 to 24 repetitions, the patient notes his or her subjective distress. The cycle is repeated 3 to 15 times until there is significant reduction in distress. Although effective, to date there is no clearly documented method of action for EMDR. There is some evidence that the eye movements are an unnecessary part of the treatment. Other psychosocial approaches with less supporting evidence in PTSD than the aforementioned treatments are psychodynamic approaches and group therapies. Psychodynamic approaches emphasize exploration of the personal meaning of the traumatic event for the individual patient. The impact of the trauma on the patient’s self-concept is examined; unresolved conflicts from earlier in life might be exacerbated by the trauma and dealt with in the treatment. The notion that CBT and psychodynamic treatments oppose each other is erroneous. Exposure cannot be effective if the patient doesn’t know what it is that they fear; uncovering therapy can help reveal this. Group treatment can be useful in providing support and information, and reducing isolation and stigma.

Pharmacotherapy of PTSD Medication can be an important part of the treatment for PTSD. It should be tailored to the stage of the illness and target specific symptoms. As in other anxiety and depressive disorders, both the selective serotonin re-uptake inhibitors (SSRIs) and serotonin norepinephrine re-uptake inhibitors (SNRIs) are considered first-line drugs in PTSD. The SSRIs sertraline and paroxetine are the only pharmacological agents that have received a US Food and Drug Administration (FDA) indication for PTSD, but other agents (e.g., fluoxetine, venlafaxine) have shown comparable efficacy in controlled studies. Dosing of

common agents is as follows: sertraline 50 to 200 mg/day, paroxetine 20 to 60 mg/day, fluoxetine 20 to 80 mg/day, and venlafaxine 75 to 225 mg/day. There is limited positive controlled data on tricyclic antidepressants (TCAs ), such as amitriptyline and imipramine, particularly for intrusive symptoms and insomnia, but their use is limited by safety and side effect considerations. The monoamine oxidase inhibitor (MAOI ) phenelzine also has limited evidence of efficacy in PTSD, particularly for intrusive symptoms, but its use is limited by drug–drug interactions and the need for careful dietary restriction. These drugs should be tried only after SSRIs have been found to be ineffective. The atypical antidepressant nefazodone , 300 to 500 mg/day, has been noted to be helpful in populations of war veterans, and mirtazapine has shown evidence of efficacy on a global measure of change in a controlled study, but not on other symptom measures. Anti-adrenergics are sometimes used to treat intrusive and hyperarousal symptoms, including nightmares. Among these, the α 1-adrenergic antagonist prazosin in a dosage up to 10 mg daily or higher, carefully titrated, has to date been found most effective in general, but also specifically for nightmares. The use of the β -adrenergic antagonist propranolol, and the α 2 -adrenergic agonists clonidine and guanfacine remains experimental. Benzodiazepines should be used with caution in PTSD; some centers actively discourage their use because they might exacerbate dissociative symptoms or promote behavioral disinhibition. Tolerance and dependence are common problems, so the use of these medications in patients with a history of alcohol or substance abuse is contraindicated. Further, some data suggest that benzodiazepines might interfere with successful exposure-based psychotherapy, and should not be prescribed concurrently. Nevertheless, in selected, reliable, non-addiction-prone patients with PTSD, their anxiolytic effect can prove beneficial. Other medications that might have some use in treatment-refractory cases include buspirone (Buspar), the anticonvulsants lamotrogine and topiramate , and second-generation antipsychotics. In a preliminary open trial, buspirone (30–60 mg/day) was reported to reduce anxiety and increased arousal in PTSD patients. When used, it is typically co-administered with an antidepressant. The anticonvulsants have had more mixed results in studies. Antipsychotic medications are generally reserved for the most disorganized and psychotic of patients because these agents carry substantial metabolic and neurological risks and their evidence base is limited for PTSD.

Unfortunately, even the best evidence-based preventions and treatments for PTSD, including CBT, pharmacotherapy, and even the combination, are typically only partially effective, making the development of new therapies imperative. The latest research into the use of propranolol, and other so-called “amnestic” agents, has shifted to attempts to reduce “reconsolidation” after the traumatic memory has been experimentally activated. A recent randomized, placecontrolled clinical trial in chronic PTSD patients found this use of propranolol to produce benefits comparable to those of CBT, with only a fraction of the exposure.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Breslau N: The epidemiology of post-traumatic stress disorder. J Clin Psychiatry . 2001; 62(suppl 17): 16–22. 3. Department of Veterans Affairs, & Department of Defense: VA/DOD clinical practice guideline for management of Post-Traumatic Stress. 2010; Retrieved from http://www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp . 4. Foa EB, Keane TM, Friedman MJ, et al, eds.: Effective Treatments for PTSD: Second Edition: Practice Guidelines from the International Society for Traumatic Stress Studies . New York: Guilford Press, 2009. 5. Friedman MJ, Keane TM, Resick PA, eds.: Handbook of PTSD: Science and Practice. New York: Guilford Press, 2010. 6. Katzman MA, Bleau P, Blier P, et al: Canadian clinical practice guidelines for the management of anxiety, post-traumatic stress and obsessivecompulsive disorders. BMC Psychiatry . 2014; 14(1): Suppl 1: S1. 7. Kessler RC, Chiu WT, Demler O, et al: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Co-Morbidity Survey Replication. Arch Gen Psychiatry . 2005; 62(6): 617–627. 8. Ornstein R: The patient following a traumatic event. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Primary Care Psychiatry . 2nd ed.

9. 10. 11.

12. 13.

New York: McGraw-Hill; 2004: 535–544. Pitman RK, Rasmusson AM, Koenen KC, et al: Biology of post-traumatic stress disorder. Nature Reviews: Neuroscience . 2012; 13(11): 769–787. Raphael B, Forbes D, Bryant R, et al: Australian guidelines for the treatment of acute stress disorder and post-traumatic stress disorder. 2013. Shalev AY, Ankri Y, Israeli-Shalev Y, et al: Prevention of post-traumatic stress disorder by early treatment: results from the Jerusalem Trauma Outreach And Prevention study. Arch Gen Psychiatry . 2012; 69(2): 166– 176. Stein DJ, Friedman MJ, Blanco C, eds.: Post-Traumatic Stress Disorder . Chichester, UK: John Wiley & Sons, Ltd.; 2011. Stein MB, Lang KL, Taylor S, et al: Genetic and environmental influences on trauma exposure and PTSD. Am J Psychiatry . 2002; 159(10): 1675– 1681.

CHAPTER Somatic Symptom and 20 Related Disorders NICHOLAS KONTOS, MD

KEY POINTS Overview Somatic symptom and related disorders are the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition reconfiguration of the former somatoform disorders category. The new categorization includes somatic symptom disorder (collapsing the former somatization disorder, undifferentiated somatoform disorder, pain disorder, and some hypochondriasis cases), illness anxiety disorder (mapping onto the remaining hypochondriasis cases), conversion disorder (no category change; criteria are a bit relaxed compared with those in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSMIV-TR]), psychological factors affecting medical illness (minimal change), and factitious disorder (brought over from its former category-unto-itself status). Epidemiology Given the new categorization, epidemiology is difficult to determine. Patients with DSM-IV somatoform disorders accounted for 10% to 24% of the primary care population. Conversion disorder cases are particularly common on epilepsy-monitoring units, accounting for 20% to 30% of patients seen in this setting. Clinical Features Patients with these disorders share the quality of presenting to the doctor with symptoms, signs, and concerns that are not “as advertised.” However, the focus is less on the “medically unexplained” nature of the complaint, and much more on the excessive distress and disability being caused. Etiology

Psychodynamic theories of these disorders are giving way to cognitivebehavioral theories based on maladaptive illness experiences, beliefs, and behaviors that might have biological correlates, such as “central sensitization.” Approaches to Evaluation and Treatment Appropriate medical vigilance, alliance-building, and limit-setting are the foundation for handling these disorders. Treatment of co-morbid mood and anxiety disorders, mind–body medicine, and psychotherapies can be built on this foundation.

Overview In the transition from the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) Fourth to Fifth editions, the category, “Somatoform Disorders,” underwent significant changes. These changes, which will be summarized below, include lumping of some diagnoses, rebranding of others, and re-categorizing still others. Perhaps most important, the unifying theme for the category has changed from “the presence of physical symptoms that suggest a general medical condition” in somatoform disorders to “the prominence of somatic symptoms associated with significant distress and impairment” in the new category, “Somatic Symptom and Related Disorders.” This switch de-emphasizes the medically unexplained nature of the somatic symptoms under concern. Instead, the clinician is guided toward a greater focus on the medically unexplained, disproportionate, or misrepresented impact of those symptoms. As such, the somatic symptom and related disorders are no longer diagnoses of exclusion; an individual can have medically-explained symptoms and simultaneously be affected by them in a “disordered” way. Over the past several years, studies have repeatedly shown that the impact of symptoms is more important than their medically-explained or unexplained nature in determining distress and functional impairment. Although around 70% of Americans experience physical symptoms in any given week, only a minority present themselves to physicians. Still, those who present with excessive functional impairment relative to diagnostic findings may represent a primary care sub-population even larger than that with major depressive disorder (MDD).

This chapter will briefly review the categorization, phenomenology, and management of somatic symptom and related disorders. When appropriate, comorbid and other associated disorders/syndromes as well as theoretical mechanisms will be mentioned, too.

The Disorders Somatic Symptom Disorder The prototypical disorder of this diagnostic category, somatic symptom disorder (SSD ) involves one or more somatic symptoms that produce disproportionate distress, dysfunction, and preoccupation in the patient. In the doctor’s office, this preoccupation tends to focus more on seeking relief and having symptoms validated than on fear about their cause(s), though a vague “anxiety” is often present, as well. The absence of a clear explanation for the patient’s suffering is neither necessary nor sufficient to make this diagnosis. The determination of whether a patient’s response to symptoms is “excessive” or disproportionate is determined by clinical judgment, and only partially on physical exam findings and diagnostic test results. The notoriously imperfect correlation between patient complaints and lumbar disc herniation on magnetic resonance imaging exemplifies an area where “objective” findings would not be incompatible with a SSD diagnosis. SSD subsumes, simplifies, and more accurately represents several diagnoses from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Somatization disorder, with its smorgasbord-style requirement of unexplained symptoms in multiple domains, was relatively infrequent, despite its being the prototype somatoform disorder in DSM-IV. Undifferentiated somatoform disorder (UDS) reiterated many criteria of somatization disorder, but required that they apply to only “one or more” symptoms. Pain disorder applied them to only pain complaints. Epidemiologically, UDS was the most common of the DSM-IV somatoform disorders. Further, its criteria rendered somatization disorder and pain disorder redundant. In recognition of these epidemiologic and phenomenologic factors, SSD maps roughly onto UDS. In Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), somatization and pain disorders are absorbed by SSD and discarded as separate diagnoses.

Illness Anxiety Disorder

The “anxiety” component of SSD is expected or intended to account for up to three-fourths of patients who would have been diagnosed with hypochondriasis. The remaining quarter of patients with marked anxiety and fear over the presence, misdiagnosis, or risk of a serious medical condition will now receive a diagnosis of illness anxiety disorder (IAD ). It is not yet clear how these two groups might be distinguished. Of note, though, as opposed to those with SSD, patients with IAD will not need to have active symptoms to meet criteria for the latter diagnosis. It is anxiety rather than symptoms that are at the core of IAD. When symptoms are present, these patients are less distressed by physical suffering (as in the patient with SSD) than they are by fears about the symptoms’ potential etiology. Both SSD and IAD tend to be chronic conditions, and the DSM-5 specifies a 6month time criterion for both. Epidemiology and prognosis are difficult to estimate given that most studies are based on the older diagnostic schema. The remaining disorders discussed here can be lasting or recurring afflictions but are generally diagnosed in the setting of episodes/exacerbations.

Conversion Disorder Conversion disorder is manifest by a loss of or change in sensory or voluntary motor function (the presenting sign should be coded as part of the diagnosis) that lacks accompanying evidence for a known neurological disorder. A few major changes to conversion disorder exist in DSM-5, but clinically they do not add up to much. Some believe that the name has changed, but “functional neurological symptom disorder” appears only parenthetically, and even though it’s permissible, its use is not encouraged. Identification of a proximate, presumably triggering, psychological stressor is no longer required; instead, we now can add it as a qualifier to the diagnosis. Finally, involuntariness has been removed as a criterion. This last change seems particularly baffling, given that involuntary manifestation of neurologic signs is the essence of conversion disorder. In fact, the text of DSM-5 explicitly states that if a clinician concludes that the sign is produced voluntarily, a diagnosis of conversion disorder should not be made, and malingering or factitious disorder be considered instead (discussed in a later subsection). It was felt, though, that along with the theoretical baggage and infrequent clarity of proximate stressors in conversion disorder, the clinical difficulty of drawing conclusions about voluntariness was impeding recognition of this not uncommon psychiatric diagnosis.

In the end, these superficially significant changes lower the diagnostic bar more than they change our understanding of the phenomenology of conversion disorder. Some psychiatrists might be concerned about lowering their diagnostic threshold due to decades-old studies suggesting that a large percentage of patients with conversion disorder are later diagnosed with “true” neurologic conditions, such as multiple sclerosis. However, more recent studies find this sort of misdiagnosis to occur in only about 5% of conversion disorder diagnoses, which is comparable to diagnostic accuracy in many other neurologic conditions. Conversion disorder accounts for about 5% of patients who present to neurology clinics, and 20% to 30% of patients evaluated for seizures on video electroencephalography monitoring units. It is more common in women, and many of its sub-types (e.g., psychogenic non-epileptic seizures) tend to peak in the third or fourth decade. Prognosis varies depending on the type and the clinical context. For example, unilateral conversion sensory or motor signs can persist for several years in the vast majority of hospitalized neurological patients.

Psychological Factors Affecting Other Medical Conditions The absence of the word “disorder” might be the most telling aspect of this diagnostic category. Psychological factors affecting other medical conditions (PFAMC ) is applied to situations in which a patient’s personality traits, coping patterns, mood, or associated behaviors are adversely affecting the course or management of a general medical condition. These “psychological factors” should not represent independent psychopathology. For example, excessive dependency and fear that is negatively affecting cardiac rehabilitation following a myocardial infarction, would not represent a personality disorder or anxiety disorder. Under other circumstances in the patient’s life, these factors would be less consequential or even absent. The line between PFAMC and an adjustment disorder can seem academic.

Factitious Disorder Formerly a category unto themselves, the factitious disorders , which can manifest with somatic or psychological signs or symptoms, and be imposed on oneself or another, are collapsed by the DSM-5 into one diagnosis with qualifiers and brought under the umbrella of the somatic symptom and related disorders. The hallmarks of factitious disorder are the intentional fabrication of symptoms (e.g., lying about chest pain, suicidal ideation) or production of signs (e.g., induction of sepsis through self-inoculation) for the purpose of securing “primary gain.”

“Primary gain” is usually translated as attaining “the sick role,” but is more complicated than this. Derived from sociologist Talcott Parsons’ work in the 1950s, the benefits of sick role status include blamelessness for the manifestation of sickness after it sets in (being stigmatized for bringing on one’s sickness is a separate issue), relief from duties incompatible with one’s illness state, and entitlement to care. More received wisdom than actual fact, the distinction between primary and secondary gain (the latter involving tangible gains, such as disability payments, drugs, hospitalization as escape) is not at all clear. It nonetheless remains a convention when distinguishing between factitious disorder and malingering, which can potentially share every element of factitious disorder except for the malingerer’s focus on secondary gain, and the malingerer not being considered “sick.” It might be more productive to think about these two deception syndromes as behaviors rather than a disorder and an essentially criminal act. Considering them this way might eliminate a false, energy-consuming, distinction, and focus clinical energy on seeking meanings to behaviors and (albeit rarely with a group characterized by lying) on attempting collaborative problem-solving.

Body Dysmorphic Disorder Body dysmorphic disorder (BDD) is no longer grouped among the former somatoform disorders in the DSM-5. Due to a variety of commonalities, it has been recategorized among the obsessive-compulsive and related disorders.

Functional Somatic Syndromes Disorders , such as chronic fatigue syndrome (now known as systemic exertion intolerance disease ), chronic Lyme disease, multiple chemical sensitivity, fibromyalgia, the functional gastrointestinal disorders (see the Rome III criteria), are sometimes collectively referred to as functional somatic syndromes (FSSs ). These syndromes are not classified psychiatrically. In fact, the term, “functional,” although sometimes taken to mean “psychogenic,” originally meant “physiologic,” and distinguished between anatomically explained diseases and those with physiologic, often hidden, mechanisms. It is best not to engage in disputes with patients or other providers about the “legitimacy” of these syndromes. More important, and the reason for their being mentioned here, is that sufferers from these conditions often manifest profoundly maladaptive illness behaviors that qualify for SSD diagnoses; and, psychiatric

co-morbidities and treatments often overlap with those seen in the somatic symptom and related disorders.

Management Communication Management strategies for the somatic symptom and related disorders (excluding factitious disorder) largely overlap. Of primary importance is the communication of the diagnosis. It is correct, but almost a cliché to admonish physicians against telling this patient population that their problems are “not real.” Still, it also is not productive to reinforce maladaptive beliefs (e.g., in disease etiology, in personal helplessness). Taking a cue from the shift in focus of the DSM-5, it can be helpful to emphasize the impact over the nature of the patient’s complaints and fears. Thus, the clinician can validate the patient’s suffering, but not necessarily commit to their model of it. It is useful to introduce and reinforce the ideas that idiopathic illness is not rare, and that cure is the exception rather than the rule in medicine—infections, surgical problems, and many cancers being those exceptions.

Direct Management Validation and education, when successful, can help transition the patient away from costly, invasive, and potentially dangerous testing, referrals, and treatments, and toward a goal of improved functioning. This approach, one of a small handful of evidence-based interventions for these disorders, derives from the “consultation letter” of stereotyped recommendations given by Smith and associates to all consultees in their well-known research in this area. Frequent, brief, targeted visits to the primary care provider can reduce the patient’s incentive to be “sick” in order to ensure medical attention and vigilance. The patient might need “training” to adhere to these measures, and a written contract, even though obviously not legally binding, can be useful, especially with regard to restricting outside consultations. Other interventions include cognitive-behavioral therapy (CBT) targeted at maladaptive illness beliefs and behaviors, graded exercise, physical therapy (particularly important yet often neglected for patients with conversion disorder), mindfulness, and biofeedback. Symptomatic medications can sometimes be useful, and have even been approved by the FDA for certain FSS’s (e.g., pregabalin for fibromyalgia). However, the clinician must be alert to this population’s greater vulnerability to side effects and to lesser susceptibility to

placebo benefits. A steady accumulation of symptomatic medications (especially analgesics) without functional improvement, is a sign that things are not going in the right direction.

Indirect Management Psychiatric co-morbidity is said to be the rule in patients with somatic symptom and related disorders. Numbers vary, but a majority might suffer from MDD, dysthymic disorder, or generalized anxiety disorder (GAD). Panic disorder can masquerade as illness anxiety if the only symptom is pseudoangina. Post-traumatic stress disorder and cluster B personality disorders are also common in this patient population, and particularly in certain manifestations of conversion disorder, such as psychogenic non-epileptic seizures. When diagnosed (and it should be kept in mind that a “checklist” psychiatric interview or inventory in this population can occasionally produce across-theboard positive responses akin to those obtained via a somatic review of systems), psychopathology should be treated as it would be in any other patient, with the aforementioned caveat regarding medication response patterns kept in mind. This treatment is administered with an eye toward reducing suffering, not toward eradicating “somatization.” It is possible that the somatic symptoms of a depressive or anxiety disorder might mimic a SSD and disappear with treatment, but this would mean that the latter was misdiagnosed, not “cured.” At most, one might expect successful treatment of, for example, a major depressive episode, to reduce the intensity of a SSD.

A Word on Factitious Disorder No evidence-based treatment exists for factitious disorder . It is crucial to remember that the patient must be treated for whatever disease they have induced. Sepsis, for example, is sepsis, regardless of how it was incurred. Advice varies as to whether to “confront” patients when they are “caught” inducing their own illness. When factitious disorder is confirmed, though, avoiding all discussion of this truth might pass up an opportunity to discuss with the patient what needs he or she is seeking to satisfy and how these needs might be more productively addressed.

Mechanisms In the sense of “functional” meaning of hidden (physiologic) etiology, the somatic symptom and related disorders remain functional. Psychodynamic

explanations remain perhaps the most familiar to physicians and involve somatization and conversion as defense mechanisms whereby intolerable (unconscious) psychological states are instead expressed somatically. Older formulations of conversion disorder even suggested that clinicians deduce the symbolic meaning of the patient’s neurologic signs. As such, though not mentioned among the aforementioned treatments, many patients receive psychodynamically oriented psychotherapy for these problems. A theory involving cognitive behavior principles proposes that patients with SSDs experience ordinary somatic states (e.g., aches, pains, tachycardia, peristalsis) in amplified ways. These experiences are then interpreted as dangerous and/or disabling, and, further, as demanding medical attention. Certain elements of this model might be supported by growing research findings on the phenomenon of central sensitization. Cognitive-behavioral therapies and mindfulness techniques target maladaptive interpretations and excessive surveillance of bodily states, respectively.

Conclusions Somatic symptom and related disorders are common problems in general medical practice. In patients with these disorders, the “medically unexplained” nature of their symptoms is less diagnostically and therapeutically important than is how the patient understands, reacts to, and lives with them. Treatment involves effective communication, a strong relationship between the patient and the primary-care provider, harm reduction (via judicious use of referrals, testing, and treatments), psychotherapies, and addressing psychiatric co-morbidities. Ultimately, the goal of care of these patients is a major one in the care of any patient suffering with a chronic medical problem: maximization of functioning in the presence of adversity.

Suggested References 1. Barsky AJ, Borus JF. Functional somatic syndromes. Ann Int Med . 1999; 130: 910–921. 2. Deary V, Chalder T, Sharpe M: The cognitive behavioral model of medically unexplained symptoms: a theoretical and empirical review. Clin Psychol Rev . 2007; 27: 781–797. 3. Gerstenblith TA, Kontos N: Somatic symptom disorders. In: Stern TA, Fava

M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry, Second Edition . Philadelphia, PA: Elsevier; 2016: 255–264. 4. Gropalis M, Bleichhardt G, Hiller W, Witthoft M: Specificity and modifiability of cognitive biases in hypochondriasis. J Consult Clin Psychol . 2013; 81: 558–565. 5. Henningsen P, Zipfel S, Herzog W: Management of functional somatic syndromes. Lancet . 2007; 369: 946–955. 6. Tomenson B, Essau C, Jacobi F, et al: Total somatic symptom score as a predictor of health outcome in somatic sy mptom disorders. Br J Psychiatry. 2013; 203: 373–380.

CHAPTER Deception Syndromes: 21 Factitious Disorder and Malingering SCOTT R. BEACH, MD; ADELE C. VIGUERA, MD; AND THEODORE A. STERN, MD

KEY POINTS Overview In deception syndromes , the individual’s goal is to consciously produce or feign signs of a medical or mental disorder. In the case of malingering, this is done to achieve a tangible goal (secondary gain), such as monetary gain, avoidance of work, or escape from legal authorities, whereas the motivation in factitious disorder is to assume the sick role (primary gain). Epidemiology Factitious disorder is thought to occur commonly in a variety of clinical settings such as medical clinics, hospital wards, and emergency departments. Some estimate that it might account for up to 5% of all outpatient physician visits, whereas specialists such as neurologists and dermatologists might be more likely to see these patients. Rates of malingering are estimated to be 1% in a general patient population, but up to 10% of psychiatric inpatients might engage in malingering, and malingering behavior might be present in up to 40% of cases involving disability. Clinical Features The cardinal features of factitious disorder are: the intentional falsification of physical or psychological signs or symptoms or induction of injury or disease that is under voluntary control and is not explained by any other underlying physical or mental disorder; the primary motivation for the behavior is to assume the sick role; and, incentives for the behavior (such as economic gain

or the avoidance of legal responsibility) are absent. Malingering is defined by the conscious falsification of physical or psychological signs or symptoms or induction of injury or disease with the conscious goal of obtaining a tangible gain or avoiding punishment. Etiology The psychodynamic underpinnings of factitious disorders are poorly understood. Afflicted individuals might perceive one or both parents as rejecting figures and physicians and staff members are perceived by the patient as being rejecting parents. Malingering is a behavior motivated by tangible gain.

Differential Diagnosis Manifestations of factitious disorders must be distinguished from those conditions that are true physical disorders. Somatic symptom disorders (e.g., Briquet’s syndrome) or conversion disorders are distinguished from deception syndromes by the fact that the production of symptoms in the former is not under the individual’s voluntary control; instead, they are a result of unconscious conflicts. Approaches to Evaluation General strategies for approaching the patient with a possible deception syndrome include: an awareness that the deceptive behavior might be nonpathological; a suspicion for deceptive behavior while still engaging in a thorough work-up; a reliance on collateral sources for information; an avoidance of early confrontation; an awareness of negative countertransference; and a consideration of neuropsychological testing. Treatment No specific psychiatric therapy has effectively treated factitious disorder or malingering. Early identification is perhaps the most important intervention because establishing the diagnosis can prevent unnecessary and potentially dangerous procedures. The clinician should focus on management rather than cure.

Overview In deception syndromes, the individual’s goal is to consciously produce or feign signs of a medical or mental disorder. In the case of malingering , this is done to achieve a tangible goal (secondary gain) such as monetary gain, avoidance of work, or escape from legal authorities, whereas the motivation in factitious disorder is to assume the sick role (primary gain). Although factitious disorder is considered a mental disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), malingering is not. Deception syndromes are conditions that are not real or natural. Although they can have a compulsive quality, the behaviors are considered voluntary even if they cannot be controlled. Factitious disorder is particularly incapacitating to the patient, who often produces severe trauma or develops untoward adverse effects from repeated surgical or medical interventions. All forms of deception syndrome can lead to serial hospitalizations that essentially make it impossible for these patients to have meaningful and sustained interpersonal or work relationships. The prognosis for deception syndromes is typically poor. Although there is no adequate data about the long-term outcome of affected patients, a few with factitious disorder appear to die prematurely because of needless medications, instrumentations, or surgeries without the disorder ever being suspected.

Factitious Disorder Epidemiology Factitious disorders are thought to occur commonly in a variety of clinical settings such as medical clinics, hospital wards, and emergency departments. The prevalence of factitious disorders is unknown. Even when the diagnosis of factitious disorder is strongly suspected or confirmed, it is generally not recorded in hospital discharge summaries; therefore, determination of the prevalence is difficult. Although often described as a rare syndrome, most clinicians have encountered at least one patient with this disorder. Some estimate that it might account for up to 5% of all outpatient physician visits, whereas specialists such as neurologists and dermatologists might be more likely to see these patients. Studies of fever of unknown origin have determined that 2.2% to 9.6% were of factitious origin. Cases of factitious illness are often memorable because the patients with this disorder tend to wreak havoc on hospital wards and induce

strong countertransference feelings of hatred in staff. Whereas the common form of factitious disorder is more prevalent in females, the so-called Munchausen variant is thought to be more common in males. Factitious disorder appears to occur most frequently among health-care workers and those who have had extensive experience with illness, injury, or hospitalization during their development.

Diagnosis Diagnostic Features The cardinal features of factitious disorder are: the intentional falsification of physical or psychological signs or symptoms or induction of injury or disease that is under voluntary control and is not explained by any other underlying physical or mental disorder; the primary motivation for the behavior is to assume the sick role; and incentives for the behavior (such as economic gain or the avoidance of legal responsibility) are absent. The DSM-5 also includes the category of factitious disorder imposed on another, which involves the falsification or production of signs or symptoms in another individual, who is typically dependent on the person engaging in the deceptive behavior. The motivation for the caretaker is to assume the patient role (albeit indirectly). The most common scenario is a parent inducing symptoms in a child, though cases also have been reported involving the elderly or disabled adults as victims.

Sub-Types The DSM-5 no longer separates between factitious disorder with physical features and factitious disorder with psychological features, though these terms are still used clinically between those presenting with physical complaints (e.g., fever, hematomas, hemoptysis, seizures, hypoglycemia, abdominal pain), and those with psychological complaints (depression, hallucinations, dissociation, suicidality, and bizarre behavior). Though the term Munchausen syndrome is often used interchangeably with factitious disorder, it refers to a particularly extreme sub-type that involves travel from hospital to hospital, pseudologia fantastica (creation of extensive and colorful elaborations of the patient’s story), and occasionally impostorship (assuming the identity of a prestigious person). It is thought to account for 10% of individuals with factitious disorders. Common factitious disorder is the most

prevalent form and it typically occurs in persons with a history of emotional deprivation or current sexual or relationship problems. The expansion of the Internet has enabled patients without medical training or experience to more easily engage in factitious disorder, and over the past decade, a new phenomenon, labeled Munchausen by Internet, has emerged. Rather than present to hospitals with symptoms, sufferers seek attention from other Internet users by feigning illness in chat rooms or on blogs or social media sites. Classic patterns of behavior in this variant of the syndrome include verbatim recapitulation of textbook descriptions of illnesses, with a description of recurrent, worsening illness followed by miraculous recovery, and a reported duration of severe illness that conflicts with the Internet user’s behavior, such as blogging about being in the intensive care unit with septic shock. Some patients even fake their own deaths in this syndrome as the ultimate ploy for sympathy. Ganser’s syndrome is considered by some to be a specific form of factitious disorder, although others have classified it as a dissociative disorder. The hallmark sign of the syndrome is the giving of approximate answers to questions. For example, if asked how many legs a horse has, a patient might respond, “Three.” Such an answer provides the correct “set” or category of the response (e.g., a number), but provides an incorrect, but close-to-correct reply. Other features include clouded consciousness, somatic complaints, and pseudohallucinations (perceptual disturbances that the patient knows are not real). Some reports have noted the emergence of Ganser’s syndrome in the setting of organic brain injuries, including stroke and traumatic brain injury (TBI).

Clinical Features Many individuals with factitious disorders fulfill the diagnostic criteria for borderline personality disorder, especially in terms of their rigid defensive structure and poor identity formation. They might have a masochistic personality in which pain serves as a punishment for imagined or real sins. Among men with factitious disorder, particularly those with Munchausen’s variant, antisocial personality traits are also common. Afflicted patients typically have normal to above average IQs, strong dependency needs, confusion over their sexual identity, and lack a formal thought disorder.

A Typical Admission Has a Characteristic Course

The patient often arrives in the emergency department late at night or on a weekend (when trainees and junior attendings tend to be working), familiar with the diagnoses that require hospital admission, medications, or interventions. He or she generally presents with an apparent acute illness or pain supported by a plausible and often dramatic case history as well as convincing medical jargon. Then, the patient appeals to the qualities of nurturance and omnipotence in the physician to convince him or her to provide treatment (e.g., a surgical procedure). In about half the reported cases, treatment with specific medications, usually analgesics, is insisted upon. After the patient is in the hospital, his or her demand for attention increases; irritation and anger develop when requests go unmet. Further, the patient often predicts worsening of the disease. Subsequently, complaints of misdiagnosis and mistreatment arise and are directed toward staff. The deception is often uncovered by discovery of the hoax; for example, insulinfilled syringes are found in a patient’s suitcase during an admission for hypoglycemia. Staff become angry and lose interest in the patient’s medical issues. This results either in swift discharge of the patient, in the patient leaving against medical advice, or in the patient eloping from the hospital. Unfortunately, the patient then arrives at a nearby hospital with a similar presentation.

Etiology The psychodynamic underpinnings of factitious disorders are poorly understood. Afflicted individuals might perceive one or both parents as rejecting figures, and they are unable to form close relationships. Feigning illness can represent an attempt to re-create the desired positive parent-child bond. The disorder can be considered a form of repetition compulsion. The patient repeats the basic childhood conflict of needing and seeking acceptance and love while expecting that such love will not be forthcoming. Physicians and staff members are perceived by the patient as being rejecting parents. Primitive defense mechanisms (including repression, regression, identification with the aggressor, and symbolization) are typically seen in factitious disorders. Many afflicted patients have suffered from childhood abuse or deprivation that has resulted in frequent hospitalizations. The inpatient stays might have been regarded as escapes from a traumatic home life, and the patients might have found a series of loving caretakers. Alternatively, afflicted patients might have identified with a close relative who was hospitalized for an illness. They might feign the same illness to reunite

magically with that relative.

Malingering Epidemiology Rates of malingering are estimated to be 1% in a general patient population, but up to 10% of psychiatric inpatients might engage in malingering, and malingering behavior might be present in up to 40% of cases involving disability. Malingering is more common in men, and though it is classically associated with antisocial personality disorder, it has been seen in otherwise psychologically-normal adults.

Diagnosis Malingering is defined by the conscious falsification of physical or psychological signs or symptoms or induction of injury or disease with the conscious goal of obtaining a tangible gain or avoiding punishment. Malingering can involve exaggeration of the nature and severity of real symptoms, simulation of new symptoms, or false imputation of symptoms. Patients who malinger by reporting physical symptoms most commonly choose symptoms that cannot be objectively measured, such as pain. Psychiatric symptoms are often easier to fake than physical symptoms, and patients might claim that they are suicidal or are suffering from hallucinations or delusions.

Clinical Features Several specific signs have been proposed that point to a greater likelihood of malingering behavior. In general, patients who malinger tend to have poor coping skills, use immature defense mechanisms, and seek medical or psychiatric care frequently. Some exhibit the charming and glib personality of a con artist and might demonstrate an over-familiarity with hospital staff. Others appear to be dependent and needy, playing to the clinicians’ sympathies, and still others are irritable and demanding. Another common feature of malingering is a long list of claimed allergies. Malingerers tend to have a list of allergies that precludes the use of entire classes of medications and is structured to guide the physician toward prescribing desired medications. For example, a malingerer who presents with pain might report allergies to ibuprofen, acetaminophen, and aspirin, insisting that opiate narcotics are the only option. Like those with factitious disorder, patients who malinger tend to have a characteristic treatment course. Presentations are more common in the evening,

particularly among those seeking shelter as their primary goal. Patients engaging in malingering behavior will frequently describe to providers a “black cloud” phenomenon, noting multiple losses and stressors that can appear in sum to be unbelievable. Patients are often vague about symptoms and have difficulty describing their experiences without using medical or psychological jargon, and they tend to be overly focused on what they need rather than on their recent experience. Persistent questioning is often met with increasing frustration and irritability. Perhaps the most consistent tell-tale sign of malingering is the escalation of symptoms in response to not having demands met. The patient who initially reports pain ranked as 5 on a scale from 1 to 10 might gradually increase the severity of the pain over the course of an emergency room visit until his or her request for opiates is heeded.

Differential Diagnosis True Physical Disorders Manifestations of factitious disorders must be distinguished from those conditions that are true physical disorders. Failure to diagnose and treat an underlying physical illness could lead to a patient’s death. It is important to keep in mind that though the presence of secondary gain is necessary for the diagnosis of malingering, it is insufficient by itself and present in many patients with true medical or psychiatric illness.

Somatic Symptom Disorders Somatic symptom disorders (e.g., Briquet’s syndrome) or conversion disorders are distinguished from deception syndromes by the fact that the production of symptoms is not under the individual’s voluntary control. The symptoms are a result of unconscious conflicts. Typically, patients with somatic symptom disorder are not savvy about hospital procedures or medical diagnoses, nor do they derive secondary gain from their complaints.

Approach to the Patient with Deception Syndromes General Strategies Keep in mind that deceptive behavior can be non-pathological. When interacting with patients who are suspected of being untruthful with providers, clinicians should keep in mind that many patients lie to clinicians for non-pathological reasons. Common reasons for lying or

manipulation of truth involve anxiety regarding potential consequences (e.g., involuntary hospitalization), shame about behaviors, and a desire to be liked. Be suspicious early but thorough in the work-up. Early suspicion is important to avoid colluding with the patient in ordering unnecessary tests and subjecting the patient to further risk of iatrogenic injury. On the other hand, premature closure in such cases carries a significant risk that the patient’s complaints will be immediately dismissed by future providers. Gather information from collateral sources. The examination should emphasize corroboration of a patient’s information with any available friend, relative, or other informant. Verification of all the facts presented by the patient concerning prior medical care is essential. Laboratory tests or imaging might also be useful in confirming elements of the patient’s story. Use of centralized medical record databases or state prescription monitoring programs might aid, as well. Avoid early confrontation. When verifying facts, it is necessary to avoid pointed or accusatory questioning that might provoke evasion, defensiveness, or flight from the hospital. It can be nearly impossible to be certain of the diagnosis during the initial encounter. Be aware of negative countertransference. Patients with deception syndromes usually evoke feelings of hostility and contempt among staff members. Clinicians should try to embrace a non-judgmental approach to the patient. Attention should be paid to keeping emotionally charged comments out of the medical record. Maintaining an awareness that the patient has a psychological problem is helpful. Consider neuropsychological testing. Embedded tests of validity in the Minnesota Multiphasic Personality Inventory (MMPI) and Psychiatric Assessment Inventory (PAI) can help to detect when patients are minimizing (faking good) or exaggerating (faking bad) symptoms. Standalone symptom validity tests are also available. Specific elements of the history that suggest the presence of a deception syndrome are shown in Table 21-1. Clinical presentations associated with factitious disorders are provided in Table 21-2. Table 21-1: Historical Elements Suggestive of Deception Syndromes

Evidence of multiple hospital admissions Numerous forms of identification, e.g., hospital cards, insurance forms Frequent travel from hospital to hospital A working knowledge of medical or psychiatric jargon A paucity of verifiable history An absence of close interpersonal relationships A history of having worked in a medically-related field An early history of sadistic or rejecting parents, chronic illness, or an important relationship with a physician A history of a personality disorder A multiplicity of scars An allergy list that includes more than ten allergens An atypical course of physical or psychiatric illness

Table 21-2: Clinical Types of Factitious Disorder with Physical Symptoms Acute abdominal type (laparotomaphilia migrans) This type is the most common; many individuals with this type have been operated on so frequently that abdominal symptoms can, in fact, be a consequence of intestinal obstruction secondary to adhesions. Hematologic type Profound anemia has been produced by surreptitious blood-letting and by ingestions and self-administration of anticoagulants. Neurologic type (neurologia diabolica) The presentation often involves loss of consciousness, paroxysmal headaches, or seizures. Dermatologic type (dermatitis autogenica) This type is frequently the result of self-inflicted wounds or chemical abrasions. Febrile type (hyperpyrexia figmentatica): These individuals often lose their fevers when thermometers are placed, monitored, and removed under observation. Endocrinologic type: Such individuals often present for the evaluation of hyperinsulinemia, hyperthyroidism, or hypoglycemia. Cardiac type Such individuals often complain of chest pain or arrhythmias. Infectious type Auto-infection of wounds with fecal material or oral flora may create complications.

Treatment No specific psychiatric therapy has effectively treated factitious disorder or malingering . Early identification is perhaps the most important intervention because establishing the diagnosis can prevent unnecessary and potentially dangerous procedures. Clinicians should focus on management rather than cure. Strategies involve reframing the patient’s desire for medical attention as a cry for help; discussing the full range of possible diagnoses, including deception syndromes; suggesting relaxation therapies as a way to manage the symptoms; and identifying one member of the team as having primary therapeutic responsibility, but apprising all team members of the treatment plan (keeping in mind, however, that even the most empathic therapeutic confrontation can be met with profound denial, resistance, and anger). Because deception syndromes can not only harm the patient by generating unnecessary tests and work-ups but also jeopardize the care of other patients through misallocation of limited resources, direct confrontation might be reasonable in cases for which the diagnosis is clear. If the provider chooses to confront the patient about his or her behavior, it might still be possible to engage the patient in a discussion of motivations for the deception and alternative options for further treatment, including psychotherapy in the case of factitious disorder and referrals to outpatient resources, such as homeless shelters and substance abuse hotlines, in the case of malingering. For this particular patient population, effective psychiatric care cannot be provided in the absence of ongoing (and collaborative) multi-disciplinary medical care. Legal interventions are sometimes needed, particularly with factitious disorder imposed on another (because it often involves children). In such cases, child welfare services should be notified and arrangements made for ongoing monitoring of child’s health.

Suggested References 1. Asher R: Munchausen’s syndrome. Lancet 1951; 1: 339–341. 2. Braun IM, Greenberg DB, Smith FA, et al: Functional Somatic Symptoms,

Deception Syndromes, and Somatoform Disorders. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: pp. 173–187. 3. Eastwood S, Bisson JI: Management of factitious disorders: a systematic review. Psychother Psychosom . 2008; 77(4): 209–218. 4. Feldman MD: Munchausen by Internet: detecting factitious illness and crisis on the Internet. South Med J . 2000; 93(7): 669–672. 5. McCullumsmith CB, Ford CV: Simulated illness: the factitious disorders and malingering. Psychiatr Clin North Am . 2011; 34(3): 621–641. 6. Meadow R: Munchausen syndrome by proxy. The hinterland of child abuse. Lancet . 1977; 2(8033): 343–345. 7. Phillips CT, Gavin MC, Luptakova K, et al: Chest pain suggestive of a lifethreatening condition: A Department of Medicine Morbidity and Mortality Conference, Psychosomatics . 2016; 57: 89–96. 8. Stern TA: Munchausen’s syndrome revisited. Psychosomatics . 1980; 21: 329–336.

CHAPTER 22 Dissociative Disorders STEVEN C. SCHLOZMAN, MD

KEY POINTS Overview Dissociative disorders have undergone some changes from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) to the fifth edition (DSM-5). Whereas DSM-IV described dissociative identity disorder (DID), derealization disorder, depersonalization disorder, psychogenic amnesia, fugue state, and dissociation disorder not otherwise specified (NOS), DSM-5 sought to contract these diagnoses into more consistently observed phenomena. Thus, DSM-5 preserved DID but added the caveats that the switching from one alter to another need not be observed by the examiner. Derealization and depersonalization disorders were collapsed to a single syndrome called depersonalization/derealization disorder, and dissociative disorder NOS became unspecified dissociative disorder. Additionally, DSM-5 added other specified dissociate disorders to include syndromes that met partial criteria for other dissociative disorders. New findings include considerable debate about whether previously conceptualized culturally-bound syndromes, such as Latah and Amok require their own categorization or are better accounted for by existing dissociative nosology.

Overview Dissociative disorders encompass a heterogeneous and often controversial set of disorders. Although the concept of dissociation is more than a century old, dissociative phenomena are currently enjoying renewed interest even as their descriptions as valid diagnostic entities continue to be questioned. This increase is in part related to a burgeoning literature addressing the effects of trauma on memory and personality as well as the apparent epidemic of dissociative disease during the 1980s. More recently, a rapidly growing body of neurobiological

inquiry has allowed a better biological understanding of dissociative symptoms. In many respects, this empirical evidence has allowed the concept of dissociation to enjoy greater consideration. Dissociative phenomena have been consistently described throughout the history of psychiatry and when appropriate should be considered in the differential diagnosis. Central to the conceptualization of dissociation is the understanding that a person’s consciousness might not be fully integrated. Indeed, this conceptual framework is key to some of the most recent neurobiological findings. Thus, a patient might undergo a distinct alteration in personality or experience, in which thoughts, feelings, or actions are not logically integrated with other self-referential experiences. Renewed interest in trauma has also brought dissociative disorders into greater consideration and acceptance. Traumatic experiences are in fact often considered etiologic factors in the development of dissociation. Although the most well known of these disorders is dissociative identity disorder (DID ) (previously called multiple personality disorder), it is important to note that current nosology involves many related syndromes that have undergone significant changes from DSM-IV to DSM-5. In addition to DID, the DSM-5 now lists dissociative amnesia including dissociate fugue, depersonalization/derealization disorder, other specified dissociative disorders, and unspecified dissociative disorders. These changes reflect the growing appreciation for different presentation of syndromes that share common features and often involve traumatic etiologies. Additionally, clinicians must be careful to consider factitious or malingered dissociative symptoms when individuals present with symptoms of dissociation. A brief history of the descriptions of dissociative symptoms helps to place the multiple shifts in diagnostic nosology into context. Importantly, the defining feature of dissociation for these historical descriptions is essentially unchanged. In all cases, patients who are thought to suffer dissociative episodes experience identities, thoughts, feelings, or actions that are not logically integrated into the patient’s sense of self. They “dissociate” their symptoms from any conscious ownership. Because these symptoms are so striking, many well known early psychological theorists were involved in the characterization of dissociation. Franz Anton Mesmer (1734–1815) is best known for his theories of “animal magnetism,” and today is recognized as one of the first clinicians to explore the clinical utility of hypnosis in treating dissociation. Pierre Janet (1859–1947) followed this work and, along with other clinicians, was instrumental in

establishing hypnosis as an important clinical intervention for dissociative symptoms. Sigmund Freud differed from Janet by suggesting that dissociation results from the ego’s vigorous defense against psychological pain. Thus, while Janet felt that the ego collapsed and fragmented under the weight of traumatic experiences, Freud felt that trauma forced a powerful ego to wall off psychological pain, after which this pain manifests itself only in dissociative states. Fascinatingly, both theories enjoy a range of recent neurobiological findings in support of their validity. In 1906, Morton Prince published The Dissociation of a Personality , in which he described his patient, Sally Beauchamp, as “The Saint, the Devil, the Woman.” His work was likely the first clinical investigation into the notion of separate dissociative identities.

Etiology of Dissociation The most consistent finding regarding the etiology of dissociative pathology is the association of those who express these symptoms with traumatic experiences. Multiple studies and case series document the relationship of trauma to dissociative states. These cases include both long-term traumatic experiences—persistent sexual or physical abuse, for example—as well as single episode traumas that are more commonly experienced among veterans of combat. Children appear more prone to dissociation than adults and can develop dissociative traits in response to trauma at a very young age. To some extent, this has been linked to incomplete formation of cortico-limbic tracts characteristic of developing brains. Some researchers have theorized that these individuals remain more susceptible to dissociation than similarly traumatized older individuals, again suggesting the differential effects of trauma on different stages of brain development. As many of the early researchers of dissociation noted, there exists a strong association of dissociative states with hypnotizability. For example, patients with dissociative disorders are more hypnotizable than are control subjects. Moreover, hypnosis might represent a valuable clinical intervention for the treatment of dissociative disorders. Finally, some studies have found that subjects who have had traumatic experiences but who do not manifest a dissociative disorder appear more hypnotizable when compared to non-traumatized individuals.

Eye Movement Desensitization and Reprocessing therapy (EMDR) has also been implicated as a potentially useful treatment intervention for all forms of dissociation. It has been suggested that the eye movement exercises characteristic of EMDR are less important than are the behavioral and cognitivebehavioral techniques that accompany the treatment. Recently, research has suggested that dissociative states (given the extent to which information about one’s self is compartmentalized in those suffering from dissociative disorders) can be explored in terms of state-dependent learning (a broad concept meant to suggest that information stored in one “state” can only be retrieved in that specific state). Complex partial seizure activity has been suggested as a cause of dissociation, but a definitive link has not yet been revealed. Although some patients with dissociative disorders have concurrent seizure disorders, the seizures themselves do not necessarily cause their dissociative symptoms. Electroencephalographic (EEG) studies of patients with dissociative disorders have been contradictory; some studies suggest EEG differences within the same patient during different dissociative states. Neurochemical and pharmacologic agents can be related to dissociative phenomena. Substances, such as lysergic acid diethylamide (LSD), phencyclidine (PCP), and ketamine, appear to provoke dissociative episodes, and some studies suggest a serotonin dysregulation as contributing to dissociative tendencies. More recently, illicit compounds, such as so-called “bath salts,” have been implicated in violent dissociative episodes. Perhaps the most exciting discoveries have come from neuroimaging research and specifically from examining the sub-type of post-traumatic stress disorder (PTSD) patients who dissociate rather than experience hyperarousal and reexperiencing. The dissociative sub-type has been linked to emotional overmodulation caused by increased activity of the rostral anterior cingulate cortex and decreased amygdala activity. Conversely, non-dissociative PTSD is characterized by increased activity of the amygdala and decreased rostral anterior cingulate cortex modulation. This distinction has been instrumental in recent discussions of the neurobiology of trauma.

Who Dissociates? Dissociation can be measured clinically using the Dissociative Experience Scale (DES ). This 28-item self-report questionnaire has achieved good reliability and validity. Higher scores represent more dissociative experiences.

However, this scale can achieve only face validity and therefore can be purposefully misrepresented by the individual. Other standardized assessments include the Structured Clinical Interview for Dissociative Disorders-Revised (SCID-D-R ) as well as the Minnesota Multiphasic Personality Inventory (MMPI ). Again, clinicians must realize that the SCID-D-R has also achieved only face validity and that the MMPI has not been validated for dissociative disorders. Nevertheless, using these scales as well as other means of assessment, several epidemiologic conclusions have been suggested regarding those who experience dissociative states. Males and females (in both psychiatric and non-psychiatric samples) have similar DES scores. Thus, no gender differences are apparent in terms of the likelihood to dissociate. Similarly, there are no discernible differences on hypnotizability scores between males and females. In addition, there appears to be a negative correlation between age and the tendency to dissociate. Younger individuals are substantially more likely to dissociate. Interestingly, similar findings have been documented for hypnotizability. It is also important to note that different dissociative disorders have epidemiological variance. For example, although the tendency to dissociate is roughly equal in men and women, DID is more common in women, whereas dissociative fugue might be more common in men (see the section that follows).

Specific Dissociative Disorders Dissociative amnesia including dissociative fugue (formerly dissociative amnesia) is defined as an inability to recall important autobiographical information that would usually be successfully stored in memory and ordinarily easily remembered. This is the most common form of dissociative disorder. Importantly, these amnestic episodes cannot be better explained through potential etiologies, such as head injury, cognitive disorders, or substance ingestion. Within the overall group of dissociative amnesia, there are three distinct subcategories. The first is localized amnesia, in which patients fail to recall all events during a specific period. The second is selective amnesia, in which patients fail to recall some but not all events during a specific period. Usually, but not always, these unremembered events are particularly traumatic. Finally, there is generalized amnesia. This is extremely rare and typically has a sudden onset, after which patients recall no details of their entire life history.

Sometimes, all forms of dissociative amnesia are accompanied by dissociative fugue. This had previously been a separate diagnosis before DSM-5, but fugue behavior was found to almost never exist in the absence of dissociative amnesia. A fugue is defined as a purposeful wandering away from familiar territory in which there is no recollection of identity. Fugues must last for an extended period, at least days and sometimes weeks or even longer. Often, patients suffering from dissociative fugue will assume entirely new identities during their fugue episode. Dissociative fugue appears to be more common during wartime or after natural disasters, and based on current estimates, it is likely the rarest of the dissociative disorders. Although men appear to be affected as often as women, the incidence of men suffering from dissociative fugue increases during war and might be a sample effect. Dissociative fugue occurs primarily in adults, usually between the second and fourth decades, and although fugues can last from a few hours to several years, most episodes last from a few days to a few months. Alternative diagnoses include brain pathology leading to fugue states, drug-induced fugues secondary to alcoholic or drug-related blackouts, and factitious disorders or malingering. In addition, some cultural syndromes (e.g., Amok and Latah ) can mimic fugue states, though the validity of these culturally-bound syndromes has more recently been questioned. Dissociative amnesia appears to be a common short-term reaction in both men and women to severe stress such as civilian disasters, and data from previous iterations of these conditions suggest that the incidence in both males and females is roughly equal. Dissociative amnesia can occur during any age, though its peak incidence appears in the third and fourth decades. Three-fourths of cases last between 24 hours and 5 days. Differential diagnosis includes organic syndromes (secondary to brain injuries, lesions, or seizures) as well as factitious disorders and malingering. Clinicians also should consider illicit or accidental ingestion of substances. Treatment aims at restoring the missing memories, sometimes through psychotherapy and free association, but at times using hypnosis or pharmacologic methods meant to decrease inhibition. Patients with dissociative amnesia and related conditions tend to recover quickly and completely. However, many patients continue to display a propensity toward amnesia in the setting of trauma. DID (formerly multiple personality disorder) has received the most attention over the past two to three decades. Nevertheless, the diagnosis has endured

considerable controversy. The positive aspects of this controversy involve an ongoing debate about the interplay of society on psychiatric nosology as well as a careful re-examination of all dissociative phenomena and their relationship to consciousness and pathology. The core feature of DID is the “disruption of identity characterized by two or more distinct personality states.” As with other psychiatric syndromes, these symptoms cannot be accounted for more appropriately through explanations such as head injury or toxic ingestions. Additionally, in children the symptoms cannot better be explained through the normal developmental features of imaginary friends and playmates. Although DID remains controversial, it is also thought to be quite common. Approximately 1% to 3% of the population suffer from this condition, and key etiologic features involve traumatic experiences that are frequent before the age of five and can include severe abuse or ongoing and painful medical interventions. Because of the unusual presentation of the disorder, only about 6% of patients with DID are diagnosed. Symptoms tend to be intermittent and varying. It is also very common to have co-morbid symptoms of PTSD with DID, further complicating the diagnosis. Contrary to popular belief, complete amnesia for different distinct personalities is not necessary. Co-consciousness can occur, in which patients are aware of separate personalities and can therefore describe different feelings from different personalities—often called “alters”—at the same time. DID is characterized by high rates of depression and often by affective symptoms that constitute the presenting complaint. Indeed, treatment studies show the highest success rates when co-morbid affective disorders are amply treated. Additionally, from one-third to one-half of cases of DID experience auditory hallucinations. Some researchers have suggested that these hallucinations are described as ‘’inner voices,” helping to differentiate these symptoms from the external voices heard by those suffering from schizophrenia and other psychotic disorders. Furthermore, in contrast to individuals suffering from schizophrenia, patients with DID are unusually hypnotizable and do not display evidence of a formal thought disorder. The mean number of personality states in DID is approximately 13. However, case series have shown that the number of alternate identities can vary from 1 to 50. DID is reported more commonly in women than in men, and prevalence estimates range from rare to 1%. Several somatic symptoms can accompany DID, including headaches, gastrointestinal distress, and genitourinary disturbances. In addition, there is an

increased rate of conversion disorders, psychogenic seizures, and self-mutilation. Finally, a number of personality disorders, most prominently borderline personality disorder, are associated with DID. DID is usually diagnosed in the third or fourth decade, though those suffering from DID usually report symptoms during childhood and adolescence. Most case series document a chronic, fluctuating course, characterized by relapse and remission. Making the diagnosis of DID in a patient is often controversial. Some clinicians have proposed that the diagnosis must be persistently pursued if a patient’s symptoms even subtly hint at the possibility of dissociation. These clinicians describe patients who are either unaware of, or who wish to hide their disorder, and need to be “educated” about DID. Critics contend that patients with DID are highly suggestible and that clinicians “create” such patients by “suggesting” symptoms. The critics emphasize that the symptoms are reinforced by clinicians who show interest and enthusiasm in the multiplicity of personalities. Still, the relative rarity of the diagnosis and the relatively common prevalence of traumatic backgrounds among patients suggests that even when this diagnosis is entertained, most patients do not endorse the symptoms consistent for meeting the criteria for DID. To this end, the possibility of somehow making a patient have DID seems less likely. Extended psychotherapy remains the treatment of choice, although approaches vary widely and remain controversial. Some clinicians describe specialized treatment for DID, including delineating and mapping the alters, inviting each to participate in the treatment, and facilitating communication between the various alters. Through careful exploration of all alternate identities, clinicians attempt to understand past episodes of trauma as experienced by each personality. Hypnosis is sometimes employed to reach dissociated states. Other clinicians focus on the function of the dissociative process in the here-and-now of the patient’s life and the ongoing treatment. They help patients become aware of using dissociation to manage feelings and thoughts within themselves and to manage the closeness and distances within relationships. All approaches seek to increase tolerance and to integrate the dissociated states within the patient. Psychopharmacologic treatments, such as anti-depressants and anxiolytics, are often useful in treating the commonly accompanying complaints of depression and anxiety. However, no pharmacological treatment has been found to reduce dissociation per se . Studies of treatment success show that the tendency to dissociate dissipates with the lessening of mood symptoms. Importantly, although benzodiazepines can reduce anxiety, these agents can also exacerbate

dissociation. Although not routinely used for dissociative disorders, antipsychotics are sometimes employed in patients who are grossly disorganized. Because of the heterogeneity of presentations for DID, the differential diagnosis can be complicated. Co-morbid psychotic syndromes, such as bipolar disorder or schizophrenia, can exist, or these syndromes might in fact represent the sole diagnosis. This phenomenological ambiguity is the suggested reason that many cases of DID are not adequately recognized or addressed. Depersonalization /derealization disorder represent two syndromes that were combined in DSM-5. Formally, these syndromes included depersonalization disorder and derealization disorder. This syndrome is characterized by the presence of depersonalization, derealization, or both. These two states are in turn differentiated in terms of context. Depersonalization is a feeling that one is separate from one’s own internal experience. Derealization is the sense that one is separate from one’s own external surroundings. In both cases, reality testing is preserved and intact. As with the other dissociative disorders, these experiences must not be better accounted for through brain injury or substance abuse. In the case of depersonalization/derealization, specific recreational drugs, such as ketamine or PCP (angel dust) need to be considered in the differential diagnosis. Treatment is difficult, and patients are often refractory to intervention. Treating accompanying psychiatric conditions (such as depression or anxiety) can help. There is also some evidence that focused cognitive-behavioral therapy can be helpful. As with other dissociative disorders, exploration of past traumatic events can prove useful. The DSM-5 added a new category for dissociative disorders called other specified dissociative disorders (OSDD). This subset was created to encompass syndromes that share much in common with other key dissociative disorders but lack certain consistent elements. DID without distinct alters falls into this category. Additionally, changes in behavior due to brainwashing, trance states, or acute dissociative reactions to immediate trauma also are categorized as OSDD. In most cases, treatment is based on the symptoms that correlate most closely with the syndrome that is most like the presenting behavior. Often patients try to hide these conditions and are ashamed or embarrassed by them. Finally, there are unspecified dissociative disorders . These correlate most closely with the DSM-IV category of dissociative disorder not otherwise specified (NOS). This diagnosis is reserved for presentations in which the predominant feature is dissociation without meeting clear criteria for any specific dissociative disorder. Note that previously, this category also included

DID without amnesia or DID in which switching alters is not observed by the clinician. Ganser’s syndrome (sometimes called “prison psychosis”) is now classified as another specified dissociative disorder. It is characterized by the provision of approximate answers, i.e., offering half-correct answers to simple inquiries, such as answering “5” to the question, “What is 2 plus 2?” The correct set of the response is given, but the answer is inaccurate. Ganser’s syndrome is often reported in incarcerated populations. Culture-bound syndromes , such as Amok in Indonesia or Latah in Malaysia as well as varying descriptions of demonic or spiritual possession are controversial, and scholars argue whether they can be validly distinguished from existing dissociative disorders.

False Dissociative Symptoms Factitious illness or malingering disorders that are characterized by the presentation of dissociation might be more common than previously realized. The motivation in these cases appears to be the assumption of the sick role, consistent with other presentations of factitious disorders. Additionally, there are case reports that detail dissociative symptoms expressed as a form of malingering. In these episodes, individuals feign dissociative symptoms for reasons other than assuming the sick role (such as avoiding criminal or financial responsibilities). Individuals attempting to feign dissociative symptoms are often extremely invested in the diagnosis of DID. They might express their symptoms only when they feel they are being observed or heard, and they might refuse collateral interviews with other individuals in which the clinician attempts to gather additional information. One study suggested that approximately 50% of those with feigned DID admit their simulation of dissociation to a caretaker. Additionally, individuals who simulate these symptoms might have substantially more exposure to, and knowledge of, popular and scientific explorations of dissociation than do those with genuine dissociative disorders. Dissociative trance disorder is not currently a formal classification. However, some researchers have suggested criteria for further study. These presentations include apparent episodes of demonic possession or religious ecstasy. The feeling of being possessed is reported commonly in those who feel guilty about perceived transgressions. Examples might involve an individual who is unfaithful to his or her spouse and who becomes convinced that demonic

possession is responsible for his or her infidelity. In these instances, it is important to rule out psychosis, malingering, and factitious disorder when considering this category.

Conclusion There is less controversy about the phenomena of dissociative symptoms than there is about the existence of discrete diagnostic categories of dissociation. In other words, little doubt exists that patients dissociate and that these episodes of dissociation are related especially to trauma. Current neurobiological research showing abnormalities in mid-brain modulation and in fact mid-brain enhancement of affective experience adds credence to the existence of dissociation and might allow future distinctions between apparent dissociation and conditions that mimic dissociative symptoms. Regarding treatment, clinicians can expect relatively positive responses of all dissociative symptoms to appropriate interventions. Therefore, patients who present with symptoms of dissociation should be carefully interviewed, diagnosed, and treated. Dismissing psychiatric suffering because the nosology seems less valid than other conditions is not consistent with the fundamental mandates of medical practice. In this same light, further research is clearly needed to better elucidate these complicated syndromes.

Suggested Readings 1. Bell V, Oakley DA, Halligan PW, et al: Dissociation in hysteria and hypnosis: evidence from cognitive neuroscience. J Neurol Neurosurg Psychiatry . 2011 Mar; 82(3): 332–339. 2. Brand BL, Classen CC, McNary SW, et al: A review of dissociative disorders treatment studies. J Nerv Ment Dis . 2009 Sep; 197(9): 646–654. 3. Coons PM: The dissociative disorders. Rarely considered and underdiagnosed. Psychiatr Clin North Am . 1998 Sep; 21(3): 637–648. 4. Dissociative Disorders. (Oct 25, 2016). Traumadissociation.com. Retrieved Oct 25, 2016 from http://traumadissociation.com/dissociative.html . 5. Lanius RA, Vermetten E, Loewenstein RJ, et al: Emotion modulation in PTSD: Clinical and neurobiological evidence for a dissociative sub-type. Am J Psychiatry . 2010 Jun; 167(6): 640–647.

6. Loewenstein RJ, Putnam FW: Dissociative disorders. In: Sadock BJ, Sadock VA, eds.: Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: pp. 1852–1853. 7. Ross CA, Schroeder E, Ness L: Dissociation and symptoms of culturebound syndromes in North America: a preliminary study. J Trauma Dissociation . 2013; 14(2): 224–235. 8. Ross EA, Watson M, Goldberger B: “Bath salts” intoxication. N Engl J Med. 2011 Sep 8; 365(10): 967–968. 9. van Duijl M, Kleijn W, de Jong J: Are symptoms of spirit possessed patients covered by the DSM-IV or DSM-5 criteria for possession trance disorder? A mixed-method explorative study in Uganda. Soc Psychiatry Psychiatr Epidemiol . 2013 Sep; 48(9): 1417–1430.

CHAPTER Sexual Disorders and Sexual 23 Dysfunction LINDA C. SHAFER, MD

KEY POINTS Incidence Sexual disorders are common, occurring in 31% of men and 43% of women in the United States. Epidemiology Sexual dysfunction is associated with older age, co-existing medical problems (such as cardiovascular disease), and other mental health disorders. Paraphilic disorders are associated with attention deficit hyperactivity disorder (ADHD). Gender dysphoria has a strong link to suicidal behaviors. Pathophysiology The human sexual response cycle concept (Masters and Johnson, Kaplan, and Basson models) provides a useful framework for understanding sexual problems. However, sexual function is in fact very complex and depends on numerous biological, psychological, social, and cultural factors, many unknown. Clinical Findings The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition has made significant revisions to the classification and diagnosis of sexual disorders, which are broadly divided into the sexual dysfunctions, paraphilic disorders, and gender dysphoria. A thorough sexual history is the treating psychiatrist’s most effective tool in facilitating an accurate diagnosis. Differential Diagnoses Medical illness, surgical conditions, medication side effects, alternative psychiatric conditions, or a combination of these factors, can all mimic or

contribute to the development of sexual disorders. Treatment Options Behavioral sex therapy techniques can be particularly useful for the sexual dysfunctions. The most well-established medical treatment is the use of phosphodiesterase type 5 (PDE-5) inhibitors (sildenafil, vardenafil, tadalafil, avanafil) for the treatment of erectile disorder. Recently FDA-approved, flibanserin became the first available—although controversial—drug for female sexual dysfunction, prescribed for women with decreased sexual desire. Hormonal therapy can be used off-label to decrease sexual urges in paraphilic disorders and suppress secondary sexual characteristics in gender dysphoria. Gender reassignment is a permanent therapy for gender dysphoria. Complications PDE-5 inhibitors are generally well tolerated; adverse effects can include headache or decreased blood pressure. Hormonal agents are linked to cardiovascular disease, thromboembolic events, and breast cancer. Prognosis Sexual disorders often require a multi-faceted treatment approach and multispecialty collaboration to achieve the best chances for clinical improvement.

Introduction Sexual problems occur frequently and cause great distress. Forty-three percent of women and 31% of men have experienced some form of sexual dysfunction. Fifty percent of American couples suffer from some type of sexual problem. Twenty-four percent of Americans will experience some type of sexual dysfunction at some time in their lives. Typically, primary-care physicians (PCPs) see the patient with sexual problems before a referral to a psychiatrist is made. The newly revised Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) divides sexual disorders into three groups: sexual dysfunctions, paraphilic disorders, and gender dysphoria. For each disorder, the International Statistical Classification of Diseases and Related Health Problems [ICD], 10th Revision (ICD-10) codes are now listed in addition to ICD-9 designations.

Sexual dysfunction refers to a clinically significant disturbance in the ability to respond sexually or to experience sexual pleasure. The definition is no longer linked to the physiological sexual response cycle and now requires at least 6 months of symptoms. Modifiers have also been added, including severity, duration (life-long or acquired), circumstances (situational or generalized), and associated features (such as medical and relationship factors). Gender-specific diagnoses have been added (e.g., male hypoactive sexual desire disorder) and others have been combined (e.g., genito-pelvic pain/penetration disorder replacing vaginismus and dyspareunia) or discarded (e.g., sexual aversion disorder). Unlike prior editions, the DSM-5 introduces the term “paraphilic disorders” to describe pathological forms of “paraphilia.” Paraphilias now refer to recurrent, intense sexual urges or behaviors that are considered atypical but within the range of normal. Paraphilic disorders are paraphilias that cause personal distress or harm to self or others. Thus, not all “paraphilias” are necessarily “disorders” in DSM-5. Gender dysphoria substitutes for the older term, gender identity disorder. The disorder is characterized by conflict between one’s birth sex and personal gender association, causing personal distress or functional impairment. Gender identity disorder included only male or female sexes. In contrast, gender dysphoria allows the possibility of an “alternative” (other) gender preference.

Evaluation of the Problem—Sexual Dysfunction General Recommendations Sexual dysfunction can be conceptualized through the stages of the normal sexual response, which vary with age and with physical and psychological status.

The Four-Step Model (Masters and Johnson) There are four phases in this model: (1) excitement: arousal; (2) plateau: the phase of maximum arousal prior to orgasm; (3) orgasm: a stage that involves muscular contractions at 0.8 second intervals; and (4) resolution: a phase leading to a return to baseline. In men, this is followed by a refractory period, which increases with age. In women, there is no refractory period.

The Triphasic Model (Helen Singer Kaplan)

This model has three phases: (1) desire; (2) excitement (arousal): a vascular phenomenon, caused by innervation of the parasympathetic nervous system (2nd, 3rd, and 4th sacral segments of the spinal cord); and (3) orgasm: a muscular reaction, caused by innervation of the sympathetic nervous system, whose reflex center is in the lumbar cord.

The Biopsychosocial Model of Female Sexuality (Rosemary Basson) Recognizing fundamental differences in the experience of sexual pleasure by women compared to men, Basson proposed a unique model of female sexuality with four overlapping components: (1) biology, (2) psychology, (3) sociocultural factors, and (4) interpersonal relationships. Basson observed that female sexual desire can be primarily or partially stimulated by non-sexual stimuli (e.g., desire for emotional closeness) and that female sexual satisfaction can be achieved even without direct sexual desire. Physical measurements of female arousal (such as increased vaginal secretions) are in fact poorly correlated with sexual satisfaction, supporting Basson’s view.

Changes in the Sexual Response Associated with Aging Older men are slower to achieve an erection and need more direct stimulation to the penis to achieve an erection. Older women have decreased levels of estrogen, which leads to less vaginal lubrication and to narrowing of the vagina.

Changes in the Sexual Response Associated with Physical and Psychological Status Medications , diseases, injuries, and psychological conditions can affect the sexual response in any of its component phases and lead to different dysfunctional syndromes (Table 23-1). Several types of sexual dysfunction can co-exist, and one sexual dysfunction can be the cause of another. A primary sexual dysfunction is one that has been present since the onset of sexual activity. A secondary sexual dysfunction is one that occurs after a period of normal functioning. Table 23-1: Classification of Sexual Dysfunctions Impaired Sexual Response Phase

Female

Male

Desire

Female sexual interest/arousal disorder

Male hypoactive sexual desire disorder

Other specified sexual dysfunction: sexual aversion

Other specified sexual dysfunction: sexual aversion

Excitement (arousal, vascular)

Female sexual interest/arousal disorder

Erectile disorder

Orgasm (muscular)

Female orgasmic disorder

Delayed ejaculation Premature ejaculation

Sexual Pain

Genito-pelvic pain/penetration disorder

Other specified or unspecified sexual dysfunction

Additional Complexities in Understanding Sexual Function Models of the human sexual response provide a useful framework for categorizing sexual disorders but are now regarded as overly simplistic. In fact, normal sexual function depends on a complex interplay of many biological systems, including neurological, hormonal, and vascular axes. For example, dopamine, melanocortin, estrogen, and testosterone all play important roles in the neuromodulation of sexual desire, arousal, and orgasm. Nitric oxide (NO) helps to regulate intra-penile blood flow and vaginal smooth muscle tone and is a target for many drug therapies. In some cases (as detailed later in this chapter), the sexual dysfunctions can no longer be neatly grouped according to traditional phases of the sexual cycle. With continued advances, greater specificity in diagnosis and treatment might be achieved.

Medical History Although most sexual disorders were once thought to have a purely psychological basis, newer diagnostic testing has identified more conditions with an organic etiology. Most sexual disorders are multi-causal and share a mixed etiology. Lifestyle factors, physical disorders, surgical disorders (Table 23-2), use of medications (including herbal agents), and drug use or abuse (Table 23-3), can affect sexual functioning directly and/or cause secondary psychological reactions, in turn causing a sexual problem. In fact, sexual symptoms, such as erectile dysfunction may be the primary presenting complaint in patients with an underlying undiagnosed medical problem. Sexual dysfunction is a common side effect that occurs in more than 30% of patients taking a selective serotonin reuptake inhibitor (SSRI). Table 23-2: Medical and Surgical Conditions Causing Sexual Dysfunctions Organic Disorders Endocrine

Sexual Impairment

Hypothyroidism, adrenal dysfunction, hypogonadism, diabetes mellitus

Low libido, (early) erectile dysfunction, decreased vaginal lubrication

Vascular Hypertension, atherosclerosis, stroke, venous insufficiency, sickle cell disorder Erectile dysfunction with intact ejaculation and libido

Neurologic Spinal cord damage, diabetic neuropathy, herniated lumbar disc, alcoholic neuropathy, multiple sclerosis, temporal lobe epilepsy

Sexual disorder-early sign, low libido (or high libido)

Local Genital Disease Male : Priapism, Peyronie’s disease, urethritis, prostatitis, hydrocele

Low libido, erectile dysfunction

Female : Imperforate hymen, vaginitis, pelvic inflammatory disease, endometriosis

Genito-pelvic pain, low libido, decreased arousal

Systemic Debilitating Disease Renal, pulmonary, or hepatic diseases, advanced malignancies, infections

Low libido, erectile dysfunction, decreased arousal

Surgical Post-operative States Male : Prostatectomy (radical perineal) abdominal-perineal bowel resection

Erectile dysfunction, no loss of libido, ejaculatory impairment

Female: Episiotomy, vaginal repair of prolapse, oophorectomy

Genito-pelvic pain, decreased lubrication

Male and female: Amputation (leg), colostomy and ileostomy

Mechanical difficulties in sex, low selfimage, fear of odor

Table 23-3: Drugs and Medicines Causing Sexual Dysfunction Drug

Sexual Side Effect

Cardiovascular Methyldopa

Low libido, erectile dysfunction, anorgasmia

Thiazide diuretics

Low libido, erectile dysfunction, decreased lubrication

Clonidine

Erectile dysfunction, anorgasmia

Propranolol

Low libido

Digoxin

Gynecomastia, low libido, erectile dysfunction

Clofibrate

Low libido, erectile dysfunction

Psychotropics Sedatives Alcohol

Higher doses cause sexual problems

Barbiturates

Erectile dysfunction

Anxiolytics Diazepam

Low libido, delayed ejaculation

Alprazolam

Antipsychotics Thioridazine

Delayed or retrograde ejaculation

Haloperidol

Low libido, erectile dysfunction, anorgasmia

Antidepressants MAO inhibitors (phenelzine) Erectile dysfunction, delayed ejaculation, anorgasmia Tricyclics (imipramine)

Low libido, erectile dysfunction, delayed ejaculation

SSRIs (fluoxetine, sertraline) Low libido, erectile dysfunction, delayed ejaculation Atypical (trazodone)

Priapism, delayed or retrograde ejaculation

Lithium

Low libido, erectile dysfunction

Hormones Estrogen

Low libido in men

Progesterone

Low libido, erectile dysfunction

Gastrointestinal Cimetidine

Low libido, erectile dysfunction

Methantheline bromide

Erectile dysfunction

Opiates

Orgasmic dysfunction

Anticonvulsants

Low libido, erectile dysfunction, priapism

Psychological causes of sexual disorders are complex; they range from superficial issues (e.g., fear of failure) to deep ones (e.g., profound depression). No direct correlation has been found between specific background factors and certain sexual dysfunctions. Predisposing, precipitating, and maintaining factors play a role in sexual problems (Table 23-4). Table 23-4: Psychological Causes of Sexual Dysfunction Predisposing Factors Lack of information/experience Unrealistic expectations Negative family attitudes to sex Sexual trauma—rape, incest

Precipitating Factors Childbirth Infidelity Dysfunction in the partner

Maintaining Factors Interpersonal issues Family stress Work stress Financial problems Depression Performance anxiety Gender dysphoria

Taking a Sexual History Not uncommonly , patients are embarrassed to bring up and to discuss sexual problems. Physicians, too, are often uncomfortable discussing sexual issues, in part because of fears of offending patients. Therefore, it is important to ask routine screening questions as part of the medical history to give the patient a chance to talk about sexual problems (e.g., “Is there anything you would like to change about your sex life? Have there been any changes in your sex life? Are you satisfied with your present sex life?”). Additional routine questions to ask in the HIV/AIDS era include: “Are you sexually active? With men, women, or both? Do you practice safe(r) sex?” Lack of knowledge of safe sex practices can contribute to the spread of HIV infection/AIDS. Physicians should be prepared to discuss the benefits of safe sex techniques, including the use of condoms and spermicides that contain nonoxynol-9. Failure to ask HIV/AIDS screening questions might result in complaints of inadequate treatment or a malpractice suit. Clinicians also should be attuned to growing patient concerns about “sexual addiction” in an era where Internet pornography and “cybersex” activities are available on-demand, anytime. The sexual history-taker should gain comfort in exploring, when necessary, the role of the Internet in the patient’s sexual and non-sexual functioning and the possibility of excessive and/or compulsive sexual activities. In part spurred by these issues, a “hypersexual disorder” was in fact proposed for inclusion in DSM-5, although ultimately rejected. Nevertheless, the

potential for impulsive, excessive sexual behaviors that cause personal distress or harm to others remains an important concern and requires appropriate screening by a skilled provider.

Interview Techniques Clinicians should attempt to be sensitive and non-judgmental, while moving from more general to more specific topics. Sexual issues can be integrated easily into the medical history during review of the systems, when discussing the initiation or introduction of a new medication, or when the chief complaint involves a gynecological or urological problem. It is helpful to be aware of covert presentations of sexual problems (e.g., headache, insomnia, and low back or generalized pelvic pain) that have no apparent medical basis. Questions should vary depending on the patient’s age, social class/occupation, and the nature of the patient’s continuing relationship with you. Taking of the sexual history should be designed to fit the patient’s needs and your time. If a sexual problem is uncovered, a detailed history should be obtained. Its onset and progression (inquiring how often it occurs and when it occurs [e.g., with all partners, on masturbation, with fantasy], should be assessed). The assessment should be completed, avoiding use of “why” questions (because this tends to make a patient feel defensive). Using “what” questions (e.g., “What do you think caused your problems?”) are helpful as are attempts at resolution of the problem (including advice the patient received from outside sources, such as books, friends, and clergy). The patient’s expectations and goals (e.g., do they wish to resolve the problem, save their marriage, use the problem as an excuse for divorce?) should be addressed.

Examination of the Patient Physical Examination A thorough physical examination is indicated on every patient, with special attention paid to endocrine, vascular, neurological, urological, and gynecological systems.

Laboratory Examination The extent of the laboratory examination depends on the nature of the problem and one’s index of suspicion (organic versus psychological). The sexual history and physical examination together help determine the extent of the organic work-up, including what special laboratory studies and diagnostic procedures

should be performed. Screening for unrecognized systemic disease should include a complete blood count (CBC), a urinalysis, a creatinine level, a lipid profile, thyroid function studies, and a fasting blood sugar (FBS). Relevant endocrine studies for assessment of low libido and erectile dysfunction include levels of testosterone, prolactin, leutenizing hormone (LH), and follicular stimulating hormone (FSH). An estrogen level and microscopic exam of a vaginal smear for vaginal dryness should be obtained. A sedimentation rate, a cervical culture, and a pap smear should be obtained for evaluation of dyspareunia. Diagnostic tests for erectile functioning include nocturnal penile tumescence (NPT) studies , ultrasonography, and angiography. Referral to a specialist in urology, gynecology, endocrinology, neurology, and/or psychiatry is made on a case-by-case basis.

Psychiatric Differential Diagnosis of Sexual Disorders Many psychiatric disorders can result in sexual symptoms. Such conditions include depression, bipolar disorder, anxiety disorders, obsessive-compulsive disorder (OCD), and schizophrenia. Paraphilic disorders, gender dysphoria, and personality disorders should also be considered. Psychosocial factors (marital dysfunction, fears of intimacy/commitment) often potentiate sexual distress (Table 23-5). Table 23-5: Psychiatric Differential Diagnosis of Sexual Disorders Psychiatric Disorder Associated Sexual Symptoms Depression Major depression Dysthymic disorder

Low libido, erectile dysfunction

Bipolar disorder—manic phase Increased libido Generalized anxiety disorder Panic disorder PTSD

Low libido, erectile dysfunction, lack of vaginal lubrication, anorgasmia

OCD

“Anti-fantasies” focusing on negative aspects of partner, low libido, erectile dysfunction, lack of vaginal lubrication, anorgasmia

Schizophrenia

Low desire, bizarre sexual desires

Paraphilic disorder

Deviant sexual arousal causing distress and/or harm

Gender dysphoria

Dissatisfaction with one’s assigned gender and sexual phenotype

Personality disorder Passive-aggressive Obsessive-compulsive

Low libido, erectile dysfunction, premature ejaculation, anorgasmia

Histrionic Marital dysfunction— interpersonal problems

Varied

Fears of intimacy/commitment Varied, deep intrapsychic issues

Diagnostic Criteria Sexual Disorders Not Caused by Organic Factors (Medical Conditions, Medications, or Drugs of Abuse) or by Another (Psychological) Axis I Disorder All of the preceding factors can cause marked individual distress and/or interpersonal difficulties.

Desire Phase Disorders Male Hypoactive Sexual Desire Disorder (ICD-9 302.71; ICD-10 F52.0) This disorder is defined by recurrent or persistent absence of sexual thoughts or fantasies and desire for sexual activity, occurring for at least 6 months. Importantly, this diagnosis is new to the DSM-5 and applies only to men. It also replaces the “hypoactive sexual desire order” applicable to both genders that appeared in previous versions of the DSM; a female “version” of the disorder no longer exists. In males, sexual desire decreases with increasing age. More than 40% of men ages 66 to 74 report decreased sexual desire, compared to 6% of men ages 18 to 44. Decreased desire is not always pathological. In fact, less than 2% of men ages 16 to 44 would meet the DSM-5 criteria for the disorder.

Arousal Phase Disorders Female Sexual Interest/Arousal Disorder (ICD-9 302.72; ICD-10 F52.22) Female sexual interest/arousal disorder (FSIAD ) is also a new diagnosis in the DSM-5, replacing the “ female sexual arousal disorder” (FSAD) appearing in previous editions. Notably, it encompasses both desire (interest) and arousal phases of the female sexual cycle. The disorder is defined by reduced or absent sexual interest, thoughts, arousal, excitement, genital sensation, and/or activity (with reluctant initiation and participation in sex). At least 3 of these components must be present for a period of 6 months or more and cause significant personal

distress. The exact prevalence of FSIAD is not known; FSAD was estimated to occur in 60% of women across their life-time.

Erectile Disorder (ICD-9 302.72; ICD-10 F52.21) Erectile disorder (formerly known as “male erectile disorder” and colloquially called “impotence”) is a condition involving the inability to attain or maintain a satisfactory erection until completion of sexual activity, occurring in at least 75% of sexual encounters. It can be life-long (present since becoming sexually active) or acquired (after a period of normal sexual function), generalized (occurring in all circumstances) or situational (limited to certain types of stimulation, situations, and partners). As many as 20 million American men suffer from erectile dysfunction (ED), including up to 50% of men older than age 60. Between 50% and 85% of cases of ED have an organic basis. In fact, ED may be the presenting symptom of more generalized vascular disorder and is also commonly seen in depression. See Table 23-6 for additional risk factors associated with ED. Table 23-6: Risk Factors Associated with Erectile Dysfuncton Hypertension

Pelvic trauma or surgery

Diabetes mellitus

Renal failure and dialysis

Smoking

Hypogonadism

Coronary artery disease

Alcoholism

Peripheral vascular disorders Depression Blood lipid abnormalities

Lack of sexual knowledge

Peyronie’s disease

Poor sexual technique

Priapism

Interpersonal problems

Orgasm Phase Disorders Female Orgasmic Disorder (ICD-9 302.73; ICD-10 F52.31) Female orgasmic disorder is a condition involving a persistent delay in, or marked decrease in frequency or intensity of, orgasm, following a normal excitement phase, occurring in at least 3 of 4 sexual encounters. Although as many as 4 in 10 women report difficulties with orgasm during their life-time, only a small proportion experience distress related to this. The ability to reach orgasm increases with sexual experience. The diagnosis should not be made for

women who can experience an orgasm with direct clitoral contact but who find it difficult to reach orgasm during intercourse; this is a normal variant. Claims that stimulation of the Grafenberg spot, or G spot, in a region in the anterior wall of the vagina will cause orgasm and female ejaculation have never been substantiated, although there remains active interest in this hypothesis. A male sexual partner with premature ejaculation may contribute to female orgasmic dysfunction.

Delayed Ejaculation (ICD-9 302.74; ICD-10 F52.32) This disorder (previously referred to as “retarded ejaculation”) is characterized by a marked infrequency of ejaculation or delay in achieving ejaculation, occurring for at least 6 months in at least 75% of sexual encounters. It replaces “male orgasmic disorder,” which was similar in concept but did not equate ejaculation with orgasm. Delayed ejaculation is rare, with less than 1% of men meeting DSM-5 criteria. Young age (younger than 35) and sexual inexperience are risk factors. In the condition, satisfactory ejaculation can usually still be achieved with masturbation or partnered manual or oral stimulation, despite difficulties with intercourse. Delayed ejaculation must be distinguished from retrograde ejaculation, where the bladder neck does not close off properly during orgasm, causing semen to spurt backward into the bladder. It is also an important diagnosis of exclusion in a couple presenting with infertility of unknown cause. The male may not have admitted his lack of ejaculation to his partner.

Premature (Early) Ejaculation (ICD-9 302.75; ICD-10 F52.4) Premature ejaculation is a condition involving persistent ejaculation with minimal stimulation before or after penetration (within 1 minute) and before the person wishes it. Early ejaculation is very common and has been reported in up to 30% of men ages 18 to 70 in an international cohort. However, fewer than 3% of men would meet the DSM-5 definition, which like other sexual disorders requires associated clinically-significant distress and symptom duration for 6 months or more in at least 75% of sexual encounters. Prolonged periods without sexual activity make premature ejaculation worse. If the problem is chronic and untreated, secondary erectile dysfunction often occurs.

Sexual Pain Disorders Genito-Pelvic Pain/Penetration Disorder (ICD-9 302.76; ICD-10 F52.6)

Genito-pelvic pain/penetration disorder is a new disorder in the DSM-5, characterized by recurrent persistent vulvovaginal pain or fear of pain during penetration or intercourse, possibly with associated marked tensing of the pelvic floor muscles. The entity combines the DSM-IV disorders vaginismus (involuntary vaginal spasm) and dyspareunia (painful intercourse) into one diagnosis. Clinically, these sexual pain syndromes often overlapped and were difficult to differentiate, lending support for this merge. However, it should be noted that the new disorder is limited to women, whereas dyspareunia also could have been diagnosed in men (albeit infrequently). Approximately 15% of North American women report persistent pain during sexual intercourse. However, the true prevalence of this new disorder is not known. Sexual trauma or co-existing medical conditions might be precipitants. Lack of adequate vaginal lubrication and other physiological contributors to sexual pain should be excluded.

Additional Sexual Disorders Substance/Medication-Induced Sexual Dysfunction (ICD-9 291.89 or 292.89; ICD-10 F10.181 - F19.981; codes tailored to substance and severity of use disorder) This disorder is defined by impairment in sexual function immediately preceded by ingestion of a specific substance or medication. There must be verifiable information about how and when the substance was taken and whether it can cause sexual impairment. Like other sexual disorders, the impairment must cause clinically significant distress. In addition, it should not occur during a state of delirium.

Other Specified (ICD-9 302.79; ICD-10 F52.8) and Unspecified (ICD-9 302.70; ICD-10 F52.9) Sexual Dysfunction These DSM-5 diagnoses should be used in lieu of their DSM-IV predecessor, “sexual dysfunction not otherwise specified.” The “specified” versus “unspecified” designation refers to whether the clinician wants to “specify” (or not specify) why a patient’s symptoms do not meet criteria for another sexual disorder. For example, “sexual aversion disorder,” a DSM-IV diagnosis characterized by extreme disinclination toward partnered genital sexual contact, has been eliminated in DSM-5 due to infrequent use and limited supporting evidence. Nevertheless, using the DSM-5 terminology, a patient with such symptoms could be diagnosed with “other specified sexual dysfunction”; the specific reason is “sexual aversion.”

Treatment Strategies for Organically-Based Sexual Disorders General Principles The initial treatment strategy should focus on potentially reversible causes of sexual dysfunction with attention to lifestyle modification (e.g., diet, exercise, smoking, use of alcohol, illicit drug use). Offending medications should be identified and modified as possible. For example, antihypertensive agents in general inhibit sexual function, but the angtiotensin II-receptor blockers (e.g., losartan) and α -blockers (e.g., doxazosin), also useful for b enign prostate hypertrophy (BPH), can lead to improvement. Treatment strategies for SSRIinduced sexual dysfunction include decreasing the dose of the current agent, switching antidepressants, and adding additional agents (Table 23-7). Any hormonal deficiencies should be corrected (e.g., thyroid hormone for hypothyroidism, bromocriptine for elevated prolactin after pituitary neuroimaging). In general, treatment of underlying medical/surgical conditions (e.g., diabetes) can improve sexual dysfunction. Additionally, treatment of underlying psychiatric disease (e.g., depression) will often concurrently ameliorate sexual symptoms (with the caveat that psychiatric medications can also lead to sexual dysfunction). Table 23-7: Treatment Strategies for SSRI-Induced Sexual Dysfunction Strategy

Comments

Decrease the dose May diminish antidepressant effect Consider in patients on high doses Switch SSRIs

Paroxetine linked to highest rates of sexual dysfunction Fluvoxamine may have fewer sexual side effects No clear evidence to support this strategy

Switch to a nonSSRI agent

Data support bupropion, mirtazapine, duloxetine (+/–), trazodone, vilazodone (limited experience), nefazodone (brand name Serzone withdrawn in United States) Consider transdermal selegiline Not FDA-approved: tianeptine, reboxetine, moclobemide, agomelatine, gepirone Venlafaxine and desvenlafaxine not superior to SSRIs

Add an “antidote” Best evidence to support PDE-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil), next bupropion, drug then buspirone (high dose) PDE-5 inhibitors not only improve erectile dysfunction but also arousal and orgasm even in some women on SSRIs

Small studies support maca root (herbal agent) Consider amantadine, dextroamphetamine, methylphenidate, gingko biloba, granisetron, cyproheptadine, yohimbine, atomoxetine (data mixed) Take a drug holiday

Limited studies show no clear benefit to this approach

Await spontaneous remission

Rarely occurs

May precipitate withdrawal and encourage non-compliance

Erectile Disorder The oral phosphodiesterase type 5 (PDE-5) inhibitors have revolutionized the treatment of erectile dysfunction. Currently available agents are sildenafil (Viagra), vardenafil (Levitra; Staxyn orally-disintegrating tablet [ODT]), tadalafil (Cialis), and avanafil (Stendra). Additional PDE-5 inhibitors in development include: mirodenafil (Mvix), udenafil (Zydena), lodenafil (Helleva), dasantafil, SLx-2011, JNJ-10280205, and JNJ-10287069. The PDE-5 inhibitors are absolutely contraindicated with concurrent nitrate use. Additional recognized adverse effects include: potential symptomatic hypotension with αblocker use; for example, for BPH and/or hypertension, a possible link to nonarteritic anterior ischemic optic neuropathy (NAION)—not confirmed in clinical trials—and possible new-onset hearing loss. The only other oral pharmacologic agent for erectile dysfunction approved by the United States Food and Drug Administration (FDA) is the α-adrenergic blocker yohimbine (Yocon). Agents under study include: dopamine agonists, sublingual apomorphine (Uprima), and carbegoline (Dostinex); the alphablocker phentolamine (Vasomax); nitric oxide (NO) precursor L-arginine (ArginMax); the opioid antagonist, naltrexone (Depade, Revia); the melanocortin receptor agonist, bremelanotide (PT-141); and the serotonin/dopamine modulator, clavulanic acid (Zoraxel). Some studies indicate a benefit of 5-HT2C serotonin receptor agonists, such as trazodone, in stimulating erection. Topical agents (not approved) include: alprostadil cream (Topiglan), minoxidil solution, and nitroglycerine ointment. Herbal agents and supplements demonstrate limited efficacy with P. ginseng , B. superba , and L. meyenii (maca root) showing the most promise. Some of these agents contain traces of PDE-5 inhibitors. One notable example is the “Stamina-Rx” men’s supplement, which was recalled after the FDA discovered that the product contained benzamidenafil, a non-approved PDE-5 inhibitor. In hypogonadal men, transdermal testosterone and/or clomiphene citrate

(Clomid) may be considered. Recently, a large-scale coordinated set of randomized controlled trials evaluating the effects of testosterone therapy on elderly men was published. The study involving nearly 800 subjects found that increasing serum testosterone from low to mid-normal levels in males age 65 or older was associated with significant improvements in erectile function as well as sexual desire and sexual activity, thus validating a potential role for hormonal therapy in this population. More invasive options (such as phar macologic erection programs [PEPs] utilizing alprostadil intracavernosal injections [Caverject] or papaverine/phentolamine/alprostadil [Trimix]; transurethral penile suppositories of alprostadil [MUSE]; external penile suction devices; penile prostheses; and vascular surgery, e.g., endarterectomy versus drug-eluting [zotarolimus] pelvic vascular stents [investigational]) may be considered when clinically appropriate. Injectable gene therapies for ED, such as hMaxi-K, are still in early clinical trials.

Premature Ejaculation Currently , there is no FDA-approved treatments for premature ejaculation. The condition can be effectively treated with SSRIs (e.g., fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil]) or tricyclic antidepressants (e.g., clomipramine [Anafranil]). The newer, rapid-acting SSRI dapoxetine (Priligy) was developed specifically for premature ejaculation, but is not approved in the United States, although it is available in several countries abroad. On-demand tramadol (under re-development for premature ejaculation as brand name Zertane) has shown some efficacy, but it is limited by potential dependency due to its opioid properties. Several topical anesthetic agents are under investigation, including the lidocaine/prilocaine eutectic mixture (EMLA cream) and topical eutectic-like mixture for premature ejaculation (TEMPE or PSD 502). PDE-5 inhibitors should be tried first if premature ejaculation is secondary to ED.

Female Sexual Dysfunction In August 2015, flibanserin (Addyi), a serotonin mixed agonist/antagonist and dopamine agonist, became the first and only medication approved by the FDA for the treatment of female sexual dysfunction. Specifically, flibanserin can be prescribed for pre-menopausal women with hypo active sexual desire disorder (HSDD). It is noteworthy that HSDD in fact no longer exists in the DSM-5, although it most closely resembles FSIAD. The decision to approve flibanserin was controversial; some believe that it was based mainly on public concerns

about gender inequality in sexual medicine rather than sound scientific inquiry. The drug had been twice rejected and showed only a modest benefit in clinical trials (number of monthly satisfying sexual events increased by 0.5 to 1 compared to placebo). At the same time, flibanserin, which must be taken daily (similar to antidepressants) is associated with serious adverse effects, including a risk of severe hypotension and syncope when taken with alcohol. Flibanserin carries a boxed warning, and prescriber’s must obtain certification through a risk evaluation and mitigation strategy (REMS) program. Whether these measures will be sufficient to ensure potential benefits outweigh the risks remains uncertain. Other than flibanserin, the only other FDA-approved medication relevant to the treatment of female sexual dysfunction is ospemifene (Osphena). This drug is an oral selective estrogen receptor modulator indicated for post-menopausal dyspareunia secondary to vulvar and vaginal atrophy. Dyspareunia is no longer a diagnosis in the DSM-5, but it is in the spectrum of the new genito-pelvic pain/penetration disorder. An alternative to medication is the EROS-CTD clitoral therapy suction device, which has been FDA-approved since 2000 for the treatment of FSAD. Again, it is important to note that FSAD has also been eliminated from the DSM-5 but it most closely resembles FSIAD. Various other hormone replacement preparations have been tried in menopausal women with heightened vigilance due to links with cardiovascular disease and breast cancer demonstrated by the Women’s Health Initiative (WHI) studies. Transdermal/topical hormone replacement therapies include: estrogen/testosterone (Estratest), testosterone (LibiGel—Phase III trials, Intrinsa —rejected by the FDA), and prostaglandin E1 (alprostadil); however, these agents are of questionable benefit. Oral therapies include estrogen for vasomotor symptoms, novel steroid tibolone (rejected), and dehydroepiandosterone (DHEA) in women with adrenal insufficiency. In an important randomized-controlled clinical trial, sildenafil was shown to reduce adverse sexual effects in women taking SSRIs. Otherwise, many approved and investigational agents for ED (listed earlier) have been tried in women with variable success. Additional therapies under study for female sexual dysfunction include: intranasal oxytocin for improving sexual satisfaction, onabotulinum toxin A (Botox) injections for reducing vaginismus symptoms, and vaginal diazepam for decreasing sexual pain. Additionally, sacral neuromodulation (Interstim), currently used to treat overactive bladder, has been

shown in small studies to increase sexual desire, lubrication, orgasm, and satisfaction.

Psychologically Based Sexual Disorders General Principles If time is limited, another appointment should be scheduled to take a detailed sexual history and to initiate treatment. Discussions should be held while the patient is fully clothed, and not conducted in the examining room. The pelvic exam can be used to teach the female patient about sexual anatomy. Clinicians can use the PLISSIT model (Annon) to recall the levels of treatment: P (permission): Help reassure the patients regarding sexual activity. Alleviate guilt about activities that a patient feels is “bad” or “dirty.” Use statistics to reinforce the range of normal activities. LI (limited information): Provide information about anatomy and physiology. Correct myths and misconceptions. SS (specific suggestions): Apply behavioral techniques used in sex therapy. There are general principles and specific techniques for each of the sexual dysfunctions. IT (intensive therapy): Patients with chronic sexual problems and/or complex psychologic issues may not respond to the above and may benefit from consultation with a mental health professional, skilled in dealing with sexual problems.

Behavior Therapy (Sex Therapy)—General Principles Communication between partners (verbally and physically) can be improved, encouraging experimentation. The pressure to perform can be decreased by changing the goal of sexual activity away from erection or orgasm to feeling good about oneself. The pressure of the moment can be relieved by suggesting that there is always another day to try.

Behavior Therapy (Sex Therapy)—Specific Suggestions Male Hypoactive Sexual Desire Disorder and FSIAD Behavioral treatment can include initiation of sensate focus exercises (nondemand pleasuring techniques) to enhance enjoyment without pressure. Erotic materials can be used and masturbation training (with fantasy to help individuals become aware of conditions necessary for a positive sexual experience) can be

considered. When phobic/panic-type symptoms are displayed, the addition of antipanic medication (antianxiety or antidepressant) might be helpful. Female arousal symptoms usually require referral to a specialist. It is helpful to suggest the use of lubrication, such as saliva or KY jelly, for vaginal dryness. Post-menopausal women might benefit from topical estrogen cream, given intermittently.

Erectile Disorder “Sensate focus” exercises can be prescribed. Intercourse with this technique should be prohibited even if erection occurs. The female-superior position (female on top of male) can be prescribed to attempt non-demanding intercourse (heterosexual couple). The female manually stimulates the penis, and if erection is obtained, she inserts the penis into her vagina and gradual movement is begun. The patient can be educated about ways to satisfy his partner without penilevaginal intercourse. Drug therapy (medication, injection, suppository) can be beneficial to restore confidence while exploring psychological issues.

Female Orgasmic Disorder For women who have never had an orgasm, suggestions include selfstimulation, use of fantasy material, and Kegel vaginal exercises (contraction of pubococcygeus muscles). For the woman who is anorgastic with her partner, sensate focus exercises (from non-genital stimulation to genital stimulation) are recommended. In addition, a back-protected position (male in seated position with female between his legs with back against his chest), or controlled intercourse in the female-superior position can be used. If the woman is anorgastic during intercourse, the “bridge technique,” in which male stimulates the female’s clitoris manually after insertion of the penis into the vagina, can be used.

Delayed Ejaculation (During Intercourse) When delayed ejaculation is present, the female can stimulate the male manually until orgasm becomes inevitable. Then, the penis is inserted into the vagina and thrusting can begin. Manual stimulation is repeated if ejaculation does not occur.

Premature Ejaculation When premature ejaculation is present, suggest an increase in the frequency of sex. Teach the “squeeze” technique, in which the female manually stimulates the

penis. When ejaculation is approaching, as indicated by the male, the female squeezes the penis with her thumb on the frenulum. The pressure is applied until the male no longer feels the urge to ejaculate (15–60 seconds). Using the female superior position with gradual thrusting and the “squeeze” technique as excitement intensifies can be beneficial. The “stop–start” method is an alternative to the “squeeze” technique. The female stimulates the male to the point of ejaculation then stops the stimulation. She resumes the stimulation for several stop–start procedures, until ejaculation is allowed to occur.

Genito-Pelvic Pain/Penetration Disorder Treatment of any underlying gynecologic problem is the first step. Treatment of insufficient lubrication is as described earlier. For involuntary vaginal spasm, the female is encouraged to accept larger and larger objects into her vagina (e.g., her fingers, her partner’s fingers, Hegar graduated vaginal dilators, and syringe containers of different sizes). The use of the female-superior position (allowing the female to gradually insert the erect penis into the vagina) is recommended. Extra lubricant (KY jelly) should be used and Kegel vaginal exercises (to develop a sense of control) can be practiced.

Evaluation of the Problem—Paraphilic Disorders General Recommendations Paraphilic disorders are defined as recurrent, intense, sexually arousing fantasies, sexual urges, or behaviors, involving non-human objects, or the suffering or humiliation of oneself or one’s partner, children, or other nonconsenting persons that occur over a period of at least 6 months (Table 23-8). The diagnosis should be made only if the individual has acted on the urges and is markedly distressed by them or the behaviors cause harm to others. Some individuals might always need paraphiliac fantasies for erotic arousal. Some individuals have paraphiliac preferences only during periods of stress. Paraphilic disorders almost always occur in males. Older terms “perversion” and “sexual deviation” are now considered antiquated. Paraphilic disorders can have legal and societal significance because they might involve non-consenting partners. A strong association exists between paraphilia and childhood atte ntion deficit hyperactivity disorder (ADHD) as well as substance abuse (64%), major depression or dysthymia (39%), and phobic disorder (42%). Table 23-8: Diagnostic Criteria of Specific Paraphilic Disorders

Disorder Definition

Features

Exhibitionistic Exposure of genitals to unsuspecting strangers in disorder public.

Primary intent is to evoke shock or fear in victims. Offenders are usually male.

Fetishistic disorder

Sexual arousal using non-living objects (e.g., female Masturbation occurs while holding the fetish object. lingerie) or intense focus on a non-genital body part. The sexual partner may wear the object.

Frotteuristic disorder

Sexual arousal by touching and rubbing against a non-consenting person.

The behavior occurs in a crowded public place from which the offender can escape arrest.

Pedophilic disorder

Sexual activity with a prepubescent child. The patient must be at least 16 years of age and be at least 5 years older than the victim.

Pedophilia is the most common paraphilic disorder. Most of the victims are girls, often relatives. Most pedophiles are heterosexual.

Sexual masochism disorder

Sexual pleasure comes from physical or mental abuse or humiliation.

A dangerous form is hypoxyphilia, in which oxygen deprivation enhances arousal, and accidental deaths can occur.

Sexual sadism Sexual arousal is derived from causing mental or disorder physical suffering to another person.

Sexual sadism is mostly seen in men. It can progress to rape. Fifty percent of those afflicted are alcoholic.

Transvestic disorder

Cross-dressing in heterosexual males for sexual arousal.

The wife (partner) may be aware of the activity and help in the selection of clothes or insist on treatment.

Voyeuristic disorder

Sexual arousal by watching an unsuspecting person who is naked, disrobing, or engaging in sexual activity.

Most commonly occurs in men, but it can occur in women. Masturbation commonly occurs.

Other specified paraphilic disorder

Paraphilic disorders that do not meet criteria for any Categories include: necrophilia (corpses), zoophilia of the above categories. (animals), urophilia (urine), and coprophilia (feces).

Unspecified paraphilic disorder

Paraphilic disorders that do not meet criteria for any Clinician chooses not specify the reason that criteria of the above categories. are not met. Insufficient diagnostic information.

Medical History Most paraphilic disorders are thought to have a psychological basis. Individuals with these disorders have difficulty forming more socialized sexual relationships. Paraphilic disorders can involve a conditioned response in which non-sexual objects become sexually arousing when paired with a pleasurable activity (e.g., masturbation). A medical evaluation should be completed to ruleout endocrine and neurologic etiologies as well as reactions to medications, to drug use, or to drug abuse. An organic diagnosis underlying a paraphilic disorder should be suspected when: the behavior begins in middle age or later; there is regression from a previously normal sexuality; there is excessive aggression; there are reports of auras or seizure-like symptoms prior to, or during, the sexual

behavior; there is an abnormal body habitus; or there is an abnormal neurologic exam.

Sexual History Most people with paraphilic disorders will not spontaneously reveal their behavior and are very secretive about their sexual activities, in part because of the illegal nature of the behavior and the impact of the behavior on close relationships. Individuals with paraphilic disorders might first come to the attention of others after their arrest by police. A variety of interview techniques exist. Screening questions that will not sound judgmental (e.g., “When you want to be sexual, do you engage in sexual activity that other people find unusual?”) should be used. Clinicians should try to appreciate the patient’s shame and embarrassment when discussing atypical sexual behavior and alert the patient of legal reporting requirements if sexual behavior is harmful or illegal (children in need of protection). If the sexual behavior is not illegal or harmful, the patient’s confidentiality should be assured. When one form of atypical sexual behavior is found, it is appropriate to ask about others.

Examination of the Patient An appropriate physical and laboratory examination (see the section “Medical History, Organic Screen”) should be performed. Penile plethysmography is used to assess paraphilic disorders by measuring an individual’s sexual arousal in response to visual and auditory stimuli.

Psychiatric Differential Diagnosis of Paraphilic Disorders The differential diagnosis includes: intellectual disability, dementia, substance intoxication, manic episodes (bipolar disorder), schizophrenia, OCD, gender dysphoria, personality disorder, sexual dysfunction, and hypersexuality/sexual addiction. Clinicians should also distinguish between paraphilic behaviors and non-paraphilic compulsive sexual acts, such as compulsive use of erotic videos, magazines, and cybersex; uncontrolled masturbation; unrestrained use of prostitutes; and numerous brief, superficial sexual affairs.

Diagnostic Criteria Disorders listed (Table 23-8) can begin in childhood or early adolescence and become better defined during adolescence or adulthood. The disorders are chronic and life-long, but fantasies and behaviors often diminish with advancing

age. The behaviors increase in response to psychosocial stress, other mental disorders, and an increased opportunity to engage in the paraphilia.

Treatment Strategies General Considerations People with paraphilic disorders rarely seek treatment, unless forced by their arrest or their discovery by a family member. The paraphilia produces intense pleasure and is difficult to give up; it is like an addiction or compulsion. Paraphilics in therapy often try to convince therapists that their behavior has stopped, when it continues. Treatment outcome for paraphilic disorders is poor, and recidivism is high. Active monitoring is required.

Specific Techniques Psychotherapy Insight-oriented and/or supportive psychotherapy can be attempted but is, in general, relatively ineffective.

Behavior Therapy Aversive therapy is used to reduce the behavior by conditioning. Desensitization is used to neutralize anxiety of non-paraphilic sexual situations by gradual exposure. Social skills training (individual or group) is used to help form better interpersonal relationships. Orgasmic reconditioning is used to teach the paraphilic to become aroused by more acceptable mental imagery.

Medications Anti-androgen drugs (e.g., intramuscular medroxyprogesterone acetate [MPA] and cyproterone acetate [not FDA-approved]) lower testosterone levels by competitive inhibition of androgen receptors, resulting in a decrease of aberrant sexual tendencies. Intramuscular injections of synthetic gonadotropin-releasing hormone analogues (approved for treatment of prostatic cancer), including leuprorelin (Prostap), triptorelin (Trelstar), and goserelin (Zoladex), decrease testosterone to castrate level (after an initial transient increase) and can completely abolish deviant sexual tendencies. Use of oral estrogen (ethinyl estradiol) has a lower success rate. Antidepressant drugs (such as the tricyclic antidepressant clomipramine as well as SSRIs, including fluoxetine, sertraline, and fluvoxamine), can lower aberrant

sexual urges by decreasing compulsivity/impulsivity of the act. Paraphilic disorders often co-exist with ADHD, and adding psychostimulants (such as methyphenidate sustained-release [SR] [Ritalin-SR]) to SSRIs has shown benefit in controlling paraphilic behaviors.

Evaluation of the Problem—Gender Dysphoria General Recommendations Gender dysphoria refers to intense personal conflict between one’s assigned gender and one’s gender association, causing significant distress or impaired function that lasts at least 6 months. It replaces the older term, “gender identity disorder,” with several important distinctions. First, the DSM-5 prefers the term “gender,” one’s public role as man or woman, to “sex,” which is grounded in biological factors and can be ambiguous. Second, the DSM-5 abandons the use of “cross-gender,” allowing the possibility of “alternative” gender to male or female. Finally, the DSM-5 distinguishes between gender “identification,” one’s personal gender preference, from “dysphoria,” the distress that can accompany a conflict in assigned gender. Gender dysphoria can manifest in childhood, adolescence, or adulthood. Although it can occur in either natal gender, it is more common among biological males than among biological females. Sexual orientation is independent of gender identification; for example, a man who identifies as a woman may express a sexual preference for men, women, or both. Adolescents and adults with gender dysphoria are more likely to contemplate, attempt, or complete a suicide.

Medical History A variety of factors in the medical history are important in assessing gender dysphoria. Disorders of sexual development, beginning in childhood, are highly associated with behaviors considered atypical for one’s assigned gender. Nevertheless, most individuals with abnormal sexual development do not endorse gender dysphoria. In later life, they might express gender confusion rather than clear identification with another gender. The risk of gender dysphoria associated with abnormal sexual development is greater if pre-natal androgen exposure is markedly elevated. Such an increase can occur when sex steroid synthesis pathways are disrupted, as in the case of congenital adrenal hyperplasia or 5-alpha reductase-2 deficiency. Genetics unrelated to sex steroids may also play a role in gender dysphoria; weak evidence suggests a heritable component of the disorder in familial and twin studies. Endocrine abnormalities can be

important; for example, some 46,XX women who identify as men have increased androgen levels (although below that of typical males). Pertinent environmental factors include having an older sibling of the preferred gender and concurrent social, psychological, or developmental difficulties. Even in the absence of other apparent contributing features, individuals who persistently prefer gender-atypical behaviors in childhood might be more likely to develop gender dysphoria in later life.

Sexual History Gender dysphoria can present at any age from the pre-school years to adult life, and clinicians must tailor the sexual history accordingly. In very young children (ages 2–4 years), pertinent history includes a persistent preference for genderatypical activities or an expressed wish to be of a different gender. Declaration that one firmly identifies with another gender is unusual. Older children approaching puberty might voice distress over their assigned sexual anatomy or preference for different genitalia, concerns that become central in adolescents and adults. Gender dysphoria can be present and persistent since childhood (early-onset form), or arise only post-puberty or in adulthood (late-onset form). Late-onset dysphoria is associated with frequent transvestic experimentation; this might lead to sexual arousal associated with the experience of becoming another gender. Sexual orientation is an important area of inquiry but does not necessarily correlate with one’s gender identification. Gender dysphoria and gender-incongruent behaviors remain highly stigmatized, and thus clinicians must take utmost care to conduct a non-judgmental interview.

Examination of the Patient As with other sexual disorders, an appropriate physical and laboratory examination (see the section “Medical History, Organic Screen”) should be performed. Of particular interest are sexual developmental, anatomic, genetic, and endocrinologic factors that can contribute to gender dysphoria. However, most patients with gender dysphoria have normal physical and laboratory findings.

Psychiatric Differential Diagnosis of Gender Dysphoria The differential diagnosis includes: non-conformity to stereotypical gender roles, transvestic disorder (“cross-dressing”), body dysmorphic disorder (e.g.,

desire to remove or alter a body part due to intense dislike rather than gender preference), and schizophrenia/psychosis (e.g., delusion that one belongs to another gender). Additionally, some individuals might desire gender reassignment for aesthetic or other reasons that are not diagnostic of gender dysphoria. Moreover, other mental health disorders, such as depression, anxiety, and substance abuse, frequently co-exist with or occur secondary to gender dysphoria. In such cases, the underlying gender dysphoria could be overlooked if there is reluctance by the patient or the provider to discuss it.

Diagnostic Criteria The DSM-5 sub-classifies gender dysphoria into disorders affecting children and disorders affecting adolescents and adults. Associated clinically significant distress or functional impairment of at least 6 months duration is required for all diagnoses.

Gender Dysphoria in Children (ICD-9 302.6; ICD-10 F64.2) Children with gender dysphoria express a strong desire to be of the opposite (or another) gender, or insist that they are of that gender. Gender-atypical behaviors are common. These range from strong preference for playmates and toys typical of the opposite gender to cross-gender roles in fantasy play and cross-dressing. Separation anxiety, generalized anxiety, and depression are frequent comorbidities. Children born males are 2 to 4.5 times more likely to develop gender dysphoria than are children born females.

Gender Dysphoria in Adolescents and Adults (ICD-9 302.85; F64.1) In contrast to the childhood form, gender dysphoria in adolescents and adults is grounded in marked conflict between one’s assigned and one’s expressed gender, rather than gender-atypical behavior. This includes a desire to rid oneself of assigned secondary sexual characteristics in favor of another gender’s features. Adolescents and adults with gender dysphoria also firmly believe that their experience of the world is consistent with an alternative gender and that they should be treated as such. In adolescence, gender dysphoria is equally common among gender-assigned males and females. In adults, the disorder is more common among gender-assigned males. Overall, up to approximately 1 in 10,000 natal males and 3 in 100,000 natal females present with the disorder. However, these statistics, which are based on gender reassignment data, are likely to under-estimate the true prevalence. Homosexual or bisexual orientation,

paraphilias, anxiety, depression, and suicidal thoughts or actions are frequent associations.

Other Specified (ICD-9 302.6; F64.8) and Unspecified Gender Dysphoria (ICD-9 302.6; ICD-10 F64.8) These disorders are characterized by symptoms of gender dysphoria that result in clinically significant distress but do not satisfy full criteria. The “other specified” label can be used to indicate the reason full criteria are not met, such as symptom duration under 6 months. The “unspecified” diagnosis might be made if the clinician chooses not to indicate the reason or there is insufficient information.

Treatment Strategies General Considerations Treatment for gender dysphoria is multi-faceted. A frequently cited resource is the Standards of Care for the Health of Transsexual, Transgender, and GenderNonconforming People, Version 7 (SOC-7) by Coleman and colleagues (2011). Gender-confirming surgery, formerly known as sex reassignment surgery (SRS), is the major treatment. A variety of hormonal therapies are also used to suppress secondary sexual characteristics. In addition, current clinical guidelines also emphasize the need to obtain real-life experience (RLE) in the preferred gender role for a period of at least 1 year prior to being considered for SRS. Finally, psychotherapy helps to clarify and confirm the patient’s wishes, assess the presence of co-existing mental health problems, and provide support for a potentially difficult social adjustment. Treatments are in evolution as the population of gender dysphoric patients becomes more diverse and societal emphasis on self-determination and autonomy continues to grow.

Specific Techniques Therapy Psychotherapy and counseling are important components of the management of gender dysphoria. Establishing a firm diagnosis and exploring co-existing and alternative mental health disorders are paramount. Gender-altering therapies, such as SRS, are now known to be associated with significant rates of regret and subsequent psychological problems. Thus, it is critical to clarify the patient’s thought process and ensure an informed decision. After gender reassignment is

medically completed, psychotherapy plays a key role in assisting with the public transition to the new gender role. Stigmatization and discrimination remain highly prevalent among the transgendered, who must cope with strained relationships, employer unrest, and even mental and physical violence. Therapy to encourage individuals to accept and find comfort in their birth-assigned gender role is no longer considered appropriate, ethical, or useful. However, as risk factors for regret after SRS, such as significant co-existing mental health disorders, are also being recognized, some argue that such counseling might not be absolutely out of the question in all circumstances.

Medication and Surgery A variety of hormonal medications such as luteinizing hormone-releasing hormone (LH-RH) agonists, gonadotropin-releasing hormone agonists (GnRH), spironolactone, cyproterone acetate (CPA) [not available in the United States], estrogen, and testosterone can be used to suppress secondary sexual characteristics. There are significant risks to such agents, including cardiovascular disease, thromboembolic complications, and osteoporosis. However, in general, hormonal therapy is associated with significantly improved psychological symptoms and quality of life in adults with gender dysphoria. Indeed, many will seek out hormonal agents without prescription or supervision. In fact, some studies even indicate that gender dysphoric adults who obtain hormonal medication without psychiatric guidance achieve more quickly the same level of psychological benefit compared to those who pursue professional channels. Gender-confirming surgery includes such operations as reduction mammoplasty, vaginoplasty, and phalloplasty. Although most adults with gender dysphoria express subjectively improved satisfaction after such procedures, psychological symptoms as measured by objective scoring systems overall do not significantly change. The eligibility criteria for SRS and age at which the procedures may ethically be pursued are controversial areas that continue to evolve with time.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013.

2. Basson R, Schultz WW: Sexual sequelae of general medical disorders. Lancet . 2007; 369(9559): 409–424. 3. Basson R: Sexual desire and arousal disorders in women. N Engl J Med . 2006; 354(14): 1497–1506. 4. Beech AR, Miner MH, Thornton D: Paraphilias in the DSM-5. Annu Rev Clin Psychol . 2016; 12: 383–406. 5. Campbell N, Clark JP, Stecher VJ, et al: Adulteration of purported herbal and natural sexual performance enhancement dietary supplements with synthetic phosphodiesterase type 5 inhibitors. J Sex Med . 2013; 10(7): 1842–1849. 6. Clayton AH, Harsh V: Sexual function across aging. Curr Psychiatry Rep . 2016; 18(3): 28. 7. Coleman E, Bockting W, Botzer M, et al: Standards of care for the health of transsexual, transgender, and gender-nonconforming people, version 7. Int J Transgend . 2011; 13: 165–232. 8. Corona G, Rastrelli G, Burri A, et al: The safety and efficacy of Avanafil, a new 2(nd) generation PDE5i: comprehensive review and meta-analysis. Expert Opin Drug Saf . 2016; 15(2): 237–247. 9. Dording CM, Schettler PJ, Dalton ED, et al: A double-blind placebocontrolled trial of maca root as treatment for antidepressant-induced sexual dysfunction in women. Evid Based Complement Alternat Med . 2015; 949036. 10. Esposito K, Giugliano D: Lifestyle/dietary recommendations for erectile dysfunction and female sexual dysfunction. Urol Clin North Am . 2011; 38(3): 293–301. 11. Fava M, Rankin M: Sexual functioning and SSRIs. J Clin Psychiatry . 2002; 63(Suppl 5): 13–16. 12. Feldman HA, Goldstein I, Hatzichristou DG, et al: Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol . 1994; 151(1): 54–61. 13. Gandaglia G, Briganti A, Montorsi P, et al: Diagnostic and therapeutic implications of erectile dysfunction in patients with cardiovascular disease. Eur Urol . 2016; 70(2): 219-222. 14. Gao L, Yang L, Qian S, et al: Systematic review and meta-analysis of

phosphodiesterase type 5 inhibitors for the treatment of female sexual dysfunction. Int J Gynaecol Obstet . 2015; 133(2): 139-145. 15. Goldstein I, Lue TF, Padma-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med . 1998; 338(20): 1397–1404. 16. Gooren LJ: Clinical practice. Care of transsexual persons. N Engl J Med . 2011; 364(13): 1251–1257. 17. Houman J, Feng T, Eilber KS, et al: Female sexual dysfunction: Is it a treatable disease? Curr Urol Rep . 2016; 17(4): 28. 18. Jordan R, Hallam TJ, Molinoff P, et al: Developing treatments for female sexual dysfunction. Clin Pharmacol Ther . 2011; 89(1): 137–141. 19. Kafka MP: Hypersexual disorder: a proposed diagnosis for DSM-V. Arch Sex Behav . 2010; 39(2): 377–400. 20. Kafka M: Psychopharmacologic treatments for non-paraphiliac compulsive sexual behaviors. CNS Spectr . 2000; 5(1): 49–59. 21. Kaplan HS: The Sexual Desire Disorders: Dysfunctional Regulation of Sexual Motivation . New York: Brunner/Mazel; 2013. 22. La Torre A, Giupponi G, Duffy D, et al: Sexual dysfunction related to psychotropic drugs: a critical review--part I: antidepressants. Pharmacopsychiatry . 2013; 46(5): 191–199. 23. La Torre A, Conca A, Duffy D, et al: Sexual dysfunction related to psychotropic drugs: a critical review part II: antipsychotics. Pharmacopsychiatry . 2013; 46(6): 201–208. 24. La Torre A, Giupponi G, Duffy DM, et al: Sexual dysfunction related to psychotropic drugs: a critical review. Part III: mood stabilizers and anxiolytic drugs. Pharmacopsychiatry . 2014 Jan; 47(1): 1–6. 25. La Torre A, Giupponi G, Duffy D, et al: Sexual dysfunction related to drugs: a critical review. Part IV: cardiovascular drugs. Pharmacopsychiatry . 2015; 48(1): 1–6. 26. Laumann EO, Paik A, Rosen RC: Sexual dysfunction in the United States: prevalence and predictors. JAMA . 1999; 281(6): 537–544. 27. Lue TF: Erectile dysfunction: N Engl J Med . 2000; 342(24): 1802–1813. 28. Maurice W: Sexual Medicine in Primary Care . New York: Mosby; 1999.

29. McMahon CC: Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol . 2012; 4(5): 233–251. 30. McNamara ER, Donatucci CF: Newer phosphodiesterase inhibitors: comparison with established agents. Urol Clin North Am . 2011; 38(2): 155–163. 31. Nurnberg HG, Hensley PL, Heiman JR, et al: Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial. JAMA . 2008; 300(4): 395–404. 32. Robinson K, Cutler JB, Carris NW: First pharmacological therapy for hypoactive sexual desire disorder in pre-menopausal women: flibanserin. Ann Pharmacother . 2016; 50(2): 125–132. 33. Rosler A, Witztum E: Treatment of men with paraphilia with a long-acting analogue of gonadotropin-releasing hormone. N Engl J Med . 1998; 338(7): 416–422. 34. Shafer LC: Approach to the patient with impotence. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw Hill; 2004: pp. 405–412. 35. Shafer LC: Approach to the patient with sexual dysfunction. In: Goroll AH, Mulley AG, eds.: Primary Care Medicine . 7th ed. Philadelphia, PA: Wolters Kluwer Health; 2014: 1501–1508. 36. Shafer LC: Approach to the patient with sexual dysfunction. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw Hill; 2004: pp. 393–404. 37. Shafer LC: Sexual disorders and sexual dysfunction. In: Stern TA, Fava M, Wilens TE, et al: eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby/Elsevier; 2016: pp. 394–402. 38. Shafer LC: Sexual disorders and sexual dysfunction. In: Stern TA, Freudenreich O, Smith FA, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 7th ed. Philadelphia, PA: Elsevier; 2018: 279–290. 39. Shafer LC: Sexual dysfunction. In: Carlson K, Eisenstat S, eds.: Primary Care of Women . 2nd ed. St. Louis, MO: Mosby; 2002: pp. 415–420.

40. Shifren JL, Braunskin GD, Simon JA, et al: Transdermal testosterone in women with impaired sexual function after oophorectomy. N Engl J Med . 2000; 343(10): 682–688. 41. Shifren JL, Monz BU, Russo PA, et al: Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol . 2008; 112(5): 970–978. 42. Snyder PJ, Bhasin S, Cunningham GR, et al: Effects of testosterone in older men. N Engl J Med . 2016; 374(7): 611–624. 43. Thompson IM, Tangen CM, Goodman PJ, et al: Erectile dysfunction and subsequent cardiovascular disease. JAMA . 2005; 294(23): 2996–3002. 44. Torre AL, Giupponi G, Duffy D, et al: Sexual dysfunction related to drugs: a critical review. Part V: α-blocker and 5-ARI drugs. Pharmacopsychiatry . 2015; 49(1): 3–13. 45. West SL, D’Aloisio AA, Agans RP, et al: Prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women. Arch Intern Med . 2008; 168(13): 1441–1449. 46. Wincze JP, Weisberg RB: Sexual Dysfunction . 3rd ed. New York: Guilford Press, 2015. 47. Yue FG, Dong L, Hu TT, Qu XY: Efficacy of dapoxetine for the treatment of premature ejaculation: a meta-analysis of randomized clinical trials on intravaginal ejaculatory latency time, patient-reported outcomes, and adverse events. Urology . 2015: 85(4) :856–861. 48. Zucker KJ, Lawrence AA, Kreukels BP: Gender dysphoria in adults. Annu Rev Clin Psychol . 2016; 12: 217-247.

CHAPTER 24

Eating Disorders LAZARO V. ZAYAS, MD; JENNIFER J. THOMAS, PHD; AND ANNE E. BECKER, MD, PHD, SM

KEY POINTS Overview Eating disorders are characterized by a disturbance in eating (e.g., avoidant, restrictive, binge-pattern eating). Both anorexia nervosa (AN) and bulimia nervosa (BN) are also associated with body image disturbance that is frequently manifest in behaviors impacting weight. In contrast, only a subset of individuals with binge-eating disorder (BED) exhibit body image disturbance, and those with avoidant/restrictive food intake disorder (ARFID) avoid food for reasons other than shape and weight concerns. Individuals with pica consume non-food items, and those with rumination disorder engage in persistent post-prandial regurgitation. Other specified feeding or eating disorders (OSFED) comprise a heterogeneous residual diagnostic category, including sub-threshold versions of AN, BN, and BED, and related presentations. Etiology The etiology of eating disorders appears to be multi-factorial, with biological, psychological, and social contribution to risk. Course Longitudinal studies support that many, if not majority, individuals with eating disorders will ultimately recover. In one epidemiological study of a Finnish twin cohort, five-year recovery rates were 69% for DSM-5 AN and 55% for DSM-5 BN. In a United States study that followed women with AN and BN longitudinally for 22 years, approximately two-thirds had recovered by study completion. Less is known about naturalistic course and outcome in BED because most

long-term follow-up data comes from treatment-seeking samples. However, not all individuals with eating disorders have a good outcome. Mortality in AN is among the highest of any psychiatric disorder; in a recent meta-analysis, individuals with AN (whether treatment-seeking or not) were 5.2 times more likely to die of any cause, in comparison to sex- and agematched controls.

Epidemiology of Eating Disorders Prevalence AN is the rarest eating disorder , with a 12-month prevalence of just 0.4% among young females. BN is slightly more common, with a 12-month prevalence of 1.0% to 1.5% among young females. BED , with a 12-month prevalence of 1.6% in women and 0.8% in men, is more prevalent than AN and BN combined. In addition, the prevalence of clinically significant partial syndromes or atypical eating disorders (OSFED) is difficult to estimate due to differing definitions of the category across studies. However, available data suggests that such presentations are more common than AN, BN, and BED combined.

Demographics Although AN and BN typically affect young adult females, BED is only slightly more common in females than males.

Onset The onset of AN is typically slightly earlier than the onset of BN. Although both generally begin during adolescence, they can also occur at much younger and older ages. Onset of BED tends to be slightly later, generally beginning in adulthood.

Sociocultural Factors Eating disorders affect individuals of diverse ethnic and socioeconomic backgrounds. Eating disorders have been reported all over the globe, but available data suggests that they are more prevalent in populations with Western cultural traditions and in industrialized societies. Several epidemiologic studies have also linked risk to immigration, modernization, and urbanization.

Diagnostic Features Diagnostic and Statistical Manual of Mental Disorders (DSM)–based diagnostic criteria for the eating disorders have undergone a substantial revision since the last edition of this book, with the publication of the American Psychiatric Association’s fifth edition (DSM-5) in 2013. These revisions comprised several notable changes. First, the eating disorders category was combined with the “feeding disorders of infancy and childhood” category into “feeding and eating disorders.” This reorganization underscored conceptual similarities among these disorders as well as the possibility of continuity of the feeding disorders across the life-span. Second, the previous diagnostic category in DSM-IV, “feeding disorder of infancy or early childhood,” was reformulated as ARFID in DSM-5. Although this chapter focuses on the eating disorders, it is helpful for clinicians to know that ARFID can share some phenomenologic features with AN (discussed momentarily). Under the previous diagnostic criteria, more than half of individuals presenting for treatment fell into the residual category (previously termed “ eating disorder, not otherwise specified,” or EDNOS), for which there was little clinical trial data available to guide evidence-based treatment. Third, specifiers for current severity and partial and full remission have been added to DSM-5. Revisions to diagnostic criteria for AN and BN resulted in the reassignment of some presentations from the residual category to full-syndrome disorders, thus reducing the proportion of individuals with a presentation previously classified within this category. In addition, BED is now formally recognized as an eating disorder. Finally, several presentations that do not meet full criteria for specific feeding or eating disorders but are nonetheless increasingly well-described or prevalent, are given as examples in the new residual category, OSFED. These presentations encompass purging disorder, night-eating syndrome, and others that do not reach frequency or other threshold criteria. Although these presentations are not operationalized with formal criteria, their clear descriptive characterization in DSM-5 will likely promote their standardization, which in turn might accelerate empirical studies that can further elucidate their presentation and course.

Anorexia Nervosa AN is primarily characterized by an eating disturbance that results in restricted intake (compared with energy requirements to maintain a healthy body weight) and a clinically significant low weight in association with a disturbance in body

image. Another key diagnostic feature is a fear of weight gain or fatness (sometimes termed “fat phobia”) that is inappropriate in light of both individual clinical features and social norms. AN criterion B has been modified in DSM-5 to encompass presentations with persistent engagement in behaviors that result in inappropriate weight loss or prevent weight gain even when individuals do not disclose or admit to fear of weight gain. This latter change means that clinicians can draw inferences from observational data and collateral clinical history. A diagnosis of AN also requires evidence of a body image disturbance, which can manifest in a variety of ways (e.g., persistent feelings of fatness despite low weight, or not appreciating that the low weight threatens health). Finally, the former DSM-IV AN criterion D, requiring amenorrhea for a diagnosis in postmenarcheal females, has been eliminated. AN is divided into two sub-types: restricting type (in which there is food restriction, fasting, or excessive exercise, but no recurrent bingeing and/or purging in the past three months), and bingeeating/purging type (in which there is recurrent bingeing and purging over the past three months).

Bulimia Nervosa BN is characterized by binge-eating episodes associated with inappropriate compensatory behaviors that recur frequently over a period of three months or more. The frequency criterion for these linked episodes has been adjusted downward to at least once weekly. Binge-eating episodes require the consumption of a very large amount of food in a relatively short period, and are associated with perceived loss of control. For example, experiencing the overeating as unpreventable or unstoppable would meet the clinical understanding of loss of control. Compensatory behaviors often involve purging, such as vomiting or laxative misuse, but also encompass a broad range of other behaviors intended to neutralize the impact of a binge on weight. These behaviors encompass selfinduced vomiting; misuse of laxatives, diuretics, prescription medication (such as stimulants or insulin), or over-the-counter diet pills, nutraceuticals, and other supplements; restrictive pattern eating (e.g., meal-skipping or fasting); driven excessive exercise; or any combination of these. Another core feature of BN is the linkage of shape or weight to perceived self-worth. If the features of BN are all present, and the patient is also very low weight, the appropriate diagnosis is AN (binge-eating/purging type).

Binge-Eating Disorder BED is also characterized by recurrent and frequent binge eating but these

episodes occur in the absence of accompanying inappropriate compensatory behaviors. With respect to the dimensions of amount of food, a discrete time period, and perceived loss of control, binge-eating episodes are defined in a similar way in both BN and BED. For BED, however, the binge eating must also be associated with pronounced distress and with at least three additional features for an individual to meet diagnostic criteria; these latter include eating abnormally quickly, eating to the point of uncomfortable fullness, eating large amounts in the absence of hunger, eating alone because of shame, and feeling sad or self-reproachful after a binge.

Other Specified Feeding and Eating Disorder OSFED comprises a residual category for related presentations associated with impairment or distress. These include presentations that substantially align with BN or BED but do not meet threshold frequency or duration criteria (i.e., BN of low frequency and/or limited duration and binge-eating disorder of low frequency and/or limited duration). Also included is atypical AN, which has all the features of AN, including marked weight loss, but the individual is not underweight. The DSM-5 also includes purging disorder and night-eating syndrome among their non-exhaustive list of examples. The label unspecified feeding or eating disorder (UFED ) also encompasses related presentations not meeting full syndrome criteria, but it is used when a clinician decides not to specify why these criteria are not met.

Differential Diagnosis Among the Eating and Feeding Disorders Despite important distinctions , some signs and symptoms of eating disorders can overlap across categories (e.g., binge eating can occur in context of AN, BN, and BED; purging, which is intrinsic to the diagnosis of BN, also occurs frequently among individuals with AN). Individuals with an eating disorder sometimes cross over from one diagnostic category to another, typically with behaviors moving from restricting to binge eating and/or purging presentations over time. In some cases, as individuals with AN and BN recover and meet criteria for partial remission, their presentation can overlap with another eating disorder, so clinicians should seek to integrate information about longitudinal course into the diagnostic assessment. Because treatment approaches differ across eating disorders, it is essential to clarify the specific eating disorder diagnosis to optimize clinical management. Although a detailed discussion of the feeding disorders pica, rumination disorder, and ARFID is beyond the scope of this chapter, clinicians should understand that these disorders can occur across

the life course and be associated with serious morbidity. Like AN, ARFID can be associated with restrictive eating, weight loss, or failure to grow as expected, but is distinguished by an absence of associated body image disturbance. DSM-5 employs a trumping system such that individuals can meet criteria for only one of the eating disorder diagnoses at any given time, with the exception of pica, which can co-occur with the other eating disorders if the associated symptoms are clinically significant enough to warrant additional intervention. Under this framework, a diagnosis of AN supersedes a diagnosis of ARFID or BN and a BN diagnosis supersedes a BED diagnosis. In addition, a feeding or eating disorder diagnosis would pre-empt an additional diagnosis of OSFED or UFED.

Evaluation and Differential Diagnosis Evaluation of the patient with a known or suspected eating disorder should comprise well-integrated medical, nutritional, and psychiatric assessments. Because individuals with eating disorders are often reluctant to seek treatment or to disclose their symptoms, their illness might go undetected for years, even in clinical settings. It is also common for some individuals to deny or actively conceal their symptoms, making the diagnostic process especially challenging. Therefore, when appropriate and feasible, available clinical observational data should be used and additional corroborating relevant information should be sought from current and prior health-care providers and from family members or other caregivers. Medical and other treatment records should be requested prior to the initial evaluation when relevant and possible, and permission for both recent and present health-care providers to communicate with one another about diagnostic assessment and case management should be established at the initial visit, if not prior to it. After a care team is established, its members should communicate at the onset of treatment to coordinate a care plan with specifics about who will follow key clinical parameters (e.g., weights), how often they will be checked, and how this information will be conveyed to the team. Communication among team members should be ongoing throughout treatment with sufficient frequency to aggregate and integrate clinical data relevant to clinical progress or deterioration and to adjust the plan as needed to ensure the patient’s safety and progress toward treatment goals.

Medical Evaluation Medical evaluation of a patient with an eating disorder centers on identification and assessment of any complications relating to underweight, overweight, rapid

weight loss, nutritional deficiencies, and behaviors aimed at weight management (e.g., purging, laxative, diuretic, nutraceutical use, stimulant or other prescription drug misuse, and/or excessive exercise). This assessment should also exclude any medical causes of appetite or weight change (e.g., thyroid disease) by medical history, physical examination, and laboratory analysis. Medical history should include a thorough review of systems, a history of weight fluctuations—including lowest and highest weights at current height— and an inventory of dietary patterns, purging behaviors, and exercise (see below). Assessment of individuals with suspected or known AN, BN, or OSFED should include specific questions in the review of systems that identify signs and symptoms associated with potential common and serious medical complications of weight loss, nutritional deficiencies, dehydration, excessive exercise, and purging (e.g., fatigue, postural and non-postural lightheadedness, palpitations, cognitive changes, peripheral neuropathy, dental caries, abdominal pain, bloating, nausea, constipation, hematemesis, delayed age of menarche, amenorrhea, oligomenorrhea, infertility, intolerance of cold temperature, hair loss, dry skin, bone fractures). Assessment of individuals with obesity associated with BED should likewise include questions about potential medical complications of obesity (including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, degenerative joint disease, and sleep apnea) to guide coordination of medical management. Current medications should be reviewed for possible contributions to appetite or weight changes as well as possible contraindications in the setting of an eating disorder. Past medical, social, substance use, and family history pertinent to moderation of the associated medical complications and risks—as well as to guide pharmacologic management, if appropriate—should be carefully reviewed. Physical examination should include measurement of height and weight, vital signs, and evaluation of potential medical complications of nutritional deficits, weight changes, purging, and/or inappropriate behaviors to control weight. Clinicians should be aware that an individual with BN will commonly have an unremarkable physical and laboratory examination, even though serious medical complications are also possible. Although individuals with BED will frequently be overweight or obese, some will not; either way their physical and laboratory examination could otherwise be unremarkable. Individuals with AN will be

underweight by definition; depending on the severity of weight loss or undernutrition, their physical and laboratory examination might not yield clinically significant findings in the early stages of the illness. This is to say that an unremarkable physical and laboratory examination would be insufficient to screen for or rule-out these disorders. Clinicians should keep in mind that eating disorders—especially AN and BN—can result in serious and even lifethreatening medical complications. Patients with an eating disorder should be weighed and measured on initial evaluation; for patients with AN, weights should be routinely monitored throughout treatment to evaluate medical risk and safety, response to treatment, and need for adjustment in care management. Clinicians should be sensitive to the discomfort individuals with an eating disorder might experience when being weighed, but should avoid estimating—rather than measuring—weight to ensure accurate assessments that can be used both to guide clinical intervention and assess interval change. Moreover, individuals with AN commonly endeavor to disguise their weight by wearing bulky or layered clothing. Ideally, weight should be measured in a location that allows for patient privacy. Blood pressure, pulse, and temperature should be evaluated initially and at regular intervals appropriate to the level of nutritional or medical compromise and/or severity of symptoms. Hypotension, bradycardia, and hypothermia are potential complications of AN, and individuals with both AN and BN can be markedly orthostatic in the setting of fluid restriction, purging, and/or nutritional compromise. Assessment of individuals with AN should include a thorough physical examination for abnormalities associated with nutritional compromise, including dry skin, yellow skin (due to carotenemia), lanugo, hair loss, acrocyanosis, mitral valve prolapse, arrhythmia, decreased bowel sounds, and peripheral neuropathy. Assessment of individuals with BN and binge-eating/purging-type AN should include examination for parotid gland enlargement, submandibular adenopathy, dental caries, hand abrasions (Russell’s sign), decreased or increased bowel sounds, and rectal prolapse. Laboratory analysis should routinely include initial and periodic assessment of serum electrolytes, given that hypokalemia and hypomagnesemia are commonly seen in BN and binge-eating/purging type AN. Assessment of hepatic and renal function is recommended initially and then as indicated by the clinical picture. Laboratory examination for individuals with AN should also include evaluation

of serum glucose (because hypoglycemia is can occur in this population and can result in serious medical compromise) and a complete blood count with differential, because leukopenia, neutropenia, anemia, and thrombocytopenia might be seen in association with AN. Assessment of individuals with electrolyte disturbances and symptomatic arrhythmias, or for those in whom psychopharmacologic intervention is planned, should include an electrocardiogram (EKG) to evaluate whether the QT interval is prolonged or whether any other abnormalities are present. Although amenorrhea associated with AN is most often due to decreased gonadotropin releasing hormone pulsatility (leading to hypogonadotropic hypogonadism and low estradiol levels), other causes (including pregnancy) should be excluded. Because significant osteopenia occurs in half of women with AN, which poses a risk for fractures and kyphosis, women with AN with a disease duration of greater than 6 months should have a dual-energy X-ray absorptiometry (DXA) evaluation of lumbar spine bone density to assess severity of bone loss. Adolescents should be offered a DXA scan at time of diagnosis, and certainly if they have been amenorrheic for more than 6 months. Follow-up studies should subsequently be arranged as indicated by the clinical situation.

Nutritional Assessment Nutritional assessment includes the evaluation of appropriateness of body weight and adequacy of energy and nutrient intake. Ascertaining whether an individual’s weight is significantly low conventionally entails comparing it with weight standards for height, age, and gender. Clinical evaluation of weight conventionally begins with a comparison of an individual’s weight with ranges described by the World Health Organization with the metric, body mass index (BMI ) for adults and BMI centile for children. These metrics allow interpretation of weight in the context of height for adults (BMI), and in the context of height, age, and gender for children (BMI centile). BMI can be calculated with a number of available tools and apps and also by using the following formula: BMI = Weight(kg) / Height(m)2 BMI can be used for adult men or women of all heights or weights. A BMI of 18.5 to 24.9 kg/m2 (inclusive) is considered to be within normal range. Whether a low weight meets the “significantly low” bar for AN criterion A is fairly straightforward at the low end of the range (e.g., at a BMI less than 17

kg/m2 for adults). However, the clinical significance of a BMI just below and near the lower bounds of the range defined as normal (18.5 kg/m2 for adults and below the fifth centile in children and adolescents) is best determined in the full clinical context. In other words, clinical judgment might also factor in body composition and build, developmental stage, growth trajectory, physical health, and weight history. Numerical values provide a reference point for evaluating the clinical implications of low weight, but they are not intended to stand as a rigid cut point for diagnostic determination; rather they should be considered a guide. In addition, if an individual has begun to recover weight after meeting full AN diagnostic criteria, he or she would potentially meet criteria for AN in partial or full remission, rather than for the residual category, OSFED.

Psychiatric Evaluation Psychiatric evaluation includes establishing the type and severity of the eating disorder, excluding other psychiatric etiologies of appetite or weight changes (e.g., major depression), evaluating co-morbid psychiatric illness, and evaluating suicide risk. The most appropriate setting and level of care should be determined as well with regard to medical safety, nutritional compromise, and capacity to care for self and to adhere to the recommended treatment plan. Because there are a number of treatment approaches with varying degrees of established efficacy, patient preferences should also be explored. History of the present illness should evaluate dietary patterns (i.e., restrictive or binge-pattern eating) and modalities, frequencies, and durations of any behaviors to lose weight or prevent weight gain as well as the psychosocial context of the illness. Sometimes termed “inappropriate compensatory behaviors” to signal their purpose in offsetting a binge, it is important to note that many patients engage in weight-control behavior without its being temporally associated with a binge episode. Educational information about the medical risks posed by these behaviors should be communicated clearly to patients—and caregivers when appropriate—at this time. For example, many patients are unaware of the extremely serious risks associated with syrup of ipecac use and over-the-counter nutraceuticals that are marketed for weight loss but not regulated by the FDA. Generally, it is advisable to pose questions in a straightforward, empathic, and non-judgmental manner because many patients feel a great deal of shame in disclosing or discussing their symptoms. However, discussion of potential insulin misuse in patients with type I diabetes can be an exception and should be approached cautiously. Whereas clinicians should consider the possibility of

insulin misuse in patients with co-morbid insulin-dependent diabetes, they should avoid a situation in which they might inadvertently be introducing the patient to a dangerous behavior. In one study, 30% of adolescents with type I diabetes admitted to intentionally over- or underdosing insulin in the previous 3 months to reduce weight, create an opportunity to overeat, intentionally harm themselves, or hide the disease from peers. It is helpful to: inquire about self-induced vomiting, and whether ipecac is or has been used to induce emesis; provide education about the medical dangers associated with ipecac; inquire about laxative abuse, including frequency of episodes and number and type(s) of laxatives typically used per episode; inquire about the type and frequency of diuretic use; and inquire about the inappropriate use of illegal substances, over-the-counter nutraceuticals marketed as weight loss agents or diet pills, stimulants (including caffeine), or misuse of other prescription medications (e.g., methylphenidate). In addition, it is useful to inquire about driven exercise. It can be challenging to discern when exercise is excessive to the point of being a symptom, given that health professional recommendations for physical activity continue to evolve and patients frequently view and frame their physical activity as health promoting. Clinicians should determine whether patients use physical activity to “compensate” for perceived overeating; far exceed an hour of exercise daily, and/or recommendations set by a coach, trainer, or physician; or continue physical activity despite being sick or injured. Another feature that should raise concern is when the patient feels that missing an exercise session will lead to unbearable guilt, or that exercise is his or her sole affect regulation strategy. Furthermore, clinicians should inquire about fasting, meal-skipping, or restrictive patterns of eating (e.g., rigid dietary rules, delayed eating, avoidance of specific foods). Here, it is often helpful to ask patients to describe their pattern of eating on a typical day (and, if applicable, on a “good” day versus a “bad” day). Clinicians should also inquire about binge eating. Clinically, an objective binge episode is defined as eating an unusually large amount of food in a short period (less than 2 hours) accompanied by a perceived loss of control. In contrast, a subjective binge episode is the consumption of a small or normal amount of food, accompanied by a similar sense of loss of control. Therefore, clinicians should inquire about distress and other features associated with binge eating, such as eating rapidly, beyond satiety, while alone, or in response to emotional or social triggers.

In addition, providers should: inquire about other non-normative eating habits (e.g., picking, chewing and spitting, regurgitating and then rechewing or reswallowing food [rumination]); eating non-food substances (such as earth or laundry starch [pica]); and about attitudes toward current body weight and shape, and any behavioral manifestations of body image disturbance (e.g., compulsive body-checking, or avoidance of specific clothing or activities). Clinicians should be aware that patients sometimes have difficulty identifying, formulating, expressing, or disclosing their weight and shape concerns. In the assessment of eating disorders in adults, clinicians should also establish a history of weight range by inquiring about highest and lowest weights at the present height. Inquiry about desired weight in relation to present weight and historical high and low weights will often allow assessment of unrealistic or rigidly adhered to weight goals. It is helpful to: assess whether there is excessive concern about the importance of body weight and shape and/or intense fear of weight gain or becoming fat; inquire about psychosocial precipitants and maintaining factors for symptoms; and, evaluate the need for patient and family education and feasibility for family intervention when appropriate to their developmental stage or dependence on family. Psychiatric history should include questions about previous treatment as well as history of other psychiatric disorders. Eating disorders are commonly seen in association with mood, anxiety, impulse-control, substance use, or personality disorders. The highest rates of co-morbidity are associated with individuals with BN. Anxiety disorders (especially childhood anxiety disorders predating the eating disorder), major depression, persistent depressive disorder (dysthymia), and obsessive-compulsive disorder are associated with AN. Major depression, bipolar disorder, substance use, anxiety disorders, and cluster B personality disorders are commonly seen with BN. Major depression, panic disorder, substance use, and personality disorders are associated with BED. A mental status examination should exclude other possible causes (such as mood or anxiety symptoms) of anorexia or hyperphagia, evaluate other signs of co-morbid psychiatric illness, and assess suicidal ideation. Suicidal ideation and behavior should be carefully assessed, as suicidal ideation affects approximately one-fifth to one-half of individuals with eating disorders, and individuals with AN are 18.1 times more likely to die by suicide than are 15- to 34-year-old females in the general population. Cognitive function should be evaluated in

patients with severe nutritional compromise, as should evidence for any social, educational, and occupational impairment. Evidence of rigid thinking, perfectionism, and overvalued ideas should also be assessed.

Treatment Treatment for eating disorders addresses medical, psychological, and nutritional needs, and utilizes a multi-disciplinary team approach that integrates these domains of care. Although members of the treatment team do not need to be at the same institution or location, a means of unfettered and regular communication among them is essential. At the outset of treatment, the clinical team should establish how information about symptoms, medical parameters, and therapeutic interventions and progress will be reported, tracked, discussed, and managed. The patient should understand how the treatment team will coordinate care and why this is essential to safe and effective treatment.

Medical Treatment Unless there is a psychiatric emergency, the initial goals of treatment often include medical and nutritional stabilization. Medical complications of the eating disorder should be addressed with appropriate therapeutic management and monitoring, particularly if the behavioral symptoms place the patient at risk of recurring physical complications. Regardless of the severity of the disorder, an individual with an eating disorder should be followed routinely by a primarycare clinician to monitor weights, vital signs, and, when appropriate, serum electrolytes and other signs of emerging or recurring medical complications. When symptoms are new, moderate to severe, or escalating, and/or have previously resulted in serious medical complications, close medical follow-up is warranted so as to allow timely therapeutic interventions. Weight restoration is a primary medical goal for the treatment of AN; a goal weight should be determined at the outset of treatment by the primary-care clinician that is within normal range and adequate to regain reproductive function and to reverse bone demineralization. Individuals with AN are, as a rule, reluctant to gain weight, so weight restoration generally requires active and collaborative intervention among the primary-care clinician, mental health specialist, and sometimes a dietitian. For pediatric patients, family involvement is essential. Patients often respond to behavioral, educational, and psychotherapeutic interventions. Enteral or total parenteral feeding are rarely necessary and generally utilized only in severe cases of AN that fail to respond to the aforementioned

interventions. Nutritional rehabilitation in severely malnourished individuals poses a risk for refeeding syndrome, which can result in profound hypophosphatemia, cardiac arrhythmia, congestive heart failure, delirium, and death. Patients with severe nutritional compromise should be managed in an inpatient hospital setting, with appropriate specialty consultation for the evaluation and management of caloric, micronutrient, and electrolyte needs. Medical monitoring requires repeated laboratory studies and physical examinations as well as telemetry to identify and respond to signs of refeeding syndrome, which requires immediate medical intervention. Patients with active purging and diuretic or laxative misuse are at risk for hypokalemia. Serum potassium levels should be closely monitored if there is a history of clinically significant hypokalemia and/or purging that is continuing or escalating in frequency or severity. Correction of hypokalemia and other electrolyte disturbances is necessary in this population to reduce the risk for cardiac arrhythmias, and might require an inpatient setting for management. For mild hypokalemia managed in an outpatient setting, oral potassium supplementation might be necessary and should be closely monitored. Patients with an eating disorder should receive calcium and vitamin D supplements so that they at least meet the recommended dietary allowance (RDA) for these micronutrients to optimize their bone health, but these supplements are insufficient to increase their bone density. The most effective therapeutic management for osteopenia in patients with AN is weight restoration and, in females, menstrual recovery. Adequate weight restoration can prove difficult for many individuals with eating disorders, which can lead to reductions in bone density. Most randomized controlled trials (RCTs) have found that oral estrogen replacement has not been effective in increasing spine and hip bone mineral density. There is some evidence to suggest that physiologic transdermal estrogen replacement with cyclic progesterone is effective in increasing bone accrual rates in adolescent females with AN—though it still does not return bone mass density to pre-morbid levels—and is an option for adolescent patients with osteoporosis or low bone density that is continuing to fall. Bisphosphonates can be effective in increasing bone density in adult women with AN. However, they should be avoided in young women of reproductive age given their long half-life and teratogenicity, and reserved to treat osteoporosis in women with AN who also have fractures.

Despite menstrual abnormalities and associated infertility seen with AN and BN, pregnancy can occur. Because a variety of obstetric complications are associated with these disorders, patients should be counseled to take precautions to avoid conceiving until they have been advised by their OB-GYN care provider that their disorder would no longer pose a risk to their health, pregnancy, or to a developing fetus. Stool softeners or non-cathartic, bulk-forming laxatives can be helpful in treating the severe constipation associated with chronic laxative abuse and withdrawal. Dental care is indicated for individuals who induce vomiting because of the increased risk of dental caries and dental enamel erosion. Weight loss treatment is generally contraindicated for individuals with active BN because it can trigger and intensify inappropriate compensatory behaviors. However, structured behavioral weight-loss programs have demonstrated some benefit in reducing both weight and binge eating among individuals with obesity and BED. In either case, it is optimal to begin with interventions designed to curtail the binge-pattern eating before embarking upon weight-loss treatment.

Psychological Therapies Psychotherapy is the treatment of choice for these disorders , whereas pharmacologic therapy can often be a useful adjunctive treatment. If the risk of psychiatric or medical compromise is high, patients might require a brief inpatient or partial hospitalization before initiation or continuation of outpatient management. Psychiatric co-morbidities and history of treatment response will also guide choice of treatment. First-line psychological therapies for eating disorders are generally behaviorally based and involve normalizing eating patterns, learning strategies to reduce symptoms (such as restricting, binge eating, or purging), and reducing body image disturbance. Cognitive-behavioral therapy (CBT) is the best-studied and best-established treatment for BN and for BED. CBT is a four-stage therapy delivered by a mental health professional that involves: (1) providing education and creating a formulated analysis of behavior; (2) identifying the primary maintaining mechanisms that perpetuate the eating disorder; (3) addressing maintaining mechanisms with emphasis on reducing body image disturbance; and, (4) developing a pragmatic plan to prevent relapse. An important piece of preliminary education in Stage 1 is the theorized link between dietary restraint and binge eating, in which successful attempts at restraint increase hunger, and

unsuccessful attempts engender feelings of failure, both of which serve to increase risk for binge eating. CBT is meant to last 20 sessions for individuals whose weight falls in the normal or overweight range (typically those with BN and BED), and 40 sessions for those who are underweight (typically those with AN). CBT has strong efficacy data for BN and BED, and preliminary evidence suggests that CBT is also efficacious for individuals with OSFED, particularly those with sub-threshold forms of BN and BED. In a recent trial of CBT among individuals with a variety of eating-disorder diagnoses, nearly half of patients had stopped binge eating and purging, and 51% endorsed eating disorder attitudes within one standard deviation of community norms, at 60-week followup. CBT appears more effective than medication for both BN and BED, but it has been less promising in AN, possibly because the egosyntonicity of symptoms and the cognitive impairments secondary to underweight might hinder cognitive approaches. Family-based treatment (FBT )—in which parents are charged with the task of refeeding their child at home—has the greatest empirical support for the treatment of AN in adolescents. FBT is a three-phase treatment delivered by a mental health professional that comprises, (1) coaching parents to serve and supervise all of the patient’s meals and snacks with the aim of increasing calories sufficiently to promote steady weight restoration; (2) gradually returning control to the adolescent in an age-appropriate manner; and, (3) assisting the adolescent in returning to valued and developmentally normative activities. FBT has strong efficacy for youth with AN. In one study comparing FBT to individual therapy for adolescents with AN at 12-month follow-up, 49% of patients had achieved full remission and 89% had achieved partial remission in the FBT group, compared to just 23% and 67% in the individual therapy group, respectively. Furthermore, although FBT was originally developed for youth aged 18 or younger, preliminary data suggest that FBT might also hold promise for older adolescents or young adults with AN who live at home. Of course, not all patients benefit from first-line treatments. In those cases, clinicians might want to consider alternative treatments that also have some empirical support. For example, interpersonal psychotherapy (IPT), which focuses on resolving relational issues (e.g., interpersonal conflicts, role transitions, bereavement, and interpersonal deficits) rather than targeting eatingdisorder symptoms directly has been shown to be equally (but not as rapidly) as effective as CBT for the treatment of BN, and has been shown effective for the treatment of BED. Similarly, specialist supportive clinical management,

cognitive remediation therapy, CBT-based couples therapy, and graduated food exposure have shown preliminary efficacy in the treatment of AN. In BN, dialectical behavioral therapy (DBT), integrative cognitive affective therapy, psychodynamic therapy, and guided self-help have also demonstrated efficacy.

Nutritional Counseling Nutritional counseling with a dietitian is a helpful and sometimes necessary adjunct to medical and psychiatric interventions. Dietary patterns and weights can be monitored in this setting and communicated with other members of the team. Caloric requirements and nutritional deficiencies should he clarified for patients and clinicians; counseling and suggested meal plans and supplements can be offered to patients who need to gain weight. For patients participating in CBT, behavioral strategies for establishing healthful patterns of eating can be reinforced in this setting (i.e., patients can be assisted with self-monitoring of dietary patterns and identifying and avoiding cues to restrict, binge, or purge). For patients engaging in alternative forms of treatment (e.g., psychodynamic therapy), such strategies can be introduced. For young people participating in FBT, the dietitian can be viewed as a consultant to the parents, in their efforts to renourish their child at home. Patients with an eating disorder often have a sophisticated knowledge of nutrition and fail to appreciate how nutritional counseling can provide support for their implementation of a dietary intervention; thus, it can be helpful to frame the counseling as more than just informational, but rather as a form of coaching that can support them in implementing their dietary plan.

Pharmacotherapy Although available evidence supports the efficacy of some medications for the treatment of BN and BED, pharmacologic management of eating disorders should generally be considered only as an adjunctive—rather than a primary— treatment strategy. In aggregate, there is insufficient data to warrant a uniform recommendation for medication management of AN or OSFED , or to recommend medication treatment strategies for eating disorders in adolescents. It is important to note that fluoxetine and lisdexamfetamine dimesylate are the only pharmacologic agents approved with an indication for an eating disorder (BN and BED, respectively) by the FDA. Although other agents show some promise for efficacy for eating disorder symptoms as later described, their use should be considered off-label. With the exception of fluoxetine in a BN trial, data has focused on short-term efficacy, and there is no available evidence supporting the

efficacy of any agent for eating disorders beyond 1 year of treatment. Given the associated high co-morbidity, it will often be clinically appropriate to use pharmacologic agents for other therapeutic targets, such as anxiety or depression, in patients with an eating disorder. In treating co-morbid medical and psychiatric illness, clinicians should be mindful of side-effect profiles that include appetite or weight changes and how these might have an adverse impact on a patient’s eating disorder. In addition, because individuals with either AN or BN can be at risk for hypotension, dehydration, hypokalemia, hypomagnesemia, and cardiac arrhythmias among other medical complications, medication therapy can pose additional risks for adverse effects among this population that should be weighed carefully against potential benefits. Bupropion has been associated with an elevated risk of seizures in patients with BN and should be avoided in patients with eating disorders. Monoamine oxidase inhibitors (MAOIs) have been associated with adverse reactions in patients with BN. Furthermore, because of the risk of developing a hypertensive crisis subsequent to a binge possibly consisting of tyramine-containing foods, MAOI’s should be avoided in this patient population. MAOIs should also be avoided in this patient population. And finally, because of the lack of clinical data regarding the efficacy and safety profile of the use of psychotropic agents in the treatment of eating disorders in children and adolescents, the recommendations that follow apply only to the treatment of adults.

Anorexia Nervosa Medication treatment trials evaluating AN are characterized by small sample sizes, poor response rates, and attrition. They have yielded findings that warrant additional research but are insufficient as a basis for general clinical guidance in the treatment of AN. There is insufficient empirical support to recommend any single pharmacologic agent for the treatment of the primary symptoms of AN.

Atypical Antipsychotics Eight small RCTs have evaluated the efficacy of the short-term use of atypical antipsychotics, including olanzapine, risperidone, and amisulpride, for the treatment of AN. Results from a meta-analysis using the data from these studies reveal that as compared to placebo, use of atypical antipsychotic medications was associated with a non-significant increase in BMI. Furthermore, the use of atypical antipsychotics had no effect on drive for thinness or body dissatisfaction. Surprisingly, the atypicals, as compared to placebo, led to an increase in anxiety and overall eating disorder symptoms. As such, the available

data does not support a recommendation for first-line or routine use of atypical antipsychotics in AN. When any are used, clinicians need to remain vigilant for potential metabolic effects and must carefully weigh these and other associated risks with benefits in the management of AN for any particular patient.

Tricyclic Antidepressants Findings from four small RCTs in the early 1980s did not yield findings supporting the efficacy of tricyclic antidepressants (TCAs) for the treatment of AN. Furthermore, given the lethal risk with overdose and the increased risk of developing a fatal arrhythmia secondary to QTc prolongation, TCAs should be avoided in patients with AN.

Selective Serotonin Re-Uptake Inhibitors (SSRIs) Fluoxetine and citalopram are the only two selective serotonin re-uptake inhibitors (SSRIs) that have been tested in RCTs for the treatment of AN, with largely negative results. In two studies comparing fluoxetine (20–60 mg/day) to placebo in low weight AN inpatients and outpatients, respectively, there was no advantage to using fluoxetine over placebo. One study found that fluoxetine (20– 60 mg/day) was helpful in stabilizing weight-recovered individuals with AN, although a second larger study did not find adjunctive fluoxetine with CBT to be superior to placebo. One study comparing citalopram (10–20 mg/day) to placebo found no differences in weight gain between the two groups, although it found that citalopram appeared to improve depression and obsessive-compulsive symptoms.

Non-SSRI Antidepressants There is no RCT data available supporting the use of mirtazapine for AN.

Lithium One small RCT from the early 1980s revealed average greater weight gain on lithium than placebo in the treatment of AN. Given the risk of lithium toxicity in patients with AN who might have reduced lithium clearance because of sodium and fluid depletion, the use of lithium in AN is not recommended.

Prokinetic Agents Gastric motility can be abnormal in patients with AN. As such, prokinetic agents (metoclopramide, bethanecol, domperidone) have been suggested as adjuvants in AN to reduce post-prandial abdominal bloating.

Dronabinol There is no RCT data available supporting the use of dronabinol for AN. In one small cross-over study of patients with AN, however, adjunctive dronabinol (a synthetic cannabinoid) was superior to placebo for weight gain; however, it did not result in any changes as compared to placebo on Eating Disorder Inventory-2 (EDI-2 ) scores. Co-morbid psychiatric illness or symptoms (e.g., depression or anxiety) should be treated with appropriate pharmacologic therapy but might have limited efficacy in severely under-weight patients. Given medical complications associated with AN (e.g., electrolyte disturbances, hypotension, orthostasis, prolonged QTc interval, and constipation), side-effect profiles of prospective medications should be evaluated to avoid either exacerbation of these conditions or other serious medical risk.

Bulimia Nervosa The symptoms associated with BN are moderately responsive to a variety of antidepressant medications in the short-term, although remission rates are relatively low. CBT has been shown to be more effective than medication for the treatment of BN, but the addition of medication to psychotherapy is often clinically useful. Of the agents demonstrated to be effective, no particular medication has been shown to have superior efficacy, so it is recommended that a medication be chosen based on its side-effect profile, history of patient response, and patient preference. Consecutive trials of agents might be necessary to achieve desired treatment outcomes for individuals with a poor response to an initial trial.

SSRIs Fluoxetine is the best studied among the medications effective against BN and is the only FDA-approved medication for its treatment. It is generally well tolerated in this population. The recommended dosage is 60 mg/day. At this dose, fluoxetine also improves depressive symptomatology, improves eating attitudes as reflected in lower scores on the Eating Attitudes Test (EAT) and EDI, and reduces binge eating of carbohydrates. Although they are in routine clinical use, few controlled trials have evaluated other SSRIs. Sertraline has been found superior to placebo in one small RCT. Because the use of fluvoxamine in clinical studies has yielded mixed efficacy data and one study raised concerns about severe adverse events (grand-mal seizure) associated with its use,

fluvoxamine should be used with caution in patients with BN and should not be considered a first-line treatment for BN. Whereas other antidepressant agents (desipramine, imipramine, and trazodone) have shown efficacy for the treatment of BN, their side-effect profiles are undesirable for this patient population. As noted earlier, MAOIs and bupropion have been associated with serious adverse events and should be avoided in patients with BN and other eating disorders.

Topiramate Two RCTs have demonstrated that topiramate (up to 250 mg/day in one and up to 400 mg/day in the other) has short-term efficacy for the treatment of BN, with improvement in binge and purge behaviors.

Naltrexone Four RCTs have demonstrated mixed results. Two RCTs demonstrated no benefit as compared to placebo with moderate doses of naltrexone (up to 120 mg/day), whereas two RCTs evaluating patients who had already failed standard antidepressant treatment, noted modest improvement as compared to placebo with higher doses of naltrexone (200–300 mg/day). Higher doses of naltrexone, however, were associated with significant elevation in hepatic transaminases and should, therefore, be used cautiously in patients with BN.

Ondansetron Ondansetron (24 mg/day in six divided doses) has been found effective in subjects with severe BN with reduction of binge/purge frequency in one controlled study.

BED Preliminary neuroimaging findings suggest that BED is associated with greater increased reward sensitivity and stronger medial orbitofrontal cortex activation while viewing food as compared to individuals with BN and healthy controls. BED is more commonly associated with obesity as compared to the other eating disorders. This association with obesity informs psychopharmacological management, as clinicians should assess the effects medications have on appetite and weight control, while also targeting binge episodes and other co-morbid psychiatric conditions. Relatedly, many agents, including stimulants, anti-obesity agents, antidepressants, and antiepileptic drugs have all been studied in the treatment of BED.

Lisdexamfetamine Dimesylate Lisdexamfetamine dimesylate (50–70 mg/day) is the only FDA-approved medication for BED. Three large RCTs found that lisdexamfetamine dimesylate led to a decrease in the number of binge episodes per week and led to few obsessive-compulsive binge-eating behaviors as compared to placebo. The safety profile and tolerability of lisdexamfetamine dimesylate in this population was consistent with previous findings of adults with ADHD. Given the risk of potential recreational abuse and/or diversion, this agent should be used with caution in individuals with a history of a substance use disorder.

Anticonvulsants In a multi-center RCT, topiramate (with dosing titrated from 25 mg/day over a period of 8 weeks to a maximum tolerated dose, up to 400 mg/day) reduced BMI, binge days, binge episodes, and resulted in greater weight loss in adults with BED and co-morbid obesity. It also induced binge-eating remission in 58% of participants, a significantly greater percentage than in the placebo group. An additional 21-week RCT demonstrated that, in combination with CBT, topiramate (with dosing gradually titrated upward as tolerated from 25 mg/day to a maximum of 300 mg/day) enhanced the efficacy of CBT with regard to the rate of weight change and binge-eating remission. Some patients do not tolerate the side effects (impaired cognition, paresthesia, taste perversion) of topiramate. In a single-center RCT, zonisamide (with flexible dosing between 100–600 mg/day) was superior to placebo at reducing binge frequency per week and at inducing weight loss; however, it was poorly tolerated throughout the study period.

Antidepressants SSRIs and SNRIs have been studied in several RCTs as an adjunctive therapy or monotherapy for BED. Of these, sertraline (flexible dose of 50–200 mg/day) and atomoxetine (40–120 mg/day) have each shown efficacy for the reduction of symptoms of BED when compared with placebo in one RCT. Data on other SSRIs cannot support a general recommendation for their efficacy in BED. Although one RCT demonstrated efficacy of citalopram, the study used a dosage range and a mean dosage in excess of current FDA recommendations for this drug, related to safety concerns. Fluvoxamine was not found to be more effective than placebo in an intention-to-treat analysis as part of a multi-center RCT nor in a second single-center RCT. In aggregate, RCT data evaluating fluoxetine does not support its efficacy in the treatment of BED either as a monotherapy or

adjunctive therapy with CBT. Duloxetine (mean dose 78.7 mg/day) was found to be superior to placebo in another RCT in reducing weekly frequency of bingeeating days and binge-eating episodes, global severity of BED symptoms, and global severity of depressive symptoms. In another RCT evaluating bupropion (300 mg/day) against placebo, there was no significant difference in reducing the frequency of binge eating. Although RCTs evaluating the serotoninnorepinephrine re-uptake inhibitor (SNRI), sibutramine, were positive for reducing binge eating and promoting weight loss as compared to placebo, it has since been taken off the market due to safety concerns (increased risk of cardioand cerebrovascular events).

Anti-Obesity Medications Two RCTs evaluating orlistat, a pancreatic lipase inhibitor, in the treatment of obese patients with BED do not support that is effective in sustaining a reduction of binge eating, although it is associated with promoting greater weight loss as compared to placebo or dietary modifications alone.

Opioid Antagonists A phase II placebo-controlled study of intranasal naloxone spray (2–4 mg/day) was associated with a greater reduction in time spent binge eating and a greater reduction in BMI as compared to placebo. Although promising, further study is needed before a general recommendation can be made.

Indications for Inpatient Management Although eating disorders can often be adequately managed in an outpatient setting, inpatient care or partial hospitalization might be essential for safe and effective management in some clinical situations. Indications for inpatient management include: serious medical risk (e.g., significant hypokalemia, bradycardia, hypotension or dehydration, ongoing ipecac abuse); very low weight (e.g., ≤ 75% expected body weight) or rapid weight loss; growth arrest; psychiatric risk (e.g., risk of self-harm or psychosis); escalating or severe symptoms (e.g., inability to eat independently, frequent purging throughout the entire day); or persistence of low weight despite appropriate outpatient interventions. At the beginning of treatment, it is often helpful to review with the patient the medical and psychiatric parameters that might signal a need for intensified care. For patients with a history of frequent hospitalization or serious symptoms, it is

useful to discuss and agree in advance how the team will manage a transition to a more intensive level of care when it is indicated. Development of a treatment contract that all members of the multi-disciplinary clinical team support can be an effective way to communicate expectations for the patient’s participation in his or her care. Both the team and the patient should agree in advance how new symptoms, clinical deterioration, and/or insufficient treatment adherence will be managed. Anticipation of the potential need for an increased level of care can avoid delays in essential therapeutic intervention as well as splitting among members of the treatment team.

Conclusions Eating disorders are associated with high psychiatric co-morbidity as well as serious medical complications; yet, they frequently go unrecognized in clinical settings and, hence, untreated. Diagnostic assessment and evaluation is made challenging by the need to ascertain cognitive and behavioral symptoms that patients might conceal, choose not to disclose, or lack the insight to recognize. Notwithstanding frequent and potentially serious associated medical complications, physical signs associated with eating disorders lack diagnostic specificity and patients with BN and BED in particular can present with an unremarkable physical exam. AN and BN are most prevalent among adolescent and young adult women, but they can also occur in men and across the lifespan. BED occurs in both women and men. Successful treatment requires collaborative team management with medical, nutrition, and psychiatric intervention (see Table 24-1). Table 24-1: Summary of Assessment and Management of Eating Disorders General

Assessment

Management

Determine onset, course, and patterning of the following:

Team members should:

Binge or restrictive pattern eating Purging and other compensatory behaviors Weight loss, gain, or cycling Excessive concern and/or distress associated with eating, body, or weight Exclude: Alternative medical and psychiatric causes of anorexia, hyperphagia, and weight dysregulation

Clarify roles in treatment to patient and to one another Establish and implement communication plan about course of signs, symptoms, and response to therapeutic interventions Identify parameters signaling psychiatric or medical danger or suboptimal treatment response,

formulate a stepped contingency management plan, and review with the patient

Medical

Evaluate for complications of purging, excessive exercise, starvation, Routinely monitor: and/or underweight or overweight via: Weights and vital signs Directed history Serum electrolytes for Vital signs patients with purging Physical exam behaviors Laboratory analyses include: For bulimia nervosa: routinely, serum electrolytes; when indicated, EKG. For anorexia Treat and follow: nervosa: routinely, serum electrolytes, glucose, and CBC; when indicated, EKG and DXA scan of the lumbar spine. Medical complications Beta-hCG, FSH, and/or prolactin may be useful in evaluating initially present or as amenorrhea associated with these disorders weight, diet, purging symptoms, or inappropriate compensatory behaviors change Refer: Individuals with self-induced vomiting for dental care

Nutritional

Evaluate: Dietary patterns/caloric and nutrient intakes Appropriateness of weight (by calculation of BMI) for adults; and by BMI centile and contextualization with growth charts/growth history in children and adolescents)

Psychological Evaluate: Excessive concern with and distress about eating, body shape, or weight Typical triggers for engaging in restricting, binge eating, and purging Co-morbid psychiatric illness and suicidality

Suggested Readings

Introduce and support: Nutritional guidelines for weight restoration or control and general health Behavioral strategies to assist in symptom control

Initiate: Psychotherapy Consider: Medication (as an adjunctive therapy when appropriate and for comorbid psychiatric illness)

1. Academy for Eating Disorders Medical Care Standards Task Force: Eating disorders: Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders . 2nd ed. Deerfield, IL: Academy for Eating Disorders; 2011. 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 3. American Psychiatric Association: Treatment of patients with eating disorders. Am J Psychiatry . 2006; 163: 4–54. 4. Attia E, Becker AE, Bryant-Waugh R, et al: Feeding and eating disorders in DSM-5. Am J Psychiatry . 2013; 170: 1237–1239. 5. Becker AE: Special Populations: Cultural Considerations. In: Walsh BT, Sysko R, Glasofer DR, et al, eds.: Handbook of Assessment and Treatment of Eating Disorders . Arlington, VA: American Psychiatric Publishing; 2016. 6. Fairburn CG: Cognitive Behavior Therapy and Eating Disorders . New York: Guilford Press; 2008. 7. Fairburn CG, Cooper Z, Doll HA, et al: Transdiagnostic cognitivebehavioral therapy for patients with eating disorders: a two-site trial with 60-week follow-up. Am J Psychiatry . 2009; 166: 311–319. 8. Eddy KT, Tabri N, Thomas JJ, et al: Recovery from anorexia nervosa and bulimia nervosa at 22-year follow-up. J Clin Psychiatry . in press. 9. Grilo CM, Mitchell JE: The Treatment of Eating Disorders: A Clinical Handbook . New York: Guilford; 2010. 10. Hudson JI, Hiripi E, Pope HG, et al: The prevalence and correlates of eating disorders in the national co-morbidity survey replication. Biol Psychiatry . 2007; 61: 348–358. 11. Keshaviah A, Edkins K, Hastings E, et al: Re-examining premature mortality in anorexia nervosa: A meta-analysis redux. Compr Psychiatry . 2014; 55: 1773–1784 12. Lebow J, Sim LA, Erwin PJ, et al: The effect of atypical antipsychotic medications in individuals with anorexia nervosa: A systematic review and meta-analysis. Int J Eating Disorders . 2013; 46(4): 332–339. 13. Lock J, le Grange D: Treatment Manual for Anorexia Nervosa: A Family

Based Approach . New York: Guilford; 2015. 14. McElroy S, Guerdjikova A, Mori N, Keck PE: Psychopharmacologic treatment of eating disorders: Emerging findings. Curr Psychiatry Reports . 2015; 17(5): 1–7. 15. Mehler PS, Andersen AE: Eating Disorders: A Guide to Medical Care and Complications . Baltimore, MD: Johns Hopkins University Press; 2010. 16. Misra M, Katzman D, Miller KK, et al: Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Mineral Res . 2011; 26: 2430–2438. 17. Misra M, Klibanski A: Anorexia nervosa and bone. J Endocrinol . 2014; 221: R163–R176. 18. Schober E, Wagner G, Berger G, et al: Prevalence of intentional under- and overdosing of insulin in children and adolescents with type 1 diabetes. Pediatric Diabetes . 2011; 7: 627–631. 19. Smink FR, van Hoeken D, Hoek HW: Epidemiology, course, and outcome of eating disorders. Current Opinion in Psychiatry . 2013; 26(6): 543–548. 20. Thomas JJ, Vartanian LR, Brownell KD: The relationship between eating disorder not otherwise specified (EDNOS) and officially recognized eating disorders: Meta-analysis and implications for DSM. Psychological Bull . 2009; 135: 407–433. 21. Walsh BT, Kaplan AS, Attia E, et al: Fluoxetine after weight restoration in anorexia nervosa: A randomized controlled trial. JAMA . 2006; 295: 2605– 2612.

CHAPTER Sleep Disorders 25 JOHN W. WINKELMAN, MD, PHD; TED AVI GERSTENBLITH, MD; PATRICK SMALLWOOD, MD; AND THEODORE A. STERN, MD

KEY POINTS Overview Ten groups of sleep disorders have been recognized by the Diagnostic and Statistical Manual, Fifth Edition . Clinical Features Insomnia disorder is characterized by difficulty falling asleep, staying asleep, or early morning awakening and is associated with dissatisfaction with sleep as well as either clinically significant distress or dysfunction in important areas of functioning. The hallmark of hypersomnolence disorder is the description of excessive sleepiness, characterized by recurrent daytime napping (which is usually unrefreshing), not feeling refreshed after at least 9 hours of sleep, or difficulty awakening from sleep that occurs at least three times per week for at least 3 months. Narcolepsy is characterized by excessive daytime sleepiness, with at least one of the following: cataplexy (sudden loss of motor tone with maintained consciousness, usually precipitated by an emotional trigger such as laughter), low cerebrospinal fluid orexin levels, or a Multiple Sleep Latency Test (MSLT) demonstrating mean sleep latencies of less than 8 minutes with at least two naps containing rapid eye movement (REM). Hypnogogic or hypnopompic hallucinations, sleep paralysis, and sleep maintenance insomnia are also common. The hallmark of sleep-related breathing disorders is apnea. Apnea is the cessation of oronasal airflow as recorded on polysomnography for greater than 10 seconds. Circadian rhythm sleep disorders emerge when societal expectations conflict

with an individual’s preferred circadian rhythm. As a result, the timing of sleep, not its quality and architecture, is adversely affected. Parasomnias are sleep disorders in which undesired behaviors or experiences arise during sleep or from the sleep-wake transition and thus are often mixtures of states of consciousness. Non–rapid eye movement sleep arousal disorders (e.g., sleepwalking, night terrors) occur mainly in NREM 3 (slow wave) sleep. REM sleep parasomnias arise from REM sleep and include nightmare disorder and REM sleep behavior disorder. The hallmarks of nightmare disorder are extremely dysphoric lengthy recalled dreams usually involving physical threat. Restless legs syndrome is a sleep-related sensorimotor disorder characterized by an overwhelming urge to move the legs, often with associated deep sensations of creeping or aching inside the legs when lying or sitting down. Substance/medication-induced sleep disorder, whether from prescription medications or recreational drugs, can cause a wide range of sleep abnormalities that are often confused with primary sleep disorders. Etiology The neurobiological basis for the sleep-wake cycle remains elusive.

Introduction Sleep, when restorative, becomes so routine as to warrant little more than a passing thought. If altered, however, this once-routine process shifts from a benign to a disordered state that can significantly impair any or all facets of daily life. In this chapter, normal sleep (including sleep stages, cycles, rhythm, and biological mechanisms) is first described. Then, we review the ten groups of sleep disorders recognized by the Diagnostic and Statistical Manual, Fifth Edition (DSM-5).

Normal Sleep History While the quest to understand sleep is as old as mankind itself, most of our understanding has come in only the past 70 years. During that time, sleep has been re-defined as an active state, complete with stages, cycles, and rhythms that are as complex as the waking state. Loomis (1935) observed that

electroencephalographic (EEG) changes were prevalent throughout sleep. Aserinsky and Kleitman (1953) detected various types of eye movements during sleep, most notably slow rolling eye movements occurring early in sleep and disappearing as sleep progressed, and rapid eye movements associated with irregular breathing and increased heart rate. They named the sleep phase associated with the slow rolling rhythmic eye movements non–rapid eye movement (NREM) sleep , and the sleep phase associated with the fast erratic eye movements rapid eye movement (REM) sleep . In 1955, Dement and Kleitman discovered that REM sleep was associated with dreaming, and, 2 years later, that REM and NREM sleep cycled over the course of the night.

Polysomnography Polysomnography , the method used to objectively evaluate sleep, involves the simultaneous recording of multiple physiological variables in a standardized fashion known as a polysomnogram (PSG ). The parameters recorded by the PSG include, but are not limited to, the following: Electroencephalogram (EEG ): A recording of the electrical activity of cortical neurons via scalp electrodes that are placed in standardized positions according to the International 10-20 System. Electrooculogram (EOG ): A recording of the eye movements. Electrocardiogram (EKG ): A recording of the heart rhythm. Electromyogram (EMG ): A recording of the activity of the left and right tibialis anterior muscles and the submental chin muscles. Respiratory flow and effort: A recording of nasal and oral airflow by means of nasal thermistors, and thoracoabdominal movements by means of strain gauges. Pulse oximetry: A recording of oxygen saturation in the blood. Snore monitor: A recording of snoring by means of a microphone placed on the lateral aspect of the neck. By employing polysomnography, wakefulness, sleep onset, NREM sleep, and REM sleep can be defined and studied. Table 25-1 summarizes the sleep stages as well as the EEG, EMG, and EOG findings that define them. Table 25-1: Human Sleep Stages and Distribution Across the Night EOG

Nocturnal

EEG Findings

EMG Findings

Alpha waves (8–14 Hz)

Muscle tone and activity Variable eye present movements

< 10%

NREM Theta waves (4–7 Hz) 1

Muscle tone and activity Slow rolling eye present movements

2%–5%

NREM Theta waves (4–7 Hz); sleep spindles (12–14 2 Hz ≥ 0.5 sec); K-complexes (triphasic)

Muscle tone and activity None present, but slowing

45%–55%

NREM Delta waves (0.5–2 Hz) 3 present ≥ 50% of the time

Marked decrease in muscle tone and activity

None

13%–23%

Absence of muscle activity

Conjugate rapid eye movements

20%–25%

Wake

REM

Relatively low-voltage mixed-frequency waves

Findings

Distribution

Sleep Cycle and Architecture NREM and REM alternate in a rhythmic fashion known as the NREM–REM cycle. In normal healthy individuals, this cycle begins with light NREM sleep (stages 1 and 2), progresses to deep NREM (stage 3), and then REM. This pattern generally repeats itself at 90 to 120–minute intervals about three to four times each night. NREM 3 is most prominent in the first half of the night and diminishes in the latter half of the night. REM sleep, however, is less prominent in the first half of the night and the duration of each REM period increases as the night progresses. Sleep latency, which is usually 10 to 20 minutes, is the time from “lights out” to sleep onset. REM latency is the time from sleep onset until the beginning of the first REM period, and is usually 90 to 100 minutes. Sleep efficiency is: [(total sleep time)/(time in bed)] x 100. Sleep architecture is the pattern and distribution of sleep stages across the night and is summarized in Table 25-1.

Circadian Rhythm The circadian rhythm or “biological clock” is an endogenous rhythm of bodily functions that is influenced by environmental cues, or zeitgebers . This cycle, unique to each person, averages just more than 24 hours. Sleep disorders related to the circadian rhythm emerge when an individual’s circadian rhythm clashes with environmental and societal expectations.

Sleep Across the Lifespan The amount of time spent in the different stages of sleep varies with age; infants spend more than two-thirds of their day sleeping, whereas adults spend less than a third of their day sleeping. The elderly, on the other hand, experience

a reduction in the intensity, depth, and continuity of sleep, because of age-related degenerative changes in the sleep mechanisms of the central nervous system (CNS) as well as the increased prevalence of sleep and medical disorders. Specific sleep changes in the elderly include: increased sleep latency; reduced NREM 3 and 4; decreased REM latency; reduced total REM amount; increased awakenings; and decreased sleep efficiency. Table 25-2 summarizes sleep patterns across the lifespan. Table 25-2: Sleep Patterns Across the Lifespan Age

Time in Bed Time Asleep Stage 1 Stages 3 and 4 REM

Birth

17–24 hours

16 hours

5%

—

50%

12 years

8.5 hours

8 hours

—

15%–20%

20%

25–45 years 7.5 hours

7 hours

—

—

20%

6.5 hours

15%

0%

20%

Old age

8.5 hours

Neurobiological Basis for Sleep The neurobiological basis for the sleep–wake cycle remains elusive. Initial insights derived from early electrolytic lesion studies suggested that specific regions of the brain are critical for wakefulness and sleep. In the past 20 years, substantial advances have been made in our understanding of the neurobiology and anatomy of sleep. Saper has proposed that control of sleep and wake is similar to a flip-flop switch in which there is mutual antagonism between groups of neurons which promote wake and those that promote sleep. Distinct cell groups at the midbrain-pontine junction which contain acetylcholine, noradrenaline, serotonin, dopamine, and histamine and project to the thalamus and cortex have been identified as essential for wakefulness. Cells in the lateral hypothalamus containing the peptide orexin also project to the cortex and support wakefulness. It is destruction of these cells that is responsible for narcolepsy with cataplexy. On the other hand, sleep is promoted by cells in the ventrolateral preoptic (VLPO) area of the hypothalamus which contain γ -amino butyric acid (GABA) and galanin.

Sleep Disorders Although several classification systems for sleep disorders exist, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

classification is the most relevant to psychiatrists. In distinction to previous editions of the DSM, inferred causal relationships between medical and psychiatric disorders and sleep disorders have been removed from the DSM-5, acknowledging that such relationships are often bidirectional, and further that independent treatment of the sleep disorder is warranted when co-existing disorders are present. The DSM-5 divides sleep-wake disorders into ten conditions, which we will briefly describe in the sections that follow.

Insomnia Disorder Insomnia disorder is characterized by difficulty falling asleep, staying asleep, or early morning awakening and is associated with dissatisfaction with sleep as well as either clinically-significant distress or dysfunction in important areas of functioning. To meet criteria, the sleep difficulty must occur at least 3 nights per week for at least 3 months and cannot be better explained by another sleep disorder or be accounted for by a substance or by a medical or psychiatric disorder. Roughly 10% to 15% of adults have insomnia disorder, which is chronic in about half of those with this complaint. It is more common in women than in men. Of those with insomnia, roughly 50% have a co-existing psychiatric disorder. A careful assessment is essential for successful treatment of insomnia, as there are often multiple contributions to the sleep disturbance, all of which must be addressed for optimal sleep. Non-pharmacological techniques, such as c ognitive-behavioral therapy for insomnia (CBT-I) should be attempted first, if time and CBT-skilled clinicians are available. Table 25-3 provides the core features of CBT-I techniques. Evidence from meta-analyses suggests that CBT is most helpful for reducing time awake at night, though it does less for extending total sleep time. A therapeutic response that is generally sustained over time is achieved in 70% to 80% of patients who undergo CBT. CBT has also been shown to be helpful for insomnia that co-exists with other medical or psychiatric conditions. If CBT is unsuccessful, use of pharmacotherapy might be appropriate. Current FDA-approved pharmacologic treatments for insomnia include several benzodiazepine receptor agonists, a melatonin receptor agonist, and an orexin antagonist. In contrast to CBT, the hypnotic drugs often produce results in the first week of treatment (though both therapies are equally effective by one month of treatment) and produce a more favorable outcome on total sleep time but the effects might not be sustained after medication discontinuation. In general, sedative-hypnotic drugs should be used at the lowest effective dose; their

ongoing use, efficacy, and side effects should be reassessed frequently as all agents used for the promotion of sleep can produce adverse effects, some of them severe, particularly in the elderly. The choice of drug should be based on clinical factors related to the individual patient as well as the pharmacological characteristics of the agent (see Table 253). For example, agents with a shorter time-to-peak blood concentration aid sleep onset, whereas those with longer half-lives can provide better sleep maintenance, though with the potential for daytime sedation. The optimal duration of treatment is not well studied and there is little empirical evidence to guide decisions regarding which drugs to use over the long term. When discontinued, hypnotics should be tapered (by dose or frequency of administration) to prevent rebound insomnia and potential physical and psychological withdrawal effects. Table 25-3: Commonly Used Medications for Treatment of Insomnia Recommended Hours to Peak Dose Range Plasma Half(mg) Concentration Life

Notable Side Effects

Benzodiazepine Receptor Agonists Zaleplon

5–20

1

1

Drowsiness, amnesia, complex sleep-related behaviors

Zolpidem

2.5–10

1.6

2.5

Same as above

Triazolam

0.125–0.5

2

2.5

Same as above

Eszopiclone

1–3

1

5–6

Same as above, unpleasant taste

Lorazepam

0.5–2.0

1

8–20

Same as above

Temazepam

7.5–30

1

6–16

Same as above

1–2.5

Drowsiness, interaction with fluvoxamine

3

9–13

Drowsiness

Amitriptyline 10–20

4–8

10–28 (including metabolite nortriptyline)

Drowsiness, dizziness, confusion, blurred vision, dry mouth, constipation, urinary retention, arrhythmias, orthostatic hypotension, weight gain

Doxepin

2–3

8–24

Same as for amitriptyline

Melatonin Receptor Agonists Ramelteon

8

0.75

Orexin Receptor Antagonist Suvorexant

5–20

Antidepressants

3–25

Mirtazapine

7.5–45

2

20–40

Drowsiness, dizziness, constipation, weight gain

Trazodone

25–100

1

7

Priapism, drowsiness, headache, orthostatic hypotension

2–4

5–7

Drowsiness, dizziness, ataxia, peripheral edema

15

6

Drowsiness, akathisia, weight gain

Anticonvulsants Gabapentin

300–900

Antipsychotics Quetiapine

25–100

Current guidelines from the American Academy of Sleep Medicine suggest starting with any of the short or intermediate-acting benzodiazepine receptor agonists or ramelteon. The initial agent is chosen based on factors such as symptom pattern, past response, cost, and patient preference. If the trial fails, an alternative drug from the same category could then be attempted. If there is still no response, a low-dose sedating antidepressant (e.g., trazodone, mirtazapine, doxepin) can be tried, especially in patients with a history of substance misuse, or with other contraindications to use of a controlled substance. These medications are generally not FDA-approved for insomnia and their efficacy for this indication alone is not well established. The melatonin agonist ramelteon can be used for those with sleep-onset insomnia, though it has inconsistent efficacy. The novel agent suvorexant was effective in controlled trials for all insomnia symptoms and has a low side-effect burden. Although evidence for the efficacy of other prescription drugs (e.g., gabapentin, quetiapine, olanzapine) is generally lacking, they might be helpful as third- or fourth-line agents or for patients who have other indications for their use (such as chronic pain and psychiatric disorders). Antihistamines, widely used over-the-counter agents for insomnia, have limited evidence for benefit in insomnia and have the potential for substantial side effects from their anticholinergic properties. Table 25-4 provides a summary of the commonly used pharmacologic agents used to treat insomnia. Table 25-4: Components of Cognitive Behavioral Therapy for Insomnia (CBT-I) Component Intended Effect

Specific Directions

Sleep restriction Increase sleep drive and stabilize circadian rhythm

Reduce time in bed to perceived total sleep time (not less than 5–6 hours)

Specific hours based on optimal circadian timing for specific patient Increase time in bed gradually as sleep efficiency improves

Stimulus control

Cognitive therapy

Relaxation therapy

Reduce cognitive and physiological arousal in bed and promote the association of bed and sleep

Attempt to sleep only when sleepy Do relaxing and distracting activities if not asleep within 30 minutes

Modifies maladaptive beliefs regarding daytime and health consequences of insomnia

Make reasonable expectations about sleep Review previous benign experiences of insomnia consequences

Reduce physical and psychological arousal in sleep environment

Progressive muscle relaxation Breathing exercises Meditation

Reduce behaviors that interfere with sleep drive or increase arousal

Limit caffeine and alcohol Keep bedroom dark and quiet Avoid daytime/evening napping Increase exercise (not close to bedtime) Remove bedroom clock from sight

Sleep hygiene

Hypersomnolence Disorder The hallmark of this disorder is the description of excessive sleepiness, characterized by recurrent daytime napping (which is usually unrefreshing), not feeling refreshed after at least 9 hours of sleep, or difficulty awakening from sleep, which occurs at least three times per week for at least 3 months. Other complaints include difficulty waking, sleep drunkenness, and headache. Like insomnia disorder, hypersomnolence disorder is associated with distress or daytime impairment, and cannot be better explained by another sleep disorder or accounted for by a substance or by a medical or psychiatric disorder. Overnight polysomnography demonstrates short sleep-onset time, high sleep efficiency, and a mean sleep-onset time that is usually less than 8 minutes on a daytime Multiple

Sleep Latency Test (MSLT). Treatment is usually with daytime stimulants, such as amphetamines, methylphenidate, or modafinil.

Narcolepsy Narcolepsy is characterized by excessive daytime sleepiness , with at least one of the following: cataplexy (sudden loss of motor tone with maintained consciousness, usually precipitated by an emotional trigger such as laughter), low cerebrospinal fluid (CSF) orexin levels, or an MSLT demonstrating mean sleep latencies of less than 8 minutes with at least two naps containing REM. Hypnogogic or hypnopompic hallucinations, sleep paralysis, and sleep maintenance insomnia are also common. Narcolepsy with cataplexy is due to loss of orexin-producing neurons in the hypothalamus, most likely as a result of an autoimmune attack. Narcolepsy is rare, with an incidence of 0.04%. The onset is usually in the late teens and early twenties, and the course is often chronic. Genetic factors play a role, as nearly 100% of Asian and Caucasian narcoleptics with cataplexy possess the human leukocyte antigen HLA-DQB1*06:02 phenotype, compared with 20% to 40% of Asian and Caucasian non-narcoleptics; in addition, the probability of developing narcolepsy is 40 times greater if an immediate family member suffers from it. For sleepiness, treatment is usually with daytime stimulants, such as amphetamines, methylphenidate, or modafinil. Alternately, sodium oxybate at night (in divided doses before bed and in the middle of the night) can be prescribed. If cataplexy is problematic, serotonergic agonists ( selective serotonin re-uptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], or low-dose tricyclic antidepressants [TCAs]) or sodium oxybate are often used.

Breathing-Related Sleep Disorders Two such disorders are described in the DSM-5: obstructive sleep apnea and central sleep apnea . The hallmark of sleep-related breathing disorders is apnea. Prior to a discussion of sleep apnea syndromes, several terms must be defined. Apnea is the cessation of oronasal airflow as recorded on polysomnography for greater than 10 seconds. Hypopnea is a 50% reduction of oronasal airflow, resulting in either an EEG arousal or at least a 3% decrease in oxygen saturation on the pulse oximeter. The apnea-hypopnea index (AHI) is the number of apneas + hypopneas per hour of sleep. An AHI > 5 is considered abnormal but often treatment is not instituted unless then AHI is > 10, unless significant symptoms are present.

Obstructive sleep apnea (OSA), the quintessential sleep-related breathing disorder, is the most common organic disorder of excessive daytime sleepiness, accounting for 40% to 50% of all patients seen in sleep disorder centers. The estimated prevalence is 1% to 2% of the adult male population in the United States; it increases to 8.5% of men between the ages of 40 and 65 years. Women account for 12% to 35% of OSA patients, with the majority of them being postmenopausal. Nocturnal signs and symptoms include snoring, choking, dyspnea, and insomnia; daytime symptoms include hypersomnolence, fatigue, or nonrestorative sleep. The most significant risk factors are male gender, age of 40 to 65 years, obesity, retro- or micrognathia, tonsillar hypertrophy (particularly in children and adolescents), and post-menopausal status in women. The principle defect is occlusion of the upper airway at the level of the pharynx during wake-sleep transitions and sleep proper, which then produces repetitive arousals from sleep and oxygen desaturation. As a result, there is a substantial increased risk of motor vehicle accidents as well as occupational injuries. Obstructive sleep apnea is also a risk factor for hypertension, myocardial infarction, and stroke. First-line therapy includes nasal continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP). Alternately, use of a mandibular advancement device can be of value in those with milder sleep apnea. In some cases, upper airway surgery can eliminate or reduce the severity of OSA, particularly if enlargement of the tonsils or the soft palate is present. Finally, weight loss is the cornerstone of OSA treatment. Two other types of sleep apnea are recognized based on etiology and the presence or absence of respiratory effort during apneic events. Central sleep apnea is a condition of repetitive apneas in which there is cessation of airflow without an attempt to initiate thoracoabdominal respiratory effort. There are multiple etiologies of central sleep apnea, including heart failure (Cheyne-Stokes respiration), opioid-induced, or idiopathic apnea.

Circadian Rhythm Sleep Disorders These emerge when societal expectations conflict with an individual’s preferred circadian rhythm . As a result, the timing of sleep, not its quality and architecture, is adversely affected. The most frequently encountered circadian rhythm disorders are shift-work sleep disorder, delayed sleep-phase disorder (DSPD , ‘’night owls”), advanced sleep-phase disorder (ASPD , “larks”), and non-24-hour-day syndrome. DSPD is most common in adolescents and ASPD is

most common in the elderly. Treatment for these disorders includes appropriately timed light and melatonin.

Parasomnias Parasomnias are sleep disorders in which undesired behaviors or experiences arise during sleep or from the sleep–wake transition and thus are often mixtures of states of consciousness. Patients with parasomnias complain mainly about the event itself rather than the quality of sleep. They are divided into those arising from NREM sleep and those that occur during REM sleep.

NREM Sleep Arousal Disorders This group of disorders occurs mainly in NREM 3 (slow wave) sleep. The most commonly encountered NREM sleep disorders include sleepwalking, and night terrors. Both of these NREM parasomnias are common in childhood (though rarely rise to become a disorder as they often are of little consequence) and, in most cases, resolve spontaneously by adolescence. However, persistence of the behaviors occurs in 1% to 5% of adults. Both NREM parasomnias are familial, with a 10-fold risk in those with affected first-degree family members. Both, especially sleepwalking, can be precipitated by benzodiazepine-receptor agonists, particularly zolpidem. Sleepwalking (somnambulism ) occurs predominantly during the first third of the night upon partial emergence from delta sleep. Individuals might walk for some distance and carry out semi-purposeful activities. Although most patients are quite adept at avoiding obstacles, serious accidents, such as tripping or falling down steps can occur. Sufferers are frequently only partially responsive to efforts to wake them, and, after they awake, are amnestic for the event. Common treatments include reassurance and provision of a safe sleep environment. In adults with life-long sleepwalking, more aggressive treatment might be indicated if these events are disturbing to sleep quality or make patients vulnerable to injury. Treatment is usually with short- to intermediate-acting benzodiazepine receptor agonists (e.g., triazolam). In adults with new-onset sleepwalking, an evaluation for underlying precipitants to these events is indicated, including psychiatric evaluation and overnight polysomnography. A specialized form of sleepwalking, sleep-related eating disorder, often has adolescent or young-adult onset, is predominant in women, and can be effectively treated with topiramate or SSRIs.

Night terrors (pavor nocturnus ) episodes, like sleepwalking, occur during partial arousal from slow-wave sleep. Patients might scream, jump out of bed and run, and experience autonomic activity, including tachypnea, tachycardia, and mydriasis. These episodes, often 1 to 10 minutes in duration, take place early in the night, when slow-wave sleep occurs. As with sleepwalking, patients are often amnestic to the episode. In children, it is often not associated with psychiatric illness, but in adults, it can be associated with post-traumatic stress disorder (PTSD). Treatment options, as with sleepwalking, include ensuring safety of the sleep environment, evaluation for underlying psychiatric and other sleep disorders (e.g., sleep apnea, restless legs syndrome), and use of short- to intermediate-acting benzodiazepine receptor agonists.

REM Sleep Parasomnias These parasomnias arise from REM sleep and include nightmare disorder and REM sleep behavior disorder. The hallmarks of nightmare disorder are extremely dysphoric lengthy recalled dreams, usually involving physical threat. Unlike sleep terror, nightmares frequently occur in the second half of the night (when REM sleep increases), terminate with rapid return to full alertness, and, distinct from REM sleep behavior disorder, are characterized by muscle atonia. Nightmare disorder is most common in young adulthood and in females, and is often co-morbid with psychiatric illness. Treatment is either with imagery rehearsal therapy (in which the patient rehearses some change to the nightmare daily while awake) or with prazosin. REM sleep behavior disorder is perhaps the most dramatic of all the sleep disorders. Because of the loss of muscle atonia during REM sleep patients actout dream content that can consist of a spectrum of behavior from verbalization to complex gross body movement. In contrast to the NREM parasomnias, which occur during the first third of the night during slow wave sleep, dream enactment in REM behavior disorder predominantly occurs during the second half of the night during REM sleep, with rapidly established alertness and often with good dream recall which is consistent with the enacted behavior. Patients usually come to medical attention because of injury to the patient (which can be substantial if they fall or jump out of bed) or to the bed partner. Diagnosis is usually made by polysomnography demonstrating dream enactment or excessive EMG activity during REM sleep. The two most common etiologies of REM sleep behavior disorder are use of serotonergic agents for mood or anxiety disorders and neurodegenerative disorders, particularly the synuceinopathies

(e.g., Parkinson’s disease). The disorder is more common in the elderly and in males. Discontinuation of a potentially iatrogenic medication (if not clinically contraindicated) is the best approach. Otherwise, use of high-dose melatonin or intermediate- to long-acting benzodiazepines, including lorazepam and clonazepam, can be helpful.

Restless Legs Syndrome Restless legs syndrome (RLS ) is a sleep-related sensorimotor disorder characterized by an overwhelming urge to move the legs, often with associated deep sensations of creeping or aching inside the legs when lying or sitting down. Movement provides temporary relief. The urge to move is most prominent, or only present, at night. After falling asleep, 90% of those with RLS have periodic limb movements of sleep (PLMS), which can further disrupt sleep quality. The prevalence of clinically significant RLS is roughly 2% of adults, more commonly with advancing age and in females. Genes producing increased risk for RLS have been identified. The prevalence is much higher in those with renal failure, iron-deficiency anemia, and pregnancy. Serotonergic agonists and dopamine antagonists can exacerbate the condition. Assessment of iron indices is essential, but polysomnography is usually not indicated. Treatment is directed toward correcting any iron deficiency (keeping ferritin > 50), and use of pharmacological agents, such as dopamine agonists (e.g., ropinirole, pramipexole) or a 2 -delta ligands (e.g., gabapentin, pregabalin).

Substance/Medication-Induced Sleep Disorder Substances , whether prescription medications or recreational drugs, can cause a wide range of sleep abnormalities that are often confused with primary sleep disorders. To make the diagnosis, the DSM-5 states that the history, physical, or laboratory examination must demonstrate that the substance is related to the sleep complaint and that the sleep disorder developed during or soon after use of or withdrawal from the substance. Generally, if the substance is a CNS depressant, intoxication causes sedation and withdrawal causes insomnia. Likewise, if the substance is a CNS stimulant, intoxication results in insomnia and withdrawal results in sedation. Because the list of substances is long, alcohol will be the only substance discussed here. Alcohol is a widely used and abused CNS depressant. In small to moderate amounts, it is sedating, and, while it induces sleep, it also causes frequent awakenings. In acute intoxication, alcohol decreases REM sleep and increases slow-wave sleep, whereas acute withdrawal

produces insomnia, increased REM sleep, and decreased slow-wave sleep. Paradoxically, chronic use frequently results in insomnia, and, if alcohol abuse or dependence is particularly long-standing, insomnia can be long-lasting after detoxification. If alcohol is the suspected cause of a sleep disorder, caution should be exercised with prescription of hypnotics (particularly benzodizepine receptor agonists) because the combined use of alcohol and sedatives can result in severe CNS depression, respiratory suppression, and death. However, if insomnia persists during abstinence, use of gabapentin has been associated with improved sleep and increased rates of long-term sobriety.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Aserinsky E, Kleitman N: Regularly occurring periods of eye motility and concomitant phenomena during sleep. Science . 1953; 118: 273–274. 3. Auger RR, Burgess HJ, Emens JS, et al: Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med . Official publication of the American Academy of Sleep Medicine. 2015; 11: 1199–1236. 4. Brower KJ: Assessment and treatment of insomnia in adult patients with alcohol use disorders. Alcohol . 2015; 49: 417–427. 5. Garcia-Borreguero D, Kohnen R, Silber MH, et al: The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med . 2013; 14: 675–684. 6. Howell MJ, Schenck CH: Rapid eye movement sleep behavior disorder and neurodegenerative disease. JAMA Neurology . 2015; 72: 707–712. 7. Jordan AS, McSharry DG, Malhotra A: Adult obstructive sleep apnoea.

8. 9. 10. 11.

Lancet 2014; 383: 736–747. Plante DT, Winkelman JW: Parasomnias. Psychiatric Clinics of North America . 2006; 29: 969–987. Saper CB, Fuller PM, Pedersen NP, et al: Sleep state switching. Neuron . 2010; 68: 1023–1042. Saper CB, Sehgal A: New perspectives on circadian rhythms and sleep. Curr Opinion in Neurobiology . 2013; 23: 721–723. Scammell TE: Narcolepsy. N Engl J Med . 2015; 373: 2654–3662.

12. Schutte-Rodin S, Broch L, Buysse D, et al: Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med . 2008; 4: 487–504. 13. Winkelman JW: Insomnia disorder. N Engl Med . 2015; 373: 1437–1444.

CHAPTER Disruptive, Impulse-Control, 26 and Conduct Disorders CHRISTOPHER M. TANGREN, MD AND MEREDITH CAITLIN BRADY, MD

KEY POINTS Overview Disruptive, impulse-control, and conduct disorders are a new category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition covering oppositional defiant disorder, intermittent explosive disorder, conduct disorder, pyromania, kleptomania, and other specified and unspecified disruptive, impulse-control and conduct disorder. These disorders fall on a spectrum between failure to control behavior (most prominent in conduct disorder) and failure to control emotions (most prominent in intermittent explosive disorder), with oppositional defiant disorder lying at the center of this spectrum. Epidemiology These disorders can affect individuals of any age, though some of the disorders (such as oppositional defiant disorder and intermittent explosive disorder) commonly begin in childhood. The prevalence for this group of disorders ranges from very rare (< 1% for kleptomania and pyromania) to more common (1%–16% for oppositional defiant disorder and 1%–5% for intermittent explosive disorder). Clinical Features These disorders share behavioral and emotional self-control problems that violate the rights of others and/or conflict with societal norms or authority figures. An experience of increased tension (e.g., dysphoria or arousal intensity) before committing the behavioral or an emotional outburst followed by a release of tension, a sense of gratification, or a sense of pleasure and relief during and after the act, continues to be a significant feature of these diagnoses.

Differential Diagnosis The differential diagnoses for these disorders includes attention deficit/hyperactivity disorder, anxiety disorder, learning disability, major depressive disorder, bipolar disorder, psychotic disorders, antisocial personality disorder, dementia, mental disorder secondary to a general medical condition, and adjustment disorder. Evaluation All the disorders discussed in this chapter are diagnosed clinically. Screening tools, such as the Minnesota Impulsive Disorders Interview may be of use. Other considerations include neuropsychological evaluation, neuroimaging, neurological evaluation, and medical assessment. Treatment There is no definitive approach to treatment of the disorders discussed in this chapter. However, for most of these disorders, a combination of pharmacotherapy and psychotherapy is useful. Other useful interventions include family therapy and parenting education.

Introduction This new category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) combines diagnoses—oppositional defiant disorder (ODD), intermittent explosive disorder , conduct disorder (CD ), pyromania , kleptomania , and other specified disruptive, impulse-control and CD, and unspecified disruptive, impulse-control and CD—that previously appeared in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). The common features of these disorders (i.e., behavioral and emotional self-control problems) involve violations of the rights of others and/or conflict with societal norms or authority figures. These disorders fall on a spectrum between failure to control behavior (most prominent in conduct disorder), and failure to control emotions (most prominent in intermittent explosive disorder), with oppositional defiant disorder lying at the center of this spectrum. An experience of increased tension (e.g., dysphoria, arousal intensity) before committing the behavioral, or an emotional outburst

followed by a release of tension, a sense of gratification, or a sense of pleasure and relief during and after the act continues to be a significant feature of these diagnoses. There can be a sense of guilt, regret, or self-reproach following the behavior. These disorders occur more commonly in men and tend to appear initially in childhood or adolescence. These disorders also share the personality features of high disinhibition and negative emotionality. This might provide some basis for the high co-morbidity among these disorders as well as among these disorders and antisocial personality disorder and substance use disorders. Controversy surrounds whether these conditions are distinct diagnoses or variants of another Axis I disorder. In some ways, they are similar to obsessive-compulsive disorder (OCD), substance dependence, mood disorders, and mental disorders due to a general medical condition. A similar etiology for OCD, eating disorders, mood disorders, paraphilias, and alcohol and substance abuse disorders is postulated because similar treatments work for each of these disorders. Patients diagnosed with impulse-control disorders have an increased risk of being diagnosed with substance abuse disorders, OCD and other anxiety disorders, eating disorders, and mood disorders. Moreover, there is an increased incidence of substance abuse disorders and mood disorders in family members of patients with impulsecontrol disorders.

Oppositional Defiant Disorder Definitions/Diagnostic Criteria Oppositional defiant disorder (ODD ) includes both behavioral and emotional symptomatology. Its diagnosis requires 6 months or more of at least four symptoms such as: frequent loss of temper; easy annoyance; frequent anger or resentment; frequent arguments with authority figures; frequent defiance or refusal to comply with rules or authority; frequent attempts to deliberately annoy others; frequent blaming of others for one’s misbehaviors or mistakes; and at least two instances of spitefulness or vindictiveness within the past 6 months. The subcategorization of these eight symptoms under the headings of Anger/Irritable Mood (symptoms 1–4), Argumentative/Defiant Behavior (symptoms 4–7) and Vindictiveness (symptom 8) is new to the DSM-5. For children under the age of 5 years, frequent means occurring most days within the 6-month window. For children 5 years and older, these symptoms must occur at least twice each week within the window. However, clinicians must also

consider what is normal for the patient’s developmental level, gender, and culture. To meet criteria for this diagnosis, the symptoms must cause distress in the patient or his social supports, or negatively affect the patient’s functioning at school, at work, or in social settings. This diagnosis cannot be made if these symptoms occur only in the context of a depressive, bipolar, psychotic, or substance use episode. The severity specifier relates to the number of settings in which the symptoms occur; mild symptoms occur in only one setting, moderate symptoms occur in at least two settings, and severe symptoms occur in at least three settings.

Epidemiology The prevalence of ODD is between 1% and 16%. Approximately 3% of children are diagnosed with ODD before their teenage years. Prior to puberty, the prevalence of ODD is higher in boys; however, after puberty, the male to female ratio equals out. Children in lower socioeconomic areas are more often diagnosed with ODD, but it occurs in all demographics. The onset of symptoms is gradual, usually appearing before the age of 8 years. Approximately onefourth of children diagnosed with ODD no longer meet the criteria after several years; others worsen and are eventually diagnosed with CD.

Evaluation/Examination Although there is no single test that diagnoses ODD, it is useful to conduct a standardized interview, to collect collateral information, to use rating scales, and create a graphic time-line of aggression. The severity of the diagnosis involves assessment of behavioral problems in different environments (e.g., school, home). It is also important to assess psychological, social, and biological risk factors. Specifically, children of parents with ODD, CD, substance use disorders, attention deficit hyperactivity disorder (ADHD), and mood disorders are more likely to develop ODD. Children in lower socioeconomic areas, with a history of family trauma (e.g., neglect, abuse), lacking appropriate supervision, with inconsistent discipline, or with a history of being bullied are at a greater risk for ODD. Additional biological risk factors include malnutrition and intrauterine exposure to drugs, alcohol, nicotine, or other toxins. Symptoms of ODD often present differently in each gender. Girls often lie and act uncooperatively, whereas boys act out with physical aggression or argue with authority figures.

Differential Diagnosis ODD is on the spectrum with CD and antisocial personality disorder. Although children and teenagers are not diagnosed with antisocial personality disorder before the age of 18, they can be diagnosed with CD if their behaviors are more severe and violate societal norms and rules. When making the diagnosis of ODD, it is important to assess for co-occurring mental health disorders, such as ADHD, anxiety disorders, mood disorders, learning disorders, and language disorders. Teens with untreated ODD are also at a higher risk for the development of substance use disorders.

Treatment Pharmacotherapy of ODD There is no FDA-approved medication for the treatment of ODD. Medications for ODD target co-morbid disorders (such as anxiety, depression, or ADHD). The atypical antipsychotic risperdone also targets aggressive behaviors in children and adolescents; however, there is little evidence to support its use in children with a diagnosis of ODD, and it has not been investigated in children under the age of 5.

Psychosocial Interventions for ODD Psychosocial interventions are the primary treatment for children and adolescents with ODD. Often individuals with ODD attribute their behavior to the faults of others and are not interested in altering their behavior. Therefore, individual psychotherapy with children is often unsuccessful. Instead, a combination of behavioral therapy, parent training, and family therapy is recommended to help children improve their frustration tolerance and develop problem-solving skills. In young children, early-intervention and school-based programs are used to supplement individual and family therapy. In adolescents, additional treatment modalities include vocational training and social skills classes. Regardless of age, parent management training has been effective when targeting both the behavioral and affective dimensions of ODD. Parent management training focuses on consistent parenting practices and behavioral management techniques to extinguish negative behaviors and promote positive behaviors. Techniques include in-vivo parent coaching, roleplaying during sessions, and home practice assignments. Three sub-types of parent management training used to target problem behaviors in older children

and teens are the Triple P–Positive Parenting Program, The Adolescent Transitions Program, and Collaborative Problem Solving; programs include: Incredible Years (for those younger than 8 years old; www.IncredibleYears.com ); Parent-child Interaction Therapy (PCIT) (for those younger than 8 years old; www.pcit.org ); Triple P–Positive Parenting Program (for those younger than 13 years old; www.triplep.net ); The Adolescent Transitions Program (aTp) (for those 11–13 years old; http://cfc.uoregon.edu/atp.htm ); and Center for Collaborative Problem-Solving (for those younger than 18 years old; www.explosivechild.com ).

Intermittent Explosive Disorder Definition Intermittent explosive disorder involves impulsive and episodic violent outbursts that cannot be better defined by a specific organic cause or by a concomitant psychiatric diagnosis. The DSM-5 diagnostic criteria require that these outbursts include either verbal or physical aggression (that occurs on average at least twice weekly over a 3-month period, not necessarily resulting in property damage or injury to animals or other people) and three outbursts during a 12-month period (resulting in property damage or destruction and/or physical injury to animals or other people). This aggressiveness must be out of proportion to any precipitating psychosocial stressors. These outbursts should not be premeditated or initiated as a means of achieving a tangible goal. The patient’s age must be at least 6 years; there must be patient distress, legal or financial consequences, or significant functional impairment. The aggressive episodes are not better accounted for by another mental disorder (e.g., antisocial personality disorder, borderline personality disorder, a psychotic disorder, a manic episode, CD, or ADHD) and are not due to the direct physiological effects of a substance or a general medical condition (e.g., head trauma). Aggressive outbursts related to an adjustment disorder should not be considered for this diagnosis in patients younger than 19 years old.

Epidemiology Although episodic violence of any type is common in our society, intermittent explosive disorder is considered rare. The prevalence is estimated to be between 1% and 5% among all psychiatric patients. However, the prevalence among those with a history of alcohol dependence or a co-morbid personality disorder may be as high as 25%. Men account for approximately 80% of the cases.

Symptoms generally start in adolescence and follow a chronic course (Olvera, 2002). Intermittent explosive disorder and personality change due to a general medical condition, aggressive type are the current diagnoses available to label a patient as having episodic violent behavior.

Evaluation Most violent behavior can be accounted for by other psychiatric, neurological, or medical conditions. The most common diagnosis for violence is personality change due to another medical condition (e.g., seizures, head trauma, neurological abnormality, dementia, delirium), aggressive or disinhibited type. Consideration should therefore be given to obtaining a neurology consultation, electroencephalography (EEG), a magnetic resonance imaging (MRI) scan, and neuropsychiatric testing. Personality disorders of the borderline or antisocial type must also be ruled-out. Psychosis from schizophrenia or a manic episode can cause episodic violence. Aggressive outbursts while intoxicated or while withdrawing from a substance of abuse would preclude the diagnosis of intermittent explosive disorder. In children, ODD and conduct disorder should be considered. Conducting a standardized interview, obtaining collateral information, and creating a graphic aggression time-line that also lists significant life events can be helpful.

Treatment Psychopharmacology is often employed in patients with intermittent explosive disorder. Placebo-controlled studies suggest that lithium, sodium valproate, selective serotonin re-uptake inhibitors (SSRIs), risperidone, and phenytoin are helpful in reducing aggressive behaviors. Controlled trials suggest some benefit from beta-blockers for those with brain injuries. Open-labeled trials have supported the use of carbamazepine to reduce aggression. Anecdotal evidence exists for the use of alpha2 agonists. Guanfacine is considered preferable to clonidine due to reports of sudden death in children taking clonidine. The acute management of aggressive and violent behavior might involve the use of physical restraints and rapid use of a combination of parenteral neuroleptics and benzodiazepines. Long-term management of outpatients with intermittent explosive disorder requires attention to the therapeutic alliance between the clinician and the patient. Behavioral techniques (including cognitive-behavioral therapy [CBT], social skills training, and behavioral management therapy) can be useful.

Conduct Disorder Diagnosis A child with CD has a pattern of behavior in which the rights of others or societal norms and rules are violated. Four categories of behavior are described: aggression toward people and animals; destruction of property; deceitfulness or theft; and serious violation of rules. The child must have at least three symptoms of the disorder from any of the aforementioned categories in the past year and at least one symptom in the past 6 months. Affected children have impairments in social, academic, and occupational function. If the individual is older than 18 years, he or she can be diagnosed with CD if the criteria for antisocial personality disorder are not met.

Subclassification and Specifiers There are three sub-types of the disorder: childhood onset (at least one criterion must be present before the age of 10 years), adolescent onset (no criteria are present prior to the age of 10 years), or unspecified onset (criteria are met, but age of onset cannot be determined). The specifier “With limited pro-social emotions” has been added in the DSM-5 to identify a group of individuals with CD who tend to demonstrate unemotional and callous traits. This specifier is given to individuals with CD who have at least 12 months of two or more of the following: lack of remorse or guilt; callousness or lack of empathy; lack of concern about performance at school or work; and shallow or deficient affect. Research suggests that individuals who meet criteria for this specifier tend to have more severe symptoms, a more limited response to treatment, and a worse prognosis.

Epidemiology There is an earlier average age of onset for boys (10–12 years) than for girls (16 years). Prognosis is worse with an earlier onset of the disorder; aggressive behavior is more common in this group. The prevalence is estimated at 2% to 10% with a range of 6% to 16% in males and 2% to 9% in females.

Differential Diagnosis The differential diagnosis for CD includes ODD, ADHD, major depressive disorder, bipolar disorder, intermittent explosive disorder, and adjustment disorder. However, none of these are diagnoses of exclusion for CD.

Treatment The mainstay of treatment for conduct disorder is behavioral therapy. There are no specific medications for the core symptoms for this disorder. The symptoms of aggression and agitation can be treated with medications (e.g., α -agonists, β blockers, mood stabilizers, antipsychotics). Regarding medications, the best evidence exists for risperidone and divalproex for aggression, and for stimulants in the setting of a CD (Epstein, 2015). It is important to assess and treat comorbid conditions.

Antisocial Personality Disorder This disorder is reviewed in Chapter 28 .

Pyromania Definitions The DSM-5 defines pyromania as the deliberate act of fire-setting on more than one occasion; increasing tension and/or affective arousal associated with the act; fascination, attraction, and curiosity about fires; obvious pleasure, gratification, or relief while setting fires, or when witnessing or participating in the aftermath of the fire-setting. To meet criteria, the fire-setting must not be executed for monetary gain, for expression of sociopolitical ideology, for concealment of criminal activity, for expression of anger or vengeance, for improvement of one’s living circumstances, in reaction to delusion or hallucination, or because of impaired judgment (e.g., major neurocognitive impairment, intellectual disability, substance intoxication). The symptoms must not be due to CD, a manic episode, or antisocial personality disorder. Pyromania is different from intentional fire-setting, which is a behavior, and arson, which is a crime.

Epidemiology Pyromania is a rare disorder with roughly 1% to 3% of repeat arsonists meeting criteria for pyromania. Recent studies suggest a considerably higher lifetime prevalence (6%) of pyromania among psychiatric inpatients. The incidence with co-morbid impulse-control disorders may be as high as 10% to 15% (Grant et al, 2007). Pyromania appears to have a preponderance in males, often with a history of fascination with fires that dates to childhood or early adolescence. Though not synonymous with pyromania, fire-setting appears to be significantly more common, occurring in approximately 8% of adolescent boys and 4% of

adolescent girls (Chen, 2003). The typical age of onset for pyromania is the midto-late teens. These patients typically present to treatment through the legal system.

Evaluation/Examination Pyromania is associated with a substantial risk of harm to self and others, and a thorough safety screen is paramount when evaluating patients who set fires. The risk of recidivism is associated with the early onset of childhood fire-setting, the total number of fire-setting offenses, verbalized threats to set fires, setting fires while alone, being unmarried, having low intelligence, a history of prolonged bed wetting, and male gender. Adolescents who set fires are more likely to have a history of physical or sexual abuse and to come from dysfunctional families. They are also more likely to have depressive symptoms that include suicide attempts and self-injurious behaviors. It is also important to differentiate the motive and circumstances related to fire setting. Primary gain (e.g., cathartic release, excitement, sexual pleasure, boredom) are more consistent with pyromania, whereas secondary gain (such as financial incentive, revenge, or crime concealment) are more consistent with antisocial personality disorder. Although there is no universal acceptance, several screening instruments (e.g., the Children’s Fire-setting Interview, the Fire-setting Risk Interview, and F.I.R.E Protocol) are available to assess for fire-setting behaviors in children and adolescents. The Minnesota Impulse Disorders Interview (MIDI) includes five questions that screen for pyromania in adolescents and adults.

Differential Diagnosis The differential diagnosis for pyromania includes intentional fire-setting (for profit, for political interests, or for revenge); delusions or hallucinations associated with schizophrenia or another psychotic disorder; fire-setting due to a manic episode with poor impulse control; dementia or another mental disorder caused by a medical condition that results in an impaired ability to acknowledge consequences of an act; as well as CD in children and antisocial personality disorder in adults. Fire-setting has also been associated with chromosomal disorders (such as Klinefelter’s syndrome, and XYY syndrome) as well as medical disorders (such as epilepsy, acquired immunodeficiency syndrome, and late luteal phase dysphoric disorder). Common co-morbidities with arson include substance intoxication and intellectual disability (Lindberg, 2005).

Treatment There is no definitive treatment for pyromania. Treatment is often multi-modal with pharmacotherapy, behavioral therapy, and family therapy (especially when children are involved). Although there is no FDA-approved medication for the treatment of pyromania, SSRIs, mood stabilizers, atypical antipsychotics, opiate antagonists, and anti-androgens have been used to reduce the symptoms of pyromania. Behavioral techniques include functional chain analyses (to identify the antecedents that lead up to fire-setting behaviors), relaxation training, firesafety instruction, and prevention programs (that aim to educate the offender on the financial, medical, and legal consequences of fire-setting).

Kleptomania Definitions More than 150 years ago, kleptomania was recognized as an out-of-character behavior of “nonsensical pilfering” in which worthless items were stolen. A characteristic increase in tension was relieved only by the act of stealing. Individuals in this category were not known to have a lifestyle of stealing or of premeditated thievery. Since its initial description, few systematic or scientifically rigorous studies have been conducted.

Diagnostic criteria The DSM-5 criteria for kleptomania include repetitive failure to resist the urge to steal objects not needed for personal use or for monetary value, an increase in tension immediately before committing the theft, a sense of pleasure, gratification, or relief associated with performing the theft, the absence of anger or vengeance while stealing, the absence of delusional or hallucinatory symptoms prompting the theft, and the absence of diagnostic criteria for a CD, a manic episode, or an antisocial personality disorder.

Epidemiology Although the prevalence of kleptomania in the general population is unknown, studies of subpopulations suggest that general prevalence might be between 0.4% and 0.7%. Shoplifting and kleptomania are not synonymous. Less than 5% of shoplifters meet criteria for kleptomania. There is often a lag time of many years (up to several decades) between the onset of the behavior and an individual’s presentation for treatment. Most individuals with this disorder begin

shoplifting behaviors in their teens and do not present for treatment until their 30s (Grant et al, 2009; Talih, 2011). Women are more likely than are men to be diagnosed with kleptomania by a ratio of 3:1 and on average present 1 to 2 decades earlier for treatment. Though no clear genetic links have been established, OCD and alcohol use disorder appear to occur more frequently in first-degree relatives of individuals with kleptomania as compared to those in the general population.

Evaluation/Examination Kleptomania tends to have its onset in later adolescence, though it can begin at any point throughout the life-span. Development in advanced age is uncommon and could be associated with the use of dopamine agonists for Parkinson’s disease. The course of kleptomania can be either sporadic and brief with long remissions, episodic and protracted, or chronic and intermittent over many years. Patients generally come to professional attention via court referral or by disclosure during treatment for a related psychiatric disorder. Ego-dystonic reactions to the behavior and to the unpremeditated nature of the stealing episodes can provide clues to the diagnosis. Scales to diagnose the disorder include the Kleptomania Symptom Assessment Scale (K-SAS) and the MIDI. Screening for common co-morbid disorders (such as mood disorders, anxiety disorders, substance use disorders, and eating disorders) should be included in the evaluation.

Differential Diagnosis The list of differential diagnoses for kleptomania includes criminal acts of shoplifting or stealing, malingering to avoid prosecution for theft, antisocial personality disorder, CD, manic episode, schizophrenia, and dementia.

Treatment Most of the literature on pharmacological treatment of kleptomania is based on case series, which often lack clear definitions. There are at present few controlled clinical trials. Treatment modalities are often guided by effectiveness in anxiety disorders and mood disorders. The strongest evidence available is for naltrexone, which was effective in two small, randomized placebo-controlled trials (Grant et al, 2002; Grant et al, 2009). Anecdotal reports of treatment success have been noted with SSRIs, specifically fluoxetine or fluvoxamine, as well as trazodone, mood stabilizers (e.g., lithium, sodium valproate), and anxiolytics (e.g., clonazepam, alprazolam). Other treatment modalities with

some promise include insight-oriented psychotherapy, CBT, using covert and aversive sensitization, and somatic therapies, including electroconvulsive therapy (ECT). A combination of psychotherapy and medication might be the most effective treatment.

Other Specified and Unspecified Disruptive, ImpulseControl, and Conduct Disorders Definition These diagnoses are used when patients do not meet full DSM-5 criteria for any of the previously discussed disruptive, impulse-control, and CDs, and yet when symptoms result in clinically-significant impairment or distress. The other specified diagnosis is used when the clinician wants to communicate the reason why the patient does not meet criteria for a specific disruptive, impulse-control, or CD (i.e., the patient has had an insufficient number of episodes). The unspecified descriptor is used in instances in which the clinician choses not to specify the reason why the diagnostic criteria are not met, as in situations for which insufficient information is available to make the diagnosis (e.g., in an urgent-care setting).

Epidemiology Much of the literature on this category focuses on repetitive self-mutilation. It is more common in women than in men. However, it is considered endemic in male prison populations. Two-thirds of self-mutilators have a history of sexual and physical abuse in childhood. Self-mutilation is also more common among those who have witnessed abuse in their family. The disorder starts in adolescence and is characterized by severe psychosocial morbidity. The incidence of self-mutilation is rising among adolescents; some studies suggest that at least 10% of adolescents self-mutilate.

Evaluation and Differential Theories about the etiologies of self-mutilation range from psychodynamic to psychobiology. Self-mutilation might give a quick sense of relief to stress and is often likened to an addiction. Evaluation should include screening for substance abuse and trauma.

Differential Diagnosis

The differential for repetitive self-mutilation includes borderline, narcissistic, and antisocial personality disorders; intellectual disability, as caused by LeschNyhan and deLange syndromes; hallucinations or delusions from a psychotic disorder; sexual sadomasochism; alcohol and substance abuse; and OCD.

Treatment Multi-modal and multi-disciplinary treatment is currently recommended (Williams et al, 2007). Prognosis is guarded and worsens with co-morbidity, with eating disorders, and with substance abuse disorders. Intentional or accidental suicide is common. Possible beneficial medications include SSRIs, serotonin norepinephrine re-uptake inhibitors (SNRIs), atypical antipsychotics (with aripiprazole and ziprasidone being the best studied), and the opioid antagonist, naltrexone (Turner et al, 2014). Other possibly helpful treatment modalities include psychodynamic psychotherapy, dialectical and CBT, emotion regulation group therapy, and involvement in self-help and 12-step programs.

Suggested References 1. Aboujaoude E, Koran LM: Impulse Control Disorders . New York: Cambridge University Press; 2010: p. 257. 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013: pp. 461–480. 3. Beck JC: Legal and ethical duties of the clinician treating a patient who is liable to be impulsively violent. Behav Sci & the Law . 1998; 16(3): 375– 389. 4. Epstein R, Fonnesbeck C, Williamson E, et al: Psychosocial and Pharmacologic Interventions for Disruptive Behavior in Children and Adolescents [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Oct. Report No.: 15(16)–EHC019-EF. 5. Folino JO, Abait PE: Pathological gambling and criminality. Curr Opin Psychiatry . 2009 Sep; 22(5): 477–481. PMID: 19571753. 6. Franklin ME, Zagrabbe K, Benavides KL: Trichotillomania and its treatment: a review and recommendations. Expert Rev Neurother . 2011 Aug; 11(8): 1165–1174. PMID: 21797657.

7. Grant JE, Kim SW: An open label study of naltrexone in the treatment of kleptomania. J Clin Psychiatry . 2002; 63: 349–356. 8. Grant JE, Kim SW, Odlaug BL: A double-blind, placebo-controlled study of the opiate antagonist, naltrexone, in the treatment of kleptomania. Biol Psychiatry . 2009 Apr 1; 65(7): 600–606. Epub 2009 Feb 12. PMID:19217077. 9. Grant JE, Odlaug BL, Davis AA, et al: Legal consequences of kleptomania. Psychiatr Q . 2009; 80(4): 251–259. 10. Grant JE, Won Kim S: Clinical characteristics and psychiatric co-morbidity of pyromania. J Clin Psychiatry . 2007 Nov; 68(11): 1717–1722. PMID: 18052565. 11. Iancu I, Lowengrub K, Dembinsky Y, et al: Pathological gambling: an update on neuropathophysiology and pharmacotherapy. CNS Drugs . 2008; 22(2): 123–138. PMID: 18193924. 12. Lindberg N, Holi MM, Tani P, et al: Looking for pyromania: characteristics of a consecutive sample of Finnish male criminals with histories of recidivist fire-setting between 1973 and 1993. BMC Psychiatry . 2005 Dec 14; 5: 47. PMID: 16351734. 13. Olvera RL: Intermittent explosive disorder: epidemiology, diagnosis and management. CNS Drugs . 2002; 16(8): 517–526. PMID: 12096933. 14. Oppositional Defiant Disorder: A Guide for Families. eAACAP on aacap.org. 2009. 15. Shatkin JP. Child & Adolescent Mental Health: A Practical, All-in-one Guide . New York: W.W. Norton; 2015. 16. Talih FR: Kleptomania and potential exacerbating factors: a review and case report. Innov Clin Neurosci . 2011 Oct; 8(10): 353–359. PMID: 22132369. 17. Turner BJ, Austin SB, Chapman AL: Treating non-suicidal self-injury: a systematic review of psychological and pharmacological interventions. Can J Psychiatry . 2014 Nov; 59(11): 576–585. 18. Williams KA, Bydalek KA: Adolescent self-mutilation diagnosis and treatment. Psychosoc Nurs Ment Health Serv . 2007 Dec; 45(12): 19–23. PMID: 18246860.

CHAPTER Adjustment Disorders, Grief, 27 and Bereavement GUY MAYTAL, MD AND ANA IVKOVIC, MD

KEY POINTS Adjustment Disorders Adjustment disorders are syndromes that occur when an individual is unable to cope or to adjust sufficiently to stressors. Symptoms of an adjustment disorder must occur within three months of the onset of the identifiable stressor(s), be out of proportion to what would normally be expected from the stressor, and lead to significant impairment of functioning. The differential diagnosis of adjustment disorders includes both normal stress reactions as well as major mental disorders. Psychotherapy is often the treatment of choice (e.g., cognitive-behavioral therapy, or supportive therapy). Pharmacotherapy can be helpful in managing symptoms (e.g., anxiety, insomnia). Grief and Bereavement Grief is a variable but normal and expected response to a significant loss. Bereavement is the emotional and cognitive process a person goes through when someone close to that person dies. A complicated grief reaction is one that causes more severe or protracted suffering and loss of functioning. If a person continues to have functional impairment (but does not meet criteria for a major mood disorder) lasting longer than a month after 6 months of bereavement, clinicians might consider a provisional diagnosis of a complicated grief syndrome. Management consists of supportive therapy and monitoring for and addressing any dysfunctional symptoms or additional psychiatric disorders.

Adjustment Disorders Overview Adjustment disorders are syndromes that occur when an individual is unable to cope or to adjust sufficiently to a stressor or life event. Although people with adjustment disorders sometimes present with symptoms similar to those of major depression (e.g., tearfulness, loss of interest, hopelessness), unlike those with depressive illness, when the stressor is removed or resolves, the symptoms of the adjustment disorder resolve, as well. A stressor is defined as an event of a serious or unusual nature that an individual or group of individuals experience. The stressors that cause adjustment disorders can range from the relatively common (e.g., a relationship ending) or can be more traumatic (e.g., being diagnosed with a terminal illness). It is thought that the more chronic or recurrent the stressor, the more likely it is to produce a disorder.

Epidemiology Epidemiologic studies report that 2% to 5% of outpatients are given the diagnosis of an adjustment disorder, though the prevalence ranges from 11% to 18% in primary-care settings and 10% to 35% of general hospital inpatients.

Clinical Features of Adjustment Disorders In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), adjustment disorders have been re-conceptualized as a heterogeneous array of stress–response syndromes that occur after exposure to a distressing (traumatic or non-traumatic) event, rather than as a residual category for individuals who exhibit clinically-significant distress. To meet clinical criteria for an adjustment disorder, the development of the emotional or behavioral symptoms must occur within three months of the onset of the identifiable stressor(s). The symptoms also must be out of proportion to what would normally be expected from the stressor, and they must lead to significant impairment in functioning. The emotional signs and symptoms of an adjustment disorder are variable and can include sadness, hopelessness, anxiety, worry, suicidal ideation, as well as neurovegetative symptoms. The behavioral signs and symptoms can include irritability, reckless behavior, ignoring important tasks, isolation, and aggressive behavior. However, unlike most other conditions in the DSM-5, adjustment disorders have no specific diagnostic criteria in terms of numbers or combinations of symptoms.

Suicidal behavior is prominent among people of all ages with adjustment disorders, and up to 20% of adolescent suicide victims might have had an adjustment disorder. However, patients with an adjustment disorder attempt suicide much less frequently than do those with depressive illness.

Etiology The biological underpinnings of adjustment disorders are largely unknown due to limited research on the disorder.

Evaluation of Adjustment Disorders To warrant a diagnosis of an adjustment disorder, the stress-related problem does not meet criteria for another mental disorder, and cannot represent an exacerbation of a previously diagnosed mental disorder. The symptoms also cannot represent normal bereavement. The DSM-5 categorizes adjustment disorders based on the predominant symptoms: depressed mood; anxiety; mixed anxiety and depressed mood; disturbance of conduct (seen frequently in pediatric populations); mixed disturbance of conduct and emotions; or is unspecified.

Differential Diagnosis of Adjustment Disorders The differential diagnosis of adjustment disorders includes both normal stress reactions as well as major mental disorders. Although difficult at times, it is important to differentiate an adjustment disorder from a normal reaction to a stressful event. At the same time, adjustment disorders must be distinguished from major mood disorders and anxiety disorders. This can pose a classification challenge because an adjustment disorder is a diagnosis based on the durations of symptoms in the setting of a stressor, whereas a diagnosis of major depression is a cross-sectional one based on the number of symptoms experienced.

Treatment of Adjustment Disorders Because an adjustment disorder is precipitated by a stressor, its treatment involves interventions that reduce the stressor (if that is possible), strengthen coping mechanisms, and maximize the patient’s support system. Psychotherapy is often the treatment of choice for such patients. Cognitive-behavioral therapy (CBT) allows the patient to think through the best strategies to manage the stressors in their lives. Also, supportive individual and/or family therapy can help the patient to express concerns in a safe environment and to obtain needed

support. For certain common stressors, such as an illness, support groups can provide information and support. Research is lacking regarding the treatment and biological underpinnings of adjustment disorders. Nevertheless, pharmacotherapy can be helpful in addressing management of anxiety or insomnia. Robust studies that demonstrate benefits from antidepressants in adjustment disorder are lacking. Treatment should not be withheld merely because a patient does not meet strict criteria for a major mental illness. In fact, an untreated adjustment disorder can, in some cases, develop into a full-blown depressive episode.

Grief and Bereavement Overview Grief is a variable but normal response to a significant loss. The terms grief, mourning, and bereavement are often used interchangeably, but they are distinct entities. The adjustment process that a person goes through after a loss is called grief. Grieving is normal and universal, and it should be expected after a significant loss. Bereavement is defined as the emotional and cognitive process a person goes through when someone close to that person dies. And, mourning is the outward expression of loss and grief after a death. Mourning often involves rituals and other actions that are specific to each person’s culture, personality, and religion. Bereavement and mourning are both part of the grieving process. The experience and expression of grief are affected by a multitude of factors, including cultural norms, personality style, and type of loss (abrupt or not, longterm relationship or not). Of note, a complicated grief reaction is one that causes more severe or protracted suffering and loss of functioning due to an inability to grieve appropriately, or the presence of a second psychiatric disorder.

Clinical Features of Grief and Bereavement Most people who experience grief can cope and recover well. However, at times the bereavement process can leave the bereaved at risk for developing secondary somatic and emotional problems. The presentation of grief often resembles a brief depressive episode, with sadness, insomnia, diminished appetite, and loss of interests. Feelings of guilt are common, as are wishes to die as a means of joining the deceased. The grieving person might experience several phases. The initial phase is often characterized by shock and disbelief. It can last for hours to days. The next phase, which can last for months, involves a

gradual realization and acceptance of the loss. It is characterized by waves of negative emotions (including sadness, anger, and hopelessness) between periods of normal functioning. These phases do not need to occur in sequence and often occur simultaneously or in a different order. If a patient experiences prolonged depression or suicidal thinking or desire, these should be taken as indicators of complicated grief or a major mental illness and treated accordingly. Typically, after 6 months to 2 years, the grieving person begins to accept the reality of the loss and begins to return to a functioning life. It is normal for the bereaved to re-experience symptoms from the first two phases when reminded suddenly of the loss, but these are much briefer and contained as compared to earlier phases. The important clinical indicator to monitor is the individual’s functioning. If the usual level of functioning is not restored, further evaluation for major mental disorders or a complicated grief reaction should be undertaken.

Evaluation and Differential Diagnosis of Grief and Bereavement Evaluation should include an assessment of the severity of depression, the presence of psychotic symptoms, alcohol or drug abuse, and suicidal ideation. Additionally, if the survivor witnessed the death, symptoms of post-traumatic stress disorder (PTSD) might appear. Particular attention should be paid to those grieving for someone who died by suicide. These individuals are at a higher risk of committing suicide themselves. The evaluation should also inquire into the patient’s network of social supports. Any symptoms of a major mental illness should be evaluated thoroughly. Although grief shares many of the neurovegetative symptoms of major depression, patients who are grieving usually can continue to function and do not have suicidal ideation. If neurovegetative symptoms and signs are severe enough to impair daily functioning, or if suicidal ideation is present, the examiner should consider the diagnosis of depression. It is noteworthy that in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the diagnosis of major depression excluded any patients with depressive symptoms that occurred for less than 2 months after the death of a loved one. This criterion was eliminated from the DSM-5. This was done for several reasons. First, the DSM-IV exclusion implied that bereavement typically lasts only 2 months, which is not the case. Second, bereavement is a psychosocial stressor that can precipitate a major depressive episode in a vulnerable individual at any time after the loss. Therefore, a person

can be bereaved and also be diagnosed with a major depressive episode at any time after a loved one’s death. If a person continues to have functional impairment (but does not meet criteria for a major mood disorder) lasting longer than a month after 6 months of bereavement, clinicians can consider a provisional diagnosis of a complicated grief syndrome. At this time, this is not an official DSM-5 diagnosis. But the DSM-5 review committee judged the body of empirical evidence to be both sufficient to establish the existence of a new psychiatric disorder, yet insufficient to unambiguously clarify its primary features. Therefore, it has been provisionally named “persistent complex bereavement disorder” (PCBD) and placed in the chapter on Conditions for Further Study in the DSM-5.

Management of Grief and Bereavement Management usually consists of being a supportive presence while the bereaved goes through the normal grief process after a death. Clinicians should monitor and address any dysfunctional symptoms (like insomnia) or any additional psychiatric disorders. Psychopharmacological interventions should be reserved for treating dysfunctional symptoms or managing any secondary depressive or psychotic disorder that are present. Psychotherapy may be helpful for prolonged grief symptoms or if the patient meets criteria for PCBD.

Suggested Readings 1. Casey P: Adjustment disorder: new developments. Curr Psychiatry Rep . 2014 Jun; 16(6): 451. 2. Clayton P, Desmarais L, Winokur G: A study of normal bereavement. Am J Psychiatry . 1968; 125(64): 168–178. 3. Powell AD: Grief, bereavement, and adjustment disorders. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry , 2nd ed. Philadelphia, PA: Elsevier; 2016: pp. 428–432. 4. Shear MK, Simon N, Wall M, et al: Complicated grief and related bereavement issues for DSM-5. Depress Anxiety . 2011; 28(2): 103–117.

CHAPTER 28 Personality Disorders GUY MAYTAL, MD AND ANA IVKOVIC, MD

KEY POINTS Overview Personality disorders are diagnosed in people with inflexible, maladaptive personality organizations that lead to significant interpersonal distress. Personality disorders are commo n, affecting 10% to 18% of the general population, 30% to 50% of outpatients, and more than 50% of inpatient populations. Given the ego-syntonic nature of personality disorders, individuals often resist treatment, and the course is typically chronic. Theories of etiology fall into several categories: genetic, biological/developmental, and psychological. In general, the mainstay of treatment for personality disorders is one of several types of psychotherapy. Psychopharmacology is reserved for targeting specific symptoms or for the treatment of co-morbid psychiatric disorders. Types of Personality Disorders Cluster A personality disorders (odd and eccentric) include paranoid, schizoid, and schizotypal personality disorders. – Paranoid personality disorder is characterized by a pervasive, persistent, and inappropriate mistrust of people. – Schizoid personality disorder is characterized by behavioral eccentricity and little desire for emotional ties or relationships. – Individuals with schizotypal personality disorder are odd and eccentric, frequently embracing beliefs (e.g., magical thinking) that exceed cultural norms. Cluster B personality disorders (dramatic, emotional, erratic) include antisocial, borderline, histrionic, and narcissistic personality disorders. – Antisocial personality disorder is characterized by repetitive unlawful acts and socially irresponsible behaviors with a disregard for the feelings and rights of others.

– Borderline personality disorder is marked by affective instability, impulsivity, and recurrent manipulative suicidal and parasuicidal behaviors. Brief reactive psychotic states or dissociative phenomena can occur with borderline personality and other personality disorders. – Histrionic personality disorder patients are overly concerned with appearance and attention and demonstrate exaggerated emotional responses, poor frustration tolerance, and impressionistic speech. – Narcissistic personality disorder is characterized by a grandiose sense of self-importance and frequent exploitation of others. Cluster C personality disorders (anxious and fearful) include avoidant, dependent, and obsessive-compulsive personality disorders. – The core feature of avoidant personality disorder is an excessive discomfort or fear in social relationships despite desiring relationships; anxiety disorders and social phobia are highly co-morbid. – People with dependent personality disorder have a strong desire for others to care for them and an extreme preoccupation with abandonment, often to the point they remain in abusive relationships. – Obsessive-compulsive personality disorder is characterized by perfectionism and a rigid adherence to rules.

Introduction Definition and Classification Defining something as central to human relationships as “personality” is a daunting task. So, for the purposes of this chapter, we offer the following general definition of personality: an enduring pattern of perceiving, relating, and thinking about the environment, others, and oneself that is seen in a wide range of social and personal situations. Personality is relatively stable and predictable over time; as such, it characterizes the individual in most situations. Most people develop personality structures that are relatively adaptable and fall into a range of flexibility that lets them engage with the world in a manner that is useful to them. However, the personality organizations of some individuals are inflexible, maladaptive, and lead to significant distress to themselves and to others. Such individuals are sometimes said to have personality disorders. Historically, many people (including clinicians) would label such patients as “bad” people who should be held accountable for their maladaptive behaviors. On the other hand, clinicians have just as frequently avoided making such diagnoses altogether out

of concern that such labels stigmatize their patients. However, it is now generally agreed that personality disorders are valid clinical syndromes that should be addressed and that can be treated. This chapter provides a general overview of personality disorders. First, we discuss the general classification system of personality disorders and theories of etiology. Then, we discuss each personality disorder and discuss of core features, prevalence, differential diagnosis, course, and treatment. The current taxonomy of personality disorders as found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) has undergone a transition. On the one hand, the official criteria for personality disorders in the DSM-5 have not changed from those in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). However, an alternative dimensional approach to the diagnosis of personality disorders was developed for the DSM-5 for further study and was included in the section “Emerging Measures and Models.” It will likely play a more central role in future editions of the DSM. Therefore, although this chapter focuses primarily on the traditional taxonomy, it also mentions the alternative approach. Some of the personality disorders share common features, so they are grouped into three categories. These are labeled clusters A , B, and C . Patients with cluster A personality disorders (which include paranoid, schizoid, and schizotypal personality disorders) appear to be odd and eccentric. Patients with cluster B personality disorders (which include antisocial, borderline, histrionic, and narcissistic personality disorders) share the common features of being dramatic, emotional, and erratic. Patients diagnosed with cluster C personality disorders (which include avoidant, dependent, and obsessive-compulsive personality distend to be anxious and fearful. Lastly, there are patients diagnosed with personality disorders whose presentation does not fall into any of the above classifications and thus fall into the category of “other personality disorders.” Given the complicated nature of human personality, patients frequently exhibit traits of more than one personality disorder. When criteria for more than one disorder are met, each disorder should be diagnosed in a hierarchical manner to identify which is primary.

Epidemiology Personality disorders are common in the general population, with an estimated prevalence of 10% to 18%. Furthermore, patients with personality disorders have a high rate of co-morbid major mental disorders. It is therefore not surprising

that the proportion of patients with personality disorders in clinical settings is much higher than it is in the general population. For example, in outpatient settings, the prevalence of patients with personality disorders is estimated at 30% to 50%, and on inpatient units, more than 50% of patients have a co-morbid personality disorder. Furthermore, of patients with major mental disorders, 34% have co-morbid personality disorders—most notably anxiety disorders and substance use disorders. And for patients who demonstrate recurrent suicidal gestures and acts, the prevalence of co-morbid personality disorders is 48% to 65%. Men and women are equally represented across personality disorders, though some personality disorders (e.g., antisocial personality disorder) have a higher prevalence in men, whereas others (e.g., borderline personality disorder) are more common in women.

Etiology Many theories have been proposed regarding the etiology of personality disorders. Although each provides helpful constructs, none fully explains so complex a process. Furthermore, given how different the personality disorders are from one another, it might be more useful to think of some of them as unique disorders with unique etiological processes. However, in general these theories fall into several categories: genetic, biological/developmental, and psychological. There is evidence to suggest that genetics plays a role in the origins of personality disorders. For example, cluster A personality disorders are more common in relatives of patients with schizophrenia; patients with cluster B personality disorders have more family members with mood disorders; and patients with cluster C personality disorders appear to have more relatives with anxiety disorders. Furthermore, genetic influence can play a larger role in some personality disorders (i.e., schizotypal and borderline) than in others (i.e., narcissistic or dependent). Developmentally, numerous studies have shown a strong correlation between childhood trauma (e.g., childhood physical or sexual abuse) and the development of certain personality disorders, especially borderline and antisocial personality disorders. Furthermore, children who grow up in an invalidating environment (even in the absence of physical abuse) are more likely to develop a personality disorder. Psychoanalytic theory is one of the oldest theories for explaining the etiology of personality disorders. Sigmund Freud argued that personality traits were the

product of fixation at a particular stage of psychosexual development. Wilhelm Reich, on the other hand, suggested that the personality arose from the pattern of defense mechanisms (unconscious mental processes that the ego uses to resolve conflict and thereby reduce anxiety and stress) that the individual consistently used. In non-personality-disordered patients, these defenses fall on a spectrum of flexibility and adaptability. In personality-disordered patients, defense mechanisms are inflexible and rigidly held, resulting in maladaptive behaviors. In other words, it can be said that such patients do not present with problems, but with “solutions that no longer work.” The pattern of defense mechanisms used by a patient can guide the clinician to the appropriate personality disorder diagnosis and treatment. Table 28-1 lists the more common defense mechanisms. Table 28-1: Common Defense Mechanisms Seen in Personality Disorders Defense Description Mechanism Projection

Unacceptable impulses and feelings are perceived and reacted to as though outside the self

Splitting

People are divided into “all good” and “all bad,” with rapid shifting from one extreme to another

Regression

An attempt to return to an earlier stage of functioning to avoid tension and conflict at the present level of development

Fantasy

An autistic retreat involving the creation of imaginary lives to avoid conflict and obtain gratification

Dissociation

A temporary and drastic replacement of an unpleasant mood state (or current personal identity) with a more pleasant mood state (or alteration in one’s sense of personal identity)

Intellectualization Excessive use of intellectual processes to avoid expression of affect Isolation

Separation of a cognitive process from its accompanying affect

Reaction formation

An unacceptable impulse is transformed to the opposite

Regression

A process by which an unwanted idea or feeling is held outside the conscious mind

Acting out

Direct observable action on an unconscious conflict to avoid being conscious of either

Passive aggression

Aggression toward others is expressed through passivity, masochism, and anger toward oneself

Treatment Personality disorders are deeply ingrained and ego-syntonic. Individuals with these disorders often resist treatment. However, as treatment modalities have developed for some personality disorders (particularly borderline personality disorder), stigma and the associated reluctance to engage in treatment has

decreased. The conventional treatment methods for these disorders are one of several psychotherapies, including cognitive-behavioral therapy (CBT), dialectical behavioral therapy (DBT ), and schema-focused therapy (SFT ). The principal goals of these modalities are to help the patient identify and address the manner in which their personality style and behavior is maladaptive, and thereby to promote change by enhancing insight, developing cognitive and interpersonal skills, and reducing or eliminating the maladaptive behavior. In general, pharmacologic treatments are not used as the primary treatment for personality disorders, because the benefits are unclear. However, in some cases, pharmacology can be used to target specific affective or behavioral symptoms (e.g., aggression, emotional lability, impulsivity, anxiety, depression, and psychosis) that are likely to respond to biological interventions.

Cluster A Personality Disorders Paranoid Personality Disorder The core feature of paranoid personality disorder is a pervasive, persistent, and inappropriate mistrust of people. These individuals are reluctant to confide in others; they assume that most people will harm or exploit them in some manner. In new situations, they search for confirmation of these expectations, and view even the smallest slight as significant. They unjustifiably question the loyalty of friends and significant others, and consequently are often socially isolated and avoid intimacy. They pride themselves on being rational and objective, but they appear to others as unemotional, affectively restricted, and hypervigilant. Their preferred defense mechanisms include projection, denial, and rationalization. One note of caution: when challenged or stressed in any significant way, these individuals can show profound anger, hostility, and referential thinking, or experience brief psychotic states that warrant acute psychiatric treatment. The prevalence of paranoid personality disorder in the general population ranges from 0.5% to 2.5%, increasing to 2% to 10% in outpatient settings, and 10% to 30% in inpatient settings. There appears to be an increased incidence in families with schizophrenia and delusional disorder. The diagnosis is much more common in men than women. The differential diagnosis for paranoid personality disorder most commonly includes delusional disorder (paranoid type), schizophrenia (paranoid type), and the other cluster A personality disorders (schizoid and avoidant personality disorders). With delusional disorder and schizophrenia, reality testing is absent

or highly impaired. But with paranoid personality disorder, reality-testing generally remains intact. In schizoid and avoidant personality disorders, there is much less paranoia (both in amount and intensity) as compared to paranoid personality disorder. As with most personality disorders, the course of paranoid personality disorder is often lifelong, with the best prognosis existing for those individuals with good ego strength and with a solid outside support system. Patients with a poorer prognosis tend to be those who have limited insight and little to no support system. Also, patients with co-morbid major psychiatric diagnoses (especially schizophrenia and substance abuse) have worse prognoses. Given that individuals with paranoid personality disorders avoid treatment, their treatment is challenging at best. In general, psychotherapy is the preferred modality when such patients engage in treatment. The emphasis is on support, consistency, and clarity. Recent studies support the use of low-dose antipsychotic agents and short-term use of benzodiazepines for paranoid ideation and at times of stress when severe anxiety, hostility, and psychotic decompensation emerge. Long-term pharmacotherapy rarely results in robust improvement, especially for non-psychotic and ego-syntonic paranoid ideation.

Schizoid Personality Disorder Individuals with schizoid personality disorder are eccentric loners who are emotionally detached and indifferent to the world around them. They have little desire for relationships or emotional ties, even with family members. In social situations, they withdraw, rarely make eye contact, and avoid spontaneous conversation. With respect to employment, they prefer non-competitive and isolative jobs with non-human themes, such as mathematics, or working night shifts (e.g., a night-time security guard). At times, these patients can have robust fantasy lives. Despite the apparent oddities, however, they possess clear thinking and intact reality testing. A helpful caricature of the schizoid personality would be the single, unfashionable, laboratory-oriented, absent-minded professor. Schizoid personality disorder affects about 1% to 7.5% of the population, with males diagnosed twice as often as females. As with paranoid personality disorder, the incidence of psychotic disorders in the relatives of these patients is higher, although this association is less robust. There is also a slightly higher incidence of this disorder in people with solitary and night jobs. The differential diagnosis for schizoid personality disorder includes schizophrenia, the other cluster A personality disorders (paranoid, obsessive-

compulsive, and avoidant), and autism-spectrum disorders. Intact reality testing, normal abstracting ability, and the absence of formal thought disorder distinguish schizoid personality disorder from schizophrenia. Patients with paranoid personality disorder experience more social involvement than do schizoid patients. Unlike patients with schizoid personality disorder, patients with obsessive-compulsive and avoidant personality disorders, although often socially isolated, view loneliness as ego-dystonic and enjoy a richer interpersonal history. Schizoid personality disorder usually begins in early childhood and has a lifelong course. Most individuals function reasonably well and have few problems that require intervention. In a few cases, however, this disorder can progress to schizophrenia or other psychotic states. Psychotherapy is the treatment of choice. Given the ego-syntonic nature of this illness, and these patients’ relative functionality, they rarely engage in therapy. When they do, supportive therapy is the mainstay, with some patients responding to insight-oriented psychotherapy. These patients generally do not desire group therapy, but after tolerating the interaction with others, groups can provide a means of improving social skills. Pharmacotherapy is often ineffective for the character pathology itself, and it should be reserved for co-morbid major psychiatric diagnoses.

Schizotypal Personality Disorder The essential features of the schizotypal personality are cognitive, perceptual, and behavioral eccentricities. Patients with this personality disorder frequently embrace beliefs (e.g., such as telepathy, clairvoyance, and magical thinking) to a degree that exceeds cultural and sub-cultural norms. Socially, they are inept and uncomfortable and therefore prefer to be alone. The style of their clothing might be inappropriate and strange, further reflecting their eccentric nature. Their speech is often vague, digressive, or inappropriately abstract, and they might talk to themselves in public. The content of that speech can also reflect ideas of reference, bodily illusions, and paranoia, but there is usually an absence of formal thought disorders, and reality testing is intact. Under periods of stress, however, these patients might decompensate into brief psychotic states. Schizotypal personality disorder affects about 3% of the population. Although there is no known genetic etiology, there appears to be a higher occurrence of this disorder in the biological relatives of patients with schizophrenia. The differential diagnosis for schizotypal personality disorder includes schizophrenia and several personality disorders. Paranoid and schizoid

personality disorder share many of the core features of schizotypal personality disorder but differ by degree and by absence of eccentricity. Borderline personality disorder shares unusual speech and an odd perceptual style, but it is associated with a stronger affect and connection to others. Patients with avoidant personality disorder, although uncomfortable and inept in social settings, are not eccentric, and they crave contact with others. Schizophrenia differs from schizotypal personality disorder in that the schizotypal patient possesses good reality-testing and lacks psychosis (except when they are in a decompensated state). The prognosis for this personality disorder is variable. Although some patients are able to establish stable relationships despite their eccentricities, others do not and can experience periods of brief reactive psychosis or schizophrenic decompensation. This observation as well as genetic data has led many clinicians to assert that schizotypal personality disorder is more phenomenologically and etiologically-related to schizophrenia than to the other cluster A disorders. Also, studies have demonstrated that about 10% of patients with this disorder commit suicide. The treatment for schizotypal personality disorder is mainly psychotherapy, with judicious use of pharmacologic interventions for psychotic symptoms and for other psychiatric disorders. Because these patients avoid social contact, they do not often present for treatment. When they do, however, the first and most important task is to establish an alliance. When this is accomplished, supportive therapy with social skills training becomes the mainstay for treatment. Pharmacotherapy should target co-morbid psychiatric disorders, with low-dose antipsychotics being used for brief psychotic decompensations.

Cluster B Personality Disorders Antisocial Personality Disorder The key features of antisocial personality disorder are repetitive unlawful acts and socially irresponsible behaviors that began prior to the age of 15 years. These individuals are generally unconcerned with the feelings and rights of others, and they often lack a sense of remorse for the harm they cause. Superficially, they can be very charming and engaging, yet beneath that surface, their world is an amoral one, frequently rife with illegal activity, deceit, and often with substance abuse and assaultive behavior. Patients with this disorder are indifferent to how their actions affect others; it is therefore not surprising that

antisocial personality disorder is perhaps the personality disorder most resistant to treatment. The National Institute of Mental Health Epidemiological Catchment Area study indicates that the prevalence of antisocial personality disorder is approximately 3% for men and 1% for women. Furthermore, up to 75% of the prison population carries the diagnosis. Patients with this disorder have an onset of conduct disorder before the age of 15 years and frequently suffer co-morbid attention deficit hyperactivity disorder, polysubstance disorders, and somatic symptom disorders. Although the exact etiology is unknown, this disorder occurs five times more commonly in first-degree relatives of men with the disorder. The differential diagnosis for antisocial personality disorder includes antisocial behavior, other cluster B personality disorders, mania, psychosis, substance abuse disorders, developmental delay (e.g., trisomy 21), and personality changes due to general medical conditions. With antisocial behavior, the actions are similar, but the history lacks a sense of degree and pervasiveness in the activities that would warrant a diagnosis of antisocial personality disorder. Patients with borderline personality disorder might perform illegal acts, yet they tend to demonstrate more repetitive suicidal and parasuicidal behaviors as well as intense affect and self-loathing—all of which is generally absent in antisocial patients. Bipolar mania can be difficult to separate from antisocial personality disorder, and patients with antisocial personalities can also have co-morbid bipolar disorders. For the most part, however, patients with bipolar disorder often lack the degree of childhood conduct problems, and their antisocial behavior is usually limited to manic episodes. Furthermore, after their mania resolves, they are likely to express remorse or regret for the antisocial behavior while manic. Patients with psychotic disorders might also perform criminal acts, but these acts are usually in response to delusions or internal stimuli. Substance abuse disorders can be especially difficult to differentiate from antisocial personality disorder because patients with antisocial personality disorder frequently engage in substance use. However, criminal behaviors associated with substance abuse disorders generally center on using and obtaining the drugs. Patients with intellectual disability might perform criminal acts, but they might be unable to appreciate that the acts are, in fact, illegal. Finally, patients with personality changes due to general medical conditions can display antisocial actions, but, for the most part, these individuals lack a criminal history prior to the precipitating condition, and the antisocial behavior resolves when the medical issue does.

Early indicators of emerging antisocial personality disorder include multiple delinquent acts before the age of 10 years, and a diagnosis of conduct disorder before the age of 15 years. The course is variable. Some improve during middle age as they come to the realization that society will no longer tolerate their behavior. Others end up in prison, experience the complications of drug dependency, or suffer violent deaths from injury, homicide, or suicide. As mentioned earlier, this disorder can be quite difficult to treat. Unfortunately, the most effective form of treatment appears to involve placement in confined settings or sustained incarceration, such as prison, where external constraints can substitute for their cognitive and affective deficits. If psychotherapy is attempted, behavioral therapy with a strong emphasis on legal sanctions is the most effective method of treatment. Pharmacotherapy should target co-morbid psychiatric disorders or dangerous and impulsive behaviors toward self and others.

Borderline Personality Disorder Borderline personality disorder is perhaps the best studied of all the personality disorders, and several effective treatments have been developed for its treatment. The salient features include: affective instability with rapidly shifting mood swings; impulsivity; identity disturbance (described as chronic boredom or emptiness); recurrent manipulative suicidal and parasuicidal behaviors (e.g., self-mutilation); and idealization/devaluation (“splitting”). Central to this disorder is an impaired capacity to form stable interpersonal relationships. When there is real or perceived separation in those relationships, these patients often react with intense fear and anger. If the fear of abandonment is realized or if they experience significant stress, the borderline patient might also experience brief reactive psychotic states or dissociative phenomena. Because such patients can exhibit symptoms that fall into both the psychotic and neurotic areas, they were given the label of “borderline.” Borderline personality disorder occurs in 2% to 3% of the population, with a 2:1 female/male ratio. It is the most prevalent personality disorder in all clinical settings (12%–15%), diagnosed in 51% of all psychiatric inpatients, and 27% of all psychiatric outpatients with a personality disorder. Such patients frequently have high levels of co-morbid mood disorders as well as co-morbid eating disorders, substance abuse, and post-traumatic stress disorder (PTSD). Additionally, about 75% of patients with borderline personality disorder will

attempt suicide during their life-time, and up to 10% will have completed suicide by the age of 30 years. There is an increased prevalence of mood disorders in families of borderline patients as well as an increased prevalence of this disorder in mothers of affected children. The differential diagnosis for borderline personality disorder includes other personality disorders, existential concerns about one’s identity, bipolar spectrum disorders, psychotic disorders, dissociative disorders, and substance use disorders. Borderline patients lack the peculiarity and referential thinking found in those with schizotypal personality disorder and the extreme suspiciousness seen in those with paranoid personality disorder. Histrionic, narcissistic, and dependent individuals have stable identities, can form solid interpersonal relationships, and rarely engage in self-mutilation or chronic suicidal behavior. Identity issues of the existential type differ substantially from borderline personality disorder in that the former are usually time-limited and linked to a developmental stage (late adolescence or early adulthood). Bipolar spectrum disorders can be challenging to distinguish from borderline personality disorder because the two can co-exist. However, the mood swings displayed by the borderline patient cannot meet criteria for manic or hypomanic episodes. Although the borderline patient might experience transient psychotic states, patients with a psychotic illness generally experience a persistent impairment in reality testing as well as a decline in overall functioning. Patients with substance use disorders frequently present with emotional lability and impulsive behavior. A diagnosis of borderline personality disorder should not be made during a substance-use episode. The symptoms of borderline personality disorder typically begin in adolescence or young adulthood. Clinicians are discouraged from diagnosing borderline personality disorder in patients below the age of 18 years. Although the course of borderline personality disorder is variable, data indicates that patients often have good prognoses. About one-third remit within 1 to 2 years of the diagnosis, whereas the rest continue to improve to some degree. The empirically-validated psychotherapeutic treatments for borderline personality disorder include psychodynamic treatment (mentalization-based and transference-based) as well as CBT, DBT, and SFTs). All these treatments have been shown to reduce symptom severity in borderline patients. DBT and mentalization-based therapies have been shown to be most effective. One of the major barriers to treatment for borderline patients is that many treaters have negative reactions toward them. It is important for staff to be aware

of such reactions and caution must be taken not to give in to those feelings when caring for these patients. Medications have not been shown to alter the course of borderline personality disorder, but they are often useful to target specific symptoms, including impulsivity, emotional lability, intermittent psychosis, and mood symptoms. Pharmacotherapy can be particularly indicated during periods when borderline patients pose more significant risk of harm to themselves or to others.

Histrionic Personality Disorder The salient features of histrionic personality disorder are pervasive overconcern with appearance and attention, exaggerated emotional response, poor frustration tolerance that ends in outbursts, and impressionistic speech that lacks detail. They view physical attractiveness as the core of their existence, and, as such, are often provocative in dress, have flamboyant mannerisms, and at times display behavior that is inappropriately seductive. They are superficially charming but in general are experienced by others as vain and lacking in genuineness. Histrionic personality disorder occurs in 2% to 3% of the general population. Although women receive the diagnosis more often, many clinicians feel that men are under-diagnosed. This disorder is more common in first-degree relatives of people with this disorder. The differential diagnosis for histrionic personality disorder includes other personality disorders, and somatic symptom disorder. Borderline personality disorder differs from histrionic personality disorder in that the borderline displays more despair and suicidal and parasuicidal behaviors. Likewise, the narcissistic patient is more preoccupied with grandiosity and envy than is the histrionic individual. The dependent personality-disordered patient, although sharing the need for acceptance and reassurance, lacks the degree of emotionality seen in histrionic personality disorder. Somatic symptom disorder can co-exist with histrionic personality disorder, but they are distinguished by the greater emphasis on physical complaints. As is the case with most personality disorders, the course is variable. Some experience an attenuation or softening of the core symptoms with age. Others experience a complicated course, including co-morbid somatic symptom disorders, dissociative, sexual, and mood disorders. Rarely, patients with histrionic personality disorder experience brief reactive psychotic states under stressful situations.

The treatment of patients with histrionic personality disorders consists primarily of individual psychotherapy, with an emphasis on emotional clarification and practical problem-solving. Psychopharmacology should be reserved for treatment of co-morbid psychiatric disorders.

Narcissistic Personality Disorder The hallmark of narcissistic personality disorder is an overwhelming and pathological self-absorption. These individuals possess a grandiose sense of selfimportance and feel that the people with whom they associate also need to have a similar world view. They often break conventional rules and exploit others to meet their self-serving ends. They generally lack empathy for others and have a difficult time understanding how the needs or goals of others can interfere with their plans. It is also often the case that beneath the facade of self-sufficiency and self-absorption these individuals are highly sensitive to any affront to their selfesteem—at times reacting with disproportionate emotional intensity, even brief psychotic decompensation. The exact prevalence for this disorder is unknown. The best estimates are that it occurs in less than 1% in the general population and 2% to 15% of the clinical population. What makes the differential diagnosis for narcissistic personality disorder so difficult is that other cluster B personality disorders often co-exist. Nonetheless, a few distinguishing features are helpful. The borderline patient differs from the narcissist in that the former is more impulsive, has a less-cohesive identity, and lives a more chaotic life. The histrionic patient, unlike the narcissistic patient, is more emotional and deeply involved with others. Although the narcissistic and antisocial patient both can exploit people, the primary motivation for the narcissistic patient is mostly control rather than specific material gain. Narcissistic personality disorder tends to have a chronic course. These patients frequently suffer from co-morbid mood disorders. Under stress, they might also experience brief reactive psychosis. Patients with narcissistic personality disorders often present to treatment for co-morbid major psychiatric disorders rather than for narcissism. The treatment of choice is combining psychopharmacology for psychiatric co-morbidities and individual psychotherapy—including analysis and insight-oriented techniques— for the personality disorder.

Cluster C Personality Disorders

Avoidant Personality Disorder The core feature of avoidant personality disorder is an excessive discomfort or fear in social relationships despite desiring relationships and human interactions. As a result of their fear, such patients generally avoid relationships with any substantial intimacy. They often experience pervasive and excessive awkwardness and shyness, and frequently have very low self-esteem. Avoidant personality disorder is common, occurring in about 1% to 10% of the general population. Temperament and disfiguring physical illnesses can be predisposing factors. It occurs equally among men and women. The differential diagnosis for avoidant personality disorder includes other personality disorders and social anxiety disorder. Unlike patients with avoidant personality disorder, those with schizoid personality disorder do not desire relationships with others. Social anxiety disorder can be very difficult to distinguish from avoidant personality disorder, and some clinicians even argue that they are the same diagnosis. However, other clinicians argue that the distinction between the two is that patients with social anxiety disorders have specific fears around social performances and being in public but can maintain close relationships with a small number of people in intimate settings. As long as the environment is perceived as safe and protective, patients with avoidant personality disorder are able to function in relationships, marry, and have families. As with most personality disorders, they are prone to mood disorders, especially depression and dysthymia. Due to the special nature of this disorder, however, they are at especially high risk for anxiety disorders and social phobia. Patients with avoidant personality disorders are frequently afraid of rejection and humiliation. Therefore, they often avoid treatment to begin with and are initially difficult to treat when they do engage. However, after they are assured of acceptance and safety, they respond to virtually all forms of therapy. Group therapy is the current standard of care, with a focus on CBT. Pharmacologically, anxiolytic medications help to manage situational anxiety, and antidepressants are effective for treating co-morbid anxiety and depression.

Dependent Personality Disorder Individuals with dependent personality disorder have a strong desire for others to care for them and an extreme preoccupation with abandonment. They fear being alone and will go to extreme lengths to preserve any relationship, no matter how difficult or even harmful it might be. They often behave in a

submissive and passive manner toward others, and fear that any direct expression of anger will end in rejection. Subsequently, they often look to others for assurance about simple daily decisions, to assure being liked or cared for. Dependent personality disorder occurs in 2% to 4% of the general population, and accounts for about 2.5% of all personality disorders, with women being more commonly affected than men. Patients with a history of childhood separation anxiety or chronic illness might be predisposed. There is no known familiar pattern of inheritance. Dependent personality disorder can be difficult to distinguish from other psychiatric conditions because many disorders have dependency as an underlying feature. The differential diagnosis for dependent personality disorder includes other personality disorders. Patients with histrionic personality disorder have issues of dependency but shorter and more numerous relationships. Borderline patients express more affect and anger around real or perceived abandonment, whereas dependent patients become more placating. When faced with rejection or termination of a relationship, avoidant patients withdraw from further contact, whereas dependent patients quickly seek out a new relationship to fill the void. The course of dependent personality disorder is rife with many co-morbid mood and anxiety disorders. Because of their dependency and lack of assertiveness, they might also become victims of physical and emotional abuse. Patients with dependent personality disorders respond well to various forms of individual psychotherapy. Group therapy with emphasis on cognitive techniques, assertive training, and social skills can be highly effective. As with the other personality disorders, pharmacotherapy should target co-morbid psychiatric disorders.

Obsessive-Compulsive Personality Disorder The major features of obsessive-compulsive personality disorder (OCPD ) are perfectionism and lack of compromise. These individuals are intensely preoccupied with rules, efficiency, trivial details, and procedures to such a degree that often they leave tasks incomplete. They maintain inflexible adherence to their own internally strict and unattainable standards. Such patients frequently possess a strong need for control and resist the authority and autonomy of others. This personality disorder is common in the general population, with men receiving the diagnosis more often than women. Although the mode of

transmission is unknown, it is more common among first-degree relatives of patients with this disorder. The principal differential diagnosis for OCPD is obsessive-compulsive disorder (OCD). Even though the two have similar names, they are substantially different disorders. Patients with OCD have true obsessions and compulsions that they find ego-dystonic. Patients with OCPD do not have compulsions or obsessions, but rather a rigid adherence to a set of self-imposed rules. Furthermore, these rules are ego-syntonic. Rarely, the two disorders co-exist, requiring a diagnosis for each. Several features of narcissistic personality disorder overlap with OCPD, particularly the desire for perfection, the need to dominate others, and a drive for achievement. However, patients with narcissistic personality disorder engage in these behaviors as a means to achieve status and recognition, whereas patients with OCPD do so in order to fulfill their internal idealized standards. The course for OCPD is variable. Even those patients who are able to negotiate intimate long-term relationship have few (if any) friends outside those relationships. With some patients, the disorder improves over time, whereas with others, depression, somatic symptom disorders, and substance abuse can emerge. Unlike other personality disorders, individuals with this disorder often realize the impact of their behavior and seek treatment on their own. They tend to improve with any number of treatment modalities, but particularly value a nondirective approach. Group therapy can be especially advantageous because it permits others to point out bothersome behaviors and call for change.

Other Personality Disorders This category includes several personality disorder diagnoses for patients that do not fit the aforementioned criteria. These include Personality Change Due to Another Medical Condition, Other Specified Personality Disorder, and Unspecified Personality Disorder. The first describes personality changes directly due to the pathophysiologic effects of a medical condition. The latter two are used for situations in which the patient does not fully meet criteria for any specific personality disorder. Other Specified Personality Disorder refers to situations in which the clinician communicates the specific reason why the patient does not meet criteria for a specific personality disorder. Unspecified Personality Disorder refers to situations in which the clinician chooses not to communicate the specific reason why the patient does not meet criteria for a specific personality disorder.

Alternative DSM-5 Model for Personality Disorders

As mentioned earlier, the DSM-5 preserved the current approach to personality disorders, but included an alternative model for further study and discussion in the section “Emerging Measures and Models.” The new approach aims to address many of the shortcomings of the current models. These include the fact that many patients meet criteria for several personality disorders. Furthermore, a diagnosis that requires a threshold number of symptoms on a checklist does not reflect that the nature of personality is dimensional. This new model involves three major changes. First, the definition of what constitutes a personality disorder has been changed. Rather than a pervasive pattern of maladaptive behavior, thinking, and feeling, the new model focuses on impairments in personality functioning and on pathological personality traits. The second change is that the categories of personality disorders now include only six personality types: antisocial, avoidant, borderline, narcissistic, obsessive-compulsive, and schizotypal. Also included is a diagnosis of Personality Disorder-Trait Specified for when a personality disorder is thought to be present, but the criteria for a specific disorder are not met. This latter category —based on moderate or greater impairment in personality functioning and the presence of pathological personality traits—gives patients and clinicians an informative diagnosis when criteria for a specific personality disorder are not met. The last innovation is that the diagnoses for personality disorders in this new model are underpinned by a dimensional structure that includes typical impairments in personality functioning and by characteristic pathological personality traits. The alternative approach purports to provide a clearer and more efficient approach for assessing and diagnosing personality disorders; however, as of now, it remains far from mainstream.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Text Revision. Washington, DC: American Psychiatric Publishing; 2013. 2. Cloninger RC Svrakic DM: Personality disorders. The Medical Basis of Psychiatry . New York: Springer; 2016: pp. 537–550. 3. Blais MA, Smallwood P, Groves JE, et al: Personality and Personality Disorders. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts

General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016: pp. 433–444. 4. http://www.psych.uic.edu/docassist/changes-from-dsm-iv-tr--to-dsm-51.pdf .

CHAPTER Psychiatric Disorders 29 Associated with the Female Reproductive Cycle RUTA M. NONACS, MD, PHD; CHARLOTTE HOGAN, MD; HELEN G. KIM, MD; ADELE C. VIGUERA, MD, MPH; AND LEE S. COHEN, MD

KEY POINTS In every age group, women have higher prevalence rates of depression than men. The National Co-Morbidity Study reported that the highest rates of depression occur in women during the reproductive years. Pre-menstrual syndrome (PMS) is variably defined as a constellation of emotional and physical symptoms that occur during the luteal phase (i.e., between ovulation and menses) of the menstrual cycle. Depending on the criteria used, the estimated prevalence for PMS ranges from 3% to 10%, although in some reports more than 80% of women experience one or two emotional or physical symptoms pre-menstrually. Although pregnancy has typically been considered a time of emotional wellbeing, recent studies suggest that up to 20% of women suffer from mood or anxiety disorders during pregnancy . Four types of risk are typically cited with respect to potential use of medications during pregnancy: risk of pregnancy loss or miscarriage, risk of organ malformation or teratogenesis, risk of neonatal toxicity or withdrawal syndromes during the acute neonatal period, and risk of long-term neurobehavioral sequelae. The baseline incidence of major congenital malformations in infants born in the United States is estimated to be 2% to 4%. During the earliest stages of pregnancy, formation of major organ systems takes place and is complete within the first 12 weeks after conception. For women with bipolar disorder, maintenance treatment with a mood stabilizer during pregnancy can significantly reduce the risk of relapse. During the post-partum period, about 85% of women experience some type of

mood disturbance. For most, the symptoms are mild and short-lived; however, 10% to 15% of women develop more significant symptoms of depression or anxiety. Post-partum psychiatric illness is typically divided into three categories: postpartum blues; post-partum depression (PPD); and post-partum psychosis. All psychotropic medications are secreted into the breast milk at varying concentrations; however, those concentrations appear to vary widely. The amount of medication to which an infant is exposed depends on several factors, including dosage of medication, rate of maternal drug metabolism, and frequency and timing of feedings.

Introduction Reproductive hormone fluctuations mark several important points in the female life cycle (e.g., around the menses, pregnancy, post-partum period, and menopause) that are often associated with mood and anxiety symptoms. Contrary to popular lore, research has not revealed a consistent association between female reproductive hormones and psychiatric symptoms but rather supports a more complicated interplay between hormonal shifts, psychiatric diathesis, and psychosocial factors.

Neuromodulatory Effects of Estrogen and Progesterone Estrogen and progesterone receptors have been identified in multiple areas of the central nervous system (CNS) including the amygdala, hippocampus, cingulate cortex, locus coeruleus, mid-brain raphe nuclei, and central gray matter. Estrogen and progesterone modulate the activity of the opioid, norepinephrine (NE), serotonin (5-HT), dopamine (DA), and γ -aminobutyric acid (GABA) neurotransmitter systems. These steroid hormones exert their effects on these neurotransmitter systems through multiple mechanisms: intracellular effects on gene transcription of factors involved in neurotransmission, direct effects on monoamine turnover and metabolism, and direct effects on nerve cell membranes and receptors. A growing body of literature suggests that estrogen and other gonadal steroids might modulate mood through their effects on the serotonergic neurotransmitter systems in the CNS. Animal studies have shown that estrogen stimulates the

down-regulation of central 5-HT2 receptors. In addition, estrogen stimulates the degradation of monoamine oxidase (MAO) and thereby increases levels of serotonin and other neurotransmitters at the synapse. Progesterone, on the other hand, inhibits the degradation of MAO, which decreases levels of these neurotransmitters. These findings are consistent with the purported antidepressant effects of estrogen and the adverse mood effects of progesterone. However, the exact neuromodulatory mechanisms as well as clinical uses of these hormones remain unclear.

Depression Through the Female Life Cycle Epidemiology In every age group , women have higher prevalence rates of depression than men. The National Co-Morbidity Study reported that the highest rates of depression occur in women during the reproductive years. The longest naturalistic, prospective study of first-episode major depression revealed no significant gender differences in time to recovery, time to first recurrence, or number of recurrent episodes (Simpson, 1997). The increased prevalence of depression among women thus might reflect increased risk of a first depressive episode in women of reproductive age.

Etiology There has been no consistent evidence that pre-menstrual-, pregnancy-, postpartum-, or peri-menopausalassociated psychiatric symptoms are correlated with abnormal levels of steroid hormones or gonadotropin release. Instead, it is believed that certain sub-groups of women might be vulnerable to changes in the female hormonal milieu and thus can develop mood and anxiety symptoms in response to fluctuations in hormone levels. History of affective illness also seems to predict potential risk for reproductive cycle-related mood disorders. This finding has led researchers to wonder whether these disorders represent separate diagnostic entities or rather exacerbations of an underlying mood or anxiety disorder. Psychosocial and psychodynamic factors also seem to be associated with increased risk of affective symptoms during different stages of the reproductive cycle.

Pre-Menstrual Syndrome and Pre-Menstrual Dysphoric Disorder Definitions Pre-menstrual syndrome (PMS ) is variably defined as a constellation of emotional and physical symptoms that occur during the luteal phase (i.e., between ovulation and menses) of the menstrual cycle. Criteria for pre-menstrual dysphoric disorder (PMDD ) are defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and specify the following symptoms, timing, and severity parameters. In most menstrual cycles during the past year, five (or more) of the listed symptoms must be present during the last week of the luteal phase and remit within a few days after the onset of menses. At least one symptom must be one of the core symptoms listed in Criterion B: (1) marked affective lability (e.g., mood swings, feeling suddenly sad or tearful, or increased sensitivity to rejection); (2) marked irritability or anger or increased interpersonal conflicts; (3) marked depressed mood, feelings of hopelessness, or self-deprecating thoughts; and, (4) marked anxiety, tension, and/or feelings of being keyed up or on edge. Other symptoms can include: decreased interest in usual activities; poor concentration; lack of energy; change in appetite; sleep disturbance; a sense of being overwhelmed; and various physical symptoms (including breast tenderness, headaches, joint or muscle pain, bloating, and weight gain). According to the criteria provided, these symptoms are associated with clinically-significant distress or interference with work, school, usual social activities, or relationships with others.

Epidemiology PMS is extremely prevalent in the general population. Depending on the criteria used, the estimated prevalence for PMS ranges from 3% to 10%, although in some reports more than 80% of women experience one or two emotional or physical symptoms pre-menstrually. PMDD affects far fewer women and has a prevalence rate of approximately 2% to 5% of reproductiveaged women in the United States.

Etiology There is no consistent evidence that PMS or PMDD are associated with abnormal levels or release of circulating gonadal hormones. Moreover, levels of other hormones (e.g., thyroid hormones, cortisol, prolactin, prostaglandins, β -

endorphins) do not differ in women with PMDD from those without this disorder. Because specific abnormalities in hormone levels have not been observed in women with PMDD, it is believed that pre-menstrual symptoms occur as a result of a differential sensitivity to the normal fluctuations in the levels of gonadal steroids that occur during the menstrual cycle. Because premenstrual mood disorders cluster in families, it is probable that the etiology of this “differential sensitivity” might be in part genetically determined. Supporting a genetic basis for this disorder is the recent identification of an allelic variation in the estrogen receptor alpha gene in women with PMDD (Huo et al, 2007). Several studies have identified various abnormalities in the serotonin system in women with PMS and PMDD, including abnormal levels of whole-blood serotonin, serotonin platelet uptake, and platelet imipramine binding. Other studies have demonstrated that women with PMDD have decreased luteal-phase levels of GABA, abnormal levels of allopregnanolone (a metabolite of progesterone and potent modulator of GABAA receptors) and decreased lutealphase sensitivity of the GABAA receptor. Imaging studies have reported altered serotonergic and GABA-ergic function in women with PMDD as compared to healthy controls with no pre-menstrual mood changes.

Assessment of the Patient with Pre-Menstrual Complaints To make the diagnosis of PMDD , women must have regular ovulatory cycles. A woman with a history of spontaneous, regular menstrual cyclicity likely has normal menstrual function. The medical history should be reviewed for syndromes that could mimic PMDD. For example, endometriosis can cause significant mood symptoms and pelvic discomfort prior to and during menses. In addition, certain conditions (e.g., migraines, epilepsy, herpes) can worsen premenstrually and can be associated with various psychiatric symptoms (e.g., anxiety, depression, sleep disturbance). The psychiatric history should include a review of symptoms during other periods of hormonal fluctuation (e.g., during pregnancy and the, post-partum period), which can reflect an increased vulnerability to PMDD. Prospective daily rating of symptoms over two consecutive cycles is essential to making the diagnosis of PMDD. Rubinow and colleagues (1984) reported that less than 50% of women who present with complaints suggestive of PMDD actually had a premenstrual pattern of symptoms on prospective scales. Different Axis I or II diagnoses can be exacerbated pre-menstrually; luteal phase symptoms that persist into the follicular phase of the cycle (after the onset of menses) go against

PMDD and instead point to a pre-menstrual exacerbation of another Axis I disorder. Careful prospective documentation of symptoms throughout the cycle can help clarify the diagnosis and lead to appropriate work-up and treatment.

Non-Pharmacologic Treatment of PMS and PMDD Lifestyle changes can help to ameliorate the symptoms of PMS and PMDD . For women with mild symptoms, these interventions should be tried before pharmacological treatment. Although solid evidence is lacking, clinicians generally recommend that patients with PMS or PMDD decrease or eliminate the intake of caffeine, sugar, and sodium. Other helpful lifestyle modifications include decreasing alcohol and nicotine use and ensuring adequate sleep. Also, regular aerobic exercise has been demonstrated to have beneficial effects on both the emotional and physical symptoms of PMS/PMDD. Certain nutritional supplements have also been shown to improve premenstrual symptomatology. A large, multi-center trial of calcium supplementation found that 1,200 mg of calcium/day significantly reduced both the physical and emotional symptoms of PMS. Other studies have demonstrated that Vitamin B6 in doses of 50 to 100 mg/day can have beneficial effects in women with PMS; however, patients must be cautioned that doses above 100 mg/day can cause peripheral neuropathy. Limited evidence suggests that magnesium (200–360 mg/day) and Vitamin E (400 IU/day) can provide modest relief of symptoms. Herbal remedies can have some role in the treatment of pre-menstrual symptoms. One recent double-blind, placebo-controlled trial concluded that agnus castus fruit extract (1 tab/day), also known as chasteberry, significantly decreased pre-menstrual symptoms of irritability, anger, headache, and breast fullness when compared to placebo. In another study, gingko biloba was found to improve PMS symptoms, particularly breast tenderness and fluid retention. Though early evidence suggested that evening primrose oil was a useful treatment of PMS, a recent review of studies found that it was no more effective than placebo. Other botanical remedies, including black cohosh, St. John’s wort, and Kava Kava , are used clinically but require further investigation. Psychotherapy offers another non-pharmacologic approach to the treatment of PMS and PMDD. A recent study found that cognitive-behavioral therapy (CBT) was as effective as fluoxetine (Prozac, 20 mg daily), in the treatment of women with PMDD. Other studies have suggested that cognitive approaches can be useful in helping to reduce pre-menstrual symptoms.

Pharmacologic Treatment of PMDD Selective serotonin re-uptake inhibitors (SSRIs) are first-line pharmacological agents for the treatment of PMDD. A significant body of evidence, including numerous double-blind, randomized studies, supports the effectiveness of SSRIs in reducing both the emotional as well as physical symptoms of PMS and PMDD. In general, women respond to low doses of SSRIs, and this treatment response usually occurs rapidly, often within several days. SSRIs can be prescribed continuously throughout the menstrual cycle, or can be given in an intermittent fashion during the luteal phase of the cycle. Studies have also questioned whether initiating medication at the onset of symptoms might be effective for some women. Other antidepressants that inhibit serotonin re-uptake, including clomipramine (a tricyclic antidepressant) and serotonin-norepinephrine re-uptake inhibitors (SNRIs) venlafaxine (Effexor) and duloxetine (Cymbalta) have also been shown to be effective for the treatment of PMDD. Among other psychotropic medications used in the treatment of PMS and PMDD, the benzodiazepine alprazolam (Xanax) has been shown to have benefit in reducing pre-menstrual symptomatology, in particular pre-menstrual anxiety. However, this medication should be prescribed cautiously, given its potential for addiction and abuse. Buspirone (BuSpar), a 5-HT1A serotonin receptor partial agonist, used at mean doses of 25 mg per day, was shown to be effective in a small, placebo-controlled, double-blind study, though larger controlled trials are needed to confirm this finding. For women who are ultimately diagnosed with a pre-menstrual exacerbation of a mood disorder, there are several treatment options. These women require treatment throughout the menstrual cycle and typically do not respond well to intermittent dosing of SSRIs. In a patient already taking an SSRI, it might be helpful to raise the dose of the antidepressant during the luteal phase and return to a lower level at the onset of menses. In addition, a recent study also found that adding oral contraceptive pills (OCPs) to the antidepressant regimen in these women can improve residual mood symptoms that occur prior to menstruation. Women with bipolar disorder who experience mood worsening pre-menstrually should consider antidepressant use carefully because switching to mania/hypomania is an associated risk with antidepressant use or increased antidepressant dosing.

Hormonal Interventions

Hormonal treatments of PMS and PMDD are based on the principle that suppression of ovulation eliminates pre-menstrual symptomatology. Results from studies using OCPs to treat PMS and PMDD have been mixed. However, one recent study supported the usefulness of an OCP (Yasmin) containing drospirenone, an analog of the diuretic spironolactone, in the management of pre-menstrual symptoms. Preliminary research also suggests that continuous treatment with OCPs may have efficacy for treating PMS symptoms. Some women need to avoid OCPs, especially if there is a history of blood clots, strokes, and migraines. Women who are 35 years of age and older and who smoke should not use OCPs. Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide, which suppress ovarian function, have been found to reduce pre-menstrual symptoms in most studies. These medications, however, cause estrogen to fall to menopausal levels and are thus associated with side effects (such as hot flashes and vaginal dryness) as well as an increased risk of osteoporosis. These side effects can be mitigated by “add-back” therapy with estrogen and progesterone. Similarly, danazol, a synthetic androgen, is an effective therapy for PMS/PMDD when given in doses high enough to inhibit ovulation. However, this medication is associated with significant androgenic side effects, including acne, hirsutism, and weight gain.

Psychiatric Illnesses During Pregnancy Introduction Although pregnancy has typically been considered a time of emotional wellbeing, recent studies suggest that up to 20% of women suffer from mood or anxiety disorders during pregnancy . Particularly vulnerable are those women with histories of psychiatric illness who discontinue psychotropic medications during pregnancy. In a recent study that prospectively followed a group of women with histories of major depression across pregnancy, of the women who discontinued antidepressant treatment proximate to conception, 68% relapsed, as compared to 26% of the women who maintained treatment throughout pregnancy. This study estimated that women who discontinued medication were five times as likely to relapse as were women who maintained treatment. High rates of relapse have also been observed in women with bipolar disorder. One study indicated that during the course of pregnancy, 71% of the women experienced at least one mood episode. The risk of recurrence was significantly

higher in women who discontinued treatment with mood stabilizers (86%) than those who maintained treatment (37%). Although data accumulated over the past 30 years has suggested that some medications can be used safely during pregnancy, knowledge regarding the risks of pre-natal exposure to psychotropic medications is incomplete. Thus, it is relatively common for patients to discontinue or to avoid pharmacologic treatment during pregnancy. Psychiatrists must help patients weigh the risks of pre-natal exposure to psychotropic medications against the risks associated with untreated psychiatric illness in the mother. Although there is increasing data to help inform these difficult decisions, there still remain many unanswered questions regarding the risks of medication exposure.

Non-Pharmacological Treatments Pregnancy often evokes feelings about one’s early life, doubts about one’s capacity to mother, and changing family and work roles. Helping women to understand these conflicting feelings can be an important therapeutic intervention both during and after pregnancy. For mild depression and anxiety, many women benefit from supportive, interpersonal, and integrative psychotherapy. For more severe symptoms during pregnancy, patients can pursue treatment with psychotropic medications, in addition to psychotherapy and other supportive interventions.

Categories of Risk Associated with Pharmacotherapy Randomized , placebo-controlled studies that have examined effects of medication use on pregnant populations are lacking and are largely considered unethical. Therefore, much of the data related to the profile of reproductive safety for a medication is derived from retrospective studies and case reports. Studies that have evaluated the reproductive safety of some medications, including antidepressants, have used a more rigorous prospective design; however, many studies have relied on large administrative databases or multicenter birth-defect surveillance programs. Four types of risk are typically cited with respect to potential use of medications during pregnancy: risk of pregnancy loss or miscarriage, risk of organ malformation or teratogenesis, risk of neonatal toxicity or withdrawal syndromes during the acute neonatal period, and risk of long-term neurobehavioral sequelae. In the past, a system established by the United States Food and Drug Administration (FDA) classified medications according to five pregnancy risk categories: A, B, C, D, and X. Because this system of

classification was often ambiguous and could lead to unwarranted conclusions regarding reproductive safety, the FDA replaced this system with the Pregnancy and Lactation Labeling Rule (PLLR) in June 2015, which requires more descriptive safety information regarding pregnancy and lactation in the drug label. This includes a risk summary, clinical considerations, and data subsections for use in pregnancy, lactation, and treatment of patients with reproductive potential. The letter classification system is now being phased out and will be replaced by these more nuanced descriptions.

Risk of Teratogenesis The baseline incidence of major congenital malformations in infants born in the United States is estimated to be 2% to 4%. During the earliest stages of pregnancy, formation of major organ systems takes place and is complete within the first 12 weeks after conception. Therefore, any discussion regarding the risks of exposures during pregnancy must take into consideration the timing of exposure, with particular vigilance surrounding exposures taking place during the first trimester. A teratogen is defined as an agent that interferes with the in utero process of development and results in some type of organ malformation or dysfunction. For each organ or organ system, there exists a critical period during which development takes place, during which the organ is susceptible to the effects of a teratogen. For example, neural tube folding and closure, which forms the brain and spinal cord, occur within the first four weeks of gestation. Most of the formation of the heart and great vessels takes place from 4 to 9 weeks after conception.

Risk of Neonatal Symptoms Neonatal toxicity or perinatal syndromes (sometimes referred to as “poor neonatal adaptation”) refer to a spectrum of physical and behavioral symptoms observed in the acute neonatal period that can be attributed to drug exposure at or near the time of delivery.

Risk of Behavioral Teratogenesis Behavioral teratogenesis refers to the potential of a psychotropic drug administered during pregnancy to have long-term neurobehavioral effects. To date, few studies have systematically investigated the impact of exposure to psychotropic medications in utero on development and behavior in humans.

Risk of Untreated Maternal Psychiatric Illness Maternal psychiatric symptoms might jeopardize the well-being of both the mother and her fetus. For instance, severe depression and anxiety can lead to decreased self-care, poor eating habits, weight loss, increased suicidality, and behaviors that can undermine a woman’s participation in routine pre-natal care. In addition, women who have untreated psychiatric symptoms during pregnancy are more likely to use tobacco, alcohol, and recreational drugs, behaviors that carry significant risk to the developing fetus. Furthermore, there is mounting evidence to indicate that the physiological changes associated with untreated psychiatric illness in the mother might contribute to poor neonatal outcomes and higher rates of obstetric and neonatal complications (e.g., lower Apgar scores, pre-eclampsia, preterm birth, low birth weight).

Antidepressants Some studies have reported an increased risk of spontaneous miscarriage in women taking antidepressants; however, the findings have been inconsistent. When compared to women with depression (as opposed to women with no history of psychiatric illness), women on antidepressants do not experience a higher rate of miscarriage. Regarding teratogenic risk, SSRIs have been studied extensively for safety during pregnancy. Large studies are reassuring; as a group of medicines, SSRIs are not major teratogens and do not increase risk of congenital malformation. Initially, some reports suggested that first-trimester exposure to paroxetine was an exception to this finding and reported that paroxetine was associated with an increased risk of cardiac defects (including atrial and ventricular septal defects). More recent assessment of the data, including independent, peer-reviewed, comprehensive meta-analyses of studies assessing paroxetine exposure during the first trimester failed to demonstrate the increased teratogenicity of paroxetine. Therefore, like other SSRIs, paroxetine can still be considered a firstline agent for women who have responded well to it before pregnancy. SNRIs , including venlafaxine and duloxetine, have been less well studied than other classes of antidepressants during pregnancy, but emerging data is reassuring that first-trimester exposure to these medications is not associated with a clinically important increase in risk of major congenital malformations. Bupropion might be an attractive option for women who have not responded well to SSRIs or SNRIs. Most data thus far has not indicated an increased risk of

malformations associated with bupropion use during pregnancy. However, one recent study suggested the possibility of a small increase in risk of cardiovascular malformations. Bupropion deserves special consideration if a woman is attempting to abstain from smoking during pregnancy because it helps with smoking cessation, and cigarettes are teratogenic. Although used less commonly, there is data to support the use of tricyclic antidepressants (TCAs). Three prospective and more than 10 retrospective studies have examined the risk of organ malformation in more than 400 cases of first trimester exposure to TCAs. When evaluated on an individual basis and when pooled, these studies do not indicate a significant association between fetal exposure to TCAs and risk for any major congenital anomaly. Among the TCAs, desipramine and nortriptyline are often preferred because they are less anticholinergic and the least likely to exacerbate orthostatic hypotension that occurs during pregnancy. With regard to other antidepressants, smaller prospective studies have evaluated outcomes in infants exposed to mirtazapine (Remeron, n = 104), nefazodone (Serzone, n = 89) and trazodone (Desyrel, n = 58); there were no significant differences among exposed and non-exposed groups with regard to rates of congenital malformations. To date, the literature does not include prospective data on the use of vortioxetine (Trintellix) or vilazodone (Viibryd). In general, it is estimated that at least 400 to 600 exposures would be required to detect a 2-fold increase in more common malformations. Thus, clinicians typically avoid the use of these antidepressants with fewer numbers of exposures in the literature and, if needed, switch to another antidepressant which is better characterized. Scant information is available regarding the reproductive safety of monoamine oxidase inhibitors (MAOIs), and these agents are generally not used in pregnancy because they can produce a hypertensive crisis when combined with tocolytic medications such as terbutaline. Despite the growing literature that supports the relative safety of fetal exposure to SSRIs, multiple reports, have described adverse peri-natal outcomes (including decreased gestational age at delivery, low birth weight, and poor neonatal adaptation). However, other reports have not noted these associations. Particular concern has been raised regarding the potential effects of latepregnancy exposure to SSRIs; some newborns who were exposed to SSRIs exhibit a transient period (limited to several days following delivery) of jitteriness, increased muscle tone, tremulousness, and tachypnea. In general, this

syndrome of poor neonatal adaptation is a benign event that does not require any specific medical intervention. Based on these findings, many women are advised to taper or discontinue treatment with an SSRI prior to delivery; however, this strategy has not been shown to change neonatal outcomes. Importantly, neonatal effects have been reported with both untreated mood and anxiety disorders as well as with medication, and limited studies have adequately teased out these variables. One important consideration is that discontinuation of, or reduction in, the dosage of medication in the latter part of pregnancy might increase the risk of post-partum depression (PPD), given that the post-partum period is a time of increased vulnerability to psychiatric illness. Conflicting reports have also raised a question about whether SSRI use in the late stages of pregnancy is associated with a serious but rare developmental lung condition, persistent pulmonary hypertension of the newborn (PPHN ). Chambers and colleagues raised this concern when they found an increased risk of PPHN with SSRI use in a nested case-controlled study. They reported the risk of PPHN with exposure to SSRIs after 20 weeks was about 1%. Other research has been reassuring, with multiple large studies showing that the risk is much lower than initially estimated, or even that there is no association between SSRI use and PPHN at all., Most recently, data from a large Medicaid database of 3.8 million pregnancy outcomes, revealed that the risk of PPHN was 0.3% for women who were treated with SSRIs, compared to 0.2% among those who were not. Readers must be mindful that PPHN is correlated with multiple risk factors, including cesarean section, race, body mass index, and other factors not associated with SSRI use. Compared to the considerable data on risk of congenital malformations with pre-natal antidepressant exposure, reproductive safety data regarding the longterm effects of pre-natal antidepressant exposure on the developing fetal brain are more limited. In children exposed to fluoxetine, TCAs, venlafaxine, or no medication, no differences have been detected in behavioral or cognitive development (in terms of intelligence quotient [IQ], language, temperament, behavior, reactivity, mood, distractibility, and activity level) among groups when followed through early childhood. Some recent studies have repo rted that rates of autism spectrum disorder and attention deficit disorder are more common in antidepressant-exposed children; however, these studies do not account for the fact that maternal psychiatric illness itself is a known risk factor for these conditions., That the higher prevalence of these disorders is more likely due to

genes and maternal illness rather than to the medication exposure is supported by studies that have controlled for confounding factors such as maternal psychiatric diagnosis and exposure to other medications. Although the data available is mostly reassuring, further investigation into the long-term neuro-behavioral effects of pre-natal exposure to antidepressants is warranted.

Mood Stabilizers For women with bipolar disorder, maintenance treatment with a mood stabilizer during pregnancy can significantly reduce the risk of relapse. However, many of the medications commonly used to treat bipolar disorder carry some teratogenic risk when used during pregnancy. Concerns regarding fetal exposure to lithium have typically been based on early reports of higher rates of cardiovascular (CV) malformations (e.g., Ebstein’s anomaly) following pre-natal exposure to this drug. More recent data suggest the risk of CV malformations following first trimester exposure to lithium is smaller than previous assessments and is estimated to be between 1 in 2000 (0.05%) and 1 in 1000 (0.1%). There is a growing body of information regarding the reproductive safety of lamotrigine (Lamictal), and this might be a useful alternative for some women. Data from the International Lamotrigine Pregnancy Registry was created by GlaxoSmithKline (GSK) and has shown no increase in the overall risk of malformations associated with lamotrigine exposure. Well studied by several pregnancy registries, lamotrigine does not appear to increase the risk of major congenital malformations above that of the general population. Although early data caused concern for an increased risk of oral clefts following lamotrigine exposure, larger registries have not observed this association. Compared to lithium and lamotrigine, pre-natal exposure to some anticonvulsants is associated with a far greater risk for organ malformation. Because pre-natal exposure to valproic acid (Depakote) carries a risk of neural tube defect ranging from 3% to 8%, this drug is often considered one of last resort in reproductive-aged women. Valproic acid exposure has also been associated with characteristic craniofacial abnormalities, CV malformation, limb defects, and genital anomalies, as well as other CNS structural abnormalities. Factors that appear to increase the risk for teratogenesis include higher maternal serum anticonvulsant levels and exposure to more than one anticonvulsant. In contrast, first trimester use of carbamazepine (Tegretol) appears to carry less risk, with an estimated 1% risk of neural tube defects.

Although newer anticonvulsants are being used more frequently in the treatment of bipolar disorder, there is limited information on the reproductive safety of these newer anticonvulsants, specifically gabapentin (Neurontin), oxcarbazepine (Trileptal), tiagabine (Gabitril), levetiracetam (Keppra), and zonisamide (Zonegran). Several recent reports have raised concerns regarding pre-natal exposure to topiramate (Topamax) and an increased risk of oral clefts. Pre-natal screening for congenital malformations following anticonvulsant exposure (including cardiac anomalies) with fetal ultrasound at 18 to 22 weeks of gestation is recommended. The possibility of fetal neural tube defects should be evaluated with maternal serum alpha-fetoprotein (MSAFP) and ultrasonography. In addition, 4 mg per day of folic acid before conception and in the first trimester for women receiving anticonvulsants is often recommended. However, the supplemental use of folic acid to attenuate the risk of neural tube defects in the setting of anticonvulsant exposure has not been systematically evaluated.

Antipsychotic Medications To date , abundant data exists that support the reproductive safety of typical antipsychotics, and no definitive association between typical antipsychotic administration during pregnancy and risk of congenital malformations has been identified. Recently, atypical antipsychotics have been the subject of increasing research regarding reproductive safety. Several large studies have released data that is largely reassuring regarding the safety of atypical antipsychotic exposure during pregnancy, with most showing either minimal or no increase in risk of major congenital malformations following atypical antipsychotic exposure. More data is required to definitively understand these risks, and newer atypical antipsychotics (such as ziprasidone and lurasidone) are under-represented in these studies, limiting understanding of risks associated with their use during pregnancy. Even though the data regarding the reproductive safety of these newer agents is limited, no studies thus far have indicated any teratogenic risk associated with this class of medications. For this reason, some women with bipolar disorder might choose to use an atypical antipsychotic agent as a mood stabilizer (especially during the first trimester) to avoid exposure to a known teratogen, such as lithium or valproic acid. Peri-natal toxicity has been reported following pre-natal exposure to both the typical and atypical antipsychotic medications, including motor restlessness,

tremor, and difficulty with oral feeding, hypertonicity, dystonia, and extrapyramidal symptoms. One recent prospective study including infants exposed to both typical and atypical antipsychotics demonstrated worse neuromotor performance, which was still evident at 6 months of age.

Anti-Anxiety Medications Three prospective studies support the absence of increased risk of organ malformation following first trimester exposure to benzodiazepines . More controversial has been the issue of whether first trimester exposure to benzodiazepines increases risk for specific malformations. Although initial reports suggested that there might be an increased risk of cleft lip and palate, more recent reports have shown no association between exposure to benzodiazepines and risk for cleft lip or palate. Currently, no systematic data is available on the reproductive safety of non-benzodiazepine anxiolytic agents such as buspirone. Peri-natal toxicity associated with benzodiazepine use around the time of delivery has included reports of temperature dysregulation, apnea, depressed Apgar scores, muscular hypotonicity, and failure to feed. However, several studies of low-dose benzodiazepines given to women around the time of delivery did not indicate significant peri-natal toxicity. Long-term neurobehavioral data following in utero benzodiazepine exposure is unavailable.

Sedative-Hypnotic Medications Several recent studies have focused on the reproductive safety of the sedativehypnotic medications including zolpidem (Ambien) and eszopiclone (Lunesta). These non-benzodiazepine hypnotics were not associated with an increased risk of congenital malformations; however, one study did note an increased risk of certain adverse outcomes (e.g., low birth weight, pre-term delivery) in women using zolpidem. Far less information is available regarding the safety of zaleplon (Sonata). Even though this data is reassuring, these studies have some limitations. Most important, there is great heterogeneity among the patterns of usage of these medications, particularly with regard to the timing and duration of treatment, because it was not included; some women might have used the drug only briefly or intermittently, whereas others might have used the drug for an extended period. By including a large number of women with minimal exposure, the studies might not accurately reflect the risks associated with exposure to medications.

Post-Partum Psychiatric Illnesses Introduction During the post-partum period, about 85% of women experience some type of mood disturbance. For most, the symptoms are mild and short-lived; however, 10% to 15% of women develop more significant symptoms of depression or anxiety. Despite ongoing controversy regarding the nosology of post-partum psychiatric disorders, studies have consistently demonstrated the deleterious consequences of post-partum psychiatric illness on the child. Recognition and appropriate treatment of these disorders not only alleviates maternal psychiatric symptoms, but also promotes healthy mother–infant attachment and infant development.

Overview Post-partum psychiatric illness is typically divided into three categories : (1) post-partum blues; (2) post-partum depression (PPD); and (3) post-partum psychosis. It can be useful to conceptualize these disorders as existing along a continuum, where post-partum blues is the mildest form and post-partum psychosis the most severe form of post-partum psychiatric illness. Post-partum blues are a self-limited constellation of symptoms that affects 50% to 85% of all women during the first weeks after the birth of a child. These symptoms usually begin 2 to 3 days post-partum and consist of mood lability, tearfulness, irritability, and anxiety. These symptoms generally represent a normal post-partum experience and resolve spontaneously without intervention. However, when symptoms persist beyond 2 weeks or significantly impair functioning, they might represent an evolving episode of major depression. PPD has been estimated to occur in 10% to 15% of all post-partum women. The course of PPD is highly variable. Although PPD typically emerges within the first post-partum month, women remain at increased risk for emergence of a mood episode during the first year after childbirth, and some women actually note the onset of depressive symptoms during pregnancy. The DSM-5 classifies PPD as an episode of major depression that emerges either during pregnancy or within 4 weeks of childbirth, using the specifier “with peri-partum onset.” PPD is clinically indistinguishable from depression occurring at other times during a woman’s life. The typical clinical features include depressed or sad mood, loss of interest or pleasure in usual activities (often manifested as difficulty in bonding with the baby), feelings of guilt, fatigue, and sleep

disturbance. In addition, women with PPD often have prominent anxiety and obsessions. Post-partum psychosis is a rare condition that occurs in 1 to 2 of every 1,000 post-partum women. Post-partum psychosis typically begins acutely, often within the first 48 to 72 hours after delivery, and represents a medical emergency. The majority of women with puerperal psychosis develop symptoms within the first 2 post-partum weeks. It appears that in most cases, post-partum psychosis represents an episode of bipolar illness; the symptoms of puerperal psychosis most closely resemble those of a rapidly evolving manic (or mixed) psychotic episode. The earliest signs are restlessness, irritability, and insomnia. Women with this disorder exhibit a rapidly shifting depressed or elated mood, disorientation or confusion, and erratic or disorganized behavior. Delusional beliefs are common and often center on the infant. Auditory hallucinations that instruct the mother to harm herself or her infant might also occur. Risk for infanticide as well as suicide is significant in this population.

Etiology The post-partum period is characterized by a rapid shift in the hormonal environment. Within the first 48 hours after delivery, concentrations of estrogen and progesterone fall dramatically. Because these gonadal steroids modulate neurotransmitter systems involved in the regulation of mood, many investigators have proposed a role for these hormonal shifts in the emergence of post-partum affective illness. Even though it appears that there is no consistent correlation between serum levels of estrogen, progesterone, cortisol, prolactin, or thyroid hormones and the occurrence of post-partum mood disturbance, some investigators hypothesize that there is a subgroup of women who are particularly sensitive to the hormonal changes that take place after delivery. This population of women might be more vulnerable to PPD and to other hormonally driven mood disturbances, such as those occurring during the pre-menstrual phase of the menstrual cycle or during the peri-menopause. Other factors might play a role in the etiology of PPD. One of the most consistent findings is that among women who report marital dissatisfaction and/or inadequate social supports, post-partum depressive illness is more common. Several investigators have also demonstrated that stressful life events occurring either during pregnancy or near the time of delivery appear to increase the likelihood of PPD.

Although all of these factors can act together to cause PPD, the emergence of this disorder probably reflects an underlying vulnerability to affective illness. Women with histories of major depression are more vulnerable to PPD. Another clear predictor of PPD is depression during pregnancy. Post-partum psychiatric illness is recurrent. Women who have had one episode of PPD have about a 50% risk of having another episode after a subsequent pregnancy. Women with a history of post-partum psychosis have a striking 70% to 90% risk of a recurrent post-partum psychosis. Furthermore, most women who have their first onset of psychiatric illness during the post-partum period will go on to have recurrent episodes of depression unrelated to pregnancy or childbirth.

Treatment Women with the post-partum blues often benefit from education about the normalcy of certain mood symptoms during the post-partum period. They should also be informed of the signs and symptoms of an evolving major depression and the importance of prompt treatment. Most women with the post-partum blues also benefit from reassurance and supportive interventions, such as childcare assistance and referrals to support agencies. PPD presents along a continuum, and the type of treatment selected is based on the severity and type of symptoms present. However, before initiating psychiatric treatment, medical causes for mood disturbance (e.g., thyroid dysfunction, anemia) must be excluded. Initial evaluation should include a thorough history, physical examination, and routine laboratory tests.

Psychotherapy Non-pharmacological therapies are useful in the treatment of PPD. In a randomized study, it was demonstrated that short-term CBT was as effective as treatment with fluoxetine in women with PPD. Interpersonal therapy (IPT ) has also been shown to be effective for the treatment of women with mild to moderate PPD. Not only is IPT effective for treating the symptoms of depression, but women who receive IPT also benefit from significant improvements in the quality of their interpersonal relationships.

Pharmacotherapy Although non-pharmacological interventions might be particularly attractive to those patients who are reluctant to use psychotropic medications (e.g., women who are breastfeeding) or for patients with milder forms of depressive illness,

women with more severe PPD might choose to receive pharmacological treatment, either in addition to or instead of these nonpharmacological therapies. To date, only a few studies have systematically assessed the pharmacological treatment of PPD. Conventional antidepressant medications (fluoxetine, sertraline, fluvoxamine, and venlafaxine) have shown efficacy in the treatment of PPD. In all of these studies, standard antidepressant doses were effective and well tolerated. The choice of an antidepressant should be guided by the patient’s prior response to antidepressant medication and a given medication’s side effect profile. SSRIs and SNRIs are ideal first-line agents because they are anxiolytic, non-sedating, and well tolerated. For women who cannot tolerate SSRIs, bupropion (Wellbutrin) can be an alternative; although one pilot study suggests bupropion might not be as effective as SSRIs and might not be as effective for the treatment of co-morbid anxiety symptoms. TCAs are less frequently used, because they are more anticholinergic, tend to be more sedating, and are associated with QTc interval prolongation. TCAs can be appropriate for women who present with prominent sleep disturbance. Given the prevalence of anxiety symptoms and sleep disturbance in this population, antidepressants are often combined with a benzodiazepine (e.g., clonazepam, lorazepam), especially during the acute phase of treatment. Post-partum psychosis is considered a psychiatric emergency that typically requires inpatient treatment. Acute treatment with either typical or atypical antipsychotic medications is indicated. Given the well-established relationship between puerperal psychosis and bipolar disorder, post-partum psychosis should be treated as an affective psychosis and a mood stabilizer is indicated. Electroconvulsive therapy (ECT) is typically well tolerated and rapidly effective for severe PPD and psychosis.

Psychotropic Medications and Breast-Feeding All psychotropic medications are secreted into the breast milk at varying concentrations; however, those concentrations appear to vary widely. The amount of medication to which an infant is exposed depends on several factors, including dosage of medication, rate of maternal drug metabolism, and frequency and timing of feedings. Serum drug levels are not typically measured in nursing infants exposed to antidepressants, unless there is reason to suspect toxicity. Particular caution should be taken if the breast-feeding infant is preterm or has other medical complications, because these infants might not be able to fully metabolize the medications and might thus be more vulnerable to toxicity.

Available data on the TCAs and the SSRIs (fluoxetine, paroxetine, and sertraline) during breast-feeding have been encouraging and suggest that significant complications related to neonatal exposure to psychotropic drugs in breast milk appear to be rare. While less information is available on other antidepressants, there have been no reports of serious adverse events related to exposure to these medications. For women with bipolar disorder, breast-feeding can be more problematic. First is the concern that on-demand breast-feeding can significantly disrupt the mother’s sleep and thus can increase her vulnerability to relapse during the acute post-partum period. Second, there have been reports of toxicity in nursing infants related to exposure to various mood stabilizers, including lithium and carbamazepine, in breast milk. Lithium is excreted at relatively high levels in the mother’s milk, and infant serum levels are typically about one-third to one-half of the mother’s serum levels, increasing the risk of neonatal toxicity. In these infants, as in the mother, levels of lithium, thyroid stimulating hormone (TSH), blood urea nitrogen (BUN), and creatinine must be assessed periodically. Exposure to carbamazepine and valproic acid in the breast milk has been associated with hepatotoxicity in the nursing infant. In these infants, drug levels and liver function tests should be followed closely.

Hormonal Therapy Few studies have looked at the efficacy of estrogen and progesterone treatment for PPD. Progesterone has not consistently proved to be an effective treatment for depressive symptoms, and several studies have demonstrated that progestinonly contraceptives might trigger the onset of depressive symptoms during the post-partum period. Several small studies have found that estrogen, either alone or in combination with an antidepressant, has been effective in treating PPD. Although these initial studies make estrogen seem like a promising option for women with post-partum illness, estrogen carries high risk of thromboembolic events in post-partum women.

Menopause Introduction Although some women experience psychiatric, cognitive, or somatic symptoms during the menopausal transition, no specific psychiatric disorder has been associated with menopause itself. The relationship between declining estrogen levels and mood symptoms remains controversial; however, studies of mood

during menopause have generally demonstrated an increased vulnerability to depression and anxiety during the peri-menopause, with a decrease in risk during the post-menopausal years.

Definitions Menopause is defined as the cessation of menses for 12 consecutive months. Women naturally enter menopause with advancing age, usually between the ages of 41 and 59 years. Women can also experience menopause as a result of exogenous hormone treatment or following bilateral oophorectomy. Peri-menopause, the transition from regular menstrual functioning and menopause, usually lasts between 5 and 10 years. Hormonal changes during this period include declining estrogen levels which are increasingly unopposed by progesterone due to anovulatory cycles. It is during this transition that there is an increased risk of both anxiety and depressive symptoms. Following peri-menopause, women enter the post-menopause, which can account for roughly one-third of women’s entire lifespan. The reproductive endocrine status of post-menopausal women is characterized by stable low levels of estrogen and progesterone. Whereas the female to male ratio of depression increases after age 45, the rate of depression in women declines in the postmenopausal period.

Etiology Although there is ample evidence to indicate that the period of transition from the reproductive years to post-menopause is a time of increased risk for depression, there are many different, and sometimes conflicting, theories to explain this increased vulnerability. The hypothesis that depression is triggered by estrogen withdrawal is supported by the fact that rates of depression are higher among women who undergo bilateral oophorectomy versus women undergoing a natural, more gradual menopause. The Massachusetts Women’s Health Study data revealed that depressed mood was predicted by estradiol levels, but when the effect of estradiol was adjusted for menopausal symptoms, including hot flashes, the relationship was not statistically significant. The “domino theory” of menopause-related affective disorders suggests that certain somatic symptoms, such as sleep disturbance and hot flashes, can lead to mood disturbance. This has led some to wonder whether the positive effect on mood some women experience while on hormone replacement therapy (HRT ) results from a direct effect on mood or from the psychological relief they experience as their menopausal somatic symptoms abate.

The Penn Ovarian Aging Study found that the strongest predictor of depressed mood was a history of depression, which adds to the debate over whether menopause-associated depression represents a separate diagnosis or merely an exacerbation of a recurrent depressive illness. Other risk factors for depressed mood in peri-menopausal women include: poor sleep; hot flashes; stressful or negative life events; poor physical health; employment status; age; and race. Psychosocial theories often indict the stress of the life changes that mark the peri-menopausal transition. Some of these psychosocial factors include: (1) losing one’s reproductive potential; (2) changing family roles; and (3) aging and the onset of physical illnesses. Although these factors might be associated with peri-menopausal depression, a causal role for psychosocial factors in perimenopausal depression has yet to be established.

Evaluation A thorough gynecologic history should include whether a patient has had a chemically or surgically-induced menopause versus a natural menopause. Patients who have had bilateral oophorectomy might experience more abrupt onset of and more severe mood and anxiety symptoms. For peri-menopausal women who are menstruating, it might be helpful to prospectively chart symptoms to determine if there is any relation of the symptoms to the menstrual cycle. A thorough evaluation should rule out any underlying medical conditions that can present with anxiety or depression, such as anemia, thyroid disease, or cardiac arrhythmia. Routine laboratory tests assessing blood count and thyroid function are indicated. Hormonal changes in menopause include a decrease in estrogen with subsequent elevations of luteinizing hormone (LH) and follicle stimulating hormone (FSH). The endocrine profile of menopause is typically defined as an FSH level above 40 IU/L and an estradiol level below 25 pg/ml. In peri-menopausal women, both estrogen and FSH levels can vary greatly. One elevated FSH level is not enough to confirm menopause. Also, in women using certain hormonal treatments, including oral contraceptives, FSH levels cannot be used to assess menopausal status.

Psychoeducation and Psychotherapy Patients often benefit from reassurance that menopause is not a disease but a natural stage of women’s reproductive life. Psychiatrists should educate patients about the hormonal changes and potential vasomotor, cognitive, and psychological symptoms that sometimes accompany menopause. Patient

education should also include clear distinctions between these normal symptoms and more disabling conditions, such as major depression and Axis I anxiety disorders. Cognitive-behavioral, supportive, and psychodynamic therapy alone or in combination with pharmacotherapy might help alleviate mild depressive or anxiety symptoms.

Hormonal Treatment HRT has been the treatment of choice to alleviate physical symptoms associated with the menopausal transition and to help in preventing the clinical consequences of an estrogen-deficient state, including osteoporosis and cardiovascular disease. However, results from several large, prospective studies (e.g., HERS, WHI) have questioned the safety of long-term use of HRT. Because of these concerns, many women have elected to discontinue or to avoid HRT. Many women might benefit from short-term treatment with HRT, which can alleviate mild mood symptoms along with certain physical symptoms such as vaginal dryness and vasomotor symptoms (e.g., hot flashes, cold sweats). These benefits, however, must be weighed carefully against possible increased risk for breast cancer and cardiovascular disease.

Psychotropic Medications Although several studies have indicated that women with menopause-related depressive symptoms might respond well to estrogen, women with menopauserelated mood and/or anxiety symptoms are most likely to benefit from treatment with conventional antidepressant and anxiolytic medications. Treatment studies indicate that menopause-related mood disorders respond to similar dosages of antidepressant as depression unrelated to menopause. SSRIs and SNRIs are typically used in this setting, and there is good evidence to indicate that women taking these serotonergic drugs might experience improvement in their vasomotor symptoms. Of the antidepressants, venlafaxine is the one most commonly used to treat vasomotor symptoms, but studies have also shown benefit with paroxetine, escitalopram, desvenlafaxine, and mirtazapine. Other psychotropic drugs that appear to improve vasomotor symptoms include gabapentin. Studies indicate that gabapentin (600–2,400 mg/day) significantly decreases hot flash frequency and hot flash severity by 45% to 71% and is comparable to HRT. Clonidine has a modest effect on vasomotor symptoms but greater risk of side effects. Sleep disturbance occurs in about 40% to 50% of women during the menopausal transition and can occur in the absence of a psychiatric disorder.

However, it has been demonstrated that women with insomnia are more vulnerable to depression and anxiety disorders. Benzodiazepines and sedativehypnotic agents are typically used in this setting. Not only do they appear to be effective for sleep, a recent study demonstrated that treatment with a sedativehypnotic (in this study, eszopiclone) had a positive effect on depressive symptoms, anxiety, overall quality of life, and night-time but not daytime hot flashes (Joffe et al, 2010).

Suggested Readings 1. Cohen LS, Altshuler LL, Harlow BL, et al: Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA . 2006 Feb 1; 295(5): 499–507. 2. de Kruif M, Spijker AT, Molendijk ML. Depression during the perimenopause: A meta-analysis. J Affect Disord . 2016; 206: 174–180. 3. Dennerstein L, Lehert P, Heinemann K: Epidemiology of pre-menstrual symptoms and disorders. Menopause Int. 2012 Jun; 18(2): 48–51. 4. Freeman EW: Associations of depression with the transition to menopause. Menopause . 2010 Jul; 17(4): 823–827. 5. Hernández-Díaz S, Smith CR, Shen A, et al: Comparative safety of antiepileptic drugs during pregnancy. Neurology . 2012; 78: 1692–1699. 6. Joffe H, Cohen LS: Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biol Psychiatry. 1998; 44: 798–811. 7. Nonacs R, Cohen LS: Post-partum mood disorders: diagnosis and treatment guidelines. J Clin Psychiatry. 1998; 59 (suppl 2): 34–40. 8. Sepede G, Sarchione F, Matarazzo I, et al: Pre-menstrual dysphoric disorder without co-morbid psychiatric conditions: A systematic review of therapeutic options. Clin Neuropharmacol. 2016; 39(5): 241–261. 9. Viguera AC, Tondo L, Koukopoulos AE, et al: Episodes of mood disorders in 2,252 pregnancies and post-partum periods. Am J Psychiatry . 2011 Nov; 168(11): 1179–1185. 10. Yonkers KA, Vigod S, Ross LE: Diagnosis, pathophysiology, and management of mood disorders in pregnant and post-partum women. Obstet Gynecol. 2011 Apr;117(4): 961–977.

CHAPTER HIV Infection and A IDS 30 OLIVER FREUDENREICH, MD; JOHN QUERQUES, MD; AND RAJESH GANDHI, MD

KEY POINTS Overview Effective antiretroviral therapy (ART) has transformed infection with the human immunodeficiency virus (HIV) from a terminal illness to a chronic, treatable condition. In patients with HIV/acquired immunodeficiency syndrome (AIDS), psychiatric and substance use disorders are common obstacles to receiving optimal medical care for HIV infection, leading to avoidable HIV-related complications. Psychiatrists can help reduce the number of new infections by screening psychiatric patients for HIV infection, linking identified patients to care, and removing psychiatric obstacles to adherence so that patients achieve sustained non-detectable viral loads. Epidemiology In the United States, 1.2 million people are living with HIV infection, 13% of whom (almost 1 in 8) are unaware that they are infected. The number of new HIV cases has remained stubbornly steady, at about 50,000 per year. Men who have sex with men continue to be most affected by HIV infection, accounting for more than half of all patients with HIV. The CDC recommends voluntary HIV testing as part of routine medical care, not just screening based on risk factors. Pre-exposure prophylaxis (PrEP) with emtricitabine/tenofivir is FDA-approved for the prevention of HIV infection. Clinical Manifestations

A high index of suspicion should be maintained for “organic” causes of psychiatric symptoms, especially at advanced stages of illness. A CD4 count below 200 cells/mm3 makes opportunistic infections more likely. Depression is the most common major psychiatric complication of HIV infection. Even in the era of effective treatment, the suicide risk for patients with HIV remains increased compared to those in the general population; this increased risk is comparable to other patient groups with chronic illnesses. HIV infection is a possible cause of secondary mania. Important primary neurological manifestations of HIV infection include HIVassociated neurocognitive disorder (HAND), HIV-associated meningitis and encephalitis, and HIV-related neuropathies. Secondary manifestations include toxoplasmosis, cryptococcal meningitis, cytomegalovirus (CMV) encephalitis, central nervous system (CNS) lymphoma, and progressive multi-focal leukoencephalopathy (PML). HAND comes in three severities: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. Although there is no gold standard for neurocognitive screening, a test battery that includes a timed component is optimal since HIV-infected patients with significant cognitive impairment have reduced processing speed. Pathophysiology HIV directly affects the brain by invading the CNS early in the course of infection. Patients with HIV infection/AIDS are sensitive to extrapyramidal symptoms, possibly because of early HIV-related damage to sub-cortical systems, including dopaminergic neurons, thereby reducing “reserve capacity.” Neurological manifestations of HIV infection are either primary (i.e., due to HIV itself or the immunopathological changes precipitated by HIV infection) or secondary (i.e., due to the failure of the immune system to suppress tumors or opportunistic infections). Treatment Current guidelines recommend instituting ART at the earliest possible time (i.e., at the time of diagnosis) rather than waiting until the CD4 count has declined. Efavirenz is a potent antiretroviral agent that is no longer first-line in the United States because of an increased risk for neuropsychiatric symptoms and possibly suicidality. Depression and active substance use (particularly alcohol use) are associated

with poor adherence to ART. Psychiatrists can play an important role in addressing these co-morbidities so that patients achieve critically important sustained viral suppression. The best treatment for HAND is early effective ART. Currently, the main objective is optimal control of viral replication in the periphery. So-called “viral CNS escape” (i.e., replication only in the CNS), while possible, appears to be a rare phenomenon.

Overview Human immunodeficiency virus (HIV) is a retrovirus that causes slow, progressive, immunologic, and neurologic disease. By depleting CD4 T-helper lymphocytes, HIV infection causes severe immunosuppression and eventually the acquired immunodeficiency syndrome (AIDS). The immunodeficiency ultimately results in opportunistic infections (OIs), cancers, and a host of neuropsychiatric complications, including dementia. Owing largely to the availability of effective antiretroviral therapy (ART), HIV infection in the United States has become a chronic, treatable, illness, albeit with the stresses and burdens associated with the management of any chronic illness compounded by the stigma still attached to this condition. This chapter addresses key elements of the diagnosis and treatment of psychiatric disorders in HIV-infected patients and the neurologic complications of HIV disease.

Epidemiology Since the first case of AIDS was reported in 1981, HIV has infected almost 78 million people worldwide, of which about 39 million have died. The worldwide prevalence of HIV is estimated to be 0.8% of adults, but there is considerable geographic variation. The region most severely affected by the pandemic continues to be sub-Saharan Africa where nearly 1 in every 20 adults lives with HIV infection; strikingly, in some regions, more than 1 in 5 people are infected. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that 1.2 million people are living with HIV infection, 13% of whom (almost 1 in 8) do not know they are infected. According to the CDC, a CD4 count < 200 cells/μL or the presence of one of the illnesses listed in Table 30-1 defines AIDS. Although the number of new AIDS cases in the United States declined in the late 1990s (due to the introduction of effective combination ART in 1996) and has since stabilized, the number of new HIV cases has remained

stubbornly steady, currently estimated to be almost 50,000 yearly. Although new infections are increasing particularly among younger men who have sex with men (MSM), in part driven by the use of crystal methamphetamine, they are decreasing among injection drug users. Regardless of race, MSM continue to be the group most affected by HIV infection: even though MSM represent only 4% of the population, the MSM group accounts for more than half of all patients living with HIV infection. In the absence of an HIV vaccine, prevention of new infections is a high priority. Pre-exposure prophylaxis—the use of ART to prevent infection—has been proven to prevent HIV acquisition and is now recommended in high-risk populations. Post-exposure prophylaxis is standardof-care following potential exposure to HIV through a blood-borne or sexual route. Table 30-1: AIDS-Defining Conditions Bacterial infections, multiple or recurrent* Candidiasis of bronchi, trachea, or lungs Candidiasis of esophagus† Cervical cancer, invasive§ Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (> 1 month’s duration) Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month Cytomegalovirus retinitis (with loss of vision)† Encephalopathy, HIV-related Herpes simplex: chronic ulcers (> 1 month’s duration) or bronchitis, pneumonitis, or esophagitis (onset at age > 1 month) Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (> 1 month’s duration) Kaposi sarcoma† Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*† Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or Mycobacterium kansasii , disseminated or extrapulmonary†

Mycobacterium tuberculosis of any site, pulmonary,†§ disseminated,† or extrapulmonary† Mycobacterium , other species or unidentified species, disseminated† or extrapulmonary† Pneumocystis jirovecii pneumonia† Pneumonia, recurrent†§ Progressive multi-focal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain, onset at age >1 month† Wasting syndrome attributed to HIV * Only among children aged < 13 years † Might be diagnosed presumptively § Only among adults and adolescents aged ≥ 13 years Adapted from: Centers for Disease Control and Prevention: 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992; 41(No. RR-17) Centers for Disease Control and Prevention: 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994; 43(No. RR-12)

Groups that have a higher rate of HIV infection include MSM, people who have used injection drugs, racial minorities, and people with serious mental illness. People with bipolar disorder, substance use, and severe personality disorders are at increased risk for HIV infection because of behavioral impulsivity, impaired risk appraisal, and an increased likelihood of swapping sex for drugs of abuse. Conversely, people at high risk for HIV infection can be more prone to psychiatric illness because, not infrequently, these individuals have poor social supports and are isolated, disenfranchised, and socially marginalized. Patients co-infected with HIV and the hepatitis C virus (HCV) constitute an important sub-group of patients with HIV infection, given that more deaths occur from liver failure than from HIV-related causes in these patients. In addition, there are now highly effective therapies that cure HCV infection in the vast majority of patients, including those with co-infection.

General Approach to the Psychiatric Care of the Patient with HIV Infection/AIDS The differential diagnosis of psychiatric disturbance in a patient with HIV infection is broad. Affective, behavioral, and cognitive symptoms might be due to primary psychiatric illness, direct effects of HIV in the central nervous system

(CNS), indirect effects of systemic HIV disease on the CNS, and side effects of ART and other medications used to treat HIV-related illnesses. Because two or more of these conditions can co-exist and because features of these conditions overlap extensively, making the diagnosis is often challenging and the etiology of mental status changes may be multi-factorial (Table 30-2). When symptoms are due to HIV CNS infection, systemic HIV disease, or adverse medication effects, response to a conventional psychotropic medication is likely to be worse, the risk of side effects greater, and its tolerability reduced, when compared to the use of these agents in patients with primary psychopathology. Optimal HIV treatment, targeted at systemic and CNS manifestations, is essential. When assessing an HIV-infected patient with psychiatric symptoms, important clinical data to know include: the severity of the CNS infection; the severity of the systemic HIV disease; the presence of active illness; the medication regimen; the presence of pre-morbid psychiatric illnesses; and the mode of retroviral infection. As a general clinical rule of thumb, the worse the systemic disease, the more compromised and more vulnerable the CNS is, and the greater the likelihood is that psychiatric symptoms are due to secondary causes (e.g., medication side effects, OIs). The stage of systemic HIV disease can be determined by the CD4 cell count, the viral load, and a history of HIV-related illnesses. Patients are most likely to develop OIs with CD4 counts < 200 cells/ μL; accordingly, such patients should receive OI prophylaxis. The initiation of ART at the time of diagnosis (as opposed to waiting until the CD4 cell count declines) can prevent AIDS- and non-AIDS-related complications of HIV, and this strategy has become the standard of care. Asking patients how they became infected often provides insight into who they are as people, how they feel about the way they were infected, and how they have coped with their seropositive status. Gathering this information helps to forge an alliance with patients and situates their treatment within a broad psychosocial and cultural context.

Psychiatric Illness in the Patient with HIV Infection/AIDS A high index of suspicion should be maintained for “organic” causes of psychiatric symptoms in the patient with HIV infection/AIDS, especially at advanced stages of illness. In general, mental status changes that are gradual in

onset are likely attributable to the primary effects of HIV on the CNS (e.g., HIVassociated neurocognitive disorder [HAND]), whereas systemic complications of HIV disease (e.g., cryptococcal meningitis) more often cause acute neuropsychiatric disturbances.

Delirium One of the most frequent psychiatric complications in hospitalized HIVinfected patients, delirium can occur at any stage of HIV infection but is more common in patients with advanced disease or with HIV-associated dementia (HAD ). In patients with asymptomatic HIV infection or with a CD4 count > 500 cells/μL, delirium is less likely to be due to HIV infection itself and more likely to be related to abuse of substances (e.g., alcohol, opioids). In symptomatic patients or in those with a CD4 count < 500 cells/μL (especially < 100 cells/μL), HIV-related conditions and medication side effects are likely culprits, though the cause can be multi-factorial. Tables 30-2 and 30-3 list the conditions and medications, respectively, that might be responsible for mental status alterations, including delirium, in patients with HIV infection/AIDS. Table 30-2: Differential Diagnosis of Mental Status Alterations in Patients with HIV Infection/AIDS Psychiatric Disorders Delirium

Psychoactive Substance Intoxication or Withdrawal Primary HIV Syndromes Seroconversion illness Acute HIV-associated meningoencephalitis HIV-associated neurocognitive disorder (HAND) HIV-associated dementia (HAD)

CNS Opportunistic Infections Fungi Cryptococcus neoformans

Histoplasma capsulatum

Coccidioides immitis

Aspergillus fumigatus

Candida albicans

Mucormycosis

Protozoa/parasites Toxoplasma gondii

Amebas

Viruses CJD virus

Herpes simplex virus

Cytomegalovirus (CMV)

Varicella-zoster virus

Adenovirus type 2 Bacteria Mycobacterium avium-intracellulare

Gram-negative organisms

Mycobacterium tuberculosis

Treponema pallidum

Listeria monocytogenes

Nocardia asteroides

AIDS-Related CNS Malignancies Primary CNS lymphoma

Non-Hodgkin’s lymphoma

Metastatic Kaposi’s sarcoma (rare)

Medication Side Effects (see Table 30-3) Endocrinopathies and Nutrient Deficiencies Addison’s disease

Hypogonadism Hypothyroidism Vitamin A, B6 , B12 , E deficiencies

Non-HIV-related conditions Complex partial seizures Head trauma

Table 30-3: Serious Neuropsychiatric Side Effects of Medications Commonly Used in Patients with HIV Infection/AIDS Acyclovir

Agitation, confusion, depersonalization, hallucinations (these are more common in the elderly)

Corticosteroids

Euphoria, mania, depression, psychosis, confusion

Efavirenz

Vivid dreams and nightmares, mood changes, drowsiness, insomnia, irritability, psychosis, suicidal ideation

Zidovudine (AZT)

Mania (with high doses)

History, physical examination, and a focus on identification of the underlying cause(s) of delirium are the cornerstones of evaluation of the delirious patient. Findings dictate the need for further testing, including neuroimaging, electroencephalography (EEG), and cerebrospinal fluid (CSF) analysis.

The hallmark of management is treatment of the underlying cause(s). Antipsychotics can be used adjunctively and for symptomatic control of agitation. Atypical and high-potency typical agents are superior to low-potency conventional antipsychotics that can worsen delirium because of their anticholinergic effects. However, the incidence of extrapyramidal symptoms (EPS) from use of high-potency antipsychotics is higher in patients with advanced HIV disease. Alterations in the blood-brain barrier and sub-cortical injuries seen in HIV-associated dementia (HAD) might be responsible for the increased frequency of side effects in this population.

Major Depression Although major depression is one of the most frequent major psychiatric complications of HIV infection, whether the occurrence of depression is due to an HIV-specific factor or is attributable to the chronicity of illness is unknown. Although CD4-cell depletion per se is not associated with mood disorder, immune dysregulation with chronic systemic inflammation and viral effects in prefrontal sub-cortical circuits might contribute to the high rates of depression seen in HIV infection. Depression can occur at any stage of illness. As a general rule of thumb, in patients with well-controlled HIV disease (suppressed viral replication and a CD4 count > 500 cells/μL), depression is likely to be primary. A recurrence of a pre-morbid mood disorder or a first depressive episode might be precipitated by an HIV-related psychological stressor (e.g., discovery of new HIV infection or need to initiate ART). In patients with more advanced infection, depression is likely to be secondary to HIV-related complications, medication side effects, or HAND. The differential diagnosis of depression includes HIV-related fatigue, which is characterized by amotivation and inanition rather than by dysphoria or despondency. Evaluation focuses on identification of psychosocial stressors; medication changes; substance use; and, in advanced cases, underlying conditions that can cause or worsen depression. Laboratory investigations are guided by history and physical findings. Pharmacotherapy with selective serotonin re-uptake inhibitors (SSRIs) and related agents is the first line of therapy. Regardless of the agent, clinicians should start with low doses and increase them slowly but still use an effective dose. Clinicians should also avoid sedating, anticholinergic, and anti-α 1adrenergic agents (the latter especially in advanced HIV disease when

hypotension is frequent). Tricyclic antidepressants (TCAs), especially nortriptyline, are particularly useful in patients with diarrhea, dehydration, wasting, and other causes of volume shifts because serum levels can be used to guide dosage. Bupropion or desipramine can be helpful for depression with marked fatigue and concentration difficulty, though bupropion’s use is complicated by heightened dose-related seizure risk. Psychostimulants (e.g., methylphenidate, dextroamphetamine, modafinil) can be used as single or adjuvant agents for HIV-related fatigue, depression characterized by apathy more than by sadness, and conditions refractory to other agents. Psychotherapy and electroconvulsive therapy might also be beneficial.

Suicide Because of psychiatric disturbance, substance use, and social disenfranchisement, many people who are at risk for HIV infection are at risk for suicide. For some, especially soon after seroconversion, suicidal ideation or a suicide attempt might be an expression of fear and anger related to a perception of a reduced quality of life with HIV infection. In the era of effective treatment regimens, the risk of suicide in the HIV-infected population is on par with that in other chronically ill patients, though still increased compared to those in the general population. Risk can be most strongly related to concurrent depression. Other risk factors include: personality disorders; active substance use; bereavement; pain; coping with a homosexual orientation; HIV-related difficulties at home or work; fear of and actual disease progression; loss of independence and autonomy; and feeling hopeless, worthless, and burdensome to others. The antiretroviral efavirenz has been associated with suicidal ideation.

Anxiety and Difficulty Coping Many of the risk factors for HIV infection already mentioned are also risk factors for poor coping. Even those with good preparation can have difficulty coping with HIV infection, in part because having a serious illness is not a lifestage-appropriate situation for many patients. Despite medical progress in the treatment of HIV infection, challenges remain due to stigma (e.g., revelation of serostatus, sexual orientation, or drug use; fear of loss of health insurance or employment) and the burdens of chronic medical illness (e.g., frequent blood monitoring, experience of symptoms, medication side effects). In addition to diagnosis and treatment of any psychiatric disorder that may have been spawned by overwhelming stress, the clinician can help the patient by analogizing coping with HIV infection/AIDS to running a marathon: training (strategies used to

handle previous adversities); cheering section (personal support system); pit stops (respite from focusing on being ill); and corporate support (primary-care physician, infectious-diseases specialist, psychiatrist). Non-pharmacologic treatment with supportive and psychoeducational psychotherapy and community- and government-based interventions focuses on establishment of missing components of the “marathon model” and maintenance and strengthening of those elements already present. Pharmacologic treatment provides symptomatic control. Short-term use of high-potency benzodiazepines in low doses is helpful for acute anxiety disorders. Long-term use can be problematic because of the potential for abuse and dependence in a population at risk for such disorders. High doses of benzodiazepines risk cognitive and motor side effects, especially in patients with dementia and intracranial lesions. SSRIs and related agents can be used for chronic anxiety disorders.

Substance Use Disorders Because misuse of substances and substance use disorders occur frequently in patients with HIV infection/AIDS, regardless of risk group, these disorders (including withdrawal states) should be considered in the differential diagnosis of any major psychiatric disorder. Active abuse or dependence compromises treatment adherence and promotes high-risk behavior. Of particular concern is the use of crystal methamphetamine and related compounds among MSM, which is driving new cases of HIV infection and is an important cause of psychosis in this population. The interactions between antiretroviral agents and methadone and buprenorphine are beyond the scope of this review. The interested reader is referred to the list of useful Internet resources and the suggested readings at the end of this chapter for relevant sources of this information.

Psychosis In patients with well-controlled HIV disease, psychotic symptoms are most likely due to a primary psychosis or to substance use (e.g., cocaine, amphetamines). Some medical treatments (e.g., corticosteroids) are associated with psychosis. In patients with advanced HIV infection/AIDS, secondary causes of psychosis should be strongly considered (Table 30-2). Notable among these are HIV CNS infection; cytomegalovirus (CMV) and herpes simplex virus infections; advanced HAND; complex partial seizures; and medication side effects (Table 30-3). Occasionally, new-onset psychosis is the presenting

manifestation of HIV infection or AIDS. Neuroimaging, an EEG, a CSF analysis, and blood tests should be ordered as clinically indicated. Management of psychosis proceeds along the same lines as that of delirium. Treatment of the underlying cause is the primary goal; symptoms are controlled with antipsychotics at regular doses. As with delirium, low doses of antipsychotics might be adequate to treat psychosis in HIV-infected patients because of HIV-related damage to sub-cortical structures, including the basal ganglia. Conversely, sub-cortical injury might also explain the increased sensitivity to extrapyramidal symptoms (EPS) in patients with HIV-related psychosis. Quetiapine is generally well tolerated with regard to EPS, probably because of its weak D2 binding. Similarly well-tolerated with regard to EPS, clozapine is not a first-line treatment because of its hematopoietic toxicity. However, HIV-infected patients whose histories indicate that clozapine is the only agent that is effective for their psychiatric symptoms should not be deprived of this treatment. Many antipsychotics cause weight gain and insulin resistance and thus pose an additive risk with antiretrovirals that also have been associated with cardiometabolic risk (particularly older protease inhibitors).

Mania In early stages of HIV infection, mania is usually due to pre-morbid bipolar disorder, substance use, or medication side effects. In more advanced disease, these remain possibilities, but new-onset mania should raise suspicion for secondary causes, including OIs, toxic/metabolic insults, and CNS spaceoccupying lesions. Secondary mania in HIV-positive patients is associated with more irritability, aggressive and disruptive behavior, talkativeness, paranoia, and cognitive impairment than HIV-negative patients with primary mania. With more advanced disease, there is greater unresponsiveness to, and intolerance of, treatment, especially combination treatment with lithium and an antipsychotic. There is limited data on the use of mood-stabilizing anticonvulsants in HIV infection/AIDS, but clinically they are widely used for both bipolar disorder and neuropathic pain. Caveats for their general use apply in the HIV infection/AIDS population. The theoretical risk of heightened viral replication with valproate has not been borne out in vivo .

Neurologic Manifestations of HIV Infection/AIDS The neurologic manifestations of HIV infection/AIDS are either primary (i.e., due to HIV infection itself or to the immunopathological changes precipitated by

the retrovirus) or secondary (i.e., due to OIs, neoplasms, or toxic/metabolic derangements). Primary manifestations include HIV-associated neurocognitive disorder (HAND), HIV-associated meningitis and meningoencephalitis, and HIV neuropathies. Secondary manifestations include toxoplasmosis, cryptococcal meningitis, CMV encephalitis, primary CNS lymphoma, and progressive multi-focal leukoencephalopathy (PML).

HAND HIV infects certain neural cells early in the course of infection and, through a variety of direct and indirect means, causes damage to the brain, though subcortical structures and deep white matter are principal targets. Seventy-five percent of AIDS patients have evidence of brain pathology at autopsy, including reactive gliosis; multi-nucleated giant cells; atrophy in sub-cortical structures and in the frontal, parietal, and temporal cortices; and sulcal and ventricular prominence. HAND is the current term for the neurocognitive derangements caused by HIV infection, encompassing asymptomatic neurocognitive impairment (mild with no functional disruption), mild neurocognitive disorder (moderate with some functional disruption), and HIV-associated dementia or HAD (severe with substantial functional disruption). In the era of effective combination treatment with ART, the incidence of HAD has declined, but the prevalence of HAND has not, likely because HIV-infected patients are living longer. Another potential reason might be variable penetration of the blood-brain barrier by different antiretroviral agents, thus allowing continued viral replication within the CNS even while plasma viral load determinations indicate viral suppression in the periphery (although this so-called “CNS escape” is rare). Thus, there has been a shift toward milder and thus subtler, and perhaps more cortical, cognitive disruption away from the sub-cortical derangements historically appreciated as the hallmarks of HAD. HAD is characterized by affective, behavioral, cognitive, and motor symptoms and signs. Affective features include apathy, abulia, dysphoria, and, in severe cases, depression, mania, or psychosis. Behavioral features include a change in social behavior, social withdrawal, insomnia, anergia, fatigue, and, in severe cases, agitation (associated with delirium). Cognitive features include deficits in

attention, concentration, short-term memory, word-finding, visuo-spatial abilities, and completion of multiple-step activities. Patients might complain that previously automatic activities require effortful concentration. Motor features include clumsiness, slowing of movements, and changes in gait and handwriting. Typical neurological findings include frontal-release signs, hyper-reflexia, disturbed smooth-pursuit eye movement, and incoordination and weakness (both worse in the lower limbs). Psychomotor slowing is the hallmark of classic, sub-cortical HAD, followed by impaired divided attention and concentration. Therefore, part B of the HalsteadReitan Trail-Making Test is an ideal screening tool because it is sensitive to impairments in psychomotor speed and divided attention and is easy to administer. Timed tasks, which are included in the HIV Dementia Scale (HDS) and the Modified HDS, are important in making the diagnosis because they test psychomotor speed. The Folstein Mini-Mental State Examination, because it mainly tests non-frontal cortical areas, is not particularly sensitive for HAD. Bedside testing can be followed by formal neuropsychological testing. Because HAD is a diagnosis of exclusion, evaluation focuses on exclusion of other causes of altered mental status in a patient with HIV infection/AIDS (Table 30-2). Laboratory investigations include neuroimaging, an EEG, CSF analysis, and blood tests. Cranial computerized tomography (CT) typically shows cerebral atrophy, ventricular enlargement, and white matter lucencies. Cranial magnetic resonance imaging (MRI) reveals cerebral atrophy, ventricular enlargement, and T2 weighted hyperintense white-matter lesions. There is a poor relationship between the degree of abnormality on MRI and the severity of clinical dementia. The white-matter abnormalities on both CT and MRI occur as multiple punctate lesions or in large, confluent areas, and they are usually symmetric. In early dementia, functional neuroimaging studies demonstrate sub-cortical hypermetabolism, especially in the basal ganglia and thalamus. Later stages are characterized by cortical hypometabolism. The EEG might show mild, non-specific slowing; it is generally helpful only if seizures are suspected based on paroxysmal psychopathology. CSF analysis shows only non-specific findings and should be ordered only if symptoms are progressive or severe or the CD4 count is < 200 cells/μL and an OI is suspected. The optimal treatment of HAD is control of viral replication through combination ART. CNS penetration of antiretroviral medications might be a

relevant variable, and different antiretroviral agents have been ranked using a CNS penetration-effectiveness score; however, the clinical utility of choosing antiretroviral medications based on this score has not been established. Medications for specific psychiatric symptoms, supportive psychotherapy to help patients cope with cognitive and functional losses, and modification of patients’ activities to capitalize on preserved cognitive strengths round out the treatment. Maintenance of routine, completion of one task at a time, and reduction of external stimuli are important elements of behavior modification.

HIV-Associated Meningitis and Meningoencephalitis HIV-associated meningitis is a rare complication of the mononucleosis-like illness that occurs during seroconversion. Acute HIV infection can also present with meningoencephalitis, and this diagnosis should be considered in patients who develop an acute confusional state and symptoms or signs of meningitis, particularly after potential exposure to HIV.

HIV-Associated Neuropathies Frequent in advanced stages of HIV disease, pain is most commonly due to painful HIV-associated distal sensory polyneuropathy (DSP ), which presents as a distal symmetric sensory polyneuropathy with numbness, tingling, and burning in the feet. DSP might be due to HIV infection itself or to nucleoside reverse transcriptase inhibitors (NRTIs), particularly the d-drugs (ddI, didanosine; d4T, stavudine; ddC, zalcitabine). These agents can cause an irreversible neuropathy. Even though the d-drugs are rarely, if ever, used in the United States any longer because of their toxicity, treatment-experienced patients might have been exposed to these agents in the past, resulting in chronic pain. A chronic progressive or relapsing inflammatory demyelinating polyneuropathy may complicate the course of advanced HIV disease. Other causes of pain are herpes zoster, post-herpetic neuralgia, myopathy, and headache. Depression, anxiety, and fear can amplify pain. The treatment approach is similar to that for any pain syndrome. Bias might be present among caregivers toward patients with a history of substance use. Asneeded dosing can be difficult for cognitively-impaired patients and can result in dangerous overuse. For patients on methadone for opioid dependence, it is preferable to use another analgesic to control pain rather than to increase the

methadone dose. Lamotrigine has been shown to be effective for DSP but can carry a higher risk of rashes.

Toxoplasmosis Toxoplasma gondii causes encephalitis and cerebral abscesses in patients with advanced HIV infection, typically when the CD4 count is < 100 cells/µL. Symptoms and signs include a rapidly progressive change in mental status, headache, and focal neurologic signs. Contrast-enhanced CT shows multiple ring-enhancing lesions. T2-weighted MRI scans demonstrate multiple foci of increased signal that have a predilection for the basal ganglia. Pyrimethamine and sulfadiazine lead to clinical and radiologic improvement, and suppressive therapy must continue until the patient achieves immune reconstitution after initiation of antiretroviral therapy.

Primary CNS Lymphoma This neoplastic disease is an important cause of neurologic illness in HIVinfected patients, particularly when the CD4 count is < 50 cells/µL. It presents as a slowly progressive neurocognitive disorder that can be mistaken for HAD before multi-focal signs and elevated intracranial pressure supervene. Symptoms and signs depend on the site(s) of the lesion(s). Lymphoma can be difficult to distinguish from toxoplasmosis on neuroimaging. The incidence of primary CNS lymphoma has fallen markedly since the introduction of effective ART.

Cryptococcal Meningitis This type of meningitis is caused by the yeast, Cryptococcus neoformans , and it presents with fever, meningismus, cranial nerve abnormalities, and papilledema. The CT scan and an unenhanced MRI can be unremarkable, but an MRI with gadolinium can show meningeal enhancement. The diagnosis is usually made by cryptococcal antigen testing or culture of the blood and CSF. Cryptococcal meningitis should be treated initially with amphotericin B and flucytosine followed by fluconazole until immune reconstitution is achieved with ART.

CMV-Associated Encephalitis A complication of late-stage HIV infection/AIDS, this condition can be difficult to distinguish from HAD. Features include a rapidly progressive delirium, seizures, and fever. MRI scans can show a peri-ventricular and subependymal abnormal signal. It is treated with intravenous ganciclovir.

Progressive Multi-Focal Leukoencephalopathy Due to Creutzfeldt-Jakob disease (CJD ), which is common in the immunocompetent population, progressive multi-focal leukoencephalopathy (PML ) follows a rapid downhill course in untreated AIDS patients. Multi-focal neurologic signs are dependent on lesion location; a progressive acute or subacute delirium can occur. CT scans shows sub-cortical non-enhancing lucencies. MRI scans show patchy areas of high signal in sub-cortical white matter. PML has become treatable with combination ART, which arrests progression (despite its name) but rarely reverses established deficits.

Treatment Considerations Clinicians must be aware of the available classes of antiretroviral medications and the importance of adherence to them; the neuropsychiatric side effects of antiretroviral medications and agents used to treat secondary OIs; the drug interactions between antiretroviral agents and psychotropic medications; the differences in response to psychiatric medications in patients with HIV infection/AIDS; and the psychotherapeutic challenges in this population. The critical goal of HIV treatment is to suppress viral replication, thereby improving the CD4 cell count and reducing morbidity and mortality. To maximize effectiveness and to reduce the development of viral resistance, the typical strategy is to use a combination of three drugs. There are six classes of antiretroviral medications: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs, non-nucleoside reverse transcriptase inhibitors [NNRTIs], protease inhibitors [PIs], integrase inhibitors, fusion inhibitors, and chemokine coreceptor antagonists). First-line regimens in the United States include two NRTIs plus an integrase inhibitor or a ritonavir-boosted PI. Initiation of ART is recommended for all HIV-infected patients, regardless of CD4 cell count. Some clinical situations (when the patient has a low CD4 cell count or an opportunistic condition) require the urgent initiation of ART. Otherwise, among the most critical factors in deciding when to initiate treatment is the patient’s commitment to life-long treatment as adherence to therapy is critical to avoid breeding resistance. For patients with psychiatric illness who have a high CD4 cell count, it is important to stabilize them maximally and to discuss with them the importance of strict adherence before starting ART. The neuropsychiatric side effects of these medications and others used to treat patients with HIV infection/AIDS are reviewed in Table 30-3. The most important of these are efavirenz and zidovudine (AZT).

Approximately half of patients started on efavirenz experience neuropsychiatric disturbances, which begin early and peak within two to four weeks. Although typically mild and transient, a small minority of patients experience severe or persistent side effects requiring discontinuation. Particular caution is advised in patients with uncontrolled psychiatric illness. In a large analysis of clinical trials that contained an efavirenz arm, efavirenz but not other antiretrovirals was associated with an increased incidence of suicidality. Based on this finding and the fact that other agents are often better tolerated, efavirenz is no longer a recommended first-line agent in the United States. However, many patients in the United States are still receiving efavirenz and this medication is still recommended by the World Health Organization as a component of first-line therapy for HIV infection. When AZT was the only available antiretroviral agent, high-dose AZT was occasionally associated with mania. However, AZT is rarely used in the United States anymore and the current dose, when it is given, is much less likely to induce a manic episode. Many antiretroviral agents are metabolized by the cytochrome P-450 system; many are also inducers or inhibitors of this enzymatic pathway. Probably the most important and dangerous of these drug–drug interactions are that between ritonavir, a potent inhibitor of cytochrome P-450 3A4, and some benzodiazepines (e.g., alprazolam, midazolam, and triazolam), which are considered contraindicated in patients receiving ritonavir because of an increase in the serum level of the latter. The antipsychotic pimozide should not be used in conjunction with ritonavir. Like ritonavir, cobicistat, which is used as a pharmacologic booster, also inhibits CYP3A4 and has similar potential for drug interactions with medications metabolized by this mechanism. A full discussion of drug–drug interactions, most of which are only very poorly described, is beyond the scope of this chapter; the interested reader is referred to the Internet resources and the suggested readings at the end of this chapter for sources of this information. Patients with advanced HIV disease have less lean body mass, metabolize drugs more slowly, and are sensitive to drug side effects. Because of blood–brain barrier compromise, the HIV-infected brain might “see” higher levels of drug than serum levels might predict. In these patients, aim for low therapeutic levels; start with low doses (as a general rule of thumb, 50%–75% of usual) and increase them slowly; and, when possible, avoid anticholinergic, anti-α 1adrenergic, and sedating medications. In patients with cognitive impairment,

avoid as-needed dosing because patients might accidentally overdose on dangerous medications. In addition to the myriad difficulties any person brings to psychotherapy, issues that arise in psychotherapy with HIV infection/AIDS patients include: difficulties coping with chronic medical illness; feelings of being punished for sexual activities and drug use; revealing sexual orientation and drug use to family and friends; conducting an intimate relationship with an HIV-negative partner; health-care decisions; and death. Psychotherapists must be aware of their feelings about all of these issues and be prepared to ask straightforward, non-judgmental questions about lifestyles or practices that are unfamiliar to them. Stigma remains an important barrier, preventing patients from taking full advantage of the benefits of the treatment cascade (i.e., diagnosis of HIV infection, linkage to care, retention in care, receipt of antiretroviral therapy, and achievement of viral suppression).

Legal Considerations Because of limitations in risk-based screening, in 2006, the CDC recommended that voluntary HIV testing be conducted as a routine part of general medical care. In the past, HIV testing could be performed only with the patient’s written informed consent; now, it is permissible to obtain verbal consent from the patient (which should be documented in the medical record) before testing (review your local laws for exact informed consent requirements). In psychiatric settings, staff members are obligated to protect others by monitoring and restricting privileges of HIV-positive patients who engage or attempt to engage in high-risk activities while in the hospital. In some jurisdictions, physicians might have a legal requirement to disclose a patient’s HIV sero-status against the patient’s wishes to protect others without direct identification of the patient. In some jurisdictions, the physician must tell the patient that this information was disclosed. Because statutes vary by geography, clinicians should consult their local medical societies in these cases.

Conclusions Infection with HIV exerts powerful biological, psychological, and social effects on patients and, directly or indirectly, is responsible for a panoply of affective, behavioral, and cognitive symptoms. The care of these patients, therefore, taps all of a psychiatrist’s skills. Not only must the psychiatrist be aware of the

differences in the diagnosis and treatment of psychiatric syndromes in HIVinfected patients and the neurologic manifestations of HIV-related illnesses and treatments, he or she must be sensitive to the often fragile and chaotic psychosocial milieu in which many of these patients live and to the obstacles they have to overcome to benefit from medical advances made in HIV infection/AIDS. The US National HIV/AIDS Strategy’s four strategic goals can serve as a blueprint for clinicians working with patients with HIV infection/AIDS: reduce new infections, increase access to care and improve health outcomes for people living with HIV, reduce HIV-related health disparities and inequities, and achieve a more coordinated national response to the HIV epidemic.

Useful Internet Resources AIDS Clinical Trials and Information Services (ACTIS) www.actis.org American Psychiatric Association Office of HIV Psychiatry www.psych.org/aids Centers for Disease Control and Prevention www.cdc.gov Johns Hopkins University School of Medicine www.hopkinsguides.com/hopkins/ub Joint United Nations Programme on HIV/AIDS www.unaids.org Project Inform Information, inspiration, and advocacy for people living with HIV/AIDS www.projectinform.org University of California, San Francisco http://hivinsite.ucsf.edu/medical University of Liverpool www.hiv-druginteractions.org/ US Department of Health and Human Services www.aidsinfo.nih.gov/

Suggested Readings

1. Colfax G, Santos G-M, Chu P, et al: Amphetamine-group substances and HIV. Lancet . 2010; 376: 458–474. 2. Heaton RK, Franklin DR, Ellis RJ, et al: HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: Differences in rates, nature, and predictors. J Neurovirol . 2011; 17: 3–16 3. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al: Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med . 2015; 373: 795–807. 4. Kenedi CA, Goforth HW: A systematic review of the psychiatric sideeffects of efavirenz. AIDS Behav . 2011; 15: 1803–1818. 5. Letendre S, Marquie-Beck J, Capparelli E, et al: Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol . 2008; 65: 65–70. 6. Molina JM, Capitant C, Spire B, et al: ANRS IPERGAY Study Group: Ondemand pre-exposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med . 2015; 373: 2237–2246. 7. Mollan KR, Smurzynski M, Eron JJ, et al: Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med . 2014; 161: 1–10. 8. Querques J, Freudenreich O: Psychiatric aspects of HIV infection and AIDS, In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016: 627–637. 9. Rabkin JG, McElhiney MC, Rabkin R, et al: Modafinil treatment for fatigue in HIV/AIDS: A randomized placebo-controlled study. J Clin Psychiatry . 2010; 71: 707–715. 10. Treisman GJ, Angelino AF: The Psychiatry of AIDS: A Guide to Diagnosis and Treatment . Baltimore, MD: Johns Hopkins University Press; 2004.

CHAPTER Catatonia, Neuroleptic 31 Malignant Syndrome, and Serotonin Syndrome SCOTT R. BEACH, MD; BRAD REDDICK, MD; GREGORY L. FRICCHIONE, MD; AND THEODORE A. STERN, MD

KEY POINTS Overview The syndromes described in this chapter each represent a complex of motoric, behavioral, and systemic symptoms derived from unclear mechanisms of neurochemical aberration. The clinical similarities among catatonia, neuroleptic malignant syndrome (NMS), and serotonin syndrome have led some to hypothesize a common pathophysiology and consider NMS and serotonin syndrome to be sub-types of catatonia. Epidemiology Several studies have suggested that the incidence of catatonia among psychiatric inpatients is between 7% and 17% (up to 20% of manic patients), whereas approximately 2% to 3% of medical inpatients who receive psychiatric consultations appear to have catatonic features. Estimates of the incidence of NMS have been as high as 3%, although more recent data suggests its incidence is 0.01% to 0.02% among patients treated with antipsychotic agents. The incidence of serotonin syndrome is unknown. Clinical Features Studies have suggested that mutism, staring, rigidity, echophenomena, posturing, and negativism are the most common signs in stuporous catatonia, present in at least half of catatonic patients. In 2011, an International Consensus study concluded that core symptoms of NMS include hyperthermia, rigidity, mental status alteration, elevated CPK,

and sympathetic nervous system lability. Serotonin syndrome is classically described as a triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that occurs in the setting of the use of serotonergic agents. Etiology Catatonia can be secondary to a psychiatric illness or to a neuromedical cause. Clinical features suggest an overarching disruption of the basal-gangliathalamo-cortical loop system, and specific neurochemical aberrations commonly associated with catatonia include hypodopaminergic states, GABAergic withdrawal, and serotonergic excess. NMS is precipitated by administration of a dopamine-blocking agent or removal of a dopamine agonist. Serotonin syndrome is related to excess serotonin, typically caused either by an overdose on serotonergic medication or polypharmacy. Differential Diagnosis The differential diagnosis of catatonia includes locked-in syndrome, persistent vegetative states, akinetic mutism, and seizures. NMS can be difficult to distinguish from malignant hyperthermia, extrapyramidal symptoms, or anticholinergic delirium. Serotonin syndrome and NMS can also appear similar to each other. Approaches to Evaluation Aside from the criteria delineated in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition , the 23-item Bush-Francis Catatonia Rating Scale is also used to rate the severity of illness and to provide a schema for examination. Laboratory tests, imaging, and an electroencephalogram can be valuable tools for ruling out other entities and further exploring the etiology of catatonic symptoms. An intravenous lorazepam challenge test can also be diagnostic in some cases. In the case of NMS and serotonin syndrome, early recognition is imperative, and attention should be paid to potential precipitating agents. Treatment Benzodiazepines are generally considered as the initial treatment-of-choice for

catatonia regardless of its cause, and intravenous lorazepam is preferred. Electroconvulsive therapy may provide definitive treatment in refractory cases and should be considered early in cases of malignant catatonia or NMS. Serotonin syndrome often responds to removal of the offending agent and supportive measures.

Introduction The syndromes described in this chapter each represent a complex of motoric, behavioral, and systemic symptoms derived from unclear mechanisms of neurochemical aberration. The clinical similarities among catatonia, neuroleptic malignant syndrome (NMS), and serotonin syndrome (SS) have led some to hypothesize a common pathophysiology and consider NMS and SS to be subtypes of catatonia. As our psychopharmacologic armamentarium grows and as drugs potent in their modulation of monoamine-action proliferate, the diagnosis and management of these complex disorders becomes even more important.

Catatonia Definition The syndrome of catatonia , derived from the Greek word katateinein (to stretch tightly), is made up of an array of motor and behavioral signs and symptoms that often occurs in the setting of neurochemical insults. The syndrome was characterized in 1874, when Karl Kahlbaum described 21 patients thought to have the disorder, which he proposed was a process of several stages corresponding to symptom severity. Though catatonia was described for decades as occurring primarily in the setting of schizophrenia, it is now thought to be more common in affective disorders and in patients suffering from general medical and neurological conditions.

Etiology The potential etiologies of catatonia are many and are outlined in Table 31-1. These can be subdivided into psychiatric conditions neuromedical conditions, and substance-related syndromes. Notably, though, delirium is currently excluded in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a cause of catatonia, most cases of catatonia involving a neuromedical etiology have a co-morbid delirium.

Epidemiology Several studies have suggested that the incidence of catatonia among psychiatric inpatients is between 7% and 17% (and is up to 20% in manic patients), whereas approximately 2% to 3% of medical inpatients who receive psychiatric consultations appear to have catatonic features. Of cases of catatonia seen in the general hospital setting, up to 50% are found to have neuromedical etiologies. The importance of paraneoplastic and autoimmune encephalitides, such as anti- N -methyl-D-aspartate receptor (NMDAR) encephalitis, as an etiology for catatonia is increasingly recognized. Table 31-1: Potential Etiologies of the Catatonic Syndrome Primary Psychiatric Bipolar disorder Major depressive disorder Schizophrenia Brief reactive psychosis Dissociative disorder Autism-spectrum disorder

Secondary Neuromedical Cerebrovascular causes Traumatic brain injury Wernicke’s encephalopathy Parkinson’s disease Paraneoplastic limbic encephalitis (especially anti-N -methyl-D-aspartate receptor antibody encephalitis) Sepsis CNS infections Endocrinopathies Systemic lupus erythematous

Substance-Induced Dopamine-blocking agents Sedative/hypnotic/alcohol withdrawal Dopamine withdrawal Hallucinogens

Lithium Opiates

Catatonia is more common in patients with neurodevelopmental disorders and in those with autism-spectrum disorders, with up to 17% of patients in the latter group displaying symptoms post-adolescence. Genetically, a link has been established with deletions on chromosome 15, such as those seen in PraderWilli.

Diagnosis A list of catatonia symptoms is provided in Table 31-2. Studies have suggested that mutism, staring, rigidity, echophenomena, posturing, and negativism are the most common signs in stuporous catatonia, present in at least half of catatonic patients. The DSM-5 defines catatonia by the presence of at least three of the following: stupor, agitation, catalepsy, waxy flexibility, negativism, mutism, posturing, mannerisms, stereotypies, grimacing, and echolalia or echopraxia. Catatonia is sub-divided as being due to another mental or another medical condition. Table 31-2: Symptoms Associated with Catatonia Impulsivity

Manifest by sudden, often unreasoned, actions.

Automatic obedience

Demonstrated by the patient’s willingness to follow even those commands that might be undesirable (e.g., “Stick out your tongue so I may put a pin in it.”)

Mitgehen

Demonstrated by instructing the patient “When I touch your hand, don’t raise it toward the ceiling.” The examiner then lightly taps the patient’s hand in an upward direction. A positive sign occurs when the patient’s hand rises dramatically.

Gegenhalten

Rigidity that increases in response to the pressure applied.

Ambitendency

Indecision or hesitance in response to contradictory verbal and non-verbal signals from the examiner (e.g., offering hand to the patient while stating “Don’t shake my hand.”)

Grasp reflex

A frontal release sign tested by gently stroking the patient’s palm. A positive sign results in the patient clasping the interviewer’s fingers.

Perseveration

Repetition of words or phrases.

Combativeness

Marked by an eagerness to fight.

Autonomic abnormality

Manifest by changes in blood pressure mediated by the autonomic nervous system.

Motoric excitement

Hyperactivity and motor unrest.

Immobility/stupor

Being incapable of movement.

Mutism

Absence or paucity of speech.

Staring

Looking fixedly, often with wide eyes.

Posturing/catalepsy Independent assuming of bizarre poses by the patient (e.g., “psychological pillow,” in which the patient lies with his neck flexed forward in the absence of external support). Grimacing

Facial expressions, often of disgust.

Echopraxia

Mimicking of the examiner’s movements.

Echolalia

Mimicking of the examiner’s speech.

Stereotypy

Bizarre, purposeless movements.

Mannerisms

Purposeful movements done in a bizarre way.

Verbigeration

Meaningless repetition of words or phrases.

Rigidity

Appearing stiff and inflexible.

Negativism

Refusal to comply with examiner’s requests (e.g., patient actively resists eye-opening).

Waxy flexibility

Initial resistance to induced movement before allowing oneself to be postured.

Withdrawal

Decreased interaction with one’s external environment, including decreasing intake of food and water

According to the DSM-5, the syndrome is thought to be the result of a general medical condition when the disturbance does not occur exclusively during the course of delirium; the disturbance is not better accounted for by another mental disorder; and there is evidence from history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition. Considering sub-types of the syndrome can facilitate management and treatment. Catatonic stupor, or retarded catatonia, is the most common form and is characterized by psychomotor slowing, rigidity, and mutism, whereas excited catatonia is marked by psychomotor hyperactivity (with restless movements, talkativeness, and frenzy). Another sub-type, malignant catatonia, can appear stuporous or excited and is complicated by autonomic instability and/or hyperthermia. Delirious mania is a unique entity, considered by some to be a form of malignant, excited catatonia. It involves confusion and disorientation, symptoms of mania (such as emotional lability, grandiosity, and insomnia), and a cluster of additional symptoms that include inappropriate toileting, denuding, and preoccupation with water. It is often sudden in onset, dream-like, with purposeless hyperactivity, and is relatively short lived when compared to manic excitement.

Differential Diagnosis Locked-In Syndrome Patients with locked-in syndromes typically try to communicate via vertical eye movements and blinking, whereas catatonic patients make little effort to communicate. Locked-in syndrome is not associated with motoric features of catatonia and it is commonly linked with lesions in the ventral pons and cerebellar peduncles.

Persistent Vegetative State Patients after a coma might remain in what is called a persistent vegetative state in which a patient has impairments of cognition and voluntary movement leaving them capable of only certain involuntary actions like breathing and eye blinking and tracking. The lower brain stem remains functional. Most of these patients have no perception of and, therefore have no ability to react to external stimuli. It is of interest that zolpidem, a GABAA agonist with effectiveness in catatonia, has been reported anecdotally to improve arousal in several persistent vegetative state cases.

Seizures Non-convulsive status epilepticus can mimic catatonia, but it can be distinguished from catatonia by an abnormal electroencephalogram (EEG).

Akinetic Mutism/Abulia Although some consider akinetic mutism and abulia to be on the same spectrum as catatonia, these syndromes typically lack classic motoric features of catatonia (e.g. waxy flexibility, gegenhalten ) and are usually associated with specific neurological lesions, most commonly bilateral frontal lobe damage or a frontal network syndrome secondary to sub-cortical damage.

Malignant Hyperthermia This condition occurs post-operatively as a reaction to inhalation anesthetics.

Parkinsonism The onset of Parkinson’s disease is typically less acute than that of catatonia. Parkinson’s disease is associated with other features, such as tremor, that are not seen in catatonia.

Deception Syndromes

Patients can appear catatonic secondary to malingering or to factitious disorder. Patients who consciously deceive their physicians will usually demonstrate inconsistent signs and symptoms that help to distinguish their condition from catatonia. After the diagnosis of catatonia has been established, the differential diagnosis remains broad; a thorough work-up should be pursued even after a diagnosis has been made.

Pathophysiology The complex array of symptoms and the many potential etiologies makes discussion of the mechanism by which the syndrome of catatonia’s etiology difficult. Familial clustering suggests a genetic component. Clinical features suggest an overarching disruption of the basal-ganglia-thalamo-cortical loop system. Specific neurochemical aberrations commonly associated with catatonia include: hypodopaminergic states; GABA-ergic withdrawal; and serotonergic excess. Alternatively, some have suggested that catatonia might be a form of limbic epilepsy; subtle ictal events involving the prefrontal cortex and the basal ganglia have been postulated, given that the use of intravenous (IV) benzodiazepines (that have antiseizure effects) can treat catatonia.

Evaluation The importance of prompt diagnosis is highlighted by the many potential medical complications associated with catatonia (Table 31-3) and the existence of effective treatments that may prevent dire complications and interrupt progression of the illness. History will often reveal clues to the existence of a pre-morbid psychotic disorder or an underlying medication trial or medical condition, such as those outlined in Table 31-1. When catatonic mutism precludes obtaining a thorough history, administration of IV lorazepam can bring on a temporary lucid interval that can facilitate data collection. Alternatively, an amobarbital interview (although rarely used in clinical practice) can also be helpful, as some reports suggest temporary recovery being more common in patients with an underlying psychiatric illness. Table 31-3: Some Medical Complications Associated with Catatonia Simple Non-Malignant Catatonia Aspiration Burns

Dehydration and sequelae Pneumonia Pulmonary emboli Thrombophlebitis Urinary retention and sequelae Malignant Catatonia Acute renal failure Cardiac arrest Death Disseminated intravascular coagulation Hypoglycemia Intestinal pseudo-obstruction Laryngospasm Necrotizing enterocolitis Respiratory failure Rhabdomyolysis Seizures Sepsis Severe hepatocellular damage Upper gastrointestinal tract bleeding

Aside from the criteria delineated in the DSM-5, the 23-item Bush-Francis Catatonia Rating Scale is also used to rate the severity of illness and to provide a schema for examination. Patients must have 2 of the first 14 items to qualify for a diagnosis of catatonia; the severity is rated on a scale of 0 to 69.

Studies An EEG is a valuable tool in the detection of an underlying seizure disorder. It can also be helpful in identifying a co-morbid or causal delirium. Although a normal EEG might not exclude partial seizures, such a finding is consistent with idiopathic catatonia and other psychiatric conditions. Neuroimaging studies can rule-out mass lesions, central nervous system (CNS)-ischemic events, and underlying neuromedical illnesses that confer vulnerability, and can help in the prediction of benzodiazepine intolerance.

Unfortunately, normal brain imaging does not rule-out many underlying neuromedical etiologies. Laboratory tests can illuminate clues to both catatonia and the risk factors for the development of NMS. Abnormal electrolyte levels, poor renal function, and elevated hematocrit might suggest dehydration and raise suspicion for NMS. An elevated creatinine phosphokinase (CPK) typically occurs in both malignant catatonia and NMS; knowledge of its presence can guide therapy in terms of preventing subsequent renal failure from rhabdomyolysis. Iron studies are also useful, as patients with low iron levels may be predisposed to developing catatonia and to suffering a switch to malignant catatonia. Blood levels of medications are also helpful in determining the underlying cause of the catatonia. As discussed below, a definitive diagnosis of catatonia is facilitated by a rapid and dramatic response to an IV benzodiazepine trial.

Treatment Discontinuation of potential offending pharmacologic agents, particularly dopamine-blockers (such as neuroleptics or metoclopramide) that can cause or worsen catatonia, should be considered. Consideration should also be given to restarting any dopaminergic agents (such as stimulants or amantadine or dopaminergic antiparkinsonians), that were recently discontinued, and treating any alcohol or benzodiazepine withdrawal. Benzodiazepines are generally considered as the initial treatment of choice for catatonia regardless of its cause; response rates are thought to be 60% to 80% over the course of hours to days. IV lorazepam is preferred due to its ease of administration, quick onset of action, higher binding affinity for the GABAA receptor, and long effective clinical activity relative to other forms. Patients will sometimes respond dramatically to an IV benzodiazepine challenge, fully resolving the catatonic state after a single dose. Close monitoring is imperative, however, because most patients will gradually relapse over the ensuing hours; repeat dosing, typically three to four times daily for several days, is often needed. Benzodiazepines used to treat catatonia should generally be held only for respiratory depression (and not sedation), as signs of catatonia are often mistaken for over-sedation. Prolonged administration of benzodiazepines in patients with catatonia can lead to medical complications (e.g., respiratory depression or aspiration). If the patient fails to respond after a few days, alternative treatments should be considered. Other medications reported as

efficacious in the treatment of catatonia include zolpidem, memantine, amantadine, valproic acid, and topiramate. Despite some reports of benefit, it is generally best to avoid dopamine-blocking agents in catatonia due to their risk for causing malignant catatonia or NMS. If necessary for treating co-occurring psychosis, low-potency atypical agents are preferred at low doses and in combination with benzodiazepines. Electroconvulsive therapy (ECT) continues to be a powerful and effective treatment of catatonia; it should be considered in cases that fail to respond to IV benzodiazepines or when other treatments for catatonia are contraindicated. Frequently two to three ECT treatments will suffice, although four to six treatments are usually given to prevent relapse. With the increasing appreciation that autoimmune limbic encephalitidies can cause catatonia, immunosuppressant treatments have also been found helpful in management. This has long been the case with catatonia secondary to CNS lupus, as well. Medical/supportive care (including hydration, nutrition, mobilization, and anticoagulation (to prevent thrombophlebitis and pulmonary embolism) is essential. Aspiration precautions are also important. After catatonia is suspected, close observation and frequent vital-sign checks are warranted. Throughout the course of catatonia, a high index of suspicion should be sustained for the development of medical complications. If hyperthermia, autonomic instability, or malignant catatonia emerge, treatment in an intensive care unit (ICU) might be indicated.

Neuroleptic Malignant Syndrome Definition NMS is an idiosyncratic, life-threatening, complication of neuroleptic therapy that confers high mortality if not treated in a prompt and skillful manner. It is thought by many to be a form of malignant catatonia related to a specific etiology.

Epidemiology Lack of uniform diagnostic criteria, concurrent use of other medications, and methodological differences used in epidemiology studies have made estimating the frequency of NMS difficult. Estimates of its incidence have been as high as 3%, although more recent data suggests its incidence is 0.01% to 0.02% among patients treated with antipsychotic agents. This perceived decline might be the

result of either greater recognition or a trend toward the prescription of atypical antipsychotics that are thought to convey less risk for developing the syndrome. Although there are clinical similarities between NMS and malignant hyperthermia (associated with general anesthesia), patients with a history of either NMS or malignant hyperthermia do not appear to be at increased risk for the development of the other. However, patients with a prior episode of NMS do appear to be at elevated risk for subsequent episodes. Mortality rates for those with NMS have decreased from 20% (as recently as 25 years ago) to 6% (currently), a downstream consequence of a greater awareness of the syndrome and its signs and symptoms. Acute respiratory failure is considered the strongest predictor of mortality.

Diagnosis No universally accepted criteria exist for NMS although attempts have been made to develop operational criteria. NMS is listed in the DSM-5 under Medication-Induced Movement Disorders and Other Adverse Effects of Medication, but no diagnostic criteria are given. In 2011, an International Consensus study concluded that core symptoms include hyperthermia (> 100.4°F on at least two occasions, measured orally), rigidity, mental status alteration, elevated CPK (at least four times the upper limit of normal), sympathetic nervous system lability (defined by the presence of two or more of: elevated blood pressure [systolic or diastolic at least 25% above baseline]; blood pressure fluctuation [change of 20 mm Hg diastolic or 25 mm Hg systolic in 24hour period]; diaphoresis or urinary incontinence), tachycardia (at least 25% above baseline), and tachypnea (at least 50% above baseline). In this algorithm, each symptom was assigned a priority score, and the total score is used to determine the likelihood of NMS. Rating scales have been developed to track its symptoms over time. Atypical NMS is being more commonly described in the literature. Though the term was initially used to describe cases of NMS presenting with atypical features or lacking common core features, its use has been conflated to include cases of NMS arising secondary to the use of atypical antipsychotic agents. Evidence suggests, however, that most cases of NMS caused by atypical antipsychotics present with classic features, though clozapine might be less likely to induce rigidity and tremor. A recent systematic review found that atypical NMS tends to have a lower clinical severity and less mortality.

Differential Diagnosis

As the clinical features of NMS resemble those of a host of medical and neurological illnesses, the diagnosis of NMS requires attention to the plethora of potential neuromedical etiologies. Table 31-4 provides a differential diagnosis for NMS. Following are several of the more common conditions to consider. Table 31-4: Differential Diagnosis of Neuroleptic Malignant Syndrome CNS Disorders Head trauma Meningitis Parkinson’s disease Status epilepticus

Systemic Disorders Hyperthyroidism Pheochromocytoma Malignant hyperthermia Heat stroke Polymyositis Sepsis

Substance-Related Conditions Anticholinergic syndrome Malignant hyperthermia Sedative/hypnotic withdrawal Serotonin syndrome

CNS infections A prodromal viral illness and localizing neurological signs may help to distinguish NMS from a CNS infection. Cerebrospinal fluid (CSF) analysis and imaging studies may provide useful data, as well.

Benign Extrapyramidal Symptoms (EPS) Although muscle rigidity may lead to an elevation in CPK, extrapyramidal symptoms (EPS) are not typically accompanied by fever, autonomic instability, elevation of the white blood cell count, and other abnormal laboratory studies.

Malignant Hyperthermia This condition is associated with administration of anesthesia and it is manifest by a characteristic histologic appearance of skeletal muscle fibers (i.e., they contract on exposure to halothane or caffeine).

Anticholinergic Delirium Manifestations of anticholinergic excess lack diaphoresis. The diagnosis can be further clarified by the administration of physostigmine, which will temporarily reverse signs and symptoms of anticholinergic excess.

Serotonin Syndrome With serotonin syndrome, tremor is a more frequently seen peripheral motor finding, fever is less frequent and less profound, and the laboratory abnormalities seen in NMS are usually absent.

Pathophysiology Although poorly understood, the mechanism thought responsible for NMS involves blockade of central dopamine receptors in the basal ganglia, the hypothalamus, and peripherally in post-ganglionic sympathetic neurons and smooth muscle. Neuroleptics have been implicated in directly altering basal temperature regulation in the hypothalamus and thus might play an added role in the development of fever. Observations that dantrolene can be beneficial in the treatment of NMS suggest that neuroleptics might directly affect skeletal muscle and result in increased cell metabolism and hyperthermia. Some have also postulated that the underlying pathophysiology more likely reflects an imbalance in central dopamine and serotonergic and/or adrenergic tone. Attempts to discover risk factors for the development of NMS have been ongoing. Identified risk factors include more pre-morbid psychomotor agitation, higher doses of neuroleptics (with greater rates of dose increases), use of highpotency dopamine blocking agents, a higher number of intramuscular (IM) injections, physical restraints, and the concurrent use of lithium. Dehydration and iron deficiency also appear to increase the risk of NMS. Up to 20% of affected patients may have had a prior episode of NMS.

Evaluation The diagnosis of NMS is based on the clustering of signs and symptoms outlined earlier in the setting of a hypodopaminergic state. A detailed history and chart review can reveal the use of either neuroleptics or non-neuroleptic

dopamine antagonists, or the recent withdrawal of dopamine agonists. Table 315 lists dopamine-blocking agents. Table 31-5: Dopamine Antagonists Antipsychotic Agents (Neuroleptics) First-Generation Agents Chlorpromazine (Thorazine) Triflupromazine (Vesprin) Mesoridazine (Serentil) Thioridazine (Mellaril) Acetophenazine (Tindal) Fluphenazine (Prolixin, Permitil) Perphenazine (Trilafon) Trifluoperazine (Stelazine) Droperidol (Inapsine) Haloperidol (Haldol) Chlorprothixene (Taractan) Thiothixene (Navane) Loxapine (Loxitane, Daxoline) Pimozide (Orap)

Second-Generation Agents Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperdal) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Paliperidone (Invega) Iloperidone (Fanapt) Asenapine (Saphris) Lurasidone (Latuda)

Other Dopamine Antagonists

Anti-Emetics Metoclopramide (Reglan) Promethazine (Phenergan) Prochlorperazine (Compazine) Trimethobenzamide (Tigan)

Other Agents Hydroxyzine (Atarax, Vistaril) Tetrabenazine

In addition to leukocytosis and an elevated CPK, other findings suggestive of NMS include transaminitis, lactic acidosis, a low serum iron, and signs of myoglobinuric renal failure. CSF studies are normal in the clear majority of cases, as is neuroimaging. EEGs typical show diffuse slowing, whereas neuroimaging findings are non-specific.

Treatment Given the high morbidity and mortality associated with NMS, prompt treatment is essential. Any dopamine antagonists (Table 31-5) should be promptly discontinued and dopamine agonists resumed. The initial management should include transfer to a general hospital where intensive hemodynamic monitoring and supportive care can be initiated. Suggested supportive measures include provision of adequate IV hydration, active cooling, and close hemodynamic monitoring. Electrolyte balance and renal function should be monitored closely, given the increased risk of renal failure associated with NMS. Dialysis might be necessary. Pharmacological management can follow the pathway outlined for simple catatonia used in a more aggressive fashion. IV lorazepam, in higher doses, has been found effective and safe in NMS. If needed, amantadine can be added. Dantrolene can be helpful in reducing muscle rigidity, extreme temperature elevations, and hypermetabolism; however, it carries risks of hepatotoxicity and respiratory failure. Bromocriptine and similar dopamine agonists like ropinirole are thought by some to be effective through their action as a central agonist at the D2 receptor, although they might potentially worsen any underlying psychosis. Other treatments that might be beneficial include use of amantadine and benzodiazepines. ECT is considered the definitive treatment, and it should be considered early in the course, preferably within 5 days as a life-saving

intervention. As with other forms of malignant catatonia, delay in the use of ECT can be life-threatening. Six to ten treatments are typically needed, and succinylcholine is generally avoided during ECT. Controversy surrounds the assumption that the development of NMS confers greater risk of developing the syndrome if rechallenged with a neuroleptic. Some have estimated that the likelihood of developing a subsequent episode of NMS might be as high as 30%. Most investigators agree that re-institution of antipsychotics should be delayed at least two weeks after an episode of NMS has resolved, with lower potency neuroleptics used preferentially during a rechallenge.

Serotonin Syndrome Definition Serotonin syndrome (SS ) is classically described as a triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that occurs in the setting of the use of serotonergic agents. As with NMS, it can be considered a form of malignant catatonia. Given the growing number of agents that directly affect central serotonergic tone, clinicians should have an awareness regarding the prevention, recognition, and timely treatment of SS. Classically, SS most commonly occurred in the setting of an interaction between a serotonergic agent and a monoamine oxidase inhibitor (MAOI), but with the decline in use of MAOIs, it now most commonly occurs in situations of overdose on serotonergic agents or polypharmacy. Symptoms of SS include changes in mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, and catatonia.

Epidemiology The incidence of SS is unknown; there is no data to suggest that age or gender differences confer any variability in predisposition to development of the syndrome. SS is almost certainly under-recognized and under-reported, given that as many as 85% of physicians might be unaware of the diagnosis. Additionally, the varying symptom severity can confound its recognition. The syndrome is thought to occur in up to 16% of patients who overdose on a selective serotonin re-uptake inhibitor (SSRI).

Diagnosis

A thorough medication history is essential for the diagnosis of SS. Among psychiatric medications, SSRIs, tricyclic antidepressants (TCAs), and MAOIs are the most common culprits, though other agents (such as lithium, valproate, atypical antipsychotics, trazodone, and buspirone) also have serotonergic effects. In addition, commonly prescribed medications with serotonin activity include meperidine, fentanyl, tramadol, ondansetron, sumatriptan, dextromethorphan, tryptophan, and linezolid. Table 31-6 provides a list of medications with serotonergic properties. Table 31-6: Serotonergic Agents SSRI Antidepressants Fluoxetine Sertraline Citalopram Escitalopram Paroxetine Fluvoxamine

Serotonin-Norepinephrine Re-Uptake Inhibitors (SNRIs) Venlafaxine Desvenlafaxine Duloxetine

TCA Antidepressants Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline

MAOI Antidepressants Selegiline Phenelzine

Tranylcypromine

Other Antidepressants Mirtazapine Vilazodone Vortioxetine

Atypical Antipsychotic Agents Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperdal) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Paliperidone (Invega) Iloperidone (Fanapt) Asenapine (Saphris) Lurasidone (Latuda)

Other Psychiatric Medication Lithium Carbamazepine Oxcarbazepine Valproic acid Methylphenidate Buspirone Cyclobenzaprine

Opiates and Pain Medications Methadone Tramadol Fentanyl Meperidine Buprenorphine Oxycodone Hydrocodone

Antibiotics Linezolid

Triptans Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmatriptan

Drugs of Abuse MDMA Methamphetamine Cocaine Syrian Rue

Other Nutmeg Ondansetron Triptans Dextromethorphan 5-hydroxytryptophan Methylene blue Metoclopramide St. John’s wort

The onset of SS is typically rapid. Patients initially experience tremor, mild confusion, and incoordination; these are followed by systemic signs (such as hyperreflexia, diaphoresis, shivering, and agitation). Mydriasis is frequently seen and patients can develop fever, clonus (typically more pronounced in the lower extremities), and diarrhea. Severe cases can develop shock, an agitated delirium, and muscle rigidity. These clinical features can develop from hours to days after the initiation of serotonergic agents and can persist if the offending agents are continued.

There are two major sets of criteria for SS. Sternbach criteria have high sensitivity, requiring three of the following ten symptoms occurring in the setting of the use of a serotonergic agent: mental status changes, myoclonus, agitation, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever. These criteria tend to overlap with other syndromes (e.g., antidepressant withdrawal, catecholamine excess, anticholinergic toxidrome), confounding the diagnosis. Hunter’s criteria are more specific, using an algorithmic approach. This set of criteria, shown in Table 31-7, focuses on the presence of spontaneous or induced clonus as the most specific symptom for SS, though the diagnosis can still be made in the absence of clonus. Hunter’s criteria tend to capture moderate to severe cases, sometimes missing mild forms of the syndrome.

Differential Diagnosis Anticholinergic Toxicity With anticholinergic excess, patients usually have normal reflexes and hypoactive, rather than hyperactive, bowel sounds.

Malignant Hyperthermia With malignant hyperthermia, severe muscle rigidity, hyporeflexia, and exposure to anesthetic agents help to distinguish this syndrome from serotonin syndrome. Table 31-7: Hunter Criteria for Serotonin Syndrome In the presence of a serotonergic agent: If (spontaneous clonus = YES) then serotonin toxicity = YES If (inducible clonus = YES) and [(agitation = YES) OR (diaphoresis = YES)] then serotonin toxicity = YES If (ocular clonus = YES) and [(agitation = YES) OR (diaphoresis = YES)] then serotonin toxicity = YES If (tremor = YES) AND (hyperreflexia = YES) then serotonin toxicity = YES If (hypertonic = YES) AND (temperature > 100.4) AND [(ocular clonus = YES) OR (inducible clonus = YES)] then serotonin toxicity = YES If serotonin toxicity = NO

NMS With NMS, the signs and symptoms tend to evolve over several days rather than a few hours, and patients are generally hypokinetic. Fever is more common and more profound in NMS, and laboratory abnormalities are more common.

Pathophysiology The presumed mechanism of SS involves multiple families of serotonin receptors, although 5-HT2A receptor agonism appears to contribute to many of the symptoms. 5-HT1A receptors, predominating in the caudal brain stem and spinal cord may be responsible for some of SS’s motoric symptoms. Other studies (as in NMS) have implicated both dopamine and serotonergic activation in the syndrome’s pathogenesis, arguing that agents with a greater ratio of serotonergic to dopaminergic properties are most likely to precipitate the syndrome.

Evaluation Typically , the history is the most important factor in establishing a temporal relationship with the initiation of psychotropic agents. Clonus, particularly of the spontaneous and ocular varieties, is the most important physical finding in establishing the diagnosis. Laboratory testing is useful to assess a patient’s underlying nutritional and hydration status, to screen for elevated CPK (raising suspicion of NMS), and to investigate the presence of an underlying medical condition (that might raise the risk of developing the syndrome and subsequent complications). Of note, certain monoamine secreting tumors (e.g., carcinoid tumors, small-cell lung malignancies) have been associated with the SS, and gastrointestinal and lung imaging may help during the initial investigation. Other non-specific laboratory abnormalities include transaminitis, metabolic acidosis, and rhabdomyolysis. As is the case in catatonia and NMS, both an EEG and neuroimaging are useful in uncovering an underlying seizure disorder or another neurological condition; however, normal studies do not rule out the presence of a neuromedical illness.

Treatment Given the lack of prospective studies evaluating the treatment of SS, strategies for treatment are derived primarily from case reports and from animal studies. Discontinuation of the serotonergic agents and institution of supportive treatment are the primary treatments. Once treatment is initiated the syndrome usually resolves within 24 hours; associated confusion can last for days. Supportive measures are essential in the prevention and treatment of potential medical complications; such interventions include use of cooling blankets (for the development of hyperthermia), anticonvulsants (if seizures arise), and antihypertensive agents, such as nifedipine (for severely elevated blood

pressure). Rarely, the syndrome progresses to respiratory failure requiring intubation (usually due to aspiration). Benzodiazepines are commonly used in SS to treat agitation, to control hyperthermia, to reduce myoclonus, and to blunt the adrenergic response. Serotonin antagonists (such as cyproheptadine) can have a role in more severe cases or when offending agents have long half-lives. Although case reports have highlighted the use of propranolol and dantrolene, they are not routinely recommended. Prevention of SS often involves a wash-out period when cross-titrating a serotonergic agent with an MAOI. Current treatment practices include a twoweek (or five half-lives) wash-out interval following the discontinuation of a MAOI. In the case of fluoxetine, a minimum of five-week wash-out period is required before the initiation a MAOI, due to its long half-life.

Suggested Reading 1. Boyer EW, Shannon M: The serotonin syndrome. N Eng J Med . 2005; 352: 1112–1120. 2. Fink M. Rediscovering catatonia: the biography of a treatable syndrome. Acta Psychiatr Scand Suppl . 2013; 441: 1–47. 3. Francis A: Catatonia: diagnosis, classification, and treatment. Curr Psychiatr Rep . 2010; 12: 180–185. 4. Fricchione G, Bush G, Fozdar M, et al: Recognition and treatment of the catatonic syndrome. J Intensive Care Med . 1997; 12: 135–147. 5. Fricchione GL, Gross AF, Huffman JC, et al: Catatonia, neuroleptic malignant syndrome, and serotonin syndrome. In, Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry, Sixth Edition . Philadelphia, PA: Saunders Elsevier; 2010: 273–288. 6. Gurrera RJ, Caroff SN, Cohen A, et al: An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry . 2011; 72(9): 1222–1228. 7. Prager L, Millham F, Stern TA: Neuroleptic malignant syndrome: A review for intensivists. J Intensive Care Med . 1994; 9: 227–234. 8. Sternbach H: The serotonin syndrome. Am J Psychiatry . 1991; 148(6):

705–713. 9. Taylor MA, Fink M: The catatonia syndrome: forgotten but not gone. Arch Gen Psychiatry . 2009; 66(11): 1173–1177.

CHAPTER Neuroimaging in Psychiatry 32 JOAN A. CAMPRODON MD, MPH, PHD; DARIN D. DOUGHERTY, MD; AND SCOTT L. RAUCH, MD

KEY POINTS Overview This chapter reviews structural and functional neuroimaging techniques of relevance to the practice of psychiatry; the technology, safety, and indication of each modality is discussed. Theoretical Basis X-rays and computed tomography (CT) use a similar principle (i.e., a source of radiation is applied to the skull and brain, and is projected over electronic sensors). The signal from these sensors is then used to reconstruct 2D or 3D radiological images. Magnetic resonance imaging (MRI) does not use radiation; instead it uses a strong static magnetic field that affects a significant portion of protons in the body (and brain), aligning them in the direction of the magnetic field. A pulse of radio-frequency is then applied, which destabilizes these aligned protons and forces them to spin out of phase with the magnetic field, though they eventually return to the aligned position. The energy required to return to alignment will depend on the environment where the proton is located (e.g., water, fat, bone), and this is captured by the sensors in the MRI coil and used to reconstruct radiological images of the brain. MRI can be used to measure structural brain properties (T1 or T2), diffusion of water molecules across axons or lesions (DWI and ADC), neurovascular changes indicative of brain activation (fMRI BOLD), or neurochemical properties (MRS). Nuclear medicine techniques include positron emission tomography (PET) and single-photon emission computed tomography (SPECT). They are based on the injection (or inhalation) of molecules with attached radioligands that emit a specific type of radiation signal. For neuropsychiatric applications, it is important that these molecules cross the blood-brain barrier. With these

techniques, clinicians can assess brain perfusion, metabolic activity, the state of neurotransmitter systems (baseline tone or dynamic changes), and pathological deposits of amyloid or tau. Classification of Methodology Sub-types Structural imaging employs plain films (X-rays) of the skull, CT, and MRI. Functional imaging involves PET, SPECT, functional magnetic resonance imaging, and magnetic resonance spectroscopy (MRS). Neuroimaging Applications in Clinical Psychiatry The indications for neuroimaging in the evaluation of psychiatric patients remain a matter of debate; a universally accepted protocol has not yet been established. Useful guidelines and indications, are summarized in Table 32-5 . The diagnostic assessment of patients with affective, behavioral, or cognitive complaints might include neuroimaging.

Introduction Neuroimaging is used as an aid in the differential diagnosis of neuropsychiatric conditions; rarely does neuroimaging alone establish the diagnosis. When one is contemplating the use of neuroimaging, a variety of factors (including the indications, risks, costs, advantages, and limitations) must be considered. This chapter reviews these factors and provides general guidelines for the use of neuroimaging in neuropsychiatric syndromes.

Structural Imaging Plain Films (X-Ray) of the Skull Technology Plain films of the skull use the same technology and physical principles of regular X-rays. A single source of radiation is used against the skull and the images are projected over film or electronic sensors. X-rays are differentially attenuated, depending on the material through which they pass (with higher attenuation of dense material [such as bone], and lower attenuation in less dense material [such as air and fluid]). High-attenuation tissues appear white or light gray and low-attenuation tissues appear black or dark gray.

Safety The safety profile of skull films is excellent, with minimal radiation needed for the test.

Indications Plain films of the skull can identify bony processes (such as skull fractures or lesions [erosions/hyperostosis]). It can also be used to rule-out the presence of foreign bodies, changes in the basal foramina, and inflammation of the sinuses and mastoids. They are also used to assess possible damage to invasive brain stimulation systems, like deep-brain stimulation (DBS) or vagus-nerve stimulation (VNS). Otherwise, plain films of the skull are rarely used these days because computed tomography of the head has the same or better sensitivity and specificity for its indications, provides more relevant information in the clinical situations in which X-rays would be considered, and it is widely available and inexpensive.

Computed Tomography Technology Computed tomography (CT ) images are made by collecting serial X-rays acquired in an axial slab-wise (i.e., tomographic) manner. The physical principles of CT are the exact same as for regular X-rays and the images reflect the same patterns of tissue attenuation. These multiple X-rays are processed with mathematical algorithms that reconstruct the data and create the tomographic images. Electronic data capture and analysis allow the manipulation of contrast for the visualization of images with an emphasis placed on specific tissues of interest (e.g., bone, parenchyma). Because data is acquired serially following the axial plane, CT images are usually presented as axial slices with a typical inplane resolution of less than 1 mm. Sagital and coronal slices can be created with mathematical algorithms, but the spatial resolution is then reduced. CT images can be enhanced with the use of intravenous (IV) contrast material. Contrast agents are radiopaque materials that fully attenuate the X-ray radiation and therefore appear white in the images. This allows for the visualization of the vascular system ( CT angiogram [CTA]) or of lesions that disrupt the blood-brain barrier (such inflammatory processes and certain tumors). CT contrast media can be either ionic or non-ionic. Non-ionic contrast is many times more expensive than is ionic contrast. However, ionic contrast has a greater risk of causing side effects and it is rarely used for neuroimaging applications.

Safety The risks of CT stem from two primary sources: the radiation and the use of contrast agents. Every year, 62 million CT scans are performed in the United States, including scans of four million children. The risks of radiation exposure are dosedependent and primarily due to the potential for genetic mutations leading to cancer and heritable pathological changes. The usual dose of radiation received from a CT scan is 10 millisieverts (mSv), which is estimated to increase the risk of fatal cancer in 1/2000. This risk is much smaller than the natural risk for cancer (1/5), but although it might have only a small impact at the individual level, it can have a more serious impact at the population level given the high number of tests performed. Idiosyncratic reactions to contrast agents occur in 5% of cases and include hypotension, nausea, flushing, urticaria, and frank anaphylaxis. Risk factors include age younger than 1 year or age greater than 60 years as well as a history of asthma, allergies, cerebrovascular disease, or prior contrast reactions. Chemotoxic reactions can occur in the brain and the kidney. Chemotoxicity can present as impaired renal function or even renal failure, with the main risk factor being pre-existing renal insufficiency. In the brain, chemotoxic reactions can be manifest as seizures. Such reactions occur in approximately 1 in every 10,000 cases but develop in up to 10% of individuals in whom gross disruption of the blood-brain barrier is present. Published guidelines for the prevention and treatment of contrast-induced complications have been prepared by the American College of Radiology.

Indications The primary uses of CT in neuroimaging are the detection of fresh blood (e.g., intra-parenchymal from hemorrhagic strokes, or perimeningeal [as in epidural, subdural, or subarachnoid bleeds]), skull and bone pathology (e.g., from fractures), and from calcium deposits (intraparenchymal or in vessels). In addition, CT also offers appropriate resolution to assess changes that affect midline structures and the ventricular system (such as herniation or hydrocephalus). Edema, certain tumors, and abscesses can also be visualized with CT, but magnetic resonance imaging is clearly superior. The greatest advantages of CT (particularly in comparison to magnetic resonance imaging) are the fast imaging time, greater availability, and cheaper costs. These pragmatic variables make it the modality of choice in emergency settings.

Magnetic Resonance Imaging Technology Magnetic resonance imaging (MRI ) exploits the magnetic properties of hydrogen atoms in water molecules to construct a representation of tissue. All molecules are under the influence of a strong magnetic field, and a significant percentage of hydrogen atoms are aligned with the magnetic field. A radiofrequency pulse is applied that disrupts this alignment. After this pulse, hydrogen atoms return to the original position by a process called proton relaxation . During proton relaxation atoms emit energy, which is captured by special MRI coils, and this energy is used to reconstruct the tomographic images. The mechanism of proton relaxation is defined by two related but independent variables: T1 and T2. T1 describes the relaxation of hydrogen atoms toward the original position aligned with the magnetic field. T2 explains the relaxation away from the unstable position forced by the radio-frequency pulse. Pulse sequences can be manipulated to maximize T1 or T2 mechanisms, and this has an impact on image quality, highlighting different aspects of tissue structure and visualization. T1-weighted images show darker gray than white matter and black CSF. T1 images are ideal for the visualization of the anatomy of the brain, particularly normal structure but also atrophy and cortical dysplasias. T2weighted images show a pattern contrary to T1 images, with lighter gray than white matter and white CSF (see Table 32-1). T2 images are ideal for identifying pathological changes (that usually involve changes in the water density), such as inflammation, edema, demyelinization, and vascular changes. In addition, both T1- and T2-weighted pulse sequences can be altered to suppress specific sources of signal and improve the diagnostic resolution. T2- FLAIR (fluid attenuated inverted recovery) sequences are T2 images in which the hyperintense (white) signal from cerebrovascular spinal fluid (CSF) has been suppressed. As a consequence, CSF appears black, and T2 hyperintense lesions can be observed with increased contrast, particularly in areas that interface with CSF-filled structures (e.g., peri-ventricular space, cortical rim). Fat-suppressing MRI sequences also exist that reduce the hyperintensity of lipid-rich structures. Table 32-1: Visual Characteristics of MRI Sequences Gray Matter White Matter Cerebrospinal Fluid T1

Dark gray

Light gray

Black

T2

Light gray

Dark gray

White

T2-FLAIR Light gray

Dark gray

Black

Similar to CT, MRI can benefit from the use of contrast materials to highlight lesions that disrupt the blood-brain barrier, in which case intravascular contrasts agents will be visualized in the parenchyma. Gadolinium is used as the contrast medium because of its para-magnetic properties. Of note, MR angiography (MRA) does not use contrast injections as does CTA, but specific MRI pulse sequences that allow the visualization of the vasculature. Diffusion-weighted imaging (DWI) is a specific MRI protocol that is able to map the flow of water molecules in the brain. A water molecule in a glass of water diffuses freely in all directions, i.e., it has isotropic diffusivity. In the brain, the motion of molecules is limited by the constraints of the cerebral anatomy and histological structure—for example, water molecules will diffuse differently in the ventricles than inside of an axon, in healthy parenchyma than in the context of inflammation and edema. DWI is able to measure water diffusivity; the greater anisotropy (limited diffusivity), the greater the intensity of the signal (white). This approach has revolutionized the management of stroke patients. The acute lack of oxygen causes cytotoxic injury to ischemic cells, inducing edema and swelling. Under these conditions, anisotropy increases due to the increased density of molecules and DWI signal intensity (thereby appearing white). Other conditions that present with limited diffusivity, and therefore DWI signal changes, include abscesses, hypercellular tumors (e.g., high-grade gliomas, lymphomas) or excitotoxic processes (e.g., traumatic brain injury). It is important to highlight that DWI images lack diagnostic value if evaluated in isolation because they must always be compared with the quantitative images of the diffusion coefficient, known as apparent diffusion coefficient (ADC) maps. True reduction in diffusivity, caused by any pathophysiological mechanism, will always appear as hyperintensities (white) in DWI and hypointensities (black) in ADC scans. If this pattern is not observed, the mechanism driving the effect is likely to be different from increased anisotropy. A well-known example, called “T2-shine through,” occurs in chronic ischemic strokes (note that acute, post-acute, and chronic strokes have different neuropathology and therefore different neuroimaging characteristics, which is critical for diagnosis). DWI images are sensitive not only to changes in anisotropy, but also to T1 and T2 relaxation mechanisms. Therefore, T1 and T2 signal changes might also show in DWI maps and could be misidentified as changes in anisotropy. Chronic strokes present with T2 hyperintensity, and might

also appear as hyperintensities in DWI but with normal or more commonly hyperintense signals in ADC maps. If a clinician were to look at the DWI image alone, the lesion could be confused with an acute stroke and the patient might be given thrombolytic therapy. But if a clinician looks at all images (DWI, ADC, and T2), it could be concluded that the changes in the T2 signal from the old stroke “shine through” the DWI scan and can be observed as a hyperintense lesions in both the DWI and ADC maps, which cannot reflect increased anisotropy. In addition, DWI sequences have been used to create diffusion tension imaging (DTI) tractography maps, which reveal the structural anatomy of white matter fiber pathways in vivo and non-invasively. Although DTI remains primarily a neuroscience research tool, its use in clinical settings is growing, particularly in the context of presurgical mapping. The use of DTI in patients with traumatic brain injury (TBI), although still not widely used in the clinical setting, is growing in importance. Patients with TBI, particularly those with mild or moderate forms, suffer from diffuse axonal injuries that are not revealed with CT or MRI but are detectable with DTI. These lesions cause significant neuropsychiatric morbidity, and early diagnosis has a major impact in clinical management and allocation of services.

Safety The risks of MRI scanning stem from three primary sources: the effects of magnetic fields, claustrophobia, and the use of contrast agents (e.g., gadolinium). Even though MRI does not pose a risk related to ionic radiation, other safety challenges must be considered. The most significant danger for the patient undergoing an MRI is due to magnetic forces (e.g., torque, dislodgement) and heating of metallic foreign bodies or devices. Patients with para-magnetic metallic implants (such as aneurism clips, pacemakers, deep brain stimulators [DBS], or vagus nerve stimulators [VNS]) are not eligible for MRI imaging. These foreign bodies could move or heat-up resulting in morbidity or mortality. In addition, certain tattoos (including permanent eyeliner) use para-magnetic metallic components as part of the injected ink and have the potential to heat up and burn the patient while in the scanner. Non-para-magnetic metals, such as titanium, are safe for MRI. Specific safety procedures and a checklist must be in place in all imaging facilities to screen patients prior to MRI scanning. In addition, clinicians should consider that the MRI scanner is a very tight space and patients with claustrophobia might be unable to tolerate the exam.

Similarly, children or patients with cognitive or behavioral impairments might not be able to undergo the test. Sedation or use of an open MRI scanner might be useful to overcome these difficulties. Gadolinium causes fewer and less severe side effects than CT contrast, with one reported death in more than five million dosings. Nevertheless, it has recently been associated with renal fibrosis, which is usually delayed by a few days to two months and has an unspecified but rare frequency.

Indications MRI is the most sensitive test to assess the structure of the brain. It offers great diagnostic resolution to assess the normal brain anatomy and disorders affecting the parenchyma, white matter tracts, and gray–white matter boundary. It is therefore the neuroimaging study of choice to visualize most lesions and patients. MRI is particularly useful to assess disorders of the posterior fossa and brain stem because CT has poor resolution in these regions. Also, when radiation is of particular concern, such as with pregnant women or young children, an MRI scan should be favored. Although cost, availability, and scanning time are its primary disadvantages, these are improving with time and the gap with CT regarding these variables is closing.

CT versus MRI Clinically, one should think about ordering a CT scan when a skull fracture or emergent mass-effect is suspected. In an emergency setting, CT scans offer the advantage of very short imaging times. CT continues to be the modality of choice for the diagnosis of acute bleeds, although modern DWI sequences provide comparable sensitivity and specificity (with longer imaging times and higher costs nonetheless) (see Table 32-2). Disorders due to calcium deposits (such as calcifying tumors [e.g., craniopharyngioma], metabolic alterations [e.g., parathyroidism], congenital disorders [e.g., TORCH infections, tuberous sclerosis] and idiopathic processes [such as Fahr’s disease]) can also be visualized with CT better than MRI because calcium has weak para-magnetic properties. Finally, clinical situations in which MRI is contraindicated due to the presence of para-magnetic metallic foreign bodies (e.g., cardiac pacemakers) or claustrophobia will require alternative imaging modalities, and CT is usually the technique of choice. For all other indications, MRI is the modality of choice. Nevertheless, non-technical and often practical variables (such as cost or availability) also need to be considered and can sometimes drive the choice

toward CT despite the clear advantage of MRI because CT might be “good enough.” As MRI technology becomes more established, the gap between CT and MRI regarding cost and availability (and to a lesser extent imaging time) is becoming narrower and these factors will play a smaller role. Table 32-2: Summary Comparisons of CT and MRI Consideration

CT versus MRI

Economy

CT ≥ MRI

Availability

CT ≥ MRI

Speed

CT > MRI

Comfort

CT > MRI

Quality of visualization Bleeding Acute (< 48–72 h)

CT > MRI

Subacute (> 48–72 h)

MRI > CT

Ischemia Acute

DWI > MRI≈ CT

Chronic

DWI≈ MRI > CT

Bone

CT > MRI

Gray matter

MRI > CT

White matter

MRI > CT

Posterior fossa

MRI > CT

Spatial resolution

CT ≥ MRI

Functional Imaging Positron Emission Tomography Technology Positron emission tomography (PET) can be used to measure a number of functional variables, including changes in regional blood flow , glucose metabolism , and neurotransmitter dynamics . Regional blood flow and glucose metabolism are indirect measures of neuronal activity. PET requires the injection of a radiopharmaceutical, which is a biological molecule labeled with a radioactive atom (a nuclide) whose regional uptake,

distribution, and washout can be quantified. Nuclides are created in a cyclotron by adding positive charges to the nucleus of chemical elements commonly found in organic molecules, such as 11-Carbon (11 C), 15-Oxygen (15 O), 18-Fluorine (18 F), and 13-Nitrogen (13 N). Because the nuclide has an excess of protons, it releases a positively-charged particle (a positron) in order to return to a more stable state. This positron collides with the surrounding negatively-charged electrons, and as a consequence of this collision (termed an annihilation event), two gamma photons are created. These gamma photons are propelled in opposite directions (180º) from each other after the collision, and eventually arrive at the detectors in the PET gamma camera. Mathematical image-reconstruction algorithms identify the exact position where the collision occurred, and show it in the tomographic brain image. The nature and chemical design of the radiopharmaceutical determines the biological function that we can measure. To measure blood flow, clinicians can choose 15 O (with a short half-life [approximately 2 minutes]) and create radioactive water molecules (H2 15 O) that are injected intravenously. Alternatively, 15 O can be used to create radioactive CO2 (C15 O2 ), which can be inhaled, avoiding invasive IV procedures. To measure metabolic activity, 18 Ffluorodeoxyglucose (18 F-FDG) is typically used. FDG will be absorbed and phosphorylated in cells just like glucose, but it won’t be processed further in metabolic pathways; therefore, it remains trapped in the cell. FDG is absorbed by the cell proportionally to its metabolic needs, just like glucose. As a result, hyperactive neurons (like those of a seizure focus) will absorb more radioactive compound, and hypoactive neurons (like those in areas of neurodegeneration) will absorb less. These changes will be reflected in the PET images as “hot” or “cold” areas, respectively. The application that is truly unique to nuclear medicine techniques is the assessment of neurotransmitter dynamics, as f unctional MRI measures variables and physiological processes similar to blood flow and metabolism. A radioligand is a specific type of radiopharmaceutical designed to cross the blood-brain barrier, be biologically inactive, have great affinity for a target of interest (usually a neurotransmitter receptor), and have a much lower affinity for all other targets. This permits its rapid clearance from the bloodstream and other structures, while it remains attached (and detectable) to the target. Newer and still experimental approaches (and radiopharmaceuticals) are in development to identify more refined biological processes (such as protein synthesis, second-messenger systems, and gene expression).

Safety No significant risks have been described for brain PET studies (particularly FDG-PET, which is the most clinically used modality). The average dose of radiation is 8 mSv (similar to that of CT). Other diagnostic applications, particularly whole-body PET-CT, present with much higher rates of radiation (23–25 mSv) and a greater risk for mutations and malignancies.

Indications The primary neuropsychiatric indications of PET are in the work-up of neurodegenerative processes (particularly dementias) and seizures. FDG-PET is most commonly used. Other indications (e.g., brain malignancies, traumatic brain injuries, movement disorders [Parkinson’s disease in particular]) have less evidence and utility, but are expanding. Alzheimer’s dementia presents with a typical pattern of temporo-parietal, often bilateral, hypometabolism, typically including mid-line structures, as well (such as the posterior cingulate cortex and precuneus). As the disease progresses, frontal areas become involved. The somatosensory and visual cortex, the basal ganglia, and the cerebellum are commonly unaffected. This pattern can be useful to differentiate between a dementing and non-dementing process, particularly in cases in which the clinical diagnosis is challenging (such as in the early phases of diagnosis, in atypical presentations, in younger patients, in patients with a high cognitive baseline, and in patients with co-morbidities [such as mood and anxiety disorders or traumatic brain injury]). In addition, after a dementia has been diagnosed, it can help differentiate among the different sub-types (i.e., Alzheimer’s versus frontotemporal dementia, which have different prognoses and respond differently to treatments). More recently, alternative PET modalities have been developed specifically for the diagnosis and work-up of neurodegenerative disorders. The (C-11)-labeled P ittsburgh compound B (PiB) is a radio-ligand with great affinity for amyloid: after it is injected, it crosses the blood-brain barrier and attaches to amyloid plaques in the brain. A newer radioligand for amyloid imaging was developed, [F-18]Florbetapir, which has a longer half-life (110 minutes as opposed to 20 for PiB) making its use more practical in clinical practice (the requirement for an on-site cyclotron is less critical). Flobetapir was approved by the United States Food and Drug Administration (FDA) in 2012. Compounds to image Tau, in addition to amyloid, are also developed but remain in experimental clinical testing phases.

The diagnosis of seizures and epilepsy is primarily based on the history, exam, and e lectroencephalogram (EEG). Nevertheless, the EEG may be normal in peri- or post-ical phases, and in cases with a deep focus, the EEG might show no abnormalities even during the ictal phase. In such cases, PET can be useful in diagnosing seizures. FDG-PET will show hypermetabolism during the ictal phase and hypometabolism during the peri- or post-ictal period. PET has a particularly relevant role for cases in which surgical resection of the focus is considered.

Single Photon Emission Computed Tomography Technology Single-photon emission computed tomography (SPECT ) also uses radionuclides for functional imaging. Commonly used elements in SPECT are technetium (99 mTc), iodine (123 I), or xenon (133 Xe). As with PET, both inhaled and IV radionuclides are available, as are radioligands for measuring indexes of gross brain activity and performing receptor characterization. The fundamental differences with PET are the physical reactions that are elicited. SPECT radionuclides do not emit positrons or any other secondary particles; the nuclides themselves collide with the surrounding electrons in search of increased electrical stability, and the reaction emits a single photon (not two as in PET). SPECT radionuclides can be attached to biological molecules to create radiopharmaceuticals, but the fit is more difficult as technetium, iodine, and xenon are not naturally present in common biologically relevant molecules. As a result, SPECT lacks the versatility of PET and its applications are more limited.

Safety The safety profile of SPECT is similar to that of PET and is related to the radiation.

Indications The indications of SPECT are usually similar to those of PET, but with worse spatial resolution and sensitivity, particularly in deep structures. Nevertheless, SPECT is much cheaper and generally more commonly available. The higher costs of PET are driven by different variables, but most significantly by the need to have a cyclotron and to have radiopharmaceutical synthesis capabilities on site. In contrast, SPECT compounds can be synthesized off site. In summary, PET is preferable to SPECT; the only reasons why clinicians would choose to

obtain a SPECT scan is lack of access to a PET facility or to minimize costs (see Table 32-3). Table 32-3: Summary Comparisons of PET and SPECT Consideration PET versus SPECT Economy Institutional

SPECT >> PET

Per scan

SPECT > PET

Availability

SPECT > PET

Spatial resolution

PET > SPECT

Temporal resolution PET ≥ SPECT Sensitivity

PET > SPECT

Signal-to-noise ratio PET > SPECT Variety of ligands

PET > SPECT

Functional Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Technology These two MRI-based imaging modalities, which have traditionally been used exclusively as research tools, are slowly finding their space in clinical contexts. Functional MRI (fMRI ) uses a specific MR pulse sequences designed to detect the ratio between oxyhemoglobin and deoxyhemoglobin. When a brain area increases its activity, for example in the context of a cognitive task, it also increases its metabolic and oxygenation needs. In this setting, two phenomena happen in parallel. First, because more oxygen is used, more oxyhemoglobin is turned into deoxyhemoglobin and the absolute quantity of the latter increases. Second, also because more oxygen is needed, a coupled neurovascular mechanism is activated that induces activity-dependent local vasodilation, which increases the regional flow of blood with oxyhemoglobin. The summation of the two processes induces an absolute and relative increase of oxyhemoglobin that correlates with an increase in brain activity. fMRI can detect changes in regional blood flow and oxyhemoglobin concentration dynamically, identifying baseline and activity-dependent changes in neuronal activation.

Magnetic resonance spectroscopy (MRS) is also an MRI-based application used to measure the relaxation properties of specific chemical bonds, beyond hydrogen atoms. Unlike the previous methods, it does not provide whole-brain measurements; instead it selects a pre-defined region of interest and measures the relative concentrations of preselected elements or molecules. It is therefore not used to measure the structure or function of the brain, but its chemical composition.

Safety Because these are MRI-based methods, their safety profile is identical to the one described for structural MRI.

Indications Although these methods are widely used in research, their clinical applications remain limited. Still, fMRI is becoming a usual tool in the presurgical mapping and planning of neurosurgical cases. MRS is finding applications for the detection of tumors, epileptic foci, vascular lesions, or areas of demyelination.

Neuroimaging Applications in Clinical Psychiatry Studies have looked at the use of CT scans to detect pathological abnormalities in psychiatric patients. Across all studies, 12% of patients have been found to have abnormalities, although most have been non-specific. The risk of presenting with an anomaly increases with advancing age, with an abnormal neurological exam, with an acute change in mental status, with a history of brain trauma, or with a history of alcohol abuse. Weinberger (1984) proposed six criteria for the use of brain imaging in psychiatric patients: Confusion and/or dementia of unknown cause First episode of psychosis of unknown etiology A movement disorder of an unknown etiology Anorexia nervosa Prolonged catatonia The first episode of major affective disorder or a personality change after the age of 50 years

With the popularization of MRIs, white-matter changes were frequently described in psychiatric patients, but as the field advanced, such changes were described with comparable prevalence in asymptomatic subjects. Rauch and Renshaw reported the findings of a study that analyzed 6,200 patients hospitalized at the McLean Hospital over the course of 5 consecutive years. Although approximately 40% of patients received an MRI scan, only 1.6% of patients had an unexpected and treatable neuroimaging finding (see Table 32-4). Of these, most presented with hemorrhage or multiple sclerosis (MS), and patients with MS complained primarily of treatment-resistant major depressive disorder. Table 32-4: Brain MRI Results in 6,200 Psychiatric Inpatients: Unexpected and Potentially Treatable Findings MRI Findings

Number of Cases

Percent

Multiple sclerosis

26

0.4

Hemorrhage

26

0.4

Temporal lobe cyst

22

0.4

Tumor

15

0.2

Vascular malformations

6

0.1

Hydrocephalus

4

0.1

Total

99

1.6

Note: Results from 6,200 consecutive MR scans performed at McLean Hospital over a 5-year period. Patients receiving MR scans represent approximately 40% of the total number of patients seen during that period. Source: Adapted from Rauch SL, Renshaw PF: Harvard Rev Psychiatry . 1995; 2: 297–312.

Despite significant progress in neuroimaging technology and neuroscience research, there is still an overwhelming lack of evidence to guide the clinician in deciding when to order a neuroimaging test in the course of a psychiatric evaluation. The decision remains a matter of clinical judgment, but a few principles can be useful. Decisions about neuroimaging testing should be based on the findings of a thorough history and exam, including a good cognitive and neurological exam. These steps are critical in the decision-making process. Neuroimaging should then be ordered when the clinician suspects that an intracranial process causing a macro-antomical structural or functional change that is responsible for the presenting signs and symptoms. Some would argue that tests should be ordered

only if the results have the potential to change the course of treatment. Nevertheless, we believe that confirming or ruling-out significant or lifethreatening etiologies, avoiding further (potentially invasive) testing, and providing prognostic information is of sufficient clinical value to justify neuroimaging, particularly if the safety profile of the test is benign as it is usually the case. In the context of these general principles, we provide the following specific recommendations to guide the use of neuroimaging (see Table 32-5). First, clinicians should consider using neuroimaging in patients who present with a change in the level of consciousness, which could in fact represent an emergency. Patients presenting with abrupt onset (within minutes) of symptoms should also be scanned because this temporal pattern is usually caused by cerebrovascular pathology, migraines, or seizures (with the exception of panic attacks). If the neurological or cognitive exam shows deficits, the anatomical correlates of these findings to the primary psychiatric symptoms should be considered and neuroimaging ordered. Also, patients with a history of head trauma (particularly with loss of consciousness), neurologic co-morbidities, cancer, or whole-brain radiation are more likely to present with structural abnormalities related to the chief complaint. Atypical presentations can reflect pathological macroanatomical changes causing the chief complaint, but a thorough differential should still be considered. With an old age of onset, even with a standard clinical presentation, a structural process (e.g., vascular, neurodegenerative, (para)neoplastic, inflammatory) should be considered and ruled-out with a good exam and neuroimaging. Table 32-5: Guidelines for the Use of Neuroimaging in Psychiatric Patients A change in level of consciousness or arousal An abrupt (minutes) onset of symptoms Deficits in the neurological exam (with anatomical relation to the chief complaint) Deficits in the cognitive exam (with anatomical relation to the chief complaint) A history of: Head trauma (with loss of consciousness) Whole-brain radiation Neurological co-morbidities Cancer Late onset of symptoms (> 50 years old) An atypical presentation (TBD on an individual basis)

First-break psychosis (TBD on an individual basis) ECT candidates (TBD on an individual basis)

Finally, we should consider the use of neuroimaging in the work-up of firstbreak psychosis and candidates for electroconvulsive therapy (ECT). Structural neuroimaging (CT or MRI) is commonly used in clinics and emergency departments to evaluate patients presenting with a first psychotic break. Although neuroimaging has been included in the evaluation guidelines of some scientific and clinical societies, the evidence to support this is weak and the practice is the subject of debate. The goal of imaging is to identify intracranial abnormalities causing the first psychotic symptoms that would require a treatment that differs from the standard of care. The percentage of cases that present with abnormal neuroimaging findings is low, and even lower in those who have changes that require an intervention. Moreover, most centers will favor the use of CT over MRI, given its price and availability, but the diagnostic yield is even lower for this modality. Nevertheless, given the very good safety profile of these tests, it is often argued that it is worth scanning to identify those few cases and confirm the lack of structural abnormalities of the brain in all other patients. The debate is often centered on the cost effectiveness of routine scanning, which is affected by multiple variables. The question remains unresolved and more data is clearly needed, but in the meantime clinicians should identify (according to the aforementioned criteria) the first-break patients for whom neuroimaging might have a higher yield (a good history and exam are key, as always). Psychiatric patients requiring ECT are usually affected by severe and treatment-resistant symptoms (e.g., depression, mania, psychosis, catatonia). These have a higher likelihood of stemming from disease mechanism that change the structure of the brain (and can be identified with imaging). However, most are not. Another potential reason to use neuroimaging in the evaluation of ECT candidates is to rule-out intracranial pathology that can present with complications in the course of treatment (e.g., masses, aneurysms, arteriovenous malformations). The decision to use neuroimaging will need to be made on an individual basis applying the general principles discussed earlier.

Suggested Readings 1. Albon E, Tsourapas A, Frew E, et al: Structural neuroimaging in psychosis:

a systematic review and economic evaluation. Health Technol Assess . 2008; 1 2(18): iii–iv, ix–163. 2. Bitar R, Leung G, Perng R, et al: MR pulse sequences: what every radiologist wants to know but is afraid to ask. Radiographics . 2006; 26(2): 513–537. 3. Bohnen NI, Djang DS, Herholz K, et al: Effectiveness and safety of 18FFDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med . 2012; 53(1): 59–71. 4. Brenner DJ, Hall EJ: Computed tomography--an increasing source of radiation exposure. N Engl J Med . 2007; 357(22): 2277–2284. 5. Camprodon JA, Stern TA: Selecting neuroimaging techniques: a review for the clinician. Prim Care Companion CNS Disord . 2013; 15(4). 6. de Lucas EM, Sanchez E, Gutierrez A, et al: CT protocol for acute stroke: tips and tricks for general radiologists. Radiographics . 2008; 28(6): 1673– 1687. 7. Dougherty DD, Rauch SL, Fischman AJ: Positron Emission Tomography and Single Photon Emission Computed Tomography. In: Dougherty DD, Rauch SL, Rosenbaum JF, eds.: Essentials of Neuroimaging for Clinical Practice Washington, DC: American Psychiatric Publishing; 2004: pp. 75– 92. 8. Dougherty DD, Rauch SL: Neuroimaging in Psychiatry. In: Stern TA, Fava M, Wilens, T, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016: pp. 815–820. 9. Hollister LE, Shah NN: Structural brain scanning in psychiatric patients: a further look. J Clin Psychiatry . 1996; 57: 241–244. 10. Huettel SA, Song AW, McCarthy G: Functional Resonance Imaging . 3rd ed. Sunderland, MA: Sinauer Associates; 2012. 11. Johnson KA, Minoshima S, Bohnen NI, et al: Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement . 2013; 9(1): e-1-16. 12. Logothetis NK: What we can do and what we cannot do with fMRI. Nature . 2008; 453(7197): 869–878. 13. Rauch SL, Renshaw PF: Clinical neuroimaging in psychiatry. Harv Rev

Psychiatry . 1995; 2(6): 297–312. 14. Shenton ME, Hamoda HM, Schneiderman JS, et al: A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav . 2012; 6(2): 137–192. 15. Weinberger DR: Brain disease and psychiatric illness: when should a psychiatrist order a CAT scan? Am J Psychiatry . 1984; 141(12): 1521– 1527. 16. Yousem DM, Grossman RI, eds.: Neuroradiology: The Requisites. 3rd ed.: Philadelphia, PA: Mosby; 2010.

CHAPTER Diagnostic Rating Scales and 33 Psychiatric Instruments DAVID MISCHOULON, MD, PHD AND MAURIZIO FAVA, MD

KEY POINTS Overview When screening for psychiatric disorders, psychiatrists typically rely on information obtained from the clinical interview, from review of medical records, and from other sources. However, administration of various standardized diagnostic instruments can be helpful, and at times necessary. Standardized questionnaires can often serve as an adjunct to the clinical interview, particularly for cases in which the diagnosis is in doubt, or when the efficacy of a treatment is unclear. Psychiatric rating scales attempt to translate clinical observations into objective and (sometimes) quantifiable information. Theoretical Basis Psychiatric diagnostic instruments generally serve three functions: to help ensure the accuracy of a diagnosis; to quantify the severity of symptoms; and to quantify the effectiveness, or lack thereof, of a given treatment modality. Ideally, a rating scale should be reliable (conveys consistent and reproducible information) and valid (measures what it intends to measure). For a diagnostic instrument to be valid, it must be reliable, although a reliable instrument might not necessarily be valid. Classification of Methodology Sub-types Diagnostic rating scales are either clinician-rated or patient- (self-) rated. Indications There are patient-rating scales for most every psychiatric condition, and some comprehensive ones that are used to diagnose based on the Diagnostic and Statistical Manual of Mental Disorders .

This chapter covers a selection of widely used instruments, including the SCID and the MINI for general diagnosis; depression rating scales, such as the Hamilton Depression Scale, Montgomery-Asberg Depression Rating Scale (MADRS), IDS, Beck Depression Inventory, Quick Inventory of Depression Symptomatology-Self Rated, and SDQ; the Clinical Global Improvement for global assessment; and other scales for schizophrenia, mania, obsessivecompulsive disorder, cognition, personality disorder, substance abuse, social functioning, drug side effects, and response to antidepressants. Clinical Applications Diagnostic instruments can be useful tools, both in psychiatric research as well as in the clinical setting. These instruments may be used independently or in conjunction with a thorough clinical interview. Important Historical Proponents The scales discussed here are widely used, and most have been validated for use in clinical trials, but may also help the clinician ascertain the degree of illness and the response to treatment over time.

Introduction Overview When screening for psychiatric disorders, psychiatrists typically rely on information obtained from the clinical interview, from review of medical records, and from other sources. However, administration of various standardized diagnostic instruments can be helpful, and at times necessary. For example, the overwhelming majority of clinical research studies rely heavily on the use of diagnostic instruments. In the clinical setting, a standardized questionnaire often serves as an adjunct to the clinical interview, particularly for cases in which the diagnosis is in doubt, or when the efficacy of a treatment is unclear. Psychiatric rating scales attempt to translate clinical observations into objective and (sometimes) quantifiable information. This chapter will review some commonly used instruments, and provide guidelines for the use of these instruments.

Uses for Diagnostic Psychiatric Instruments Psychiatric diagnostic instruments generally serve three functions: to help ensure the accuracy of a diagnosis; to quantify the severity of symptoms; and, to quantify the effectiveness, or lack thereof, of a given treatment modality.

Reliability and Validity Reliability refers to a scale’s ability to convey consistent, reproducible information. Diagnostic instruments are usually tested for their reliability by having more than one rater administer them, and then comparing the results with those of others (i.e., inter-rater reliability). If the instrument is designed to measure phenomena that are consistent over time, test–retest reliability is the measure used. Validity refers to the scale’s ability to measure what it intends to measure. For a diagnostic instrument to be valid, it must be reliable, although a reliable instrument might not necessarily be valid.

Types of Diagnostic Instruments: Self-Rated versus Clinician-Rated Clinician-Rated Instruments These instruments are administered by the clinician. They are advantageous in that they are generally valid and reliable. Most diagnostic instruments are of this kind.

Self-Rated Instruments These are instruments that the patient must complete. Self-rating scales have the advantage that they require less clinician time, which makes them especially useful for screening purposes. However, the reliability of self-rated scales is often difficult to assess, and some patients might be too impaired to complete them. The concordance rate between self-rating and observer scales is not well established for many instruments. Recent efforts have focused on improving patient instruction on how to complete self-rating scales more accurately, though without influencing their actual answers.

Diagnostic Interviews Structured clinical interviews were developed because of a perceived unreliability of psychiatric diagnoses. This problem was especially serious with

regard to international studies, as psychiatrists from different countries or cultural backgrounds often had a different conceptualization of mental disorders. Several scales were developed, including: the Present State Examination (PSE ); the Structured Clinical Interview for Axis I Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (SCID-5 ); the Schedule for Affective Disorders and Schizophrenia (SADS ); the Diagnostic Interview Schedule (DIS ); the Composite International Diagnostic Interview (CIDI ); and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN ). The SCID-5 will be reviewed here because it is the most commonly-used diagnostic instrument in psychiatry. The MINI will be reviewed, as well.

The Structured Clinical Interview for DSM-5 (SCID) The SCID-5 is a semi-structured interview that applies the new Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) criteria to a patient. It is organized into modules that cover most of the major Axis I disorders (mood [depressive] disorders, psychotic disorders, bipolar disorders, substance use disorders, anxiety disorders, obsessive-compulsive disorders, sleep-wake disorders, eating disorders, somatic symptom disorders, externalizing disorders, trauma disorders, and adjustment disorders). The SCID-5 is organized such that some disorders are considered “optional” and do not need to be assessed unless necessary for a particular study (e.g., separation anxiety disorder, hoarding disorder. Trichotillomania, intermittent explosive disorder). Other notable DSM-5 changes reflected in the SCID-5 include the elimination of the bereavement exclusion for a major depressive episode, and the re-categorization of obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and acute stress disorder as separate from anxiety disorders.

Administration of the SCID The SCID is administered by a clinician, sometimes as an exclusive diagnostic tool, and is often used in combination with a quantitative symptom scale (such as the Hamilton-D Hamilton Depression Scale [HAM-D] or the Beck Depression Inventory [BDI]). The SCID begins with a general introductory section on demographics, general medical and psychiatric history, and use of medications. Questions here tend to be more open ended. It then proceeds by modules to the different Axis I disorders. Questions here are asked exactly as written, and each is based on the individual criteria from DSM-5. Answers are generally rated on a scale of 1 to 3 (1 = doubtful, 2 = probable, 3 = definite), and based on the

number of positive answers, a diagnosis is determined. A SCID-based interview may take up to two hours to complete, depending on how complicated a patient’s history is, and on the patient’s ability to provide a good history. There is a SCIDCT version, more specifically tailored and streamlined to specific clinical trials, but which is not considered a comprehensive clinical assessment.

Value of the SCID Because completing the SCID is time consuming, it is used almost exclusively in the research setting. It is probably the most reliable means of diagnosing psychiatric disorders. In some instances, clinicians may use only a portion of the SCID, such as the mood disorder module.

The Mini-International Neuropsychiatric Interview Overview and Administration of the Mini-International Neuropsychiatric Interview The Mini-International Neuropsychiatric Interview (MINI ) 7.0 is a short, structured, diagnostic interview for diagnosis of the DSM-5 and the International Statistical Classification of Diseases and Related Health Problems (ICD-10) disorders. It is similar to the SCID, and administered by clinicians. The MINI differs from the SCID in that it is more compact and questions are answered on a “yes/no” basis rather than on a numerical scale. The MINI can easily be administered in 15 to 30 minutes. Other differences with the SCID include the addition of a module on antisocial personality disorder and a section with detailed questions on suicidality. The MINI covers melancholic depression but not atypical depression. There are several MINI-derived instruments, such as the MINI-Plus and the MINI-Kid.

Value of the MINI The short and focused but accurate nature of the MINI, along with its ease of administration, makes it especially useful in clinical trials as well as in epidemiologic studies for which a brief assessment might be required. Increasing numbers of researchers are implementing the MINI in randomized clinical trials. The MINI has been validated against the SCID and the Composite International Diagnostic Interview for ICD-10 (CIDI) in various languages. The National Institute of Mental Health (NIMH) has endorsed the MINI as a validated alternative to the SCID and CIDI. Because of its greater time efficiency, it is becoming increasingly used in clinical trials.

Depression Scales Hamilton Rating Scale for Depression Overview of the HAM-D The Hamilton Rating Scale for Depression (HAM-D ) aims to quantify the degree of depression in patients who already have a diagnosis of major depression. Questions focus on symptoms experienced only over the past week. It is administered by the clinician, and it generally does not require more than 20 minutes to complete. The HAM-D is a useful tool for measuring the progress of a patient during treatment, either in the research or clinical setting.

Description of the HAM-D Several different versions of the HAM-D exist; they differ only in the number of questions included. The longest version includes 31 items; the shortest includes only six items. The longer versions include questions about atypical depression symptoms, psychotic symptoms, psychosomatic symptoms, and symptoms associated with OCD. The standard form which is generally used in research studies is the 17-item Hamilton D (HAM-D-17). Shorter versions of the HAM-D, such as the HAM-D-6, have been adapted to cover shorter symptom periods of 1 to 3 days in some clinical trials of potentially rapidly-acting therapies, such as ketamine.

Scoring of the HAM-D There is a structured version of this instrument in which questions are asked exactly as written and are rated on a scale of 0 to 4 or 0 to 2, depending on the answers given by the patient. Other versions allow more open-ended questioning. Overall scores on the HAM-D-17 typically fall into the following ranges: not depressed: 0 to 7; mildly depressed: 7 to 15; moderately depressed: 15 to 25; and, severely depressed: more than 25.

The HAM-D As a Research Tool Research studies rely on the Hamilton-D to quantify responses to a given treatment over time. Research studies will often cite a change in the Hamilton-D score as a criterion for response. For example, a decrease of 50% or more in the Hamilton-D score is considered to be a positive response to treatment, whereas a score of 7 or less is considered typical of remission. The HAM-D is the most widely studied instrument for depression, and its reliability and validity are high.

The Montgomery-Asberg Depression Rating Scale The Montgomery-Asberg Depression Rating Scale (MADRS ) is another scale for measuring depressive severity in individuals diagnosed with depression. It is used primarily in the research setting, often as an alternative or adjunct to the HAM-D scale. Although proposed to be more sensitive to antidepressant-related changes than the HAM-D Scale, the two scales correlate well statistically. The MADRS contains 10 items, which are graded on a scale of 0 to 6, reflecting the severity of symptoms, with a maximum possible total score of 60. The MADRS generally covers a similar range of symptoms as the HAM-D-17 item version, including reported and apparent sadness, tension and anxiety, reduced sleep and appetite, concentration difficulties, lassitude, anhedonia, pessimism/guilt, and suicidal thoughts. The 10-item version of the MADRS is not so well suited for assessing atypical depression, because it does not examine increased appetite or sleep, among other issues. There is, however, a 15-item version used in some clinical trials; the longer version covers atypical depressive symptoms, such as hyperphagia and hypersomnia.

Clinical Global Improvement Scale The Clinical Global Improvement (CGI) scale is a three-item instrument used as an adjunct in the treatment of psychiatric disorders. It is administered by the clinician after a history has been obtained, and after the HAM-D or other instruments have been completed and reviewed by the clinician. It measures, based on history and scores on other instruments: CGI-S (severity), measuring the current condition of the patient on a scale of 1 to 7 (1 being normal, and 7 being among the most severely ill patients); CGI-I (improvement), measuring the degree of improvement (as perceived by the clinician) since the start of treatment on a scale of 1 to 7 (1 being very much improved, and 7 being very much worse); and PGI (patient global improvement), measuring the degree of improvement on the same scale of 1 to 7 (as assessed by the patient). Improvement in CGI ratings is often used in research to determine the degree of improvement over time with a given treatment.

Inventory of Depressive Symptomatology The Inventory of Depressive Symptomatology (IDS ) measures depressive signs and symptoms. There is a clinician-administered version (IDS-C) and a patientadministered self-report version (IDS-SR). There are 28-item and 30-item versions of these instruments. The IDS has been shown to correlate well with the

HAM-D scale as well as the Beck Depression Inventory, but it has the advantage of providing more thorough coverage of symptoms of atypical depression. The IDS is thought to be a good instrument for measuring changes in symptom severity during antidepressant clinical trials. It is thought to be useful for assessing most types of depression, including dysthymia.

Beck Depression Inventory Overview of the Beck Depression Inventory The Beck Depression Inventory (BDI ) is a 21-item questionnaire for the assessment of degree of depression is probably the most widely used self-rating scale; moreover, it can be completed in a few minutes. It is often used as a screening tool for determining the likelihood of a patient meeting criteria for major depression. A clinician can also use it to determine the degree of improvement over time. Questions are different from those found on the HAMD, in that they focus more on cognitive symptoms of depression.

Scoring of the BDI Patients generally must choose between four answers on each item (numbered 0 to 3 for degree of severity of depression). Scores correlate with severity of depression as follows: normal: 0 to 7; mild depression: 7 to 15; moderate depression: 15 to 25; and, severe depression: more than 25. The BDI correlates well with the HAM-D and the CGI, and because of its sensitivity to change over time, it is often used in antidepressant drug trials.

Quick Inventory of Depressive Symptomatology-Self-Report The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR ) is a self-rated instrument derived from the IDS; it measures 16 important depressive signs and symptoms. The QIDS-SR is a good instrument for measuring self-reported changes in symptom severity during antidepressant clinical trials. Each question is rated on a scale of 0 to 3. The total score is obtained by the sum of the scores on most of the individual items as well as by the sum of the highest scores in each of three categories of symptoms (sleep, appetite/weight, and psychomotor activity). The highest possible total score is 27.

Symptoms of Depression Questionnaire The Symptoms of Depression Questionnaire (SDQ ) is a 43-item, self-report scale designed to measure the severity of symptoms across several sub-types of

depression. As such, the SDQ includes items that inquire about an extensive number of depressive symptoms mapping on the dimensional approach of the Research Domain Criteria (RDoC). Items reflect a broad and heterogeneous collection of depression-related symptom features relevant to the multiple symptom domains affected by depression. Moreover, it includes several items that inquire about anxiety symptoms often present among depressed patients. The SDQ has been used in early phases of drug development to obtain a “finger printing” of the therapeutic effects of novel compounds.

Schizophrenia Scales The complexity of schizophrenia requires that clinicians use several different instruments to assess and study this illness. Scales have been designed to assess positive and negative symptoms, social and vocational adjustment, and medication side-effects. Virtually all schizophrenia scales must be administered by a clinician, given that many patients would not be able to complete a selfrated form.

Brief Psychiatric Rating Scale The Brief Psychiatric Rating Scale (BPRS ) includes between 16 and 24 items; each is rated on a scale of 1 to 7. Items primarily cover symptoms of psychosis, but they also address depression and anxiety symptoms. Ratings are expressed as a sum of all items. The scale is brief and can be administered in 15 to 30 minutes. One limitation of the BPRS is that some definitions of items tend to be vague and are subject to interpretation. However, the scale has shown high interrater reliability.

Positive and Negative Symptoms Scale As its name implies, the Positive and Negative Symptoms Scale (PANSS ), similar to the BPRS, focuses more on the positive and negative symptoms. This scale is frequently used in trials of antipsychotic drugs, largely because of its inclusion of negative symptoms. However, it requires more time to complete than does the BPRS. It has excellent inter-rater reliability and has been validated against other instruments.

Scale for the Assessment of Positive Symptoms The strength of the Scale for the Assessment of Positive Symptoms (SAPS ) is its focus on formal thought disorder, which is less emphasized on the previously

mentioned scales.

Scale for the Assessment of Negative Symptoms (SANS) The Scale for the Assessment of Negative Symptoms (SANS ) was the first scale developed to assess negative symptoms, and it provides the standard against which other scales are compared. It focuses on five groups of symptoms: alogia, affective flattening, avolition-apathy, anhedonia-asociality, and inattention. Ratings are based on clinical observations of the rater as well as other staff and family members.

Anxiety Scales Anxiety Disorder Interview Scale, Revised The Anxiety Disorder Interview Scale, Revised (ADIS-R ) is a semi-structured interview used for arriving at DSM diagnoses of anxiety disorders. It provides information on panic, generalized anxiety, and phobic avoidance, and also measures one’s degree of disability. The scale includes the Hamilton-A and HAM-D scales for anxiety and depression, respectively. Its inter-rater reliability is high for most of the anxiety disorders, except generalized anxiety disorder (GAD).

Hamilton Rating Scale for Anxiety The Hamilton Rating Scale for Anxiety (HAM-A ) is the most widely used scale for measurement of anxiety. It is used for patients with diagnosed anxiety disorders. It is similar to the HAM-D, in that it emphasizes somatic symptoms and experiences. It has reasonable validity and reliability.

Fear Questionnaire This is a self-rated instrument used for assessing phobias, including agoraphobia, blood injury phobia, social phobia, and total phobia.

Yale-Brown Obsessive-Compulsive Scale The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS ) is the most widely used scale for assessment of severity of OCD symptoms. It includes 10 items, and a symptom checklist. Inter-rater reliability is excellent. This scale has been used extensively in medication trials for measuring changes in severity of OCD symptoms.

Mania Scales Manic State Rating Scale The Manic State Rating Scale (MSRS ) is a 26-item scale; it is rated on a 0 to 5 scale, and is based on the frequency and intensity of symptoms , particularly elation-grandiosity and paranoid-destructiveness. The MSRS is designed primarily for use on inpatient units, and has been found to be reliable and valid.

Young Mania Rating Scale The Young Mania Rating Scale (Y-MRS ) has 11 items, and is scored following a clinical interview. Four items (irritability, speech, thought content, and aggressive behavior) are given extra weight and scored on a 0 to 8 scale, whereas the other items are scored from 0 to 4. The scale has a high inter-rater reliability; scores on the Y-MRS correlate well with length of hospital stay.

Cognitive Impairment Scales Cognitive scales are useful as an initial screen for organic psychopathology; results of these scales can help the clinician decide whether to request formal neuropsychological testing or imaging studies. These scales, however, can be influenced by the patient’s intelligence, level of education, and literacy; consequently, clinicians need to be careful not to make erroneous conclusions based on scores of these scales.

Mini-Mental State Examination (MMSE) The Mini-Mental State Examination (MMSE ) is the most widely used instrument for measuring cognitive impairment. It is a highly structured instrument that can be administered by non-clinicians. It includes questions about orientation, memory, attention, naming, as well as ability to follow commands, write a sentence, and copy intersecting polygons. The MMSE can be administered in less than 10 minutes; it has established reliability and validity.

Blessed Dementia Scale The Blessed Dementia Scale (BDS ) includes 50 items that assess orientation, recent and remote memory, and the ability to carry out activities of daily living. It is used primarily to diagnose Alzheimer’s dementia.

Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire

The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ ) is a self-administered instrument that contains seven items (labeled a through g) covering a variety of cognitive symptoms (e.g., motivation, wakefulness, energy, focus, memory, word-finding, mental acuity). Items are graded on an ordinal scale of 1 to 6 (1 = greater than normal, 2 = normal, 3 = minimally diminished, 4 = moderately diminished, 5 = markedly diminished, and 6 = totally absent). This instrument is used primarily in the research setting.

Personality Disorder Scales The accurate diagnosis of personality disorders is difficult under most circumstances. Most diagnostic scales have demonstrated poor reliability, largely due to the subjective quality of the criteria, patient unreliability, and the tendency for many patients to meet criteria for more than one disorder at a time. Diagnostic reliability of these scales needs to be improved.

Structured Clinical Interview for DSM-5 Personality Disorders The Structured Clinical Interview for DSM-5 Personality Disorders (SCID-II ) instrument is used for the diagnosis of personality disorders. As with the SCID5, the SCID-II is organized around different personality disorders; questions are based on the criteria for each personality disorder, and are answered “yes” or “no.” The instrument covers ten DSM-5 personality disorders. This instrument is time consuming to administer and is used almost exclusively for research purposes. There is a SCID-II Personality Questionnaire that can expedite administration of the SCID-II. The subject fills out the Personality Questionnaire in a few minutes, and then the clinician circles the numbers to the left of the SCID-II items that were answered “yes” by the subject. The clinician can then administer the SCID-II, asking only about the items already endorsed by the patient. This can save a lot of time in the assessment.

Personality Disorder Examination The Personality Disorder Examination (PDE ) is a lengthy and semi-structured interview consisting of 359 items; it is rated on a three-point scale (absent, clinically significant, or doubtful). It requires 1 to 2 hours to complete, and provides rich information, which places less burden on the assessor’s judgment.

Substance Abuse Scales

CAGE Questionnaire This brief instrument is widely used as a screening tool. The name of the scale is an acronym for: Have you ever felt a need to C ut down on drinking? Have people A nnoyed you by criticizing your drinking? Have you ever felt G uilty about drinking? Have you ever had an Eye-opener? Answering “yes” to two or more of these questions strongly suggests an alcohol-related problem, particularly in a male population.

Michigan Alcoholism Screening Test The Michigan Alcoholism Screening Test (MAST ) consists of 25 true-false questions that can be self-rated or administered by the clinician. Briefer versions have been developed, with comparable validity to the original. The Drug Abuse Screening Test (DAST) is similar to the MAST but can discriminate between alcohol and drug abusers.

Addiction Severity Index The Addiction Severity Index (ASI ) assesses severity of problems with drug and alcohol abuse, with medical illness, with the legal system, with the family system, as well as with one’s system of support (social and employment). It appears to be a valid instrument that is useful in research as well as in treatment planning. It can be administered in less than an hour.

Social Functioning Scales These scales are often used to assess the outcome of an illness or its overall effect on the patient.

Global Assessment of Functioning Scale The Global Assessment of Functioning Scale (GAF ) is used on Axis V of the DSM-IV; it is based on collected information on psychological, social, and occupational function. It rates the patient on a scale of 1 to 100, with a higher score indicating higher function. Usually there are two ratings made: one for current function, and one for highest function in the past year.

Social Adjustment Scale The Social Adjustment Scale (SAS ) assesses social functioning during the past month. Subjects answer questions about work role, household role, parental role, extended family role, sexual roles, social and leisure activities, and overall wellbeing. This scale covers the widest domain of social function, but can be less useful for severely dysfunctional patients, who might be unable to work and/or who have very limited social contacts.

Drug Side-Effect Scales Abnormal Involuntary Movement Scale The Abnormal Involuntary Movement Scale (AIMS ) is widely used to measure late-onset movement disorders , such as tardive dyskinesia. Movements of the head, trunk, and extremities are observed, and rated on a scale of 1 to 5. It is routinely used in patients receiving antipsychotic medication; typically, it is administered every 3 to 6 months.

Systematic Assessment for Treatment Emergent Effects The Systematic Assessment for Treatment Emergent Effects (SAFTEE ) is used for assessment of side-effects in clinical drug trials. It includes a general inquiry form with open-ended questions, and a systematic inquiry form, which asks more specific questions about different systems.

Massachusetts General Hospital Sexual Functioning Questionnaire This self-rated, five-item instrument measures sexual functioning over the past month. It can be used to assess medication-related sexual side-effects during a clinical trial of a psychotropic medication, or to evaluate the patient’s general sexual function in studies of treatment for sexual function disorders. Each item is graded on an ordinal scale from 1 to 6, identical to the CPFQ. Questions cover interest in sex, ability to become aroused, ability to experience orgasm, and overall sexual satisfaction. This instrument is used primarily in research studies.

Scales for Assessing Efficacy and Adequacy of Previous Antidepressant Trials Antidepressant Treatment Response Questionnaire (ATRQ)

The Antidepressant Treatment Response Questionnaire (ATRQ ) is used in research studies as a means of determining what particular antidepressants a patient has taken, and whether these trials may be considered “adequate” when assessing treatment response or non-response. The instrument is administered by a clinician who asks the patient about past antidepressant trials. Depending on the entry criteria of the clinical trial, the clinician may use the ATRQ to characterize all life-time antidepressant trials or just focus on trials during the most recent depressive episode. Patients are asked to review each separate trial, the maximum dose taken, the duration of the trial, and the degree of improvement, usually reported on a 4-item ordinal scale that includes: less than 25% improved; between 25% and 49% improved; between 50% and 75% improved; and, more than 75% improved. In general, an improvement of less than 50% is considered as a failed trial, provided the duration is adequate (usually 6 to 10 weeks) and the dose falls in the therapeutic range defined in the instrument’s medication list. The ATRQ considers augmentation or combination regimens as separate trials; for example, a patient who fails to respond to an adequately dosed selective serotonin reuptake inhibitor (SSRI) for 6 weeks and then also fails to respond after adding a tricyclic antidepressant (TCA) to the SSRI, would be considered as having failed two trials. In many cases, the augmentation or combination trial that follows the failed monotherapy trial can be considered adequate after only 3 weeks, and regardless of the dose of the second agent. In the context of the ATRQ, a case of tachyphylaxis or “poop-out,” which occurs when a previously effective antidepressant stops working, is not considered a failed trial; however, if a dose increase or combination treatment is attempted unsuccessfully after the poopout, this would be considered a failed trial.

Conclusion Diagnostic instruments can be useful tools, both in psychiatric research as well as in clinical settings. These instruments can be used independently or in conjunction with a thorough clinical interview. They can serve to measure results in a research study and to help the clinician ascertain the degree of illness and the response to treatment over time.

Suggested References

1. Andreasen NC: Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychiatry . 1982; 39: 784–788. 2. Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry . 1961; 4: 561–571. 3. Beigel A, Murphy D, Bunney W: The manic state rating scale: scale construction, reliability, and validity. Arch Gen Psychiatry . 1971; 25: 256. 4. Blessed G, Black SE, Butler T, et al: The diagnosis of dementia in the elderly. A comparison of CAMCOG (the cognitive section of CAMDEX), the AGECAT program, DSM-III, the Mini-Mental State Examination and some short rating scales. Br J Psychiatry . 1991; 159: 193–198. 5. Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry . 1968; 114: 797–811. 6. Chandler GM, Iosifescu DV, Pollack MH, et al: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neurosci and Therapeutics . 2010; 16: 322– 325. 7. Di Nardo P, Moras K, Barlow DH, et al: Reliability of DSM-III-R anxiety disorder categories. Using the Anxiety Disorders Interview ScheduleRevised (ADIS-R). Arch Gen Psychiatry . 1993; 50: 251–256. 8. Endicott J, Spitzer RL, Fleiss JL, et al: The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry . 1976; 33: 766–771. 9. Fava M, Iosifescu DV, Pedrelli P, et al: Reliability and validity of the Massachusetts General Hospital cognitive and physical functioning questionnaire. Psychotherapy and Psychosomatics . 2009; 78: 91–97. 10. Fenton WS, McGlashan TH: Testing systems for assessment of negative symptoms in schizophrenia. Arch Gen Psychiatry . 1992; 49: 179–184. 11. First MB, Williams JB, Karg RS, et al: User’s Guide for the Structured Clinical Interview for DSM-I5 Disorders, Research Version (SCID-5-RV). Arlington, VA: American Psychiatric Association; 2015. 12. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Res . 1975; 12: 189–198.

13. Frank E, Prien RF, Jarrett RB, et al: Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry . 1991; 48: 851– 855. 14. Goodman WK, Price LH, Rasmussen SA, et al: The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry . 1989; 46: 1006–1011. 15. Goodman WK, Price LH, Rasmussen SA, et al: The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry . 1989; 46: 1012–1016. 16. Gur RE, Mozley PD, Resnick SM, et al: Relations among clinical scales in schizophrenia. Am J Psychiatry . 1991; 148: 472–478. 17. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry . 1960; 23: 56–62. 18. Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol . 1959; 32: 50. 19. Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull . 1987; 13: 261–276. 20. Labbate LA, Lare SB: Sexual dysfunction in male psychiatric outpatients: validity of the Massachusetts General Hospital Sexual Functioning Questionnaire. Psychotherapy and Psychosomatics . 2001; 70: 221–225. 21. Levine J, Schooler NR: SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacology Bull . 1986; 22: 343– 381. 22. Lewis SJ, Harder DW: A comparison of four measures to diagnose DSMIII-R borderline personality disorder in outpatients. J Nerv Ment Dis . 1991; 179: 329–337. 23. Loranger AW, Sartorius N, Andreoli A, et al: The International Personality Disorder Examination. The World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration international pilot study of personality disorders. Arch Gen Psychiatry . 1994; 51: 215–224. 24. Marks IM, Matthews AM: Brief standard self-rating for phobic patients. Behav Res Ther . 1979; 17: 263–267. 25. Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry . 1979; 134: 382–389.

26. Oldham JM, Skodol AE, Kellman HD, et al: Diagnosis of DSM-III-R personality disorders by two structured interviews: patterns of co-morbidity. Am J Psychiatry . 1992; 149: 213–220. 27. Overall JE, Gorham DR: The Brief Psychiatric Rating Scale. Psychol Rep . 1962; 10: 799. 28. Pedrelli P, Blais MA, Alpert JE, et al: Reliability and validity of the Symptoms of Depression Questionnaire (SDQ). CNS Spectr . 2014 Dec; 19(6): 535–546. 29. Rush AJ, Giles DE, Schlesser MA, et al: The Inventory for Depressive Symptomatology (IDS): Preliminary findings. Psychiatry Res . 1986; 18: 65–87. 30. Rush AJ, Gullion CM, Basco MR, et al: The Inventory of Depressive Symptomatology (IDS): Psychometric properties. Psychol Med . 1996; 26: 477–486. 31. Rush AJ, Trivedi MH, Ibrahim HM, et al: The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and selfreport (QIDS-SR): A psychometric evaluation in patients with chronic major depression. Biol Psychiatry . 2003; 54: 573–583. 32. Shear MK, Maser JD: Standardized assessment for panic disorder research. A conference report. Arch Gen Psychiatry . 1994; 51: 346–354. 33. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al: Reliability and Validity of the M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.): According to the SCID-P. Eur Psychiatry . 1997; 12: 232–241. 34. Williams JB: A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry . 1988; 45: 742–747. 35. Williams JB, Gibbon M, First MB, et al: The Structured Clinical Interview for DSM-III-R (SCID). II. Multi-site test-retest reliability. Arch Gen Psychiatry . 1992; 49: 630–636. 36. Williams JB. Structured interview guides for the Hamilton Rating Scales. Psychopharmacology Series . 1990; 9: 48–63. 37. Young RC, Biggs JT, Ziegler VE, et al: A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry . 1978; 133: 429–435. 38. Zimmerman M: Diagnosing personality disorders. A review of issues and research methods. Arch Gen Psychiatry . 1994; 51: 225–245.

CHAPTER Psychological Assessment 34 SAMUEL JUSTIN SINCLAIR, PHD; MICHAEL J. ROCHE, PHD; SHEILA M. O’KEEFE, EDD; AND MARK A. BLAIS, PSYD

KEY POINTS Overview Psychological assessment is a complex process involving the systematic acquisition, integration, and interpretation of multiple clinical data sources (e.g., clinical interview/life history, psycho-diagnostic testing, performancebased techniques, measures of neuropsychological/cognitive functioning, personality assessment, informant report) in order to address specific clinical question(s) posed by the medical team. Psychological assessment can be useful in addressing questions relating to differential diagnosis, psychiatric co-morbidity, prognosis, capacity/competency, discharge planning, personality style, and/or level of functioning. Psychometrics Psychometrics is the science of measuring psychological constructs (e.g., depression, affective instability). Three paradigms have guided the construction of psychometric tools: Rational Approach : Psychological theory informs the development of items and scales. Empirical Approach : Items/scales are chosen based on how they empirically differentiate known clinical groups (e.g., those with and without depression). Construct Validation Approach : Items/scales are developed based on theory, but are empirically refined to meet basic psychometric (statistical) assumptions. Basic assumptions of test reliability and validity: Reliability refers to the repeatability, stability, and consistency of a given instrument in measuring a given construct. It can be evaluated by

comparing test administrations at different points in time (test-retest reliability) as well as by assessing the comparability of two raters’ scores (inter-rater reliability). Validity refers to whether an instrument truly measures its intended construct. Approaches to Psychological Assessment Objective Psychometric Tools : Standardized instruments where patients are asked to rate items relating to a given construct (e.g., depression) along a specific Likert -based scale (e.g., “not at all” to “extremely”). Examples include: The Personality Assessment Inventory The Minnesota Multiphasic Personality Inventory-2 The Psychopathology Spectra Inventory Performance-based Tools : Instruments that require patients to respond to ambiguous test stimuli (ink blots) in less structured ways, which in turn provides information about psychological functioning and personality style. Examples include: Rorschach Inkblot Test Thematic Apperception Test Clinical Applications Psychological assessment batteries address a range of referral questions across levels of care: Inpatient: to inform discharge/aftercare planning; to identify potential barriers to treatment non-compliance; to inform legal questions relating to capacity and/or competency; to better understand the interplay between psychological, personality, and neurocognitive factors that might affect the course of treatment in the near term. Outpatient: to inform differential diagnosis (e.g., a primary psychotic disorder versus a mood disorder with psychotic features); to rule-in or rule-out the presence of specific psychiatric conditions (e.g., a bipolar affective disorder); to provide a baseline level of functioning prior to initiating pharmacotherapy or psychotherapy, or to evaluate changes in functioning over time as a function of treatment; to assess for personality characteristics/disorders that might also be affecting the course of treatment; to better understand the psychological dynamics that might underlie impulsive behavior and/or behavioral dysregulation

Introduction The purpose of this chapter is to present a basic framework for understanding and interpreting psychological and personality assessment. This is accomplished by reviewing: the methods used to construct valid tests of personality and psychopathology; the major categories of personality tests (including detailed examples of each category); and the application of these instruments in clinical assessment. In addition, issues related to requesting consultations for personality assessment and understanding the assessment report are discussed.

A Brief History of Modern Psychological Assessment In the late 1800s, the first generation of psychologists, such as Sir Francis Galton (1822–1911), focused their efforts on the measurement of sensorimotor functions (e.g., reaction times), and tried to associate these measurements with life achievement (e.g., educational level, occupation, social status). James McKeen Cattell, an American psychologist, coined the term “Mental Test” in 1890. At about the time that sensorimotor measurement was fading out, Alfred Binet (1857–1911) and Theodore Simon were commissioned by the French School Board to develop a test to identify students who might benefit from special education programs. Binet’s 1905 and 1908 instruments form the basis of our current intelligence tests. In fact, the development of Binet’s 1905 scale marked the modern era of psychological testing. The development of instruments to measure personality and psychopathology began around the time of World War I. To aid in the war effort, Woodworth developed a self-report test of psychopathology (called the Personal Data Sheet) designed to screen potential army recruits. Although this effort was unsuccessful, it provided the methodology for the later development of the Minnesota Multiphasic Personality Inventory (MMPI), a self-report test still in use today. In addition, Jung’s Word Association Test (1918) represents the first attempt to integrate psychological measurement with psychoanalytic theory. The result was the first projective test of psychopathology. This was followed by both the Rorschach Inkblot Test (which was published in 1921), and the Thematic Apperception Test (Murray, 1938). The second half of this century has seen intensive efforts focused on the further development of these initial breakthrough assessment methods.

Psychometrics and the Science of Test Development Three basic test development paradigms have guided test construction in the past century: rational , empirical , and construct validation methods. Rational test construction relies on a theory of personality or psychopathology (like the cognitive theory of depression) to provide a framework that guides item selection and scale construction. Scales are developed that reflect a particular theory. For example, within the context of Cognitive Theory, items can be written to measure the extent to which people engage in cognitive distortions (e.g., catastrophization, categorical thinking, helplessness) that underlie common anxiety, mood, and other psychiatric disorders. In contrast, empirically guided test construction relies initially on many items (also called an item pool), and utilizes a variety of statistical procedures to determine which items perform the best in differentiating between known groups (e.g., people who have been diagnosed with depression, anxiety, or a psychosis and a normal control group). This method is also called the empirical keying approach to scale construction, and is the approach that led to the development of the MMPI. Items that successfully differentiate one group from another are then aggregated to form a scale regardless of their thematic content. Another assessment tradition that utilized empirically driven methods to develop scales is the Five Factor Model . In short, factor analysis was employed to reduce approximately 18,000 words from the English dictionary (identified as relating to a description of personality) into five large personality dimensions, which include: Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness (Costa and McCrae, 1992). Items were then developed and aggregated into scales to measure where people fall along these five dimensions of personality. The construct validation method combines aspects of both the rational and empirical test construction methodologies. Within this framework, a large pool of items is written to reflect a theoretical construct (e.g., impulsivity), and then these items are tested to determine if they differentiate subjects who are either high or low on the construct (impulsive versus non-impulsive subjects). Items that successfully differentiate between the groups are retained for the scale. In addition, if theoretically important items do not differentiate between the two groups, this finding can lead to a revision in the theory. The construct validation methodology is considered the most sophisticated strategy for test development.

Reliability and Validity Reliability To be useful , psychological instruments must demonstrate two basic psychometric properties: reliability and validity . Reliability refers to the extent to which an instrument demonstrates repeatability, stability, and consistency of a test score for a given person. Reliability is typically represented as some form of a correlation coefficient ranging from 0 to 1.0. Instruments used in research settings can have reliabilities as low as 0.70, whereas clinical instruments should have reliabilities in the high 0.80s to low 0.90s (Nunnally and Bernstein, 1994). This variation is because research instruments are interpreted as group measures, whereas clinical instruments are interpreted for a single individual (and thus require a higher level of precision). There are several ways to assess the reliability of a given test. For example, internal consistency reliability refers to the degree to which items perform together (or co-vary) in measuring a given construct (e.g., depression), as opposed to varying randomly. Cronbach coefficient alpha is perhaps the most common method for evaluating internal consistency. Test-retest reliability refers to the consistency of a test score over time, where the same instrument is administered either a few days or a few weeks to a year later. The extent to which score estimates are stable across time is further evidence of an instrument’s ability to yield reliable information. Finally, inter-rater reliability for observer-judged rating scales reflects the degree of agreement between raters usually corrected for chance agreement; this is measured by the Kappa statistic. Unreliability (the amount of error present in a test score) can be introduced by variability in the subject (subject changes over time), the examiner, or the test itself (given under different instructions, use of old hard-to-read forms).

Validity Validity is a more difficult concept to understand and to demonstrate than reliability. The validity of a test reflects the degree to which the test measures the construct it was designed to measure. Validity is typically represented as correlation coefficients ranging from 0 to 1.0. Multiple types of validity data are needed before test scores can be considered valid. Content validity assesses the degree that an instrument covers the full range of the target construct. For example, a test of depression that did not include items covering disruptions in sleep and appetite would have limited content validity.

Similarly, predictive validity refers to the ability of the instrument to predict some future manifestation of the construct. For example, a scale measuring treatment motivation would be expected to predict which people will seek psychiatric treatment (i.e., those high on the scale) versus those who do not (i.e., those low on the scale). Concurrent validity refers to how well a given measure (e.g., the Beck Depression Inventory [BDI]) correlates with another independent measure assessing the same construct (e.g., the Hamilton Depression Scale [HAM-D]). Following on this last point, convergent and divergent validity refers to the ability of a scale to demonstrate significant positive correlations with similar scales while also having low or negative correlations with scales measuring different constructs. For example, the BDI would be expected to have higher correlations with the HAM-D Scales (convergent validity) than the Hamilton Anxiety Scale (divergent validity). Taken together, the convergent and divergent correlations indicate the specificity with which the scale measures its intended construct. In a comprehensive review of the literature, Meyer and associates (2001) found that psychological tests possess validity comparable to that of most widely-used medical tests. They also found that, in many circumstances, psychological tests provide incremental validity (for detecting psychiatric disturbances) above and beyond the diagnostic interview alone. However, it is important to realize that no psychological test is universally valid. Tests are considered valid or not valid for a particular purpose (e.g., detecting psychosis).

Definition of a Psychological Test Ideally , a psychological test is a measurement tool made up of a series of standard stimuli (i.e., questions or visual stimuli). These test stimuli are administered following a standard format and set of instructions. The patient’s responses are recorded and scored according to a standardized methodology (ensuring that a given response is always scored the same way). The patient’s test results are then interpreted against a normative sample allowing for an accurate evaluation of the patient’s performance relative to a given norm.

Major Categories of Psychological Tests Intelligence Tests

Intelligence is a difficult construct to define and to measure. Wechsler wrote that, “Intelligence, as a hypothetical construct, is the aggregate or global capacity of the individual to act purposefully, to think rationally, and to deal effectively with the environment” (Matarazzo, 1979). This definition helps us see both what the modern tests of intelligence quotients (IQ) attempt to measure (adaptive functioning) as well as why intelligence or IQ tests can be important instruments in clinical assessment, particularly in treatment planning. If IQ is an indicator of effective functioning, IQ tests must measure aspects of adaptive capacity. Although there are multiple measures of intelligence (IQ) available, the Wechsler IQ series are the most common instruments used in the United States, and they cover most the human age range. The series starts with the Wechsler Preschool and Primary Scale of Intelligence (ages 4–6 years), progresses to the Wechsler Intelligence Scale for Children-IV (6–16 years), and ends with the Wechsler Adult Intelligence Scale-IV (16–90 years) (Wechsler, 2003, 2008). The recently developed Wechsler Abbreviated Scale of Intelligence-II (WASI-II; Wechsler, 2011) is a briefer scale of intelligence that provides an estimate of IQ based on two or four WAIS-III subtests thought to be central to the concept of intelligence. Although older versions of the Wechsler scales typically yielded three major IQ test scores (the Full Scale IQ, Verbal IQ, and Performance IQ), more recent versions of the tests have provided a more nuanced view of intellectual functioning and include four composite scores (Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed) in addition to Full Scale IQ. All IQ estimates are scaled to have a mean of 100 and a standard deviation (SD) of 15 in the general population, which allows for immediate comparison to the normative standard. This statistical feature means that a 15point difference between a subject’s Verbal IQ and Performance IQ can be considered both statistically significant and clinically meaningful. Table 34-1 presents an overview of IQ categories. Table 34-1: IQ Categories with Their Corresponding IQ Scores and Percentile Distribution Full-Scale IQ Score Percentile IQ Categories Normal Distribution ≥ 130

Very superior

2.2

120–129

Superior

6.7

110–119

High average

16.1

90–109

Average

50.0

80–89

Low average

16.1

70–79

Borderline

6.7

≤ 69

Extremely low

2.2

It is important to realize that IQ scores represent a patient’s ordinal position— their percentile ranking, as it were—on the test relative to the normative sample. These scores do not represent a patient’s innate intelligence and there is no good evidence that they measure a genetically determined trait known as intelligence. However, they do reflect some degree of the patient’s current adaptive functioning. Furthermore, because obtained IQ scores are not totally reliable (all test scores contain some degree of unreliability due to measurement error) they should be reported with confidence intervals indicating the range of scores in which the subject’s true IQ would fall. The Wechsler IQ tests are composed of 10 to 15 subtests which were developed to tap various intellectual domains, including Verbal Comprehension (VCI: Similarities, Vocabulary, Information, Comprehension), Perceptual Reasoning (PRI: Block Design, Matrix Reasoning, Visual Puzzles, Figure Weights, Picture Completion), Working Memory (WMI: Digit Span, Arithmetic, Letter-Number Sequencing), and Processing Speed (PSI: Symbol Search, Coding, and Cancellation). Each of the Wechsler subtests is constructed to have a mean score of 10 and standard deviation of 3. Given this statistical feature, we know that if two subtests differ by 3 or more scaled score points, the difference is significant. All IQ scores, index scores, and specific subtests are also adjusted for age.

Tests of Personality, Psychopathology, and Psychological Functioning Objective tests of personality and psychopathology, also called self-report psychometric tests, are designed to clarify and quantify a patient’s personality functioning and psychopathology across an array of domains. Objective tests use a patient’s response to a series of true/false or multiple-choice questions to broadly assess personality and psychological function. These tests are called “objective” because their scoring involves little speculation. Objective tests provide excellent insight into how the patient perceives his or her level of function within and across these domains, as well as how he or she wants others (e.g., clinical care providers) to see and respond to them.

The Personality Assessment Inventory The Pe rsonality Assessment Inventory (PAI ; Morey, 1991, 2007) is one of the newest objective measures of psychological functioning available. The PAI was developed using a construct validation framework with equal emphasis placed upon theory-guided item selection and the empirical functioning of the items and scales. The PAI contains 344 items and utilizes a four-point response format (False, Slightly True, Mainly True, and Very True). These 344 items map onto 22 non-overlapping scales, include four validity and response style scales, 11 clinical scales, five treatment scales, and two interpersonal scales, and covers a range of psychopathology and other variables relevant to interpersonal functioning and treatment planning (e.g., the PAI has scales designed to measure suicidal ideation, resistance to treatment, and aggression). The PAI possesses outstanding scaling features (e.g., Siefert et al, 2009), and also contains an embedded short-form comprising the first 160 items with sound psychometric properties (Sinclair et al, 2009; Sinclair et al, 2010). As such, it is an ideal test for broadly assessing multiple domains of relevant psychological functioning.

The MMPI-2 The MMPI-2 (Butcher et al, 1989) is a 567-item true/false, self-report test of psychological functioning. Utilizing a criterion-keying approach to test development, it was designed to provide an objective measure of abnormal behavior, to separate subjects into two groups (normals and abnormals), and then to further sub-categorize the abnormal group into specific classes (Graham, 2006). The MMPI-2 contains 10 Clinical Scales that assess major categories of psychopathology, and three Validity Scales designed to assess test-taking attitudes. MMPI-2 validity scales are: (L) Lie, (F) Infrequency, and (K) correction. The MMPI-2 Clinical Scales include: (1) Hs, Hypochondriasis; (2) D, Depression; (3) Hy, Conversion Hysteria; (4) Pd, Psychopathic Deviate; (5) Mf, Masculinity/Femininity; (6) Pa, Paranoia; (7) Pt, Psychasthenia; (8) Sc, Schizophrenia; (9) Ma, Hypomania; and (0) Si, Social Introversion. More than 300 “new” or experiential scales have also been developed for the MMPI-2. MMPI raw scores are transformed into T-score to have a mean of 50 and standard deviation of 10; a T-score of 65 or more indicates clinical psychopathology. The MMPI-2 is interpreted by determining the highest two or three scales, which is called a “code type.” For example, a 2-4-7 code type indicates the presence of depression (scale 2), anxiety (scale 7) and impulsivity (scale 4) and the likelihood of a personality disorder (Graham, 2006).

Building on the strengths of the full-length MMPI-II, a shorter version of the test (the MMPI-RF) was recently developed using more modern psychometric methods, which contains 338 of the original 567 items (Tellegen and Ben-Porath, 2008; Ben-Porath, 2012). This newer version of the test focuses more on the Restructured Clinical (RC) scales as the centerpiece, and has utilized newer and more theoretically-driven approaches to scale development. The degree of correspondence between the original MMPI-2 and the MMPI-RF is still being investigated.

The Millon Clinical Multi-Axial Inventory-IV The Mi llon Clinical Multi-axial Inventory-IV (MCMI-IV ) is a 195-item true/false, self-report questionnaire designed to identify both common clinical disorders and personality pathology, and was recently updated to be consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) classification systems (Millon, Grossman, and Millon, 2015). The personality pathology scales resemble, but are not identical to, the DSM-5 personality disorders. Computer scoring and interpretive reports are also available through the test publisher (Pearson). Given its relatively short length (195 items versus 567 for the MMPI-2) the MCMI-IV can have advantages in the assessment of patients who are agitated, whose stamina is significantly impaired, or who are just suboptimally motivated.

The Psychopathology Spectra Inventory The Ps ychopathology Spectra Inventory (PSI ) is a 96-item self-report measure of general psychological functioning, whose development was guided by the quantitative model of psychopathology (Blais and Sinclair, in preparation). The PSI is composed of 12 lower-order clinical scales (Depression, Anxiety, Social Anxiety, PTSD, Alcohol Problems, Drug Problems, Antisocial Behavior, Severe Aggression, Psychosis, Paranoid Ideation, Manic Activation, and Grandiose Ideation), which map onto three higher-order spectra (Internalizing, Externalizing, and Reality Impairing) that have been shown to explain the comorbidity/co-variance among DSM disorders. These 12 lower-order scales were selected to measure clinically important conditions and provide a broad, balanced assessment of the three higher-order spectra. The PSI is unique among existing assessment instruments in that it assesses the degree of pathology present across the three primary spectra while also identifying prominent clinical conditions currently being expressed. Considering its brevity and advanced

empirical conceptualization of psychopathology, the PSI has the potential for application across a broad range of clinical and research settings.

The Personality Inventory for DSM-5 and Personality Inventory for DSM-5 Brief Form The Pe rsonality Inventory for DSM-5 (PID-5 ) is a 220-item measure that was developed in 2012 to assess to assess the five higher-order domains (or dimensions) that are included in Section III of the DSM-5, which have been shown to explain a significant amount of the variance observed across the personality disorders: Negative Affect, Detachment, Antagonism, Disinhibition, and Psychoticism. These five overarching domains subsume 25 lower order “facets,” which themselves represent different features of the higher-order construct. The PID-5 yields scores at both the domain and facet levels, whereas the Pe rsonality Inventory for DSM-5 Brief Form (PID-5-BF) is a shorter 25item measure designed to yield scores at the domain level only. Initial psychometric testing of these measures has been promising, and in many ways these tools reflect more recent conceptualizations of personality functioning— where the combination and severity of these traits are seen to have more predictive power than a simple criteria-based approach alone.

Validity Scales and Other Considerations Certain response styles or sets can have a negative impact on the accuracy of a patient’s self-report. Validity scales are incorporated into all major objective tests to assess the degree to which a patient’s response style might have distorted the findings. The three most typical response styles are: careless or random responding (which may indicate that someone is not reading or understanding the test), attempting to “look good” by denying pathology, and attempting to “look bad” by over-reporting pathology (a cry for help or malingering). With respect to the first response styles and in addition to careless and/or random responding that can affect the validity of the test, it is also important to consider both education/grade level and other cultural factors (e.g., English as a second language) that can affect a patient’s ability to adequately attend to and fully comprehend item content. Finally, and with respect to the latter, it is equally important to consider the multitude of reasons why someone might portray themselves in an overly positive or negative way, and to interpret the test findings accordingly.

Many of the objective tests of psychological functioning that are used currently include computer-generated reports, which are created after a patient’s responses to the test items are entered into a scoring program. The reports available from these programs frequently provide suggested DSM diagnoses. However, at best these diagnoses are informed suggestions and at worse they are marketing gimmicks. Psychological tests do not make clinical diagnoses, clinicians do.

Performance-Based Psychological Tests Projective , or performance-based, measures of psychological functioning differ from objective tests in that they are less structured and require more effort on the part of the patient to make sense of, and to respond to, the test stimuli. Even the instructions for the projective tests tend to be less specific than those of objective tests. As a result, the patient is provided with a great degree of freedom to demonstrate his or her own unique personality characteristics and psychological organizing processes. Whereas the objective test provides a view of the patient’s “conscious” or explicit self-presentation, the performance-based tests provide insight into the patient’s typical style of perceiving, organizing, and responding to ambiguous external and internal stimuli. When combined, data from objective and projective tests can provide a fairly complete picture or description of a patient’s range of functioning.

The Rorschach Inkblot Method The Rorschach inkblot method was developed by Hermann Rorschach (Rorschach, 1942/1921). The Rorschach method involves presenting 10 cards with ambiguous inkblots on them (five are black and white; two are black, red, and white; and three are various pastels) to the patient. The test is administered in two phases. During the first phase, the patient is presented with the 10 inkblots, one at a time, and asked to tell “what might this be.” The responses are recorded verbatim and the examiner attempts to get two responses to each of the first two cards. In the second phase, the examiner reviews the patient’s responses with him or her and inquires about where on the card the response was seen (known as “location” in Rorschach language) and what made it look that way (known as the “determinants”) with the patient. For example, if a patient responded to card V with, “A flying bat,” (inquiry: “Where on the inkblot did you see that?”) “Here, I used the whole card,” (“What made it look like a bat?”) “The color, the black made it look like a bat to me,” this response would be coded:

Wo FMa.FC’o A P 1.0. In the past, Rorschach “scoring” has been criticized for being too subjective. However, over the past 30 years John Exner Jr (Exner, 1986, 2003) and his colleagues have developed a Rorschach system, called the Comprehensive System, which has demonstrated acceptable levels of reliability. Over the past decade, the Rorschach Performance Assessment System (R-PAS ) has also been developed as a means of improving upon the comprehensive system while also updating available normative data. Currently, inter-rater Kappa scores of 0.80 or better are required for all Rorschach variables reported in published research studies. For comparison, Kappas in this range are equal to or better than the Kappas reported for structured interview DSM diagnoses. Rorschach data is particularly useful for quantifying a patient’s reality contact and the quality of their thinking.

Thematic Apperception Test The Thematic Apperception Test (TAT ) is useful in revealing a patient’s dominant motivations, emotions, and core personality conflicts (Murray, 1938). The TAT consists of a series of 20 cards depicting people in various interpersonal interactions. The cards were intentionally drawn to be ambiguous. The TAT is administered by presenting 6 to 10 of these cards, one at a time, with the instructions to, “Make up a story around this picture. Like all good stories it should have a beginning, middle, and an ending. Tell me how the people feel and what they are thinking.” Although there is no one accepted standard scoring method for the TAT (making it more of a clinical technique than psychological test proper), when sufficient cards are present, reliable information can be obtained. A few standardized scoring methods have been developed for the TAT, including the Social Cognition and Object Relations Scale (Stein et al, 2012). However, these are often limited to specific aspects of psychological functioning, such as level of defense operations and degree of psychological maturity. Psychologists typically assess TAT stories for emotional themes, level of emotional and cognitive integration, interpersonal relational style, and view of the world (is it seen as a helpful or hurtful place). This type of data can be particularly useful in predicting a patient’s response to psychotherapy and to the psychotherapist.

Projective Drawings

Psychologists often employ projective drawings (freehand drawings of human figures, or of a house, tree, and person) as a supplemental assessment procedure. They represent clinical techniques more than tests, given that there are usually no formal scoring methods. In fact, the interpretation of these drawings often relies heavily upon psychoanalytic theory. Despite their poor psychometric properties, projective drawings can sometimes be very revealing. For example, psychotic subjects might produce human figure drawings that are transparent with internal organs. Still it is important to remember that projective drawings are less reliable and less valid than are other tests reviewed in this chapter.

Behavior Rating Scales Behavior rating scales are the most commonly used form of measurement with children and adolescents. They are also useful for those populations that are unable to complete a self-report of personality (such as adults with severe psychotic disorders, dementia, or mental retardation). Behavior rating scales have the benefits of being inexpensive, cost effective, and easy to administer. Forms for teachers and parents allow psychologists to obtain ratings of patient behaviors that might differ across settings. Common examples of behavior rating scales are the Child Behavior Checklist (Achenbach, 1991), and the Behavior Assessment System for Children (Reynolds and Kamphaus, 1992).

Assessment of Children Although advances in the psychological assessment of children have generally lagged behind those in adult assessment, more and more measures and procedures are being developed for use with younger patients. The assessment of children is often challenging due to several special issues including difficulties with affective and cognitive labeling, developmental fluctuations, cognitive development, familial context, and reliance on others for accurate and reliable reporting. The Rorschach Inkblot Test can be used with children as young as five years, and TAT-style storytelling tests, such as the Roberts Apperception Test and the Children’s Apperception Test , are very common. Projective drawing techniques (such as House-Tree-Person and Kinetic Family) are also used with young and non-verbal children. Several child and/or adolescent self-report measures are also available including the MMPI-Adolescent (Butcher et al, 1992), the Youth Self-Report (Achenbach and Edelbrock, 1991), and the Personality Inventory for Youth (Lachar and Gruber, 1995). However, as was

stated earlier, the most common form of measurement with children is behavior rating scales.

Outcomes Monitoring Routine outcome monit oring (ROM ) is the repeated tracking of patient progress over regular intervals to facilitate treatment planning and evaluate quality of care. ROM measures can assess for some or all of the following: psychological functioning (e.g., social functioning, work functioning), violence and suicide risk, general health concerns (such as sleep quality), specific clinical domains (e.g., psychosis, depression, substance abuse), and quality of therapy alliance (for a review of measures, see Pascual-Leone, Singh, Harrington, and Yeryomenko, 2014). The SOS-10 is one measure of overall psychological health that can be used to monitor patient progress (Blais et al, 1999). ROM can also be applied in a more specific and personalized manner. Thought records, which are common tools for cognitive-behavioral therapy (CBT), can be thought of as a patient-specific implementation of ROM. Treatments, such as social rhythm therapy for bipolar disorder expect that changes to routines throughout the day can predict the onset of manic symptoms, and routinely track daily symptoms of sleep, timing of social events, and mood in order to evaluate and control mood symptoms (Frank, Swartz, and Boland, 2007). Although the standard for years has been paper-based tracking systems, recently advances in technology and smartphone apps have made it possible for patients to track symptoms on their smartphones . Evidence shows that even though the completion rates are comparable for paper versions and on-line versions, the online implementation affords other advantages, such as time-stamping to ensure the patient completes records each day (Bolger et al, 2006). At Massachusetts General Hospital, the Eating Disorders Clin ical and Research Program (EDCRP ) routinely uses the app Recovery Record for patients to track their eating disorder symptoms electronically (for a review of eating disorder apps, see Fairburn and Rothwell, 2 015). The repeated monitoring of symptoms over time can also be incorporated at the initial stage of patient contact for assessment purposes. In comparison to singleoccasion assessments, tracking symptoms over a brief interval (e.g., two weeks) can provide more accurate data because the patient can report on daily levels of symptoms rather than relying on retrospective self-report, which can be influenced by myriad cognitive and situational biases. This longitudinal assessment approach can also uncover patient-specific triggers in their daily life

that can guide treatment-planning and serve as a benchmark to compare against in future assessments. Such assessment approaches are increasingly common in research (for review, see Trull and Ebner-Priemer, 2009) but have not been standardized into a readily accessible package for clinical use (for an example of such a package, see Roche et al, 2014).

Integrating Assessment Data Psychological assessment does not rely on the linear interpretation of singular test scores. This simplistic and overly reductionist use of psychological instruments misses their true value and, in turn, their ability to provide meaningful clinical information is limited (Groth-Marnat, 2003). Rather, psychological assessment focuses on integrating clinical data that is derived in a multi-method, multi-source evaluation (e.g., clinical interview and corroborating sources, objective and performance-based psychological instruments, measures of abnormal/maladaptive and normal/adaptive personality) in an attempt to arrive at a complex and dynamically rich picture of the person. In the past, this data integration was achieved by employing overarching psychological theories. Unfortunately, the field no longer has a dominant theory of personality. Recognizing this need, Blais and Smith (2008) proposed a “model” of personality which organizes multi-source, multi-method data into overarching psychological systems. This includes an overall self-awareness and regulation system that governs other psychological domains, such as the quality of a person’s thinking (perceptual accuracy and associational), emotion processing and affective experience, sense of self (the identity system), and interpersonal functioning. As Blais and Hopwood (2010) noted, although the field might lack a grand theory of personality at present, there has been considerable work done over the past half-century demonstrating how these various systems relate to one another and how they can be integrated in a larger way to organize personality.

The Assessment Consultation Process and the Report Requesting an Assessment Consultation The referral of a patient for an assessment consultation should be like the referral to any professional colleague. Psychological testing cannot be done “blind.” The psychologist will want to hear relevant information about the case and will explore with you what question(s) you want answered (called the referral question ) with the consultation. For example, a clinician might have

specific diagnostic questions present, such as whether there is evidence for psychotic process or mania, and might also be interested in level of cognitive functioning and whether there are any deficits present that can affect daily living. Based upon this case discussion the psychologist will select an appropriate battery of tests designed to obtain the desired information. Most comprehensive psychological test batteries include self-report (and/or parent report if the patient is a child) and performance-based measures of personality as well as a measure of overall cognitive ability. Differing perspectives allow for a more comprehensive and valid picture of the patient’s functioning. It is helpful if clinicians prepare the patient for the testing by reviewing with him or her why the consultation is desired and that it will likely take a few, perhaps three, hours to complete. Clinicians should expect the psychologist to evaluate your patient in a timely manner and to provide you with verbal feedback (a “wet read”) within a few days after the testing. The written report should be available within 2 weeks.

Using the Test Results The relevant findings from the consultation should be reviewed with the patient. This helps confirm for the patient the value of the testing and the time the patient invested in it. If either the provider or the patient has questions about the findings the provider should contact the psychologist for clarification. Ultimately, if necessary, the psychologist should be willing to meet with the referring clinician or with the patient to explain the test results. It is generally not a good idea for the patient to read the professional report given the technical nature of it as well as the possibility that the patient might misunderstand or misinterpret the findings.

Understanding the Assessment Report The report is the written statement of the psychologist’s findings. It should be understandable and it should plainly state and answer the referral question(s). The report should contain several key fields of information including: relevant background information and reason for the referral; a list of the procedures used in the consultation; a statement about the validity of the test results and the confidence the psychologist has in the findings; a detailed integrated description of the patient, based upon test data, clinical interview, and observation;

diagnostic impressions (not confined to the current DSM diagnosis) and tailored treatment recommendations. The test findings should be presented in a logical manner, providing a rich integrated description of the patient (not a description of the individual test results). It should contain some raw data (e.g., IQ scores), which will allow any follow-up testing to be meaningfully compared to the present findings. It should conclude with a list of tailored recommendations. To a considerable degree, the quality of a report (and a consultation) can be judged from the recommendations provided. A good assessment report should contain a number of useful recommendations. Clinicians should never read just the summary of a test report; this results in the loss of important information, given that the entire report is already a summary of a very complex consultation process.

Suggested Readings 1. Achenbach TM, Edelbrock C: The Child Behavior Checklist and Revised Child Behavior Profile . Burlington, VT: University Associates in Psychiatry; 1991. 2. Ben-Porath YS: Interpreting the MMPI-2-RF . Minneapolis, MN: University of Minnesota Press; 2012. 3. Blais MA, Hopwood CJ: Personality focused assessment with the PAI. In: Blais MA, Baity MR, Hopwood CJ, eds.: Clinical Applications of the Personality Assessment Inventory . New York: Routledge; 2010: pp. 195– 209 4. Blais MA, Lenderking WR, Baer L, et al: Development and initial validation of a brief mental health outcome measure. J Personality Assessment . 1999; 73(3): 359–373. 5. Blais MA, Sinclair SJ: Initial construction, psychometric evaluation, and validation of the Psychopathology Spectra Inventory (PSI): A measure based on quantitative models of psychopathology. In preparation. 6. Blais MA, Smith SR: Improving the integration process in psychological assessment data organization and report writing. In: Archer R, Smith S, eds.: Personality Assessment . New York: Routledge; 2008; pp. 405–439. 7. Bolger N, Shrout PE, Green AS, et al: Paper or plastic revisited: let’s keep them both—reply to Broderick and Stone (2006); Tennen, Affleck, Coyne,

Larsen, and DeLongis (2006); and Takarangi, Garry, and Loftus. Psychological Methods . 2006; 11: 123–125. 8. Butcher J, Dahlstrom W, Graham J, et al: MMPI-2: Manual for Administration and Scoring . Minneapolis, MN: University of Minnesota Press; 1989. 9. Butcher JN, Williams CL, Graham JR, et al: MMPI–A: Minnesota Multiphasic Personality Inventory–A: Manual for Administration, Scoring, and Interpretation . Minneapolis, MN: University of Minnesota Press; 1992. 10. Costa P, Widiger T: Personality Disorders and the Five Factor Model of Personality . 2nd ed. Washington, DC: American Psychological Association; 2002. 11. Costa PT, McCrae RR: Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) Manual . Odessa, FL: Psychological Assessment Resources; 1992. 12. Exner J: The Rorschach: A Comprehensive System . Vol. 1, 4th ed. New York: Wiley; 2003. 13. Fairburn CG, Rothwell ER: Apps and eating disorders: a systematic clinical appraisal. Int J Eating Disorders , 2015; 48(7): 1038–1046. 14. Frank E, Swartz HA, Boland E: Interpersonal and social rhythm therapy: an intervention addressing rhythm dysregulation in bipolar disorder. Dialogues in Clin Neuroscience . 2007; 9(3): 325–332. 15. Graham JR: The MMPI-2 Assessing Personality and Psychopathology . New York: Oxford University Press; 2006. 16. Groth-Marnat G: Handbook of Psychological Assessment . 4th ed. New York: Wiley; 2003. 17. Hathaway SR, McKinley JC: The Minnesota Multiphasic Personality Inventory , Rev. ed. Minneapolis, MN: University of Minnesota Press; 1943. 18. Kamphaus RW, Frick, PJ: Clinical Assessment of Child and Adolescent Personality and Behavior . Needham Heights, MA: Allyn & Bacon; 1996. 19. Lachar D, Gruber CP: Personality Inventory for Youth (PIY) Manual: Technical Guide. Los Angeles: Western Psychological Services; 1995. 20. Maruish M: The Essentials of Treatment Planning . New York: Wiley;

2002. 21. Matarazzo J: Wechsler’s Measurement and Appraisal of Adult Intelligence . New York: Oxford University Press; 1979. 22. Meyer GJ, Finn SE, Eyde LD, et al: Psychological testing and psychological assessment: A review of evidence and issues. Am Psychologist . 2001; 56: 128–165. 23. Millon T, Grossman S, Millon, C: Millon Clinical Multiaxial Inventory-IV Manual . Bloomington, MN: Pearson; 2015. 24. Morey L: The Personality Assessment Inventory: Professional Manual . Odessa, FL: Psychological Assessment Resources; 1991. 25. Morey L: The Personality Assessment Inventory: Professional Manual . 2nd ed. Odessa, FL: Psychological Assessment Resources; 2007. 26. Murray H: Explorations in Personality . New York: Oxford University Press; 1938. 27. Nunnally JC, Bernstein IH: Psychometric theory . 3rd ed. New York: McGraw-Hill; 1994. 28. Pascual-Leone A, Singh T, Harrington S, et al: Psychotherapy progress and process assessment. Multimethod Clinical Assessment of Personality and Psychopathology . 2014: 319–344. 29. Roche MJ, Pincus AL, Rebar AL, et al: Enriching psychological assessment using a person-specific analysis of interpersonal processes in daily life. Assessment . 2014; 21(5): 515. 30. Siefert CJ, Sinclair SJ, Kehl-Fie KA, et al: An item level psychometric analysis of the personality assessment inventory clinical scales. Assessment . 2009; 16: 373–383. 31. Sinclair SJ, Antonius D, Shiva A, et al: The psychometric properties of the personality assessment inventory-short form (PAI-SF) in inpatient forensic and civil samples. J Psychopath and Behav Assess . 2010; 32: 406–415. 32. Sinclair SJ, Siefert CJ, Shorey H, et al: A psychometric evaluation of the personality assessment inventory – short form (PAI-SF) clinical scales in an inpatient psychiatric sample. Psychiatry Res . 2009; 170: 262–266. 33. Stein MB, Slavin-Mulford J, Sinclair SJ, et al: Exploring the construct validity of the Social Cognition and Object Relations Scale through clinical assessment. J Personality Assessment . 2012; 94(5): 533–540.

34. Tellegen A, Ben-Porath YS: MMPI-2-RF (Minnesota Multiphasic Personality Inventory-2 Restructured Form): Technical Manual . Minneapolis, MN: University of Minnesota Press; 2008. 35. Wechsler D: Wechsler Abbreviated Scale of Intelligence – Second Edition: Manual. Bloomington, MN: Pearson Publishers; 2011. 36. Wechsler D: Wechsler Adult Intelligence Scale – Fourth Edition: Administration and Scoring Manual . San Antonio, TX: Pearson Publishers; 2008. 37. Wechsler D: Wechsler Intelligence Scale for Children – Fourth Edition: Administration and Scoring Manual . San Antonio, TX: Pearson Publishers; 2003.

CHAPTER Neuropsychological 35 Assessment SAMUEL JUSTIN SINCLAIR, PHD; MARK A. BLAIS, PSYD; AND JANET C. SHERMAN, PHD

KEY POINTS Overview Neuropsychology is the science of assessing brain–behavior relationships and specific behavioral manifestations of brain dysfunction. Using a battery of reliable and well-standardized instruments, the neuropsychologist’s primary goal is to establish which aspects of cognitive functioning are impaired for a patient and which aspects are preserved. The pattern of cognitive strengths and weaknesses identified in a neuropsychological evaluation provides important information regarding the nature of the underlying neurological impairment and its etiology as well as important prognostic and practical information that can guide therapeutic programs aimed at recovery of function. Core Domains Assessed Overall intellectual functioning (IQ) Attention, concentration, and processing speed Expressive and receptive language Immediate and delayed memory (for verbal and visual information) Visual-spatial/constructional abilities Executive functioning/cognitive flexibility Sensorimotor functions Psychological/emotional functioning Goals of a Neuropsychological Evaluation The main goal of a neuropsychological evaluation is to relate a patient’s test performance to both the status of their central nervous system and their realworld functional capacity. Specific aims include the following:

– Diagnosis : to determine whether there is evidence of cortical damage or dysfunction; to localize cortical damage based on behavioral deficits; to distinguish different neurological conditions based on the behavioral data; and to discriminate psychiatric from neurologic symptoms. – Prognosis : to monitor patients over the course of a disease; for example, cognitive decline in the case of a dementia; to recover function following surgical or psychopharmacologic intervention; or to recovery from insults to the brain, including stroke and/or head trauma. – Patient care and planning and to evaluate a patient’s : capacity for selfcare; ability to benefit from a therapeutic program; ability to return to work; ability to make financial or legal decisions; and ability to make judgments required when driving.

Introduction Neuropsychology is a science dedicated to the study of brain–behavior relationships. In its clinical practice, neuropsychology is concerned with the behavioral expression of brain dysfunction. The aspect of behavior that is the focus of a neuropsychological assessment is cognition, with the neuropsychologist’s primary goal to establish which aspects of cognitive functioning are impaired for a patient, and which aspects are preserved. The neuropsychologist relies on a battery of reliable and well-standardized techniques in measuring a spectrum of cognitive functions and behaviors. The pattern of cognitive strengths and weaknesses identified in a neuropsychological evaluation provides important information regarding the nature of the underlying neurological impairment and its etiology as well as important prognostic and practical information that can guide possible therapeutic programs aimed at recovery of function.

History of Neuropsychological Tests Neuropsychology and the field of neuropsychological assessment represent relatively recent developmental lines within applied psychology. The term “neuropsychology” was first introduced into psychological parlance by Karl Lashley (1936). Early approaches to the understanding of brain damage treated it as a unitary phenomenon of “organicity.” Based on this approach, the assumption was made that some sort of common functional deficit would underlie all forms of cerebral dysfunction, with the concomitant assumption that

patients with brain damage could be assessed and diagnosed based on a single test (e.g., the Bender-Gestalt Test). As the scientific understanding of brain– behavior relationships evolved, the global concept of “organicity” was increasingly seen as limited, with the recognition that organic impairment could be present in a variety of cognitive functions. This more advanced understanding of brain functioning and dysfunction led psychologists to develop assessment instruments that could evaluate specific cognitive functions and possible sources of cognitive deficits. With this increased understanding, as well as a greater need for neuropsychological assessment during World War II due to soldiers suffering head wounds, Halstead (1947) developed one of the first neuropsychological test batteries. Reitan later refined this series of tests into the battery known today as the Halstead-Reitan (H-R) Neuropsychological Test Battery .

Current Approaches to Neuropsychological Assessment The modern neuropsychologist is trained to assess brain–behavior relationships utilizing a range of standardized neuropsychological instruments. Most neuropsychologists today utilize a composite and flexible test battery, characterized by a range of tests that are designed to measure specific cognitive functions/domains. The choice of particular tests is flexible in that it varies with the individual patient and the nature of the disorder. In contrast to this approach, fixed batteries are also currently utilized. The H-R battery is the oldest standardized neuropsychological assessment battery. The H-R battery is an elaborate and time-intensive set of neuropsychological tests. It was developed from more than 27 tests used by Halstead in the 1940s to measure cerebral functioning and biological intelligence. The Halstead battery was refined by Reitan, and today the standard H-R battery consists of eight core tests, with supplemental tests being added as indicated. Analysis of an H-R battery is almost exclusively quantitative. The H-R profile is interpreted at four levels: (1) impairment index (a composite score reflecting the subject’s overall performance); (2) lateralizing; (3) localizing signs; (4) and pattern analysis for inferences of etiology (see Reitan, 1986). The Luria-Nebraska Battery (L-NB ) was developed in an attempt to standardize the innovative work of Luria and his Russian colleagues. Although Luria’s work represents a thorough and well-conceptualized approach to neuropsychological assessment, the degree to which the L-NB had been

successful in standardizing this approach is not clear. The L-NB is not widely used in the United States and several prominent United States neuropsychologists have criticized the L-NB, suggesting that it is diagnostically unreliable. A newer and more flexible approach to neuropsychological assessment is The Boston Process Approach . In this approach, a small core test battery (usually containing one of the Wechsler IQ tests) is administered and hypotheses regarding cognitive deficits are developed based on the patient’s performance. Other tests are administered to further evaluate and refine initial hypotheses about the patient’s cognitive deficits. The Boston approach focuses on both quantitative and qualitative aspects of a patient’s performance, with the qualitative focus on the manner or style of the patient’s performance, not just the patient’s accuracy. According to this approach, review of how a patient failed an item or test can be more revealing than whether the item was passed or failed. In this way, the Boston approach reflects an integration of features from behavioral neurology and psychometric assessment.

Goals of a Neuropsychological Assessment The main goal of a neuropsychological evaluation is to relate a patient’s test performance to both the status of their central nervous system (CNS) and their real-world functional capacity. These questions arise for any patient who has suffered neurological disease or damage, and for whom there is a question of possible behavioral dysfunction. Individuals referred for a neuropsychological evaluation cover the entire age span, and include individuals with both acquired and developmental impairments. Acquired impairments are those deficits brought about by brain disease or damage, typically occurring after the CNS has already developed. Included in this class of impairments are cerebral vascular accidents, head injury, brain tumors, and dementing illnesses, as well as toxic, metabolic, and viral conditions. Note that acquired impairments are more common in adults than in the pediatric population. Moreover, when acquired impairments are seen in children they are characteristically different, with generalized CNS insults far more common in childhood, and localized cerebral pathologies more common in adulthood. In addition, recovery profiles differ in the two populations due to both the greater plasticity of the brain in childhood as well as the greater vulnerability of the developing versus the mature brain. Developmental impairments arise when the brain fails to develop normally, the cause of which is often unknown. These disorders, which are far more common

within the pediatric population than are acquired impairments, include learning disabilities, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and intellectual disability. Questions concerning developmental disorders are addressed for adults as well as children, with the neuropsychologist often asked to assess the impact of a developmental impairment in light of increased school or work demands that arise in adulthood. The specific goals of a neuropsychological assessment include diagnosis, prognosis, patient care, and planning for the future.

Diagnosis Included within this goal are questions regarding whether the patient’s test performance provides evidence to suggest the presence of cortical damage or dysfunction; localization of cortical damage based on behavioral deficits (although given increasingly sophisticated neuroimaging techniques, this question is less critical than in the past); distinguishing different neurological conditions based on the behavioral data; and discriminating psychiatric from neurologic symptoms.

Prognosis Cognitive deficits have been highly predictive of a patient’s outcome (Keefe, 1995). The precision of neuropsychological data also allows for monitoring patients over the course of a disease (e.g., cognitive decline in the case of a dementia; recovery of function following surgical or psychopharmacologic intervention, or recovery from insults to the brain, including stroke and head trauma).

Patient Care and Planning The precise descriptive information provided by a neuropsychological assessment can help in the appropriate management of many neurological disorders. Management questions for which a neuropsychological assessment can be helpful include those pertaining to a patient’s capacity for: self-care; ability to benefit from a therapeutic program; ability to return to work; ability to make financial or legal decisions; and ability to make judgments required when driving. The information provided by a neuropsychological assessment can also be utilized to determine how a program of rehabilitation should be structured. Finally, neuropsychological test results can be utilized to help improve selfawareness and set realistic goals by informing the patient (and family members) about the patient’s cognitive strengths and limitations.

Methods in a Neuropsychological Assessment The neuropsychologist relies on multiple sources of information in his or her evaluation, including the patient’s history (e.g., medical, education, personal); qualitative observations of the patient’s behavior; and quantitative methods, specifically performance on standardized tests designed to assess an individual’s behavior in an objective and formalized manner (Snyder et al, 2006). Tests utilized in a neuropsychological assessment have the following important characteristics: they are norm-referenced (allowing the examinee’s performance to be compared with individuals who share important demographic characteristics with the patient [e.g., age, education, gender]); reliance on standard scores (with raw test scores transformed to have a given mean and standard deviation); and standardized methods (such that tests are administered and scored in the same manner across all individuals in different settings). It is important to note that the usefulness of neuropsychological test data can be limited by the quality of the norms employed. Unfortunately, this varies greatly from test to test. In a composite test battery, tests are chosen to sample a wide range of behaviors to obtain a comprehensive assessment of an individual’s cognitive status. In assessing a patient with an acquired impairment, the neuropsychologist must also estimate the patient’s pre-morbid level of cognitive function. Given that direct data (e.g., test scores obtained prior to onset of disease) is rarely available, the neuropsychologist relies on indirect methods in this determination. These methods include obtaining historical and observational data, including information regarding a patient’s educational and occupational history, and the “present ability approach,” based on the fact that brain damage does not uniformly affect all aspects of cognitive functioning. Certain aspects of cognitive functioning–in particular vocabulary knowledge–general fund of knowledge, and reading abilities tend to be more resistant to effects of neurologic disease. Thus, measures of these functions provide a relatively reliable estimate of pre-morbid level of functioning. A neuropsychological evaluation includes assessment of intellectual functioning (IQ testing). Intelligence Quotient (IQ ) is a derived score used in many test batteries designed to measure a hypothesized general ability. Although there is considerable controversy regarding what intelligence tests measure, there is a solid scientific basis for IQ testing, which has been shown to be the best available long-range predictor of outcome and adjustment. Within neuropsychology, it is important to recognize the important role that IQ testing

plays as well as to recognize its limitations. Intelligence testing plays an important role in assessing individuals with developmental impairments, addressing important questions regarding whether the child’s deficits are more global or specific in nature. In acquired impairments, intelligence testing plays a valuable role in helping to determine the individual’s overall level of cognitive functioning. However, it is important to recognize that IQ scores do not bear a direct relationship to size of brain lesion and are often impervious to certain neuropsychological deficits. As is discussed in greater detail in Chapter 34 , the most commonly used IQ measures (Wechsler Scales of Intelligence) include measures of verbal (e.g., Verbal Comprehension Index) and non-verbal (e.g., Perceptual Reasoning Index) functioning, which provide a “rough” measure of left and right hemisphere functions, respectively. In addition to the assessment of intelligence, a complete neuropsychological evaluation includes assessment of different aspects of cognitive functioning , including the following: Attention and concentration Language (expressive and receptive) Memory (immediate and delayed) Visual-spatial/constructional Executive functioning and abstract thinking, and sensorimotor and motor functions Neuropsychological evaluations cover similar areas to those assessed in the mental status examination (MSE) used in neurology and psychiatry. However, these evaluations differ in that a neuropsychological evaluation is far more comprehensive and is based on the use of precise normative data, allowing for a more refined and quantified assessment of the major cognitive functions. In the following sub-sections, we review some of the specific neuropsychological tests that are often used to compose a battery or to assess specific cognitive functions. (For a specific description of these tests, see Lezak et al, 2012; Strauss et al, 2006.) Note that this review is not meant to be exhaustive but rather illustrative.

Attention and Concentration

Attention and concentration are central to most complex cognitive processes and are among the most commonly impaired functions associated with brain damage. Some patients who complain of memory disorders have impaired attention and concentration rather than memory dysfunction. Aspects of attention typically assessed in a neuropsychological assessment include: measures of short-term attentional capacity (e.g., digit span); sustained attention (e.g., continuous performance measures); divided attention (e.g., Paced Auditory Serial Addition Test ); visual scanning (e.g., letter cancellation tasks; TrailMaking Test, Part A ); and alternating attention (e.g., Trails B).

Receptive and Expressive Language Because of the importance of documenting deficits in communication skills secondary to a brain insult, the evaluation of language functioning is an important part of a neuropsychological assessment. Language measures included in a neuropsychological evaluation assess: comprehension of language at single word and sentence levels; confrontation naming; reading decoding; reading comprehension; verbal fluency; and writing. Frequently used measures of language functioning are: the WAIS-IV Verbal Subtests ; the Boston Naming Test ; Controlled Oral Word Association Test (F-A-S; Category Fluency [also used to assess executive functioning, specifically initiation of behavior]); reading (North American Adult Reading Tests [NAART ]; Nelson-Denny Reading Comprehension tests ); and written expression (a writing sample).

Memory Functioning The assessment of memory is extremely important in a neuropsychological battery because impaired memory is both a very common reason for referral and a strong predictor of treatment outcome. Anterograde memory impairment (difficulty acquiring new memories) is also the hallmark and one of the earliest neuropsychological impairments in cortical dementia (e.g., Dementia of the Alzheimer’s Type). Normative data utilized in a neuropsychological assessment can be extremely helpful in distinguishing age-related memory changes from those that characterize a dementia, and can also help distinguish memory complaints that accompany depression (“pseudodementia”) from those of dementia. An evaluation of memory in a neuropsychological evaluation covers both the visual and auditory memory systems; measures immediate and delayed recall (usually with a 30-minute delay); assesses the pattern and rate of new learning; and can determine whether memory impairments are due to difficulties with encoding, recall, or retrieval deficits, as these distinctions provide important

diagnostic information. In patients with disruption to temporolimbic areas, as is the case in Alzheimer’s disease, the ability to consolidate new information in memory is impaired, as is impaired storage of information as evidenced by poor recall of information following a delay. In contrast, patients with disruption of fronto sub-cortical systems (for example, in patients with Parkinson’s disease and multiple sclerosis) exhibit impairments in “strategic memory functions,” including the ability to encode information in an organized manner and to retrieve information. Patients with strategic memory impairments, who also include depressed individuals, tend to perform better in a recognition format, indicating that they can effectively store information in memory but have difficulty actively retrieving the information. Following are reviews of three memory tests commonly used in a neuropsychological assessment: The Wechsler Memory Scale-IV (WMS-IV ) (Wechsler, 2009) is one of the principal memory inventories. The WSM-IV comprises 11 subtests that tap auditory and visual memory at both an immediate and 20- to 30-minute delayed recall. It also provides indications of auditory and visual learning efficiency (new learning ability). Like the Wechsler IQ scales, this memory battery is well standardized. The age-adjusted mean performance for the major memory scores is set at 100 with a standard deviation of 15. The memory subscales all have a mean of 10 and a standard deviation of 3. These statistical properties allow for a detailed evaluation of memory functioning. In fact, in their most recent revisions, the Wechsler IQ and Memory Scales are co-normed, allowing for a meaningful comparison between IQ and memory performance. List learning measures (e.g., California Verbal Learning Test-II [CVLT-II ], Hopkins Verbal Learning Test-Revised [HVLT-R ]) are also commonly used to assess an individual’s ability to learn and remember less contextually supported verbal information. These measures provide important information regarding learning strategies as well as recall of verbal information following short and long delays. Importantly, the CVLT-II and HVLT-R have alternate forms, allowing for reduction of practice effects when individuals are re-evaluated to determine progression of disease. The Three Shapes and Three Words Memory Test is a less demanding test of language-based (written) and visual memory. This brief test in which three shapes are presented with written words below each one also provides

measures of learning rate as well as immediate and delayed recall phases. This test is helpful for bedside memory testing, although unlike the memory measures utilized within a neuropsychological evaluation, it is not well normed (Weintraub and Mesulam, 1985) and provides a more qualitative assessment.

Visual-Spatial Constructional Ability Many aspects of visual perception and construction can be impaired in acquired and developmental disorders. Assessment of these functions provides information as to the integrity of the right parieto-temporo-occipital network processing. These tests assess a patient’s ability to make basic perceptual distinctions, including visual scanning and visual recognition (i.e., object or face recognition) and visual organization (ability to make sense of incomplete, ambiguous, or fragmented visual stimuli). Ability to integrate visual and motor skills, typically assessed in visual construction tasks provides information concerning an individual’s visual organization strategies as well as more basic perceptual and motor skills. Some of the tests that tap visual-spatial functioning include: the Beery Visual Motor Integration Test ; Rey-Osterreith Complex Figure Test ; Benton Visual Form Discrimination Test ; Benton Judgment of Line Orientation Test ; Hooper Visual Organization Test ; and the Perceptual Reasoning Subtests of the WAIS-IV .

Executive Functions and Abstract Thinking Executive functioning refers to several higher-order cognitive processes (such as judgment, planning, logical reasoning, and the modification of behavior [or thinking] based upon external feedback). These processes, associated with functioning of frontal sub-cortical network processing are critical in enabling a person to engage in independent and purposeful, goal-directed behaviors. Individuals with impaired executive functioning, even in the context of otherwise preserved cognitive functioning, can be incapable of self-care, working, or maintaining normal social relationships. Tests utilized to assess executive functioning must be novel and complex, requiring the individual to integrate information. One of the most commonly used tests of executive functioning is the Wisconsin Card Sorting Test (WCST ), which requires the individual to sort 128 response cards that vary in three dimensions (color, form, number). The patient is not told the sorting criteria, nor that the criteria shift during the test. Instead, the patient

must determine the (predetermined) correct responses based on the examiner’s limited corrective feedback (“right” or “wrong” to each sort). One of the primary scores from the WCST is the number of perseverative errors committed, providing a measure of the patient’s cognitive flexibility. Tests that assess other aspects of executive functioning include: tests of working memory (Digit Span Backward [WAIS-IV ]; Letter-Number Sequencing [WAIS-III ]); tests of behavioral initiation (Verbal and Design Fluency measures from the Delis Kaplan Executive Function Systems ); tests that assess behavioral inhibition (Stroop Color Word Test ); tests of processing speed and shift of attentional set (Trail Making Test , Parts A and B); and tests of abstract reasoning (Similarities and Comprehension subtests of the WAIS-IV ).

Motor and Sensory Functioning Measures of tactile sensitivity, motor strength, and speed have long been important in the clinical or bedside neurological examination. Neuropsychologists also measure these functions, employing more sensitive instruments that allow a patient’s performance to be compared to standardized norms. Typically, neuropsychologists are interested in both the absolute magnitude of the patient’s performance (how well did the patient perform relative to the test’s norms), as well as any noted hemispheric differences (the left-right discrepancies). Tests of motor functioning include the Finger-Tapping Test (the average number of taps per 10 seconds with each hand), Hand Dynamometer (a test of grip strength), and Grooved Pegboard Test (a test of fine motor dexterity and speed). Sensory ability tests include Finger-Localization Tests (naming and localizing fingers on the subject’s and examiner’s hand) and Two-Point Discrimination and Simultaneous Extinction test (measures two-point discrimination threshold and the extinction or suppression of sensory information by simultaneous bilateral activation).

Emotional Function Many psychiatric conditions, particularly anxiety and depression, can affect cognitive functioning. Therefore, a complete neuropsychological assessment also includes self-report instruments of psychopathology, such as the Personality Assessment Inventory (PAI ) (see Chapter 34 ). Including such a test in the battery allows the neuropsychologist to evaluate the possible contribution of psychopathology to the cognitive profile and can help determine etiology of deficits.

Brief Neuropsychological Assessment Tools Several brief neuropsychological assessment tools are used in clinical practice today. Brief assessment tools are not a substitute for a comprehensive neuropsychological assessment, but they can be useful as screening instruments or when patients cannot tolerate a more complete test battery. Three such brief tests are the Dementia Rating Scale (DRS-II ); the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS ); and the Measurement and Treatment Research to Improve Cognition in Schizophrenia’s (MATRICS ) Consensus Cognitive Battery (MCCB ). These tests provide a reasonable and brief assessment of the major areas of cognitive functioning (attention, memory, language, reasoning, and construction). The DRS-II is a useful tool for assessing elderly (65 years and up) patients who are suspected of having dementia. It takes between 10 and 20 minutes to administer and it provides six scores. The total score and the scores from the Memory and Initiation/Perseveration sub-scales have been shown to be useful in identifying patients with dementia of the Alzheimer’s type (DAT). The DRS was designed to a low performance “floor.” This means that the test contains many items tapping low levels of functioning, which allows the test to track patients further as their functioning declines. This quality makes the DRS a useful tool for monitoring DAT patients across the course of their illness. The RBANS (Randolph, 1998) was initially developed as a screening procedure for dementia, and sought to address the limitations of longer neuropsychological test batteries that might not be feasible for older and/or more impaired adults to complete, as well as shorter cognitive screening measures (e.g., the Mini-Mental State Examination) that might lack adequate sensitivity in detecting dementia. The RBANS consists of 12 brief subtests measuring the following cognitive domains: Immediate and Delayed Memory for verbal auditory and visual information; Visuospatial/Constructional, Language, and Attention. An overall “total score” is also calculated as a more global indication of someone’s cognitive functioning. Although not a substitute for more comprehensive neuropsychological assessment, the RBANS is an ideal screening tool for more acute settings (e.g., during hospitalization) and for individuals who lack the ability to complete these longer assessments. The instrument’s norms are based on a standardization sample of 540 adults ranging from 20 to 89 years and the test also has the advantage of having two different

forms, enhancing its usefulness for tracking a patient’s cognitive function without the confound of “practice” effects. Finally, the MATRICS Consensus Cognitive Battery was developed more recently to evaluate seven cognitive domains (Kraus and Keefe, 2007): Speed of Processing Attention/Vigilance Working Memory Verbal Learning Visual Learning Reasoning and Problem-Solving Social Cognition From a large pool of 90 existing instruments, 10 were retained based on their reliability and favorable psychometric properties. The final test battery was normed in a sample of 300 community control subjects; it takes approximately 65 minutes to complete.

Common Neuropsychological Assessment Referral Questions Depression versus Dementia The differentiation of depression from dementia in the elderly is a very common neuropsychological referral question (see Chapter 34 for a discussion of “referral question”). Depression in the elderly is often accompanied by apparent cognitive deficits, and depression often accompanies dementia, making differential diagnosis sometimes difficult. Evaluating the profile of deficits obtained across a battery of tests, a neuropsychologist can help establish the differences between these two illnesses. For example, the depressed patient tends to have problems with attention, concentration, and memory (encoding and retrieval), whereas a patient with early dementia has problems with delayed recall memory (retention of information) as well as with semantic memory (as demonstrated by impaired confrontation naming and category fluency). Both types of patients can display problems with executive functioning. However, the functioning of the depressed patient will often improve with cues or strategy suggestions, whereas this typically does not help the patient with dementia. Although this general pattern

will not always be true, it is this type of contrasting performance that allows neuropsychological assessment to aid differential diagnosis.

Independent Living Whether a patient can live independently is a complex and often emotionally charged question. Neuropsychological test data can provide one piece of information needed to make a reasonable medical decision in this area. In particular, neuropsychological test data regarding memory functioning (both new learning rate and delayed recall) and executive functioning (judgment and planning) have been shown to predict failure and success in independent living. However, any neuropsychological test data should be thoughtfully combined with information from an occupational therapy (OT) evaluation, assessment of the patient’s psychiatric status, and family input (when available) before rendering any judgment about a patient’s capacity for independent living. Assessment of Activities of Daily Living (ADLs ) is also frequently included within a neuropsychological evaluation, especially when addressing the question of dementia in which impaired ADLs is required for diagnosis.

ADHD Neuropsychological assessment has a role in the diagnosis and treatment of adults and children with ADHD (predominantly inattentive type and predominantly hyperactive/impulsive type). However, as in the question of independent living status, it provides just a piece of the data necessary for making this diagnosis. The evaluation of ADHD should include a detailed review of academic performance, including report cards and school records and always also includes completion of ADHD symptom checklists by multiple informants (e.g., self, parent, teacher). When possible, in the evaluation of adults for ADHD, living parents should also be interviewed for their recollections of the patient’s childhood behavior. The neuropsychological evaluation should focus upon measuring intelligence, academic achievement (expecting to see normal or better IQ with reduced academic achievement), and multiple measures of attention and concentration (with tests of passive, active [shifting] and sustained attention). Although the neuropsychological testing profile might aid in the diagnosis of ADHD in adulthood, the diagnosis can usually be made solely based upon historical data. The neuropsychological test data or profile is often more helpful in allowing the patient, family, and treaters to understand the impact of the disorder on the patient’s behavior and cognitive functioning and to determine how to best employ behavioral strategies to help structure and

organize the patient’s environment. A neuropsychological evaluation can also help to determine if there are co-morbid disorders (such as learning disabilities) that are very common in individuals with ADHD.

Neuropsychological Assessment and Treatment Planning Neuropsychological assessments can often aid in the treatment planning of patients with moderate to severe psychiatric illness. Although this aspect of neuropsychological testing is somewhat underutilized at present, in the years to come, this might prove to be the most beneficial use of these tests. Neuropsychological assessment facilitates treatment planning by providing objective data and the test profile regarding the patient’s cognitive skills (deficits and strengths). The availability of such data can help clinicians and family members develop more realistic expectations about the patient’s functional capacity (Keefe, 1995). This can be particularly helpful for patients suffering from severe disorders (e.g., schizophrenia). The current literature indicates that neuropsychological deficits are more predictive of long-term outcome in schizophrenic patients than are either positive or negative symptoms. In fact, it is now well established that neuropsychological deficits are common in many psychiatric conditions; when these deficits are not identified and properly addressed, patients often have worse outcomes (Putnam and Blais, 2010).

The Neuropsychological Assessment Report In contrast to the written report from a psychological assessment (reviewed in Chapter 34 ), the written neuropsychological testing report tends to be less integrated. The test findings are provided and reviewed for each major area of cognitive functioning (intelligence, attention, memory, language, reasoning, and construction). These reports typically contain a substantial amount of data (both raw and standardized scores) because this is crucial for any meaningful retesting comparison. In addition, the neuropsychological assessment report provides a summary reviewing and integrating the major findings and their interpretation in terms of the integrity of CNS function, possible underlying diagnosis, and meaningful treatment recommendations. As with all professional consultations, the examining psychologist should be willing to meet with the referring physician and/or the patient and his or her family to review the findings and their implications in person.

Suggested Readings

1. Keefe R: The contribution of neuropsychology to psychiatry. Am J Psychiatry . 1995; 152: 6–14. 2. Kolb B, Whishaw IQ: Fundamentals of Human Neuropsychology . 4th ed. New York: W.H. Freeman and Company; 1996. 3. Kraus MS, Keefe RS: Cognition as an outcome measure in schizophrenia. Br J Psychiatry . 2007; 19146–19151. 4. Lezak MD, Howieson DB, Bigler ED, et al: Neuropsychological Assessment . 5th ed. New York: Oxford University Press; 2012. 5. Matarazzo J: Wechsler’s Measurement and Appraisal of Adult Intelligence . New York: Oxford University Press; 1979. 6. McCarthy RA, Warrington EK: Cognitive Neuropsychology: A Clinical Introduction . San Diego, CA: Academic Press; 1990. 7. Milberg W, Hebben N, Kaplan E: The Boston process neuropsychological approach to neuropsychological assessment. In: Grant I, Adams K, eds.: Neuropsychological Assessment of Neuropsychiatric Disorders . New York: Oxford University Press; 1986. 8. Putnam MC, Blais MA: Neuropsychology in adult psychiatry. In: Arzubi ER, Mabrino E, eds.: A Guide to Neuropsychological Testing for Health Care Professionals . New York: Springer Publishing; 2010: pp. 323–342. 9. Randolph C: The Repeatable Battery for the Assessment of Neuropsychological Status: Manual. San Antonio, TX: The Psychological Corporation; 1998. 10. Rentz DR: Neuropsychological Assessment of Dementia. Presented at Dementia: A Comprehensive Update. Cambridge, May 2002. 11. Reitan R: Theoretical and methodological bases of the Halstead-Reitan neuropsychological test battery. In: Grant I, Adams K, eds.: Neuropsychological Assessment of Neuropsychiatric Disorders . New York: Oxford University Press; 1986. 12. Shallice T: From Neuropsychology to Mental Structure . New York: Cambridge University Press; 1990. 13. Sherman JC, Leveroni C, Pollak LN: Neuropsychological assessment. In: Stern TA, Fava M, Wilens TE, Rosenbaum JF, eds. Comprehensive Clinical Psychiatry . 2nd ed. Elsevier; 2016; pp. 82–95. 14. Snyder PJ, Nussbaum PD, Robins DL, eds.: Clinical Neuropsychology: A

Pocket Handbook for Assessment. Washington, DC: American Psychological Association; 2006. 15. Strauss E, Sherman EMS, Spreen O: A Compendium of Neuropsychological Tests. Third Edition. New York: Oxford University Press; 2006. 16. Wechsler D: Wechsler Adult Intelligence Scale – Fourth Edition : Administration and Scoring Manual . San Antonio, TX: Pearson Publishers; 2008. 17. Wechsler D: Wechsler Memory Scale . 4th ed. San Antonio, TX: Pearson; 2009. 18. Weintraub S, Mesulam MM: Mental state assessments of young and elderly adults in behavioral neurology. In: Mesulam MM, ed.: Principles of Behavioral Neurology . Philadelphia, PA: FA Davis; 1985.

CHAPTER Laboratory Tests and 36 Diagnostic Procedures FRANKLIN KING, IV, MD; FELICIA A. SMITH, MD; AND MENEKSE ALPAY, MD

KEY POINTS Introduction History and examination are the mainstay of psychiatric diagnosis, but laboratory and other objective testing are critical adjuncts in the appropriate circumstances. Diagnostic Tests History of chronic medical illness as well as use of certain medications and substances are common scenarios that might suggest a non-psychiatric etiology. A thorough physical examination might yield evidence of an organic etiology to a psychiatric presentation. New-onset psychosis and delirium warrant a thorough work-up to exclude medical and neurological etiologies. Geriatric Patients Geriatric populations represent an additional group in which medical comorbidity is high, necessitating consideration of organic contributions. Anemia, thyroid dysfunction, polypharmacy, and neurocognitive disorders are more common in the elderly. Specific Tests Neuroimaging is used to exclude structural pathology, to evaluate prognosis in neuropsychiatric disorders, and for research purposes. Magnetic resonance imaging is often superior to computed tomography for evaluation of smaller or subtler lesions due to higher level of detail. Functional neuroimaging is mostly used for research purposes, although

positron emission tomography can be helpful in differentiating neurodegenerative disease. Electroencephalography is a useful modality for diagnosing seizures as well as other neuropsychiatric diseases. Psychotropic Medication Monitoring Many psychotropic medications require screening labs and/or maintenance studies (e.g., thyroid and renal function for lithium; platelet and liver function assays for valproate).

Introduction Diagnoses in psychiatry are made by identification of symptom patterns that constitute psychiatric illnesses as outlined in the Diagnostic and Statistical Manual, Fifth Edition (DSM-5). While the mainstay of making a psychiatric diagnosis relies on a careful interview and mental status examination (MSE), laboratory tests (such as blood work, neuroimaging, and an electroencephalogram [EEG]) are critical adjuncts in the appropriate clinical circumstance. These tests and procedures can be used to help diagnose medical or neurological causes of psychiatric symptoms and might help with monitoring of the progression of certain diseases. In addition, these modalities are often critical in working with populations at high risk for medical co-morbidities, such as the elderly, the indigent, the chronically medically ill, and those with a history of state hospitalization or those who abuse substances. Finally, laboratory tests can be used to check blood levels of psychotropic medications and to help predict drug-induced side effects. This chapter covers the wide range of tests and procedures currently used for psychiatric assessment.

Diagnostic Tests Overview The initial and most important steps in any psychiatric assessment are the compilation of a comprehensive history, physical examination, and MSE. A carefully conducted initial assessment serves to characterize the nature of psychiatric symptomatology, to suggest an underlying organic etiology, and to direct further tests and studies. A thorough history can reveal evidence for medical conditions, substance-related effects, history of medical or psychiatric

illness, family history of medical or psychiatric illness, or psychosocial stressors that could precipitate or aggravate psychiatric symptoms. A detailed MSE characterizes the current mental state. Physical examination can reveal further signs and symptoms indicative of an underlying medical condition and can provide important information suggestive of underlying pathophysiologic mechanisms to direct testing choices.

Diagnostic Strategies A well-taken history accurately characterizes the presenting symptomatology and offers clues to the underlying etiology. Temporal proximity to physical states (including medical conditions, medical/surgical procedures, traumatic events, or the administration or withdrawal of certain substances) may suggest a cause and effect relationship. In general, the initial onset of psychiatric symptoms after the age of 40 years is concerning for an organic etiology. A history of chronic medical illness, medication use, or alcohol or substance use raises the possibility of recurrence of an illness that presents with neuropsychiatric symptoms. Family history of certain genetic psychiatric illnesses (such as bipolar disorder or schizophrenia), or certain heritable medical conditions (e.g., Huntington’s disease) increases the possibility that these conditions are related to the presentation. Presence of endocrine and metabolic disorders (e.g., thyroid dysfunction, pheochromocytoma) needs to be taken into consideration when making a psychiatric diagnosis because these conditions can cause behavioral symptoms that mimic a primary psychiatric illness.

Physical Examination Physical examination provides information that can aid in the diagnosis of either a primary psychiatric diagnosis or an underlying medical diagnosis. Particularly important elements of the physical exam include vital signs and appearance, the neurological examination, and the cardiac examination. In terms of vital signs, elevated temperature (as well as a decreased temperature in infants and the elderly) indicates a possible infectious etiology. If significant temperature abnormalities are present, localizing signs should be assessed to ascertain the location of infection. Significantly elevated temperature (given the appropriate clinical circumstances) could suggest neuroleptic malignant syndrome (NMS) or a central nervous system (CNS) infection (such as meningitis or encephalitis), which are clinical emergencies. Blood pressure and pulse are important because they serve as markers for cardiovascular function, and for adequate cerebral perfusion.

General appearance is also a key component of the physical exam as is examination of specific organ systems. Assessment of level of consciousness can facilitate the diagnosis of a CNS lesion (such as subdural hematoma) or can be suggestive of intoxication or overdose. Body habitus (including weight and height) can be indicative of an eating disorder or a malnourished state, and obesity can be a marker of endocrine disease or a metabolic side effect associated with significant morbidity from neuroleptic medications. Examination of the skin can reveal stigmata of syphilis, liver dysfunction, chronic alcohol use, or intravenous (IV) drug administration. New lesions might indicate recent trauma. Lesions such as scars can be examined to ascertain the severity of past attempts at self-injury. Pupillary examination aids in the diagnosis of substance (particularly of opioids) intoxication or withdrawal. Kayser-Fleisher rings around the pupil is a sign of Wilson’s disease; Argyll-Robertson pupils and other papillary abnormalities are seen in late-stage syphilis infection. Papilledema, as seen on funduscopic examination, is associated with increased intracranial pressure. In regard to examination of the neck, a positive Kernig or Brudzinski sign might suggest meningitis. Palpation of the thyroid should be conducted to assess for any change in size or consistency, which might suggest thyroid dysfunction. Finally, examination of the abdomen can yield clues about possible renal, hepatic, gastrointestinal (GI), or urinary tract involvement. Respiratory and cardiac examinations assess the overall oxygenation of the body (including the brain). Any instability in either system could suggest possible cerebral hypoxia. In addition, respiratory and cardiac examinations are important in distinguishing psychiatric symptoms of anxiety and panic, as opposed to anxiety and panic associated with medical conditions (such as mitral valve prolapse or pheochromocytoma). Neurological deficits are often associated with psychiatric presentations. Certain physical deficits might represent underlying focal lesions (e.g., stroke, tumors) that could also explain psychiatric symptoms. In addition, other neurologic illnesses (e.g., seizure disorders, Parkinson’s disease, Huntington’s disease, multiple sclerosis) might have associated neuropsychiatric manifestations. Furthermore, increased tone (e.g., rigidity) may be a side effect of psychotropic medications. A comprehensive and detailed neurologic examination is a mainstay of psychiatric differential diagnosis and treatment.

Mental Status Examination

The mental status examination (MSE ) is central to the initial evaluation insofar as it characterizes the nature of the patient’s mental state. In addition, certain findings can be suggestive of organic dysfunction and should prompt further diagnostic testing tailored to the specific finding in question. For example, a decline in level of consciousness or agitation might indicate a state of delirium with an underlying organic etiology and would prompt a screening battery of tests as well as consideration of neuroimaging. Impairments of speech, cognition, or memory all implicate specific areas of brain dysfunction and should be evaluated with further testing. Discrete psychiatric symptoms, such as visual and olfactory hallucinations (especially when of recent onset) are also suggestive of an organic etiology and merit a full laboratory and imaging workup. Specific studies are discussed in further detail in the subsequent sections of this chapter.

Types of Studies Laboratory Tests The most common studies used by psychiatrists are laboratory tests, which include analysis of serum chemistries, hematologic tests, and drug screens (Tables 36-1 and 36-2). In addition, endocrine studies can be particularly important for those with a psychiatric presentation (Table 36-3). Serological studies, including tests for syphilis, human immunodeficiency virus (HIV) infection, hepatitis, antinuclear antibodies (ANA), and other immunologic studies can help to detect infectious/immune-mediated etiologies of psychiatric presentations (Table 36-4). Analysis of other bodily fluids (urine, cerebrospinal fluid [CSF]) and stool might be indicated under certain clinical conditions, as well. Finally, toxicology screens (such as for carbon monoxide and methanol) can be very useful in situations of both intentional and inadvertent exposures (Table 36-5).

Other Techniques Radiologic techniques might include plain radiography, such as a chest X-ray or more sophisticated brain imaging techniques, such as computerized tomography (CT), magnetic resonance imaging (MRI ), or positron emission tomography (PET) scans. Cardiac function can be assessed through a number of studies, including an electrocardiogram (EKG), an echocardiogram, and Holter monitoring. Respiratory function can be determined via assessment of an arterial blood gas (ABG), pulse oximetry, and pulmonary function tests. Vascular studies

(e.g., carotid doppler ultrasonography) can be used to assess the integrity of the vascular system. Other studies, such as an EEG , electromyography, and polysomnography , assess the function of the CNS and peripheral nervous system. The following sections describe some of these studies in more detail.

Routine Screening and Choosing Specific Tests Routine Screening There is no consensus with regard to a battery of routine screening tests for those who present with new-onset psychiatric symptoms. Decision-making around ordering screening tests, therefore, relies on consideration of the likelihood and implications of abnormal results, ease of administration, sensitivity and specificity, and cost. Because clinical presentations are quite varied, conventional algorithms fail to direct the diagnostician to the proper test. Presentations that are especially suggestive of a medical cause of psychiatric symptoms (e.g., history of chronic medical illness, onset after the age of 40 years, sudden onset or rapidly progressing symptoms) should prompt a screening battery of tests. In clinical practice, these tests most often include the complete blood count (CBC), serum chemistries, serum and urine toxicologies, levels of vitamin B12 , folate and thyroid stimulating hormone (TSH) level, and a rapid plasma reagent (RPR). A pregnancy test is essential in women of childbearing age for both diagnostic and treatment purposes. Additional tests (e.g., liver function tests [LFTs], urinalysis, chest X-ray [especially in high-risk populations such as substance users, elderly, and homeless]) can be helpful. Table 36-1: Serum Chemistries Test

Pertinent findings

Alanine aminotransferase (ALT)

↑ Hepatitis, cirrhosis, liver metastasis ↓ Pyridoxine (B6 ) deficiency

Albumin

↑ Dehydration ↓ Malnutrition, hepatic failure, burns, multiple myeloma, carcinomas

Aldolase

↑ Ipecac abuse

Alkaline phosphatase

↑ Paget’s disease, hyperparathyroidism, hepatic disease/metastases, heart failure, phenothiazine use ↓ Pernicious anemia (B12 deficiency)

Ammonia

↑ Hepatic encephalopathy/failure, GI hemorrhage, severe congestive heart failure

Amylase

↑ Bulimia nervosa, pancreatic disease/cancer

Aspartate aminotransferase (AST)

↑ Hepatic disease, pancreatitis, alcohol abuse

Bicarbonate

↑ Bulimia, psychogenic vomiting ↓ Hyperventilation, panic, use of anabolic steroids

Bilirubin-total

↑ Hepatic, biliary, pancreatic disease

Bilirubin-direct

↑ Hepatic, biliary, pancreatic disease

Blood urea nitrogen

↑ Renal disease, dehydration, lethargy, delirium

Calcium

↑ Hyperparathyroidism, bone metastasis ↑ Can cause depression, psychosis, anorexia ↓ Hypoparathyroidism, renal failure ↓ Can cause depression, irritability, delirium

Carbon dioxide

↑ Hyperventilation, panic, anabolic steroid abuse

Ceruloplasmin

↓ Wilson’s disease

Chloride

↓ Bulimia, psychogenic vomiting ↓ Hyperventilation (mild) , panic

Complete blood count (CBC) Hemoglobin, hematocrit

↓ Associated with depression

White blood cell count

↑ Associated with lithium use and neuroleptic malignant syndrome (NMS) ↓ Associated with some psychotropic medications

Platelets

↓ Associated with some psychotropic medications

Mean corpuscular volume

↑ With alcohol use, vitamin B12 or folate deficiency

Reticulocyte count ↓ With certain anemias (megaloblastic, iron deficiency, chronic disease) Creatinine phosphokinase (CK, CPK)

↑ NMS, IM injection, rhabdomyolysis, restraints, dystonic reactions, antipsychotic use

Creatinine

↑ Renal disease

Ferritin

↓ Iron deficiency (most sensitive test)

Folate

↓ Associated with fatigue, agitation, dementia, delirium, psychosis, alcoholism, phenytoin use

Gamma glutamyl transpeptidase (GGT)

↑ Alcohol, cirrhosis, liver disease

Glucose

↑ Delirium ↓ Delirium, agitation, panic, anxiety, depression

Iron-binding capacity

↑ Iron deficiency anemia; associated with fatigue

Iron, total

↓ Iron deficiency anemia; associated with fatigue

Lactate dehydrogenase (LDH)

↑ Myocardial infarction, pulmonary infarction, hepatic disease, renal infarction, seizures, cerebral damage

Magnesium

↓ Alcohol abuse (associated with agitation, delirium, seizures) ↑ Associated with panhypopituitarism

Phosphorus

↑ Renal failure, diabetic acidosis, hypoparathyroidism ↓ Cirrhosis, hyperparathyroidism, panic, hyperventilation

Potassium

↑ Hyperkalemic acidosis ↓ Cirrhosis, metabolic alkalosis, laxative abuse, diuretic abuse, bulimia, psychogenic vomiting, anabolic steroid use

Protein, total

↑ Multiple myeloma, myxedema ↓ Cirrhosis, malnutrition, overhydration May affect protein-bound medication levels

Sodium

↓ Hypoadrenalism, myxedema, congestive heart failure (CHF), diarrhea, polydipsia, syndrome of inappropriate anti-diuretic hormone (SIADH) secretion, use of anabolic steroids; may be caused by numerous psychotropic medications ↓ More sensitive to lithium use

Urine aminolevulinic acid & porphobilinogen

Increased in acute intermittent porphyria

Vitamin A

↑ Hypervitaminosis A; associated with depression, delirium

Vitamin B12

↓ Results in megaloblastic anemia, dementia, psychosis, paranoia, fatigue, agitation, dementia, delirium

↑ = increase in lab value, ↓ = decrease in lab value

Table 36-2: Detection of Drugs in Serum and Urine Agent

Serum

Urine

Alcohol

1–2 days

1 day

Amphetamine

Variable

1–2 days

Barbiturate

Variable

3 days–3 weeks

Cocaine

Brief

2-3 days

Propoxyphene

8–34 hrs

1–2 days

Buprenorphine

—

3–10 days

Codeine, Morphine, Heroin

Variable

1–2 days

Methadone

15–29 hrs

3–10 days

Benzodiazepine

Variable

2–3 days

Delta-9-THC

—

~30 days

Phencyclidine

—

8 days

Adapted from Roffman JL, Silverman BC, Stern TA: Diagnostic rating scales and laboratory tests. In: Stern TA, Fricchione GL, Cassem NH, et al, eds: Massachusetts General Hospital Handbook of General Hospital Psychiatry , 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: p. 66.

Table 36-3: Neuroendocrine Tests Associated with Psychiatric Manifestations Test

Pertinent Findings

Adrenocorticotropic hormone (ACTH)

Increased in Cushing’s disease, primary adrenal insufficiency, stress response, steroid use Decreased in secondary adrenal insufficiency

Catecholamines (urinary and plasma)

Increased in pheochromoctyoma

Cortisol

Increased in Cushing’s disease Decreased in adrenal insufficiency

continues Estrogen

Decreased in menopause and pre-menstrual syndrome (may be associated with depression)

Follicle-stimulating hormone (FSH)

Increased in post-menopausal women Decreased in panhypopituitarism

Gonadotropin–releasing hormone (GnRH)

Decreased in schizophrenia; variable in depression and anxiety

Growth hormone

Variable association with schizophrenia and depression

Luteinizing hormone (LH)

Decreased with panhypopituitarism; associated with depression

Parathyroid hormone

Decrease associated with anxiety Dysregulation associated with cognitive deficits

Prolactin

Increased with antipsychotic use, cocaine withdrawal, acute seizure, prolactinoma

Testosterone

Increased with anabolic steroid use Decrease contributes to decreased libido, impotence

Thyroid-stimulating hormone

Increased in hypothyroidism (lithium therapy) Decreased in hyperthyroidism

Thyroxine (T4)

Increased in hyperthyroidism Decreased in hypothyroidism (lithium therapy)

Adapted from Smith FA: Laboratory tests and diagnostic procedures. In: Stern TA, Rosenbaum JF, Fava M, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . Philadephia, PA: Mosby Elsevier; 2008: p 34.

Table 36-4: Serological Studies and Psychiatric Manifestations

Test

Pertinent Findings

Antinuclear antibody

Positive in SLE and drug-induced lupus—associated with depression, delirium, and psychosis

Epstein-Barr Virus (EBV) (Monospot)

Causative agent for mononucleosis—can manifest with symptoms of depression, fatigue

Erythrocyte sedimentation rate Elevated in infection, autoimmune, or malignant disease (ESR) Hepatitis B surface antigen, hepatitis B core antigen

Active hepatitis B infection linked with depressive symptoms

Hepatitis C antibody (screening)/HCV RNA (confirmatory)

Chronic infection associated with neurocognitive deficits

Human immunodeficiency virus antibody/HIV viral load

Acute infection can present with mood or psychotic symptoms. CNS involvement may cause delirium, dementia, mood and psychotic symptoms, and personality change.

Venereal Disease Research Laboratory (VDRL), RPR

High titers in syphilis (CNS involvement with tertiary syphilis)

Adapted from Smith FA: Laboratory tests and diagnostic procedures. In: Stern TA, Rosenbaum JF, Fava M, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . Philadephia, PA: Mosby Elsevier; 2008: p 36.

Table 36-5: Laboratory Work-Up of Selected Toxins Agent

Source

Manifestation

Test

Carbon monoxide

Generators, faulty heating systems, mining

Cherry-red skin, headache, irritability, confusion Hypoxic injury to brain, liver, renal tubules

Carboxyhemoglobin level

Methanol

Solvents, antifreeze

Intoxication, blindness, anion gap acidosis

Serum toxicology, arterial blood gas, electrolytes, CBC

Lead

Paint, pipes

Encephalopathy, apathy, ataxia, irritability, cognitive Urine heavy metals, serum dysfunction, abdominal pain level (> 200 mg/mL severe encephalopathy)

Mercury

Industrial contamination, fish

Psychosis, fatigue, apathy, memory dysfunction, emotional lability, tremor Personality changes with chronic poisoning

Urine heavy metals

Manganese Ore refineries, brick working, steel castings

“Manganese madness” (emotional lability, pathological laughter hallucinations, aggression), Parkinsonism

Urine heavy metals

Arsenic

Fatigue, blackouts, hair loss, renal and hepatic dysfunction, encephalopathy

Urine heavy metals

Mining, insecticides, silicon-based computer chips

Adapted from Smith FA: Laboratory tests and diagnostic procedures. In: Stern TA, Rosenbaum JF, Fava M, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . Philadephia, PA: Mosby Elsevier; 2008: p 41.

Beyond the initial routine screening, any further studies should be based on the specific clinical situation. In patients with a history of high-risk behaviors, HIV and HCV infection should be assessed. A history of significant weight loss might indicate an occult malignancy or infection and might require further evaluation. In a malnourished patient, a nutritional assessment, including the level of vitamins and minerals, should be obtained. Patients with an eating disorder might demonstrate a decreased erythrocyte sedimentation rate (ESR) in anorexia, an increased aldolase in bulimia, or a positive phenolphthalein assay in stool or urine for laxative abuse. The list of studies of possible relevance to a psychiatric presentation is long.

Specific Testing Psychosis and Delirium The initial presentation of psychosis or delirium warrants a full and systematic medical and neurological work-up. Multiple causes of psychosis must be ruledout, including CNS lesions, CNS infections, seizure disorders, toxic effects of drugs, alcohol withdrawal, and metabolic or endocrine abnormalities. The potential morbidity (or mortality) associated with these conditions makes prompt diagnosis crucial. An inclusive yet tailored approach begins with a detailed history, a review of systems, as well as physical and MSEs. Based on the presence of specific findings, the clinician would then choose appropriate diagnostic tests (in addition to the screening battery already discussed) to help confirm or refute particular diagnoses in the differential. For example, tachycardia and agitation with auditory and visual hallucinations as well as diaphoresis and tremor is suggestive of delirium tremens associated with alcohol withdrawal. The astute clinician would treat the withdrawal, look for other physical findings suggestive of cirrhosis (e.g., spider nevi, palmar erythema, abdominal distention), and order appropriate diagnostic tests, including serum and urine toxicologies, LFTs, a prothrombin time (PT)/international normalized ratio (INR), a serum ammonia level, and possibly abdominal imaging. For instances in which neurologic findings are present, neuroimaging is warranted. Of note, many experts would suggest that neuroimaging is warranted in any case of new-onset psychosis or acute mental status change without a clear cause. An EEG can also be useful if seizures or a toxic metabolic encephalopathy are in the differential. A lumbar puncture (LP) is indicated in a patient who presents with mental status changes in conjunction with high fever, neck stiffness, headache,

or photophobia; intracranial lesions or increased intracerebral pressure must be ruled-out prior to performing the LP. A history of risky sexual behavior or IV drug use (IVDU) should prompt consideration of HIV and hepatitis C testing. Myriad other tests can be useful (Table 36-6) and should be based on presenting symptoms and clinical suspicion. Table 36-6: Approach to the Evaluation of Psychosis and Delirium Screening tests CBC Serum chemistry panel Liver function tests Toxicology (urine and serum) Urine or serum beta-HcG TSH Syphilis serologies Further laboratory tests based on clinical suspicion Vitamin B12 level Folate level Calcium Phosphorus Magnesium Ammonia Ceruloplasmin Urinalysis Blood or urine cultures HIV test ESR Serum heavy metals Paraneoplastic studies

Diagnostic studies based on clinical suspicion Lumbar puncture (cell count, appearance, opening pressure, Gram’s stain, culture, specialized markers) EEG EKG

Chest X-ray Arterial blood gas Neuroimaging CT MRI PET scan Adapted from Smith FA, Hogan C: Laboratory tests and diagnostic procedures. In: Stern TA, Rosenbaum JF, Fava M, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadephia, PA: Mosby Elsevier; 2016: Box 3-2.

Mood Disorders Depression is a common psychiatric symptom . Although it is often a primary psychiatric symptom, depression can also be associated with a number of medical conditions. Clinical findings indicative of thyroid dysfunction, folate deficiency, Addison’s or Cushing’s disease, pituitary adenoma, systemic lupus erythematosus (SLE), neurodegenerative disorders, anemia, or certain cancers (especially pancreatic) should guide further diagnostic testing. Symptoms consistent with new-onset mania merit a full work-up along the lines of psychosis and delirium that were previously discussed.

Anxiety Anxiety can be associated with a wide range of organic etiologies, as well. Underlying medical conditions that can account for anxiety symptoms include: seizure disorders; post-concussive syndrome; thyroid dysfunction; parathyroid dysfunction; hyperadrenocortisolism; hypoglycemia; pheochromocytoma; drug effects; alcohol or barbiturate withdrawal; cardiac disease (myocardial infarction, tachyarrhythmias); respiratory compromise (e.g., chronic obstructive pulmonary disease [COPD]); menopause; and porphyria. To rule-out these organic causes, work-up can include pertinent laboratory testing, serum glucose or glucose tolerance testing, endocrine testing, a cardiac work-up, pulmonary function tests (PFTs), a chest X-ray, a urine vanillylmandelic acid (VMA), urine porphyrins, and an EEG.

Special Populations Pediatrics

When psychiatric problems occur in children, they are often secondary to an organic etiology. For instance, a change in mental status can occur from an infection, injury, or exposure to toxins (e.g., heavy metals). CNS infection can be ruled-out by LP and by CSF analysis (including culture, fungal, and viral studies). If there is a question of head injury, CT or MRI scans can be crucial to obtain. Toxic exposures can be assessed through laboratory examination.

Geriatrics In the elderly , there is an increased likelihood of having an underlying or concomitant medical condition. As a result, it is important to recognize that one (or more) organic causes may underlie psychiatric symptoms. Similar to the assessment of younger patients, there is no consensus as to which studies to obtain. Because there is a higher likelihood of co-morbid medical illness and delirium in the elderly, diagnostic studies that might be particularly useful in this population (in addition to the screening battery) include: a urinalysis; chest Xray; serum B12 level; and an EKG. As with all other populations, further testing is based on presenting symptoms and examination. Because anemia, thyroid dysfunction, and neurocognitive disorder are more common among the elderly, testing for these conditions will be described in further detail. Anemia is common in elderly patients and it can lead to symptoms of weakness, fatigue, depression, lack of motivation, agitation, or confusion. Although a CBC will document the hemoglobin and hematocrit, other studies aid in the diagnosis of the anemia. Anemias can be microcytic, normocytic, or macrocytic. Microcytic anemias may be caused by iron deficiency and further work-up of this condition includes serum iron studies as well as fecal occult blood studies. Macrocytic anemias can result from B12 or folate deficiency. Serum B12 or folate levels or erythrocyte folate levels, which are more accurate, can help with diagnosis. Normocytic anemias can be associated with either increased destruction or decreased production of red blood cells (RBCs) (e.g., chronic disease, renal problems, or endocrine disorders). Other useful tests include studies of RBC morphology, a Coombs test (to assess hemolytic anemia), and endoscopy or colonoscopy (to identify sites of blood loss). Thyroid disease is also common (especially in the elderly, and can be atypical in presentation). TSH is first checked as a screening measure; if abnormal, additional thyroid function tests (TFTs) are then performed. Major neurocognitive disorder (NCD, i.e., dementia) is characterized by a chronic and lasting decline in memory and cognition. Although not a normal or

inevitable effect of aging, major NCD in the elderly is common and has multiple etiologies; specific causes of NCD often have a characteristic presentation. Although a careful history and physical is the best diagnostic test for dementia, in addition, a CBC, serum chemistries, TFTs, a screening test for syphilis, as well as B12 and folate levels are recommended. If clinically indicated, further testing could include a CT scan, an EEG, a MRI scan, and an LP. A chest X-ray, carotid studies, HIV testing, immunologic screens, and screens for toxins/medications can also be useful.

Substance Abuse Substance use (intoxication, overdose, and withdrawal) is a major cause of mental status changes. Because a patient’s history is not often clear in these cases, is important to obtain objective data regarding substance use. Commonly, serum and urine are tested for substances (Table 36-2). Alcohol is also routinely checked through breath analysis (breathalyzer). Other methods, such as hair or saliva analysis, have also been developed, but are less routinely used in clinical practice. Chronic alcohol use can cause liver injury, resulting in increased liver transaminases (ALT, AST, GGT) as well as decreases in serum protein/albumin levels and an increased PT/INR. A macrocytic anemia might develop from decreased folate levels. In advanced alcohol dependence, a global decrease in the mass of the cortex and cerebellum often results, and can be noted on head imaging studies. Clinical correlation can include Wernicke’s encephalopathy and Korsakoff’s amnestic syndrome. With regard to alcohol withdrawal, blood alcohol concentration (BAC) levels do not necessarily correspond to severity or timing of withdrawal symptoms because of tolerance variation by individual.

Neuroimaging Neuroimaging in psychiatry is used to narrow the differential diagnosis and to determine the prognosis of patients with neuropsychiatric disorders. It is a noninvasive and powerful tool helpful to assess brain structures and function. Contemporary neuroimaging modalities include structural and functional neuroimaging.

Structural Neuroimaging A CT scan uses X-ray beams like regular X-rays to determine the attenuation when passing through different densities of the organ systems. Detectors are arranged in a ring-like fashion with the patient in the center so those beams from different angles penetrate the different organs of the patient; the detectors

generate images. During the process, the patient is advanced through the gantry of the scan after each slice (tomogram) is completed. When the films are completed, high attenuation (bone) appears white, low attenuation (gas) appears black, intermediate attenuation (soft tissue) appears in shades of gray. When contrast material is used, it travels intravascularly and leaks out where the blood–brain barrier (BBB) is compromised. Approximately 5% of patients have an allergic reaction to contrast—a careful allergy history should be completed before ordering a contrast CT. Because chemotoxic reactions with contrast material may also cause renal insufficiency or failure, a serum creatinine should be measured prior to contrast administration to help weigh the risks versus benefits of the test. Contrast enhancement occurs in CNS pathology (such as tumors, bleeding, infection, inflammation, metastasis, and abscess). CT is particularly useful for visualizing acute bleeds, but it does not show subtle white matter or posterior fossa lesions well. It is contraindicated in pregnancy (women of childbearing age should undergo a pregnancy test before having a CT scan). CT is often cheaper and more available than MRI. MRI uses the magnetic properties of the water molecules of the body. In the magnetic field of the MRI scan, hydrogen atoms in water molecules align themselves as dipoles with or against the magnetic field. When the radio frequency is applied, some of the dipoles will absorb the radio frequency energy and align against the magnetic field (high-energy dipoles). When the radio frequency is turned off, they will return to the lower energy state where they are aligned with the magnetic field. This emission of energy (dipoles from highenergy alignment against the magnetic field to low-energy alignment with the magnetic field) is detected with a coil, and a MRI scanner measures the signal. Images are constructed by applying magnetic field gradients during the radio frequency irradiation. MRI images are obtained by using different acquisition parameters referred to as T1-weight and T2-weight. T1-weight images represent neuroanatomy clearly, whereas T2-weight images highlight areas of pathology. On T2-weighted images, regions with extravasated blood appear dark due to the para-magnetic effects of iron, and areas with tumor, plaques, and edema appear light due to increased water content. Ischemia is best seen by the technique known as diffusion-weighted imaging (DWI), which tracks the movement of water in tissue. As in CT scanning, contrast material can be used to highlight areas of a compromised BBB. Gadolidium (the contrast used in MRI) is generally safer than CT contrast, although it, too, can be associated with nephrotoxicity,

particularly in at-risk patients. MRI is contraindicated in patients with metallic implants because the large magnet can heat them and induce burns. It is safer in pregnancy (though still only advised in emergency situations). MRI takes longer and is more difficult to tolerate for those with claustrophobia.

Indications for Structural Neuroimaging Decisions about when to obtain structural imaging need to be made on a caseby-case basis after a thorough evaluation of the patient. Although there is no consensus on the matter, there are a number of situations that merit neuroimaging studies to decrease the possibility of missing a brain lesion associated with a treatable general medical condition. These include acute onset mental status changes with neurologic abnormalities, significant head trauma, or for those who are 50 years of age and older. As previously described, neuroimaging should also be considered with new-onset psychosis or delirium of unclear etiology. Finally, neuroimaging is also indicated prior to initiation of electroconvulsive therapy (ECT) to rule-out a space occupying lesion.

Functional Neuroimaging Functional neuroimaging modalities— positron emission tomography (PET ), single-photon emission computed tomography (SPECT ), and functional MRI (fMRI)—can demonstrate neuronal activity, cellular metabolism, and neuroreceptor profiles with the use of radioactive substances (tracers), which are given intravenously or via inhalation. The tracer arrives in the CNS and is distributed according to the regional blood flow, glucose metabolism, and receptor metabolism. It emits a signal that is detected by the scanner and either blood flow or metabolism is recorded by tomographic imaging. PET scanning requires an on-site cyclotron to prepare the positron emitter tracers, which have a short half-life. It uses fluoro-deoxyglucose to assess glucose metabolism, oxygen-15 to assess brain blood flow, and specific radioligands to assess receptors for specific neurotransmitters. SPECT scans use single photon-emitting nuclides rather than positron-emitting nuclides. PET’s resolution is greater and more uniform when compared to SPECT, but it is much more expensive. The use of fMRI is generally limited to research. It relies on the magnetic distortions produced by deoxygenated hemoglobin (the amount of which decreases as cerebral blood flow increases, in response to increased demand), allowing the comparison of baseline to active states, and identification of localized areas of cortical activity involved in specific cognitive tasks. Although these modalities are often used for research purposes in psychiatry,

clinical roles have become more common (especially at larger centers). For example, functional neuroimaging has been shown to be both sensitive and specific in differentiating major neurocognitive disorders. PET also has a role in diagnosing and localizing seizure activity (especially deep activity that often goes undiagnosed by the EEG). In this regard PET offers the advantage of measuring both ictal and inter-ictal activity rather than only relying on catching the patient during an episode of ictal activity.

EEG The EEG records low-voltage electrical activity of the brain. In organic brain disease, there are changes in this electrical activity and the EEG is helpful in the diagnosis and differential diagnosis of these disorders. The frequency of the electrical activity is measured in hertz (Hz), a measure of cycles per second. These frequencies are named with Greek letters: delta (0–4 Hz), theta (4–7 Hz), alpha (8–12 Hz), and beta (>12 Hz). Alpha waves are the predominant form while awake. Normal sleep is divided into stage 1 (alpha and beta), stage 2 (theta and delta), stages 3 and 4 (delta activity) and rapid eye movement (REM) sleep. The EEG is often used to diagnose seizure activity. The most common epileptiform discharges are spikes and sharp waves. When testing for seizures, several methods (e.g., sleep deprivation, hyperventilation, photic stimulation) can activate a seizure focus. Serial studies, long-term monitoring (LTM), and/or the placement of nasopharyngeal (deep) leads can also increase the yield. The EEG shows characteristic patterns in different types of seizures (e.g., complex partial, absence, generalized), and can also aid in the diagnosis of delirium, medication toxicity, or mental status change due to a neurodegenerative disorder. An EEG can help to distinguish seizures from pseudoseizures; however, it is not diagnostic in this regard, because a single EEG can miss true seizure activity in up to 40% of cases.

Monitoring Psychotropic Medications Antidepressants There are no established guidelines for monitoring levels of antidepressants . In the treatment of the medically ill, physicians should consider side effects of the antidepressants as well as the effects of the illness on the metabolism of psychotropics. In patients with liver disease, the antidepressant dosage needs to be carefully adjusted and LFTs need to be monitored for the possibility of increased LFTs induced by the psychotropic. In patients with substantial risk

factors for developing torsades de pointes (including cardiac disease, family history of sudden death, and other QT-prolonging medications), an EKG, potassium, and magnesium should be checked prior to initiating citalopram. Use of tricyclic antidepressants (TCAs) in a cardiac patient needs to be monitored closely (EKGs and levels of TCAs should be checked at base-line and during ongoing care) due to their effects on cardiac conduction (e.g., PR, QRS, QTc prolongation), which can lead to deadly arrhythmias. Blood levels of TCAs are monitored in patients with problems with adherence, a poor response while taking a therapeutic dose for a reasonable time, older age, medical illness, and serious depression with concern for suicidal ideation.

Mood Stabilizers Lithium Lithium is commonly used in patients with mood disorders, and it affects many organ systems (including the kidneys, thyroid, heart, and the CNS). Serum electrolytes, blood urea nitrogen (BUN), creatinine, TFTs, and an EKG should be checked routinely. Additionally, in patients with kidney problems, assessment of 24-hour urine test for creatinine and protein clearance is recommended. Steady states are reached in 4 to 5 days. Because lithium has a narrow therapeutic range (generally 0.6–1.0 mEq/L), levels should be checked routinely and urgently if signs of lithium toxicity develop.

Carbamazepine Carbamazepine affects mainly the liver, the hemopoietic system, and the cardiac conduction systems. A fatal side effect is agranulocytosis. Therefore, it is important to include a CBC before the initiation of treatment, every two weeks for the first two months, and thereafter, once every three months. Platelet count, reticulocyte count, serum electrolytes, EKG, liver function tests (AST, ALT, LDH, alkaline phosphatase) need to be checked before and after one year of the initiation of treatment. Females of child-bearing age must have a pregnancy test before initiation due to carbamazepine’s teratogenicity. Discontinuation is recommended when the white blood cell (WBC) count is less than 3,000/mm3 , the hemoglobin is less than 11mg/dl, the platelet count is less than 100,000/mm3 , and the reticulocyte count is less than 0.3%.

Valproic Acid

Valproic acid mainly affects the liver, but it can also affect the hemopoietic system and the pancreas. Initial tests include a CBC with a differential, LFTs, and pregnancy test. These should be checked at regular intervals (along with a valproic acid level) during dose escalation and then less frequently (in the absence of side effects) after a stable dose is achieved. Therapeutic blood level range is 50 to 100 mEq/L.

Antipsychotics The only antipsychotic that requires close laboratory monitoring is clozapine because of the possibility of agranulocytosis in 1% of the patients taking this medication. Baseline and subsequent absolute neutrophil counts (ANC), checked at regular intervals, are mandatory when prescribing this medication. If mild neutropenia (ANC 1,000–1,499 cells/µL) develops, the patient needs to be monitored closely and ANCs should to be checked three times a week until the ANC reaches 1,500 cells/µL. In case of moderate neutropenia (ANC 500–999 cells/µL), the treatment must be interrupted and the ANC should be checked daily until it reaches 1,000 cells/µL. This is followed by three-times-weekly ANC checks until a level of 1,500 cells/µL is reached. Hematology consultation is also recommended. Clozapine therapy can be continued after normalization of the blood count. Finally, if severe neutropenia develops (ANC < 500 cells/µL), the same precautions are taken and clozapine can be resumed only after a careful risk-benefit analysis. Use of other bone-marrow suppressants should be avoided. Additionally, an EEG can be helpful if the dosage of the clozapine needs to be raised beyond 600 mg because of an increased incidence of seizures. For patients taking any antipsychotic, if they have cardiac disease or risk factors for developing QTc prolongation or torsades de pointes, an EKG should be performed due to the risk of serious cardiac conduction disturbances.

Conclusion Although the mainstay of psychiatric diagnosis consists of a careful interview, MSE, review of systems, and targeted physical examination, diagnostic modalities and laboratory tests are important adjuncts. These studies can help diagnose medical and neurological diseases that present with psychiatric manifestations and assist in the monitoring of disease progression and medication use. Populations at high risk for medical co-morbidity or medication side effects (such as the elderly, the chronically ill, the indigent and patients who use substances) can benefit in particular. This chapter has provided a framework

by which to order particular tests to help clarify diagnosis and management. Subsequent chapters will provide additional information with regard to specific illnesses.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Anfinson TJ, Kathol RG: Screening laboratory evaluation in psychiatric patients: a review. Gen Hosp Psychiatry . 1992;14: 248–257. 3. Badrakalimuthu VR, Swamiraju R, de Waal H: EEG in psychiatric practice: to do or not to do? BJPsych advances . 2011; 17: 114–121. 4. Beach SR, Celano CM, Noseworthy PA, et al: QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics . 2013; 54: 1–3. 5. Beck BJ: Mental disorders due to a general medical condition. In Stern TA, Herman JB, Gorrindo TL, editors: Massachusetts General Hospital Psychiatry Update and Board Preparation . 3rd ed. Boston: MGH Psychiatry Academy Publishing; 2012: pp. 73–84. 6. Becker AE, Thomas JJ, Russell KS, et al: Patients with an eating disorder. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: pp. 189–210. 7. Bierer MF, Bierer BE: Psychiatric Symptoms of Medical Illness and Drug Toxicity. In: Hyman SE, Tesar GE, eds.: Manual of Psychiatric Emergencies . 3rd ed., Boston: Little, Brown and Company; 1994. 8. Chopra S, Terrault N: Screening for chronic hepatitis C virus infection. In: UpToDate ®; 2016. 9. Dougherty DD, Rauch SL, Luther K: Use of neuroimaging techniques. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw-Hill; 2004: pp. 61–66 and pp. 257–262. 10. Falk W: Approach to the patient with memory problems or dementia. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital

11.

12.

13.

14. 15.

16.

17.

18.

19.

Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw-Hill; 2004: pp. 197–212. Gastfriend DR, O’Connell JJ: Approach to the cocaine or opiate-abusing patient. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 2nd ed. New York: McGrawHill; 2004: pp. 513–519. Huffman JC, Brennan MM, Smith FA, Stern TA: Patients with neurologic conditions I. Seizure disorders (including non-epileptic seizures), cerebrovascular disease, and traumatic brain injury. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: pp. 237–254. Hurley, RA, Hayman, LA, Fisher RE, et al: Clinical and functional imaging in neuropsychiatry. In: Yudofsky SC, Hales RE, eds.: The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences . 5th ed. Washington, DC: American Psychiatric Publishing, Inc; 2008. Kolman PBR: The value of laboratory investigations of elderly psychiatric patients. J Clin Psychiatry . 1984; 45: 112–116. Peebles T, Haughton VM: Neuroradiology and endocrine disease. In: Besser MG, Thorner MO, eds.: Comprehensive Clinical Endocrinology . 3rd ed. Elsevier Science Limited, CD-ROM, 2002. Pollack MH, Smoller JW, Lee DK: Approach to the anxious patient. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw-Hill; 2004: pp. 137–152. Powell A, Heckers, S, Bierer M. Approach to the patient with hallucinations and delusions. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw-Hill; 2004: pp. 157–164. Roffman JL, Silverman BC, Stern TA: Diagnostic rating scales and laboratory tests. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: pp. 61–72. Rose TA, Choi JW: Intravenous imaging contrast media complications: the

basics that every clinician needs to know. American J Med . 2015; 128: 943–949. 20. Rosenbaum JF, Fava M: Approach to the patient with depression. In: Stern TA, Herman JB, Slavin PL, eds.: Massachusetts General Hospital Guide to Primary Care Psychiatry . 6th ed. New York: McGraw-Hill; 2004: pp. 111– 125. 21. Rosse RB, Deutsch LH, Deutsch SI. Medical assessment and laboratory testing in psychiatry. In: Kaplan HI and Sadock BJ, eds.: Comprehensive Textbook of Psychiatry . 9th ed. Baltimore, MD: Williams and Wilkins; 2009. 22. Sachs GS, Dupuy JM, Wittmann CW: The pharmacologic treatment of bipolar disorder. The J Clin Psychiatry . 2011; 72: 1–478. 23. Sadock BJ, Sadock VA: Kaplan & Sadock’s Synopsis of Psychiatry . 11th ed. Philadelphia, PA: Lipincott Williams & Wilkins; 2014. 24. Sax PE: Acute and early HIV infection: Clinical manifestations and diagnosis. In: UpToDate ® ; 2016. 25. Smith FA: An approach to the use of laboratory tests. In: Stern TA, ed.: The Ten-Minute Guide to Psychiatric Diagnosis and Treatment . New York: Professional Publishing Group, Ltd; 2005: pp, 318–373. 26. Smith FA, Hogan C: Laboratory tests and diagnostic procedures. In: Stern TA, Rosenbaum JF, Fava M, et al, eds., Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadephia, PA: Mosby Elsevier, 2016; pp. 20–38. 27. Smith FA, Querques J, Levenson JL, et al: Psychiatric assessment and consultation. In: Levenson JL, editor: The American Psychiatric Publishing Textbook of Psychosomatic Medicine . 2nd ed. Washington, DC: American Psychiatric Publishing; 2011. 28. Stahl SM: Antidepressants. In: Essential Psychopharmacology, Neuroscientific Basis and Practical Applications . 4th ed. New York: Cambridge University Press; 2013.

Neurologic Disorders

S E C T I O N T H R E E

CHAPTER Functional Neuroanatomy 37 NICHOLAS KONTOS, MD AND JOAN CAMPRODON, MD, MPH, PHD

KEY POINTS Overview Knowledge of brain–behavior relationships is critical to the evaluation of the demonstrably “organic” conditions that comprise neuropsychiatry and behavioral neurology. As the field progressively incorporates localized, circuit-based, and network models of neuroanatomy, this knowledge might finally be en route to being part of the general psychiatrist’s day-to-day life. Theoretical Basis Among the billions of neurons and synapses in the brain, a relatively small number of structures form the epicenters, hubs, and notes that are critical to human behavior. Object identification, visuospatial functioning, language, executive function/comportment, and memory/emotion are the bluntest groupings of this behavior. Clinical Applications For syndromes with demonstrable lesions, knowledge of functional neuroanatomy directly informs evaluation and management. For idiopathic psychopathology, this knowledge informs scientific inquiry, clinical hypothesizing, and neuromodulation interventions.

Overview

It has been said that the human brain is the most complex object in the known universe. Any attempt to encapsulate its structure and function(s) cannot help but be an oversimplification. This chapter summarizes some anatomic principles and “facts” underlying several critical functions that the brain is set up to perform. The approach we take is that of behavioral neurology and clinical neuropsychiatry. More complex circuitry and networks are believed to underlie much of human behavior and psychopathology (see the chapters on individual psychiatric disorders for details). Here we focus on a general framework that informs not only board preparation, but also the discernment and understanding of demonstrably “organic” psychiatric disorders.

Neuropsychological Functional Systems Mesulam suggested that the processes underlying complex human behavior can be categorized into five basic (but overlapping) domains that have neuroanatomic correlates. As we will soon see, two of these categories are sufficiently vague that this statement ends up being less reductionist than it might initially seem. Object identification is just what it sounds like. Purposeful behavior requires that the organism executing it be able to identify those elements of the environment to which it must respond. This identification occurs at various levels of elaboration from category, to type, to specific exemplar. For example, we might recognize a four-legged, cushioned, upright object as a piece of furniture, as a chair, or as our own television-viewing recliner. Visuospatial functioning involves abilities to attend to and manipulate our environment based on characteristics such as distance, size, and directionality. Appreciation and execution in this neuropsychological domain apply not just to the external environment, but also to our own body, as with the organization of motor acts, like combing a child’s hair or driving a car. A more complex and evolutionarily-advanced function, language involves the ability to communicate using symbols. Clinically, these symbols are generally words. Comprehension and expression are partially dissociable aspects of the tasks of decoding and using these symbols, respectively. Executive function and comportment cover a lot of neuropsychological territory. Akin to what most people consider “thinking,” executive function informs organized behavior, and involves planning, sequencing, inhibiting distractors, monitoring errors, and purposeful shifting and sustaining of one’s cognitive focus. All of these are components of response selection. The balance between

this kind of deliberation and more automatic decisions based on visceral drives, conditioning and other sources of motivation, determines one’s comportment, or bearing. The topics of memory and emotion could each occupy volumes. That they mutually inform each other might explain their overlapping anatomy (see the section that follows). Their wide-spanning qualities and definitions might explain why that anatomy turns out to be the least “focal” of all the aforementioned functions.

Cortical Anatomy Principles Grossly , the human brain is composed of the cortex (with regions ranging from being unlayered to a six-layered cellular architecture depending upon one’s definitions/schema), white matter, sub-cortical nuclei, and the cerebrospinal fluid-filled ventricular system. The cerebral cortex can be conceptualized cytoarchitectonically (e.g., Brodmann’s areas), macroanatomically (e.g., lobes, gyri, sulci), or functionally (e.g., Broca’s area). The cortical organization of complex human behavior blends all three. Unlike the “focality” of the traditional neurological examination, the neuropsychological functions mentioned earlier are distributed across brain networks. They each utilize many, far-flung, densely interconnected brain regions, but information flow to, and from, these regions coalesces at functionally specific and critical epicenters (more complex network neuroscience also identifies densely interconnected hubs and nodes ). By way of explanation and example, the recognition of a particular person’s face requires that information get from the retina to the primary visual cortex (via the optic tracts and lateral geniculate nuclei) in the occipital poles, then to the facial recognition area in the ventral temporal lobe (fusiform gyrus). However, to be struck blind does not eliminate the ability to recognize familiar people, and auditory input traveling from the cochlea to the primary auditory cortex (via the medial geniculate body) in the superior temporal lobe will eventually reach lateral temporal areas co-segregated with the facial recognition area, allowing recognition based on voice. In this example, note that particular parts of the cortex receive information from sensory organs and pass that information along for processing en route to integrating areas. The receiving areas are referred to as primary sensory cortices;

these include the occipital pole (visual), Heschel’s gyrus in the superior temporal lobe (auditory), and the post-central gyrus (somatosensory). Adjacent to each of these primary areas we find unimodal association cortices that integrate sensory information from independent sensory qualities (e.g., groups of lines with different angles and colors) into complex forms (e.g., a face) that can be accessed and manipulated for conscious perception. Unimodal areas are also thought to be recruited in recall and imagining. Thus, perception, memory, and imagination involving similar information are thought to involve overlapping brain areas. This observation has been employed in explanations of psychiatric phenomena (such as hallucinations and “false memory”). In contrast to primary and unimodal cortices that predominantly process information of single sensory modalities, multi-modal areas process information from multiple modalities. The uni-directional, serial elaboration of information portrayed in this section is a colossal over-simplification of processes that also occur in parallel/converging/diverging pathways, entail modulatory bidirectional feedback, and “skip” processing steps. All of the neuropsychological functions described earlier require multi-modal processing and have their epicenters in multi-modal regions of cortex. Multi-modal regions in the parietal and lateral temporal lobe play important roles in the symptomatologies of some dementing illnesses. We now turn our attention to two specific multi-modal areas and some of their psychopathological implications.

Prefrontal Cortex and Its Sub-Divisions The frontal lobes are bounded posteriorly by the central sulcus, anterior to which lie the vertically-oriented primary and association motor cortices, successively. Prefrontal cortex (PFC ) refers to all areas in the frontal lobe anterior to the motor association cortex. The PFC is most broadly sub-divided into three regions that have important cognitive and behavioral affiliations.

Dorsolateral Prefrontal Cortex The dorsolateral prefrontal cortex (DLPFC ) occupies the convexities of the PFC (and, functionally, extends a bit medially and inferiorly). Portions of this large area comprise the main epicenter for executive functioning as well as subserve aspects of attention and working memory. Anatomic or functional lesions to this region are associated with deficits in problem-solving, sequencing and organizing, and sustaining attention or shifting it from one source of stimulation to another. The cognitive deficits of schizophrenia overlap significantly with this dysexecutive syndrome and correlate with impaired demand activation of the

DLPFC. Various patterns of so-called “hypofrontality” are also noted in attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), and several other forms of psychopathology, not to mention certain dementias. As more complex brain networks come to light, the idea of “hypofrontality” might fall by the wayside. Already, a more distributed “action selection system” that goes beyond executive functioning to involve motor programming, regulation, and calibration involves regions of the parietal lobe, basal ganglia (see section on sub-cortical structures later in this chapter), and cerebellum. Medial prefrontal cortex (MPFC ), particularly the anterior portion of the cingulate gyrus, is a major nexus between streams of externally-derived, cognitively-processed material and more visceral, emotionally-associated material. The anterior cingulate is conceptualized as an epicenter for assigning the motivational valence of behavior and its targets. Lesions in this region produce states of reduced initiation of behavior (i.e., abulia), which find their ultimate, almost absolute, expression in akinetic mutism, produced via bilateral anterior cingulate lesions. Dysfunction of the anterior cingulate has been implicated in mood disorders, and the sub-genual cingulate (that portion of the cingulate gyrus inferior to the genu of the corpus callossum, and part of the “visceral effector region”) is a major target of current work in the field of deepbrain stimulation for MDD. The inferior or orbitofrontal (prefrontal) cortex (OFC ), particularly its posterior and medial portions, is another nexus of internally and externallyderived material. Better known by its dysfunction—“disinhibition”—than its function, the OFC is an epicenter involved in the mediation of behavior based on social and environmental constraints. Lesions of the OFC have been associated with impaired extinguishing of un-reinforced or punished behavior; loss of empathy; pursuit of immediate internal needs/desires without regard to longterm goals/rewards; environmental constraints; and imitation and utilization behaviors. Hypoactivity of the OFC has been noted in studies of patients with primary sociopathy, whereas hyperactivity (synchronous with caudate activation [see the section on this later in this chapter]) is a classic finding of obsessivecompulsive disorder (OCD) that resolves with effective treatment, whether pharmacologic or cognitive-behavioral. Although clinically useful, the involvement/connectivity of the OFC (lateral and medial components) in the action selection and motivational systems, shows the limitations of a focal or modular brain–behavior framework. This comes to

light particularly in disorders such as addiction, which every day seems to be found to affect just about all of the “prefrontal” structures and functions.

Medial Temporal Structures The cingulate and OFC are structurally and functionally related to medial temporal areas often thought of as critical components of the limbic system. The amygdala , located in the anterior, medial portion of the temporal lobe, is a heterogeneous collection of nuclei that has been linked to human emotional processing/experience, with its strongest link being to fear. Like other limbic areas, the amygdala enjoys robust connections with both sensory cortex and areas (such as the hypothalamus) that regulate visceral responses. These connections as well as a complex modulatory relationship with the PFC might help explain findings that link the amygdala to various forms of conditioning, and thereby to syndromes, such as addiction, phobias, and post-traumatic stress disorder (PTSD). The so-called “extended amygdala” is co-extensive with the amygdala proper via the stria terminalis. This curved fiber bundle terminates inferior to the anterior commisure in the bed nucleus of the stria terminalis . The latter structure is one of several structures (also including ventral extensions of the basal ganglia [the ventral striatum ], the basal nucleus of Meynert, the diagonal band of Broca, and the substantia innominata) in the basal forebrain . The bed nucleus of the stria terminalis shares many of the amygdala’s efferent targets and might play a role in generalized anxiety disorder (GAD). Posterior to the amygdala and wrapped into the medial temporal lobe, the hippocampus is contiguous with the parahippocampal gyrus. The entorhinal cortex and subiculum are components of the parahippocampal gyrus, which, respectively, are major input and output areas for the hippocampus. The integral role of the hippocampus in anterograde declarative memory formation is long established, and anatomically, if not functionally, justifies its place in the wellknown Papez circuit. Further, the hippocampus is important in “place” memory or conditioning; functional and volumetric abnormalities in this brain region are found in PTSD and might account for the inappropriate generalization of the fear response that is a hallmark of that disorder.

Hemispheric Specialization When stating that in most individuals (including up to 70% of left-handers) the left hemisphere is “dominant,” it is important to bear in mind that this dominance is specific to language. Some other higher-order functions are, in

fact, “right dominant”; for example, visuospatial functioning. The predominant model of visuospatial processing explains that although both parietal lobes process visuospatial information from the right hemispace, only the right hemisphere processes information from the left hemispace; hence the finding of left hemi-neglect in patients with certain right parietal lesions. There is also evidence of hemispheric specialization along language-versus-visuospatial lines in other domains of cognition, such that PFC or hippocampal lesions can produce predominantly verbal or non-verbal dysexecutive or amnestic findings depending on lesion laterality. The role of the individual hemispheres in affective processing is an area of study and debate. One theory upholds that the right hemisphere is dominant for all emotion mediation; another that the right hemisphere selectively mediates negative emotions, whereas the left mediates positive emotion. Evidence supporting each theory can be found in studies of affective changes in patients with destructive (e.g., stroke) and activating (e.g., seizure) lesions, and the matter is far from settled. Interestingly, in patients with ordinary left-sided language dominance, prosody—the appreciation and expression of the nonverbal communication of affect—is noted to be localized in the right hemisphere in an anatomic pattern loosely analogous to that of Broca’s and Wernicke’s areas in the left hemisphere.

Sub-Cortical Structures and the Cerebellum The basal ganglia , including the caudate, putamen, nucleus accumbens (NAcc), globus pallidus (GP), and olfactory tubercle, are a set of sub-cortical paired nuclei that are psychiatrically most noteworthy as components of (frontal) cortical -striatal -thalamic -cortical loops (CSTCL; simplified in Figure 37-1). The caudate nucleus is involved in circuits originating and terminating in the DLPFC and the OFC, whereas the NAcc is the first stop/synapse in the circuit originating and terminating in the MPFC. The NAcc (along with the olfactory tubercle and parts of the caudate) is a component of the aforementioned ventral striatum , which extends inferiorly to the anterior commissure and it is considered to be part of the limbic system. This categorization is in keeping with its affiliation with the functions of the MPFC.

Figure 37-1: Schematic of the cortical-striatal-thalamic-cortical loops. The CSTCL, after synapsing in the caudate or nucleus accumbens, proceed to the GP and, depending on whether this synapse occurs in that nucleus’ internal or external subdivision, might make a detour through the sub-thalamic nucleus before returning to the GP. After a penultimate stop in either the ventral anterior or dorsomedial nucleus of the thalamus (depending on which CSTCL is involved), the loop is completed in the same region of the PFC from which it originated. Less important than memorizing the specific anatomy of each CSTCL is awareness of their general composition; that is, PFC, basal ganglia, thalamus, and intervening white matter. This appreciation informs logical explanations as to why lesions (structural or functional [i.e., pathological hyper- or

hypoactivation]) to any part of the loop can cause cognitive, behavioral, and/or affective deficits similar to those caused by lesions to the PFC itself. Hence, the “frontal” deficit profiles—apathy, disinhibition, dysexecutive functions—of patients with white matter disease (e.g., multiple sclerosis), sub-cortical dementias (e.g., from HIV infection, vascular dementia, Parkinson’s and Huntington’s diseases), and head trauma (e.g., with diffuse axonal injury). Another structure that can contribute to “frontal” deficits is the far-from-frontal cerebellum, located posterior to the brain stem and inferior to the occipital lobes. Long thought to be behaviorally irrelevant, extensive connections have been found between medial and lateral cerebellar regions and limbic and cognitive areas of cortex, respectively. Lesions to these cerebellar areas or their efferents have been associated with a cerebellar cognitive affective syndrome that might represent the thought and feeling analogues of motor ataxia.

Neurotransmitter Loci Neurotransmitter function is discussed extensively elsewhere in this text. Here, we will merely point out that some neurotransmitters are diffusely expressed and active, whereas others are locally expressed but diffusely active. For example, every synapse in every “closed” CSTCL is either glutamatergic (excitatory) or γ -amino butyric acid (GABA)-ergic (inhibitory); but the loops receive extensive modulatory neurotransmitter (especially dopaminergic) input from brain stem nuclei. The locally synthesized neurotransmitters are remarkable for their being made by only a few tens of thousands of the tens of billions of neurons in the brain. Table 37-1 outlines some loci of synthesis and action of the major neurotransmitters. Table 37-1: Anatomy of Neurotransmitter Systems Neurotransmitter Locus of Synthesis Dopamine

Ventral tegmental area (mesencephalon)—mesocortical pathway Ventral tegmental area (mesencephalon)—mesolimbic pathway Substantia nigra (mesencephalon)—nigrostriatal pathway Arcuate nucleus of the hypothalamus—tuberoinfundibular pathway

Norepinephrine

Locus ceruleus (pons)

Serotonin

Dorsal raphe (mid-line of brainstem)

Acetylcholine

Nucleus of Meynert (basal forebrain /substantia innominata)

GABA

Diffuse

Glutamate

Diffuse

From Brain Regions to Brain Circuits—A Final Word As alluded to several times earlier in this chapter, although traditional behavioral neuroanatomy has focused on the functional relevance of specific cortical and sub-cortical brain regions, it is now evident that other levels of biological resolution are also key to understanding neuropsychiatric pathophysiology and developing safe and effective treatments. Small molecules, structural and functional proteins, genes, cells (neurons and glia), synapses, brain regions, brain circuits, cognitive and behavioral functions, clinical signs and symptoms, syndromes, individual patients, population dynamics, cultural and spiritual factors are all inter-dependent and relevant to understand the complexities of healthy brain function and psychopathology. That said, it is at the level of the circuit that cognition, behavior, and affect are processed, and therefore this is a critical level of biological resolution for the clinician. Different models have defined a specific number of brain networks, like Alexander, DeLong, and Strick’s five frontal cortico-striatal-pallidal-thalamocortical loops. However, it is unlikely that one could list a fixed number of systems. Structural connections are fixed at a given time, but neurons and regions dynamically interact with one another using patterns of coherent physiological activity to establish functional networks that efficiently and adaptively process brain functions. This neurobiological paradigm has revolutionized the clinical neurosciences in the past 15 years, and has allowed the practical development of clinical tools that are changing clinical practice, such as neuromodulation therapies (see Chapter 51 ). A circuit-based approach to clinical interviewing, creating a differential diagnosis, and planning treatment may change the practice of Psychiatry and Neurology in the near future, integrating traditional syndromal approaches with dimensional clinical models of psychopathology and pathophysiology, and allowing a more direct translation from clinical observation to clinical neurobiology and associated treatments.

Suggested Reading 1. Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci . 1986; 9: 357–381. 2. Filley CM: Neurobehavioral Anatomy . 3rd ed. Boulder, CO: University

Press of Colorado; 2011. 3. Green RL, Ostrander RL: Neuroanatomy for Students of Behavioral Disorders . New York: WW Norton and Co; 2009. 4. Mesulam MM, ed.: Principles of Behavioral and Cognitive Neurology , 2nd . New York: Oxford University Press; 2000. 5. Pennington BF: Explaining Abnormal Behavior : A Cognitive Neuroscience Perspective . New York: The Guilford Press; 2014.

CHAPTER 38 The Neurologic Examination JOAN A. CAMPRODON, MD, MPH, PHD

KEY POINTS Overview This chapter summarizes the neuropsychiatric exam, including the “psychiatric mental status exam,” the cognitive bedside exam, and the traditional neurological exam. Specific examples are provided with instructions for each domain. Theoretical Basis The neuropsychiatric exam was developed between 1850 and 1930 because of the clinical correlation between exam findings and post-mortem pathological findings. Classification of Methodology Sub-types The psychiatric mental status exam includes assessment of appearance, attitude, speech, motor behavior, mood and affect, thought process, thought content, perceptions, insight and judgment. The cognitive bedside assessment should include evaluation of the patient’s level of consciousness, orientation, attention, memory, language, visuo–spatial function, and executive function. The neurological examination involves assessment of the cranial nerves as well as examination of motor and sensory function, coordination, gait, and reflexes. Indications and Clinical Applications The neuropsychiatric assessment is indicated in all clinical encounters, as the primary source of objective data leading to a differential diagnosis and treatment plan.

Overview

Most clinical encounters attempt to obtain subjective and objective data about relevant organ systems to facilitate an assessment that includes a differential diagnosis as well as a treatment plan. The clinical exam is the primary source of objective data, which can be supplemented as needed with further clinical tests. The psychiatric exam is geared toward the evaluation of disorders of affect, behavior, and cognition and the testing of these higher-order functions and the brain circuits that sustain them. Although these circuits are segregated, they are also densely interconnected. Therefore, it is common for a functional or structural lesion of one circuit to affect anatomically-related regions and their functions. In major depressive disorder (MDD), for example, changes in mood (e.g., sadness) that are processed in ventromedial frontal structures are accompanied by neurovegetative symptoms (e.g., anorexia, insomnia) localized in the hypothalamus as well as deficits in concentration that are sustained primarily by circuits involving the dorsolateral prefrontal cortex. The territories involved are discrete and segregated, but also inter-connected. Alternatively, a more localized macro-anatomical lesion, such as a frontal ventral meningioma, can also present with symptoms in different domains (e.g., olfaction, vision, impulse control). Given the dense inter-connectivity of brain circuits, the overlap of their anatomic boundaries, and the spatial resolution of certain pathological and iatrogenic processes, the clinician who assesses disorders of the central nervous system (CNS) should be comfortable examining different brain functions and symptom categories. A psychiatrist assessing a mood-related chief complaint also needs to examine behavior and cognition as well as motor, sensory, and coordination functions, within a general neuroanatomical, psychopathological, and pathophysiological framework. The neurologic examination does not need to be comprehensive in every patient. Although the medical student and junior resident should practice the full exam to become comfortable with its parts and the range of normal and pathological findings, clinicians need to select the components that are relevant to the case they are assessing. Examination of the snout reflex might be unnecessary (and perhaps off-putting) to the 20-year-old with a numb hand, but might be an important part of an evaluation of dementia or traumatic brain injury (TBI). A general screening exam of all functions is usually performed with more detailed assessment directed by the history, the positive findings in the exam, and the suspected pathophysiological mechanism.

Traditionally, the psychiatric and neurologic exams have been separated with some overlap in the testing of cognitive functions. For pedagogic reasons, we will keep this traditional structure and discuss in sequence the “psychiatric” mental status exam, followed by the bedside “cognitive exam” (also described in some sources as the “neurologic” mental status exam), and then finish with the “neurologic exam.” The main components of these evaluations are presented in Table 38-1. Comfort with these skills will ensure appropriate examination of affective, behavioral, cognitive, motor, sensory, and coordination functions and lead to a comprehensive assessment of CNS disorders; it will also guide appropriate work-up and creation of treatment plans.

Mental Status Exam The mental status examination (MSE) has historically been separated into “psychiatric” and “neurologic” components. Even though this division is somewhat arbitrary, the distinction is used here for convenience.

The “Psychiatric” MSE The psychiatric MSE assesses affect, behavior, and cognition at the time of the interview. Some of the descriptors are composite measures that reflect more than one function (e.g., appearance can reflect cognition and behavior). This is similar in the cognitive exam, for which most tests assess more than a single cognitive function (e.g., performing serial sevens tests attention and calculations). The MSE begins with observation (including appearance, attitude, speech, and [psycho] motor behavior) and is followed by a description of the emotional state (mood and affect), thought process and content, perceptions, and, finally, insight and judgment (Table 38-1). The psychiatric MSE was developed at a time when these functions did not map well to the neuroanatomy of behavior; these are descriptors that map better to syndromal diagnostic classifications (e.g., as listed in the Diagnostic and Statistical Manual of Mental Disorders [DSM] or the International Statistical Classification of Diseases and Related Health Problems [ICD]). Table 38-1: The Complete Neurologic Exam “Psychiatric” Mental Status Exam Observational assessment Appearance

Attitude toward examiner Speech Motor behavior Mood/affect Thought process/content Perceptual disturbances Insight and judgment Cognitive Exam or “Neurologic” Mental Status Exam Level of consciousness Orientation Attention Memory (verbal and non-verbal) Registration Recall Remote Language Fluency Comprehension Repetition Naming Reading/writing Visuo–spatial (constructional and attentional) Executive Abstraction Calculation Praxis Right-left orientation Face and object recognition Neurologic Exam Cranial nerves Motor Sensory

Coordination Gait Reflexes (DTRs, plantar, primitive)

Appearance: The clinician will describe the patient’s appearance with an emphasis placed on gender, ethnicity, body habitus, hygiene, clothing, and body art (e.g., tattoos, piercings). Attitude: The assessment of the patient’s attitude toward the examiner and overall demeanor is performed throughout the exam and should be reported in simple descriptive terms without equivocal jargon (e.g., avoid terms like “hysterical” or “borderline” that can have different meanings to different people). The patient’s social ability, the degree of cooperation with the interview, and the quality of the eye contact made should be noted. Speech: Speech is the verbal output of language (it is different from language). Clinicians should describe the quantity, volume, and rate of speech, as well as its rhythm or prosody. Additional variables can describe the flow, the pronunciation, and the presence of an accent. Motor behavior: This term is mostly descriptive and different from the motor component of the neurologic exam. Here we assess the degree of psychomotor depression or agitation, the presence of posturing or echopraxia, and abnormal movements (e.g., tremors, dyskinesias, dystonias, akathisia). A comprehensive exam should always be followed by a neurologic exam with a focus on muscle bulk, tone, and strength. Mood and affect: These terms are analogous to the symptoms (mood) and signs (affect) of emotional disturbance. Mood represents how the patient feels and it is often reported as a direct quote (between quotations marks). Affect is how the patient displays that mood to the world. A useful description of affect will provide a qualitative static description (e.g., sad) followed by a report of the dynamic qualities of displayed emotion (e.g., range, reactivity). Thought process: The expression of thought should be a goal-directed process in which thoughts are connected and presented in a logical manner. Abnormality of thought process lies on a continuum from subtle parenthetic comments to a complete lack of connection between ideas. Attention should be directed to the organization and linear structure of the patient’s narrative,

presence of circumstantiality or tangentiality, loose associations, thought blocking, perseveration, and echolalia. Thought content: Our inner world of beliefs, convictions, and moment-tomoment ideas is hidden from even the savviest psychiatrist. Thought content can therefore be assessed only by direct inquiry (“What are you thinking about?”), an analysis of speech, or inference from behavior. Particular attention should be paid to content related to safety (e.g., thoughts of suicide [intention and plan], self-injurious impulses, thoughts of homicide or violence). In addition, psychotic content with an emphasis on delusions (including paranoid ideation, ideas of reference, thought insertion, thought withdrawal, and thought broadcasting), obsessions, and intrusive thoughts should be elicited. Perceptions: A description of perceptions is sometimes framed under thought content, but it is useful to note them separately. Here the focus is on illusions and hallucinations with a review of different modalities (auditory, visual, somatosensory, olfactory, and, less frequently, taste). Insight and Judgment: These are general measures that reflect the patient’s insight into the illness and his or her judgment and decision-making abilities in the context of presenting symptoms.

The Cognitive Exam or “Neurologic” MSE The cognitive exam is also known as the neurologic MSE or bedside neuropsychological assessment . This assessment tests specific cognitive functions with relatively well-known neuroanatomical correlates. A thorough cognitive exam can involve hours or days of detailed neuropsychological testing (covered in a separate chapter) that might feel daunting or too complex to be performed by most clinicians. In this section, we present the “bedside” cognitive exam, which is the first step to the assessment of cognition that can be performed easily. This exam can lead to more specific testing, usually performed by a neuropsychologist, to reveal and quantify subtle deficits. As noted earlier, most tests are composites that assess more than a single cognitive function (e.g., drawing a clock will test executive and visuo–spatial functions, word recall will test short-term memory and language). When noting errors in a specific cognitive domain, clinicians might want to perform more than a single test to isolate and clarify the deficit (e.g., testing attention with digit span, spelling the word “world” backward). Unlike other features of the neurologic exam, it is

important that the different components be done in order because certain basic functions (e.g., attention) must be intact to perform more complex tasks. Level of consciousness : Consciousness (aka arousal) lies on a continuum from full alertness to coma. Although these two extremes are obvious, the middle ground can be subtle and caused my multiple etiologies (e.g., poor sleep, intoxication, disordered mood, delirium). It is important to note that we are providing a quantitative assessment of consciousness (i.e., more or less alert), not a qualitative report (e.g., perceptions). A standard measure of the level of consciousness is the Glasgow Coma Scale (Table 38-2), but clinicians should not always be compelled to use it, given that more descriptive terms (e.g., alert, somnolent, lethargic) derived from the observation of the general interview are acceptable. As a general rule for the entire neuropsychiatric exam, the greater the impairment the greater is the need for quantification. You will note that some textbooks and authors talk of level of consciousness and attention as if they were indistinguishable. However, these are related but different functions and they are sustained by segregated neuroanatomical systems. Therefore, describing them separately is clearer and of greater diagnostic utility. Sustained alertness is required to assess other cognitive functions. Therefore, impairment of consciousness can invalidate assessment of other functions and should be assessed first. Table 38-2: Glasgow Coma Scale Eyes (4 points) 1. No eye opening 2.Eye opening in response to pain 3. Eye opening in response to verbal command 4. Eye opening spontaneously Verbal (5 points) 1. No verbal response 2. Incomprehensible sounds (moaning) 3. Inappropriate but discernible words 4. Confused conversation, but able to answer questions 5. Oriented Motor (6 points) 1. No motor response

2. Extension to pain (decerebrate response) 3. Flexion to pain (decorticate response) 4. Withdrawal in response to pain 5. Localizes pain (purposeful movements) 6. Obeys commands for movement Range: 3–15; Normal: 15; Mild: 13–14; Moderate: 9–12; Severe: 3–8

Orientation: Clinicians will often test orientation to self, place, and time. Additionally, clinicians can test orientation to circumstances (why the evaluation is being conducted). Findings are usually reported as O x 3 or O x 4, but this is of limited value. Common to the whole neuropsychiatric assessment, it is preferable to be descriptive because patients might be oriented to “hospital” but not to the specific hospital, city, or floor. Similarly, being oriented to the year, season, month, and day of the week conveys different levels of severity. Attention: People are constantly being bombarded by stimuli from the external and internal environment that exceed the processing capacity of the brain. Therefore, many stimuli are minimally processed by the brain and only a subset of those become conscious. Attention is the capacity to select specific stimuli to enter awareness for detailed processing. In the exam, we typically focus on volitional attention (our capacity to select what stimuli we want to examine and what to inhibit) but a related yet anatomically segregated function is stimulus-driven attention (e.g., responsible for the shift in focus and head turn when we hear a loud noise in the back of a quiet library). Intact attention is required to participate in further cognitive testing and it should therefore be tested before most of the exam is performed. A number of techniques can be used to test attention; we will describe some of the most common techniques. Digit span: The examiner might have the patient repeat a randomly presented list of digits, starting with just a few numbers (two or three) and increasing the size of the list until two mistakes are made. The examiner should ask the patient to repeat the numbers in the same order in which they were presented (forward digit span) and once their limit of performance is reached the same exercise will be repeated by asking the patient to repeat the list of number in reverse order, e.g., if the examiner says, “1, 5, 3,” the patient should say, “3, 5,

1” (backward digit span). A normal capacity is between five to seven digits forward and three to five backward. Serial Sevens: The examiner might ask the patient to subtract 7 from 100, and then to continue serially subtracting 7 from the remainder; the examiner can stop after five subtractions. This test is limited by its reliance on calculation ability, which can be more a function of education than attention. Backward spelling/naming: The examiner might have the patient spell a fiveletter word (e.g., “world”) backward. Alternatively, the patient can name the days of the week or months of the year backward. Memory : Memory function is generally divided into three components. It can be useful to test not only verbal, but also non-verbal memory (e.g., spatial or procedural memory). Working memory: Working memory is primarily an executive function that allows immediate recall of information (e.g., remembering a phone number given by the operator long enough to dial it). Registration and working memory are tested together by both digit span (described earlier) and phrase repetition (see the “Language” section). The examiner might ask the patient to repeat (immediately) three named items (e.g., red, table, honesty). Short-term memory: Short-term memory involves the ability to store information for later use. Asking the patient to reproduce the three previously named items after a span of 3 to 5 minutes is a common test. A similar test for spatial memory involves hiding objects in three different locations in the room and then asking the patient where they are hidden after the same amount of time has elapsed. When deficits in short-term memory are identified, semantic or phonemic cues can be used (e.g., the word is a color or starts with the letter “r”). Correct responses after cues will separate amnestic (storage) from retrieval deficits: an amnestic patient never stored the information and so cannot access it even with the help of cues, whereas a patient with a retrieval deficit can use the cue to access information that was properly stored. Long-term memory: Long-term memory involves the recall of past events. This is nearly impossible to test accurately at the bedside because the examiner is rarely privy to details of remote events from the patient’s life. Asking about well-known national events or people (e.g., How did JFK die?) is usually a good strategy, although it is dependent on the age and educational background of the patient. The examiner can also ask about biographical

information confirmed by trustworthy collateral sources (e.g., hospital records, family members). Language: Language is how we present our thoughts to one another. Like other cognitive functions, language can be extraordinarily complex, with entire texts of psycholinguistics and aphasiology dedicated to its study. The bedside clinical exam will assess four primary components of language that will test the integrity of the circuit: fluency, comprehension, repetition, and naming. These components should be assessed in oral and written language. Is the language fluent or non-fluent?: The analysis of spontaneous speech will determine if the patient can communicate with normal articulation and flow, using grammatical sentences with appropriate syntax and choosing words correctly. Verbal fluency can be formally tested with word-list generation , in which the examiner asks a patient to name, in one minute, as many animals as possible (semantic fluency; 18 ± 6 is normal) or as many words starting with a certain letter, usually F, A, or S (phonemic fluency; 15 ± 5 is normal). Is comprehension normal or abnormal?: Does the patient seem to understand what you are saying? A request to complete a one- to three-step command (though complex commands might test more than just receptive language function) best assesses this. Asking simple “yes/no” questions (e.g., “Were you born in Mexico?” or, “Are we in the kitchen?”) is another common method. Is repetition normal or abnormal?: Having the patient repeat a phrase, such as “no ifs, ands, or buts,” is quite sensitive, given the difficulty of repeating conjunctions. Can the patient name objects appropriately?: Presenting the patient with a series of objects and asking him or her to name them (using high-frequency and low-frequency words such as “watch” and “face of the watch” respectively) is useful. Reading and writing: Because language is not based on a specific sensory modality but is a higher-order function that involves several modalities, the examiner should test oral comprehension and speech as well as reading and writing. Asking the patient to follow a written command (such as, “close your eyes”) and writing a sentence on a piece of paper are meaningful tasks.

Visuo–spatial function: These components of the exam assess both visuo– spatial construction and spatial attention. Figure drawing: Copying a three-dimensional figure (a cube) or complex (intersecting pentagons) figure tests the capacity to organize spatial information. Clock: The examiner can ask the patient to add numbers to a circle to represent a clock and then ask him or her to set the hands at 10 minutes to 2 (asking it as “ten to two” adds complexity). Abnormalities can occur in planning (poor spacing of numbers) or in positioning of the hands, which might belie frontal (executive) dysfunction. Absence of detail on one side of the clock (usually the left) may indicate a hemi-neglect syndrome, commonly, though not exclusively, associated with a (right) parietal lesion with a deficit in spatial attention. Line bi-section: More specific to deficits in visual attention and neglect, this test presents a horizontal line and asks the patient to cross it with a vertical line exactly in the middle. Significant right-sided biases are seen in patients with left hemi-spatial neglect. For added complexity, the examiner can present multiple horizontal lines in the four quadrants of the paper and assess not only if the vertical lines have a spatial bias, but if the horizontal lines in the left hemi-space are neglected or reveal even stronger spatial biases. For this test, it is important that the paper be placed directly in front of the patient. Extinction : Patients with extinction will identify individual stimuli in the left and the right hemispace; however, when double stimuli are presented on both sides simultaneously they can only identify objects in the healthy ipsi-lesional side (usually the right side for left hemispatial extinction). Because attention is also a multi-modal function, one can identify deficits in extinction with visual (e.g., asking the patient to look toward the examiner’s nose while the examiner shows fingers in left and/or right quadrants) and somatosensory stimuli (e.g., using light touch on the left and/or right extremities). Basic sensory functions (vision and touch) must be intact for proper assessment. Executive Function: Executive function (aka frontal function) is computed in frontal cortico sub-cortical circuits and allows us to solve problems. Complex and fundamental to adaptation, it consists of the capacity to choose a task, plan a strategy, develop the strategy, inhibit distractors, and assess performance by monitoring and correcting errors. Many of the tasks described in the cognitive exam require the appropriate use of executive function and intact fronto sub-

cortical circuits. Tests of attention and concentration (e.g., digit span, serial sevens), word-list generation or complex visuo–spatial constructions require (and therefore test) executive function and the capacity to program a response. The following are commonly used tests of executive function: Clock-drawing: Described earlier, this is a good approach to testing organizational and planning (executive functions) in the spatial domain. Luria three-step command: Named after the famous Russian neuropsychologist, this test of frontal function begins by showing the patient how to perform a three-step motor sequence and then asking for it to be repeated several times. The sequence traditionally begins with a light tap on the table of the right hand closed in a fist, followed by a second tap with the hand open and the palm facing medially and finishes with a third tap with the hand open facing downward. Patients with dysexecutive symptoms might be unable to perform this organized motor plan, might show rapid extinction with deterioration of the task over time, or might perseverate due to inability to switch from one position to the other. Complex sequence drawing: The patient is presented with a drawing that presents a repeating series of alternating triangles and squares, and is asked to copy the drawing. Similar deficits due to disorganization or perseveration can be observed For the sake of not extending this section further, we will not describe the testing of other functions (such as calculation, praxis, object and face recognition, and right-left recognition). For more detailed descriptions, see the section “Suggested Readings” at the end of this chapter.

Neurologic Examination Cranial Nerves Olfactory Nerve (CrN I) Testing of the first cranial nerve is almost uniformly neglected, with the entire cranial nerve examination often described as “II-XII WNL.” This notation not only indicates little regard for the first cranial nerve, but also communicates little about the individual features of the exam. It should therefore be abandoned. The first cranial nerve runs along the orbital surface of the frontal lobe. Lesions in this area (e.g., frontal lobe meningioma, head trauma) can produce unilateral

anosmia, occasionally as a unitary symptom or with cognitive and behavioral symptoms (e.g., disinhibition, personality changes). Neurodegenerative disorders (such as certain dementias or Parkinson’s disease) also present with anosmia, which sometimes explains lack of interest in food and weight loss (because the experience of taste is mostly olfactory) or poor hygiene and being malodorous (because a patient is not aware that they smell). These symptoms can be thought to be secondary to mood, reward, or cognitive deficits, but they could be primarily sensory. Also, anosmia may be an early symptom of certain dementias, and identifying it can help direct clinicians to an informed differential diagnosis. Routine testing of smell is therefore quite important. Clinicians should consider that deficits in the sense of smell are also normal as age advances. Carrying a small vial of coffee is a simple and convenient method for testing smell. Each nostril should be tested separately.

Optic Nerve (CrN II) The optic nerve, unlike other cranial or peripheral nerves (except for a component of the acoustic nerve) is myelinated by oligodendrocytes, not Schwann cells. It can therefore be considered as part of the CNS and is subject to disease processes (e.g., multiple sclerosis, migraines) that affect this part of the nervous system. The second cranial nerve and its posterior optic radiations run the entire length of the brain under the orbitofrontal cortex, over the pituitary gland, into the posterior thalamus (lateral geniculate nucleus), where the optic radiations course through the temporal and parietal lobes into the pericalcarine occipital cortex. A separate branch of the optic nerve synapses in the midbrain and brings the sensory (afferent branch) of the pupillary light reflex. From the midbrain, the efferent limb (part of the oculomotor or third cranial nerve) determines pupillary size by innervating the ciliary muscle. Therefore, it is important to note two different pathways emerging from the optic nerve: a retino-thalamo-cortical pathway sustaining vision, and a retino-midbrain pathway providing the sensory information that regulates pupillary size. Different disease processes and focal lesions can affect these two circuits selectively, leading to dissociable exam findings (e.g., lack of vision but appropriate light-dependent pupillary control after an occipital stroke). A thorough visual examination can therefore be quite informative to assess brain dysfunction and psychogenic processes. The assessment involves five components:

Funduscopic examination: The optic nerve is the only nerve that can be visualized directly. The physician should take advantage of this fact in assessing its integrity. A good funduscopic exam will also reveal much about the systemic vascular system and is a critical guide to the presence of increased intracranial pressure. Visual acuity: Testing of visual acuity is frequently ignored in the adult patient. This is unfortunate because poor vision can profoundly impair a patient’s functioning and is often reversible with corrective lenses or surgery. Acuity should be assessed in each eye separately while wearing current corrective lenses. Confrontational visual fields: Lesions anywhere along the retino-thalamocortical visual pathway will lead to visual field cuts. Importantly, the patient is often unaware of this abnormality of vision; careful testing is therefore required to elucidate it. Sitting directly in front of the patient, and having him look in your eyes, allows for testing of each eye separately by bringing an object (pin or wiggling finger) into each visual quadrant. For the patient who is unable to cooperate in this fashion, simply having him or her count fingers displayed in each quadrant is another option. Pupillary measurement: Pupillary size represents the delicate balance between sympathetic and parasympathetic input to the cilliary muscles of the eye. The presence of abnormally large or small pupils reflects an imbalance, and can be an important sign of disease or psychotropic use or withdrawal states. Similarly, an inequality in pupillary size (anisocoria) can be an important hallmark of severe intracranial pathology. Each pupil should be measured in millimeters, with measurements clearly documented for further reference. This assessment tests more than just the optic nerve, including the efferent oculomotor nerve and the autonomic structures and pathways that control pupillary size. Pupillary reaction: The direct and consensual pupillary reaction to light, and the near reaction (accommodation), should be tested routinely. This will assess any damage in either the afferent or efferent pathways that comprise the pupillary response. A penlight and close observation are all that is necessary.

Eye Movement (CrNs III, IV, and VI) These three cranial nerves are considered together given their relation to innervation of the extraocular musculature involved in eye movement. There are

two main categories of eye movement: Saccades: These are rapid eye movements that allow for brisk transition between items in the visual field. Saccades are tested by having the patient look to the ceiling, to the floor, and to the left and right sequentially. Asking the patient to look quickly at your nose and then at the thumb of your laterally extended arm is another method. Pursuits: These are slow voluntary eye movements that allow for smooth tracking of a moving target. They are tested by having the patient follow your finger through a full range of motion (up, down, left, and right). In the assessment of eye movements, the examiner should take note of the resting position of the eye (is there a gaze preference?) and the fullness of movement (are there any limitations in eye movement?). The presence of any nystagmus (involuntary oscillation of the eyes) should be noted with attention to the direction and frequency of the movement (vertical or horizontal, count of beats per second), whether it is at rest or in a specific position (e.g., when looking upward) and the possible presence of a slow and rapid component. Last, the examiner should note over-shooting and dyscoordination of saccadic movement suggesting dysmetria of ocular movements. Benzodiazepine intoxication or Wernicke-Korsakoff syndrome are common examples in which the eye movement exam presents with positive findings important for diagnosis.

Trigeminal Nerve (CrN V) The trigeminal nerve provides sensory innervation to the face (including the afferent limb of the corneal reflex) and motor innervation to the muscles of mastication. It is evaluated as presented in the paragraphs that follow. Facial sensation: As with sensory testing in general (see the “Sensory Exam” section), the examiner can test different somatosensory components, but typically testing light touch is sufficient unless the patient has a specific sensory complaint (e.g., a numb chin or facial pain). The trigeminal nerve has three sensory branches bilaterally (V1 , V2 , and V3 ). Each of these six territories should be tested separately. Asking the patient to “quantify” the degree of difference is generally not a fruitful exercise. Simply asking, “Does this feel normal on both sides?” saves time and will generally detect any abnormalities worth further investigation. The somatosensory sensation (touch) of the anterior two-thirds of the tongue is carried by the V3 branch.

Corneal reflex: The corneal reflex involves the direct and consensual blink response to corneal irritation. Although it can be helpful in the localization of brain-stem dysfunction (usually in the comatose patient), it is unfortunately both non-specific and insensitive. It is therefore not done routinely. For more detailed information, you will need to refer to other sources. Muscles of mastication: The motor branches of the trigeminal nerve innervate the muscles that open and close the jaw. Denervation abnormalities lead to noticeable jaw mal-alignment. Palpation of the major muscles (masseter) and brief observation of jaw motion are sufficient in the patient without localized complaints. Alternatively, the examiner can ask the patient to open his or her mouth against the examiner’s resistance.

Facial Nerve (CrN VII) The facial nerve provides motor innervation to the muscles of facial expression. To assess its function, the examiner can observe the overall appearance of the face, realizing that subtle facial asymmetries are common. Next, asking the patient to wrinkle the forehead, shut the eyes tightly, and smile or show the teeth is fruitful. Weakness in these muscle groups should be apparent. The distinction between central and peripheral facial nerve palsies can be a source of great confusion (and frequent debates during morning rounds!). Central facial nerve palsy refers to a disruption of the upper motor neuron (corticobulbar) fibers that innervate the facial nuclei, whereas peripheral facial nerve palsy is a disruption of the facial nerve itself. Because there is bilateral corticobulbar innervation only to the portion of the facial nerve that sub-serves the forehead, a unilateral upper motor neuron (UMN) lesion will spare the forehead and will present with contra-lesional weakness of the muscles of the lower face only. A lesion of the facial nerve itself (Bell’s palsy) will cause ipsilesional complete hemi-facial weakness. This differentiation is critical because the mechanisms that lesion the central pathways versus the peripheral nerve are very different. Of note, the sensation of taste in the anterior two-thirds of the tongue are carried by a branch of the CrN VII.

The Acoustic/Vestibular Nerve (CrN VIII) Lesions of this nerve are an important cause of sensori-neural hearing loss, nystagmus, and vertigo. At the bedside, the clinician should test each ear separately; for example, by rubbing the fingers close to the patient’s ear and

asking if he or she can hear the noise. To differentiate between conduction and sensory-neural hearing loss, the Rinne and Weber tests can be performed. These tests compare air versus bone conduction of sound. In the Rinne test, the clinician places a vibrating tuning fork close to the ear canal (to test for air conduction) and ask if the patient can hear it. Then, the maneuver is repeated by placing the tuning fork against the mastoid (to test for bone conduction), and ask if the sound is louder or softer than it was near the ear. Air conduction uses the peripheral auditory organs, whereas bone conduction can bypass that and transmit the sound directly to the inner ear. A patient with normal hearing will report better air conduction; a patient with conduction hearing loss will report better bone conduction; and a patient with sensori-neural hearing loss will report that both air and bone conduction are impaired. As a follow-up, the clinician should perform the Weber test by placing the vibrating tuning fork in the middle of the forehead or on the mid-line of the head and ask the patient on which side the sound is louder. A patient with normal hearing will report no difference, but a patient with lateralized hearing loss will report a lateralized effect. The Rinne and Webber tests are usually performed and interpreted together. For example, a patient reporting lateralization of the Weber test to the right might suffer from right conductive or left sensori-neural hearing loss. The Rinne test will be able to clarify this question.

Glossopharyngeal and Vagus Nerves (CrNs IX and X) These two nerves innervate the palate, pharynx, and larynx and are critical for speech and swallowing. The glossopharyngeal nerve also conducts taste and touch sensation for the posterior third of the tongue. Lesions of CrNs IX and X are usually clinically obvious because they produce dysarthric, hoarse, or aphonic speech, dysphagia, and drooling (due to an inability to swallow secretions). The usual method of testing these nerves, the gag reflex, is highly variable and often unhelpful. Inspection of the oral cavity is probably sufficient in the asymptomatic patient.

Spinal Accessory Nerve (CrN XI) This nerve provides motor innervation to two muscles: the trapezius and the sternocleidomastoid. A strong shoulder shrug and head turn provide evidence of intact innervation of each muscle, respectively.

Hypoglossal Nerve (CrN XII)

The hypoglossal nerve provides motor innervation to the tongue. Denervation is usually not subtle and will often cause an audible lisp. Having the patient protrude his or her tongue and look for deviation to one side is a standard technique. Clinicians can also ask the patient to move the tongue left and right. Dyskinesias (e.g., tardive dyskinesia) related to the use of neuroleptic medications can be apparent. Small spontaneous movements of the protruded tongue can be a normal finding.

The Motor Examination Muscle Bulk Muscle bulk is assessed by visual inspection or palpation. Muscle atrophy is an important sign of lower motor neuron (LMN) disease. Assessment of muscle bulk can be extraordinarily difficult, even for the seasoned clinician, due to natural variations in body habitus and the role of weight lifting or exercise (i.e., “bulking up”). Muscles that are unaffected by weight lifting or exercise (e.g., the facial muscles or the intrinsic muscles of the hand) can therefore provide the best estimate of overall muscle bulk.

Motor Tone Motor tone refers to the resistance of a limb to passive movement through its normal range of motion. To examine for tone, having the patient fully relax the arms and/or legs to allow passive manipulation by the clinician is useful. An increased level of tone, noted by rigidity or spasticity, is an important finding that can belie an UMN or extrapyramidal lesion (e.g., parkinsonism). LMN disorders present with decreased muscle tone and atrophy. Cogwheel rigidity and Froment’s sign (increased tone of a muscle group when the contralateral limb is engaged in an activity) might be observed in extrapyramidal disorders. Waxy flexibility is commonly seen in catatonia and described as mild to moderate resistance to passive movement with maintenance of the final position. Gegenhalten (aka paratonia ) describes a moderate resistance in all muscle groups that is proportional to the strength or velocity of passive movement, with stronger and faster mobilization maneuvers eliciting greater resistance. Gegenhalten is often observed in advanced diffuse neuropathological processes, such as dementias.

Motor Power (Strength)

Muscle strength is graded from zero (complete weakness or plegia) to five (normal strength) through different degrees of partial weakness or paresis (Table 38-3). It is impractical (and unnecessary) to test each of the several hundred muscles in the human body. Should the patient have a focal motor complaint, knowledge of major muscle groups in the proximal and distal limbs becomes important. Table 38-3: Grading of Muscle Strength 0: No evidence of muscle contraction 1: Muscle contraction without movement of the limb 2: Muscle movement but not against gravity 3: Muscle movement against gravity 4: Muscle movement against partial resistance 5: Muscle movement against full resistance

Observation of gait is an excellent screening test for the patient without focal weakness. If the patient can rise briskly and independently from a seated position and walk independently, gross motor deficits can be confidently ruledout. The ability to walk on heels and toes further assures distal lower-extremity strength. Gait must be tested in all patients, particularly in the elderly for whom falls are a life-threatening event.

Abnormal Movements Abnormal involuntary movements should be noted and described. They are discussed in detail in Chapter 45.

The Sensory Examination Primary Sensory Modalities Sensation allows tactile exploration of our environment. Even the most thorough examiner could not test every square inch of the body for intact sensation, nor would this be necessary. Knowledge of the full sensory exam is important for the patient with a focal sensory complaint, and we refer you to other texts for detailed information on this peripheral nerve exam. The main sensory modalities include the following: Pain: Tested by pinprick (using disposable sterile pins).

Temperature: Tested by touching the skin with a cold metal object (tuning fork). Light discriminatory touch: Tested by simply brushing the patient’s skin with your hand or a moving wisp of cotton. Vibration sense: Tested by applying a “buzzing” tuning fork. Proprioception or joint-position sense: Tested by asking the patient to close the eyes, move the tip of a finger or toe upward or downward and asking the patient to report the position of the joint. The Romberg maneuver also tests proprioception. When positive, it identifies lesions to peripheral nerves (e.g., neuropathies from diabetes, alcohol) or posterior columns (tabes dorsalis from syphilis, B12 deficiencies, trauma). Asking the patient to stand with the feet as close together as possible while still maintaining stability, and then asking the patient to close his or her eyes while assuring that you will not let him or her fall is a standard tactic. The patient with poor proprioception will be stable with eyes open but will begin to sway and lose balance after closing the eyes. It is important to remember that pain and temperature information travel together in the spinothalamic tract, which crosses to the contralateral side of the spinal cord approximately two segments proximal (i.e., higher) to the entry sensory dorsal root ganglion. The other modalities (light touch, vibration, proprioception) travel in the posterior columns, which remain ipsilateral up to the level of the medulla, where they cross. This has important implications for the exam.

Cortical Sensory Modalities The aforementioned primary sensory modalities provide input to the brain about the external environment. The sensory cortex integrates these “building blocks” to form complex sensory experiences. Because higher-level sensory processing requires reliable primary input, testing these cortical sensory modalities is unnecessary in the patient with primary sensory deficits. Two types of advanced sensory processing are recognized. Stereognosis: The ability to reach into your pocket and distinguish a quarter from a dime is an example of stereognosis. Simply, it is the ability to recognize objects using touch. It is tested by placing common objects in the patient’s hand and asking him or her to name them with their eyes closed.

Graphesthesia: Graphesthesia is the ability to recognize numbers or letters “written” on the skin, most often on the palm. As with stereognosis, primary sensory modalities must be intact for this test to have meaning.

Coordination Testing Gait Testing Coordination reflects the ability to orchestrate and control movement, and is crucial in the translation of movement into productive activity. Although the cerebellum probably plays the lead role in motor coordination, several other structures (e.g., basal ganglia, red nucleus) are also clearly involved. Walking is an extraordinarily complex motor skill that requires significant coordination of trunk and limbs. Its actual complexity makes it an ideal screening test for coordination ability. Humans have a particularly narrow base when standing upright; with any degree of incoordination (ataxia), patients will need to widen their base to remain upright. Balance becomes even more difficult when other sensory information is removed, forming the basis for the Romberg maneuver . The sensitivity of screening is increased by having the patient walk heel to toe (as on a tight rope). The ability to do this smoothly and quickly rules out any major impairment in coordination.

Diadochokinesia This term reflects the paired nature of agonist and antagonist muscle activity in coordinated limb movement. Abnormalities of this function are given the lengthy label dysdiadochokinesia, and are detected by several simple maneuvers: Finger-to-nose: Having the patient alternate between touching your finger and touching his or her nose, and looking for inaccuracy of movement (dysmetria) and presence of tremor (intention tremor) is usually effective. Clinicians should pay special attention to dysmetria (failing to reach the target) and intentional tremor, which might be more pronounced as the finger gets closer to its target. Heel-to-shin: This maneuver tests the same functions as the finger-to-nose but in the lower extremities. Having the patient run the heel of one foot down the shin of the opposite leg (from knee to ankle) as accurately as possible is a standard tactic.

Rapid alternating movements: These movements include rapid pronation/supination of the forearm (e.g., screwing in a light-bulb), fingertapping, or toe-tapping. Having the patient tap out a rhythm is an excellent way to assess coordination ability. With cerebellar damage, the rhythm will be poorly timed, with emphases in the wrong places. Abnormalities are also observed in movement disorders, such as parkinsonism.

Reflex Testing Proprioceptive Reflexes These reflexes , also known as deep tendon reflexes (DTRs ), are based on the simple reflex arcs that are activated by stretching (or tapping). Because they are influenced by the descending corticospinal tracts, DTRs can provide important information on the integrity of this pathway at several levels. You are likely familiar with the methods used to elicit the five major DTRs, which test reflex arches at different segments (Table 38-4): biceps, triceps, brachioradialis, quadriceps (knee), and Achilles (ankle). The grading of each reflex is on a fourpoint scale, with two (2+) designated as normal (Table 38-5). Table 38-4: Root Levels Tested with DTRs Biceps: C5 –C6 Brachioradialis: C6 Triceps: C7 –C8 Quadriceps (knee): L3 –L4 Achilles (ankle): S1 –S2

Table 38-5: Grading of Reflexes 0: Absent 1+: Diminished 2+: Normal 3+: Increased without clonus 4+: Increased with clonus

Clonus is a series of involuntary muscle contractions and relaxations that occur after certain maneuvers, such as the stimulation of DTRs. The presence of clonus

is usually significant for UMN dysfunction (see Table 38-6 for differential findings of UMN versus LMN dysfunction). Clonus is usually examined at the level of the ankle (by briskly dorsiflexing the foot and keeping that position) or the knee (by briskly bringing the patella downward with a straight relaxed leg). More than three beats with the ankle maneuver is abnormal, but any beats with the patellar maneuver are considered abnormal. Table 38-6: UMN versus LMN Findings UMN Lesion

LMN Lesion

Spastic paralysis (increase tone) Flaccid paralysis (decreased tone) Hyper-reflexia

Areflexia

Clonus

No clonus

Babinsky

No Babinsky

No fasciculations

Fasciculations

Atrophy (decreased use)

Atrophy (denervation)

Nociceptive Reflexes These reflexes are based on reflex arcs located in the skin (rather than muscle tendons) and are therefore elicited by scratching or stroking. These include the abdominal reflexes , cremasteric reflex , and anal wink , none of which is extensively used clinically. The major nociceptive reflex of clinical value is the plantar reflex. Stroking the lateral aspect of the sole of the foot should elicit plantar flexion of the toes. Babinski’s sign , marked by an extensor response (i.e., dorsiflexion) of the toes, often with fanning of the toes and flexion of the ankle, is seen in healthy infants and in diseases of the pyramidal tract. In its extreme form (severe spinal cord injuries) one can observe triple synergistic flexion of toe, knee, and hip away from the noxious stimulus. The plantar reflex is also considered a primitive reflex, but it does not reflect frontal dysfunction.

Primitive Reflexes (Release Reflexes) These reflexes are present at birth but disappear in early infancy. Their reappearance later in life is abnormal and is often reflective of frontal lobe disease of different etiologies (e.g., delirium, TBI, fronto-temporal dementia).

Glabellar tap reflex (Myerson’s sign): This consists of continued blinking with repetitive tapping of the glabellar region (between the eyebrows). A normal response will show adaptation and after a few initial blinks; the blinking will stop despite continuous tapping. Snout reflex: Gentle tapping over the patient’s upper lip will cause a puckering of the lips. Sucking reflex: Gentle stimulation of the patient’s lips will cause sucking movements of lips, and possibly also the tongue and jaw. Root reflex: Light stroking of the lip commissure or cheek will lead to reflex head turn toward the stimulated side. Grasp reflex: Stroking the patient’s palm will lead to an automatic clutching of your finger between his or her thumb and index finger. Palmomental reflex: Unilateral contraction of the mentalis muscle (chin) after stroking the ipsilateral thenar eminence of the hand.

Conclusion The brain is an organ that is unmatched in its elegance. Unlike the anginal grip of cardiac disease or the choking dyspnea of respiratory dysfunction, illness of the brain can send many different messages. Deciphering these messages using the neurologic examination can be complex and at times bewildering. This should not discourage the practicing psychiatrist from using the examination described in this chapter as a routine part of every patient evaluation.

Selected References 1. Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience . New York: Oxford University Press; 2003. 2. Campbell WW: DeJong’s The Neurologic Exam . 7th ed. Philadelphia, PA: Lippincott-Williams & Wilkins; 2012. 3. David AS, Fleminger S, Kopelman MD, et al: Lishman’s Organic Psychiatry . 4th ed. Oxford, UK: Blackwell Science; 2012. 4. Nicolson SE, Chabon B, Larsen KA, et al: Primitive reflexes associated with delirium: a prospective trial. Psychosomatics . 2011; 52(6): 507–512. 5. Samuels MA, Feske S: Office Practice of Neurology . 2nd ed. Philadelphia,

PA: Saunders; 2003. 6. Samuels MA, Ropper AH: Samuel’s Manual of Neurologic Therapeutics . 10th ed. Philadelphia, PA: Lippincott-Williams & Wilkins; 2010. 7. Samuels MA: Videotextbook of Neurology for the Practicing Physician, Volume 2: The Neurologic Exam . Boston: Butterworth-Heinemann; 1996.

CHAPTER 39 Neuropsychiatric Dysfunction NICHOLAS KONTOS, MD

KEY POINTS Overview Abnormalities of cognition, behavior, affect, perception, or arousal can all occur as a result of demonstrable lesions. However, a “find-the-lesion” approach to neuropsychiatric dysfunction is complicated and enriched by the network (as opposed to focal) organization of the human brain. Theoretical Basis and Methodology Higher brain functions are distributed and have a basic functional hierarchy. Arousal must be assessed first, followed by attention and motivation, the latter of which is assessed more impressionistically. If these are not intact, other aspects of the exam might be valuable but are of questionable validity. Language, praxis, visuo–spatial orientation, the various types of memory, and executive function can be assessed more or less separately if the examiner knows how to interpret his or her findings. Indications and Clinical Applications Acute onset, atypical age of onset, and unusual longitudinal course should raise concern for demonstrably organic etiologies of psychopathology. Accompaniment of new symptoms by new sensorimotor, language, coordination, or gross disorientation should also trigger a thorough neuropsychiatric assessment. Diagnostic testing, such as neuroimaging and electroencephalography, should be guided by hypotheses generated through this assessment.

Overview

Neuropsychiatric dysfunction involves abnormalities of cognition, behavior, affect, perception, or arousal as a result of demonstrable organic etiologies. In contrast to more routine psychiatric examinations, neuropsychiatric assessments pursue linkages between patients’ subjective complaints and objective diagnostic findings. In contrast to more routine neurologic examinations, the goals of neuropsychiatric assessments often do not adhere to “find the lesion”–type focality, and sometimes involve pathology that is as challenging to understand as it is to find. The skills and techniques utilized are extensive, and therefore must be judiciously mobilized, both among patients and within a given one. The utility of neuropsychiatric assessment, however, goes beyond the pursuit of strokes, tumors, and the like. With cognitive deficits being a prominent feature of many idiopathic psychopathologic entities (e.g., schizophrenia, attention deficit hyperactivity disorder [ADHD], depression), the ability to perform and to interpret a structured and efficient cognitive exam, for instance, is an important skill for any psychiatrist to have. This chapter seeks to provide some basic principles and techniques for an organized and efficient neuropsychiatric assessment.

Guiding Principles As alluded to earlier, localization is the goal of any examination of the central nervous system (CNS). However, whereas complex psychological functions have critical cortical “epicenters,” the kinds of symptoms and signs of interest to psychiatrists are subserved by distributed, overlapping cortical networks that also involve underlying white matter, sub-cortical nuclei, and brain stem modulatory neurotransmitters. The clinician is never looking for one particular lesion through the neuropsychiatric assessment, but rather for feasibly explanatory ones. The cognitive exam outlined in the section that follows exploits the important distinction between what Mesulam calls state and channel-dependent functions . Some other authors utilize the partially corresponding terms, fundamental and instrumental functions, respectively. In a hierarchy of cognition, state-dependent functions are those whose impairment compromises the expression (and screening) of all “inferior” functions. Arousal, attention, and motivation are the state-dependent functions. If you imagine a smart phone, these might correspond to the battery, reception, and location (i.e., in your possession, or in a drawer out of earshot), respectively. The channel-dependent functions (e.g., language, object identification, praxis) are dependent on intact state-dependent functions, but are

at least theoretically dissociable from one another; they might correspond to the individual applications stored on the phone.

Patient Selection It is neither feasible nor necessary to perform much more than a cursory cognitive assessment on every patient seen in a general psychiatric practice. Deciding who gets a more thorough one can be difficult, but a few concepts are highly useful. Time is a critical consideration. Acute onset, atypical age of onset, and unusual longitudinal course should raise the clinician’s level of concern for demonstrably organic etiologies of psychopathology. For example, there are only three entities in psychiatry in which consciousness and cognition fluctuate: delirium, Lewy body dementia, and catatonia. Also, grossly detectable cognitive impairment (especially disorientation) of abrupt onset or perceptible decline is not a typical feature of the idiopathic psychiatric disorders. In terms of the symptoms themselves, compromised consciousness and visual hallucinations are well known as warranting a neuropsychiatric work-up. Note, though, that visual hallucinations are much more common in schizophrenia than is often taught; it is present in the histories of one-third to one-half of these patients. Disorientation, language impairment (as opposed to communication impairment associated with disorganized thought process in schizophrenia or a manic episode), apraxia, and profound anterograde amnesia should also trigger a clinician to scrutinize (neuropsychiatrically) a patient. Obviously, pre-existing psychopathology is no vaccine against neuropsychiatric illness, and striking symptomatic deviations from patients’ prior presentations are quite concerning. Finally, context matters. In the short run, known head trauma, toxin ingestion, infection, cerebral hypoperfusion (even if it occurred weeks prior to symptom onset, as in delayed post-hypoxic leukoencephalopathy), and malnourishment are only a few of the misfortunes that might explain even a “typical” psychiatric presentation. In the longer run, knowledge of the patient’s past medical history beyond straight-forward neurologic diseases is critical; for example, vasculopathy, human immunodeficiency virus (HIV) infection, certain neoplasms, and rheumatologic diseases all place patients at risk for neuropsychiatric disease. It almost goes without saying that coincidence between acute somatic and psychiatric complaints is to be taken seriously—though this can be an especially challenging mandate in patients who tend to somatize.

History

Whereas the cognitive exam is what most clinicians might think of as a neuropsychiatric assessment, and although most interviewing principles are the same in every diagnosis-focused interview, there are some elements of historygathering worth mentioning briefly. Perhaps even more so than in other psychiatric contexts, consult questions and chief complaints in neuropsychiatry should be taken only as suggestions as to where inquiry should be focused. Patients are quite likely to have compromised self-monitoring, and collateral information sources (including health-care providers) are prone to misunderstand the relevant phenomenology (e.g., referring to all cognitive impairment as “memory” problems). Nonetheless, collateral information is rarely more crucial than it is in neuropsychiatric assessment. When it comes to interviewing the patient, clinicians should never presume that cognitive impairment obviates the need to obtain a subjective history. Even in a profoundly compromised patient who cannot provide much diagnostic information about the domain of interest, history-taking can reveal unanticipated areas of concern, identify what is important to the patient—and thus to the physician, whether diagnostically, for the identification of barriers to care, or for relationship building—assess the presence or absence of distress, and contain some covert cognitive screening. The latter two points are of special importance. In the absence of clearly effective and safe treatments, distress and dysfunction can determine whether clinicians expose a patient to risky interventions. A “covert” cognitive exam occurs in every interview, even if it is also covert from the clinician’s point of view. Arousal, attention, motivation, and language are often taken for granted when they are obviously normal. More active covert techniques are concessions to the fact that many patients will not (fully) cooperate with the cognitive exam. Nonetheless, insinuating casual questions about verifiable recent personal events crudely screens anterograde memory function and, if highly accurate, can raise the clinician’s eyebrows if later responses to memory screens are incongruously poor. Asking “How do you spend your day?” leads to information about meal preparation, bill payment, driving, pastimes, and grooming that might speak to sequencing abilities, spatial orientation, and motivation. Casually touching one’s face or putting down a pen near the patient offer opportunities to observe certain behaviors associated with “frontal” dysfunction (see the discussion on this later in this chapter).

Ancillary Information

The potential helpfulness of the past medical history, medication (and past medication) list, family and social histories goes without saying (despite having just been said). Clinicians should be particularly aware of the presence of medications with anticholinergic effects or γ -amino butyric acid (GABA) crossreactivity. Even if not causing the problem at hand, they can be aggravating factors. Otherwise, bypassing detail in this section of the chapter in the interest of space is not an endorsement of bypassing it in real life.

Cognitive Examination Arousal Unless the patient’s level of arousal is intact, everything else in the cognitive examination is called into question. Those working in general hospital settings are well aware that in patients with compromised arousal, others’ invocations of “underlying” depressive or anxiety disorders are notoriously unreliable. These patients are presumed delirious until proven otherwise. With normal wakefulness, the patient is rousable to voice (perhaps loud voice or light touch is needed if initially asleep), capable of ordinary, meaningful conversation upon waking, and able to maintain that level of alertness without supplemental stimulation. This description of normal wakefulness contains three parameters that are useful in describing all other states of arousal: what it takes to rouse the patient; what level of alertness is achieved; and, what, if any, stimulation is required to maintain that level of alertness. Terms such as “lethargic,” “somnolent,” “obtunded,” and “stuporous” are used loosely by most clinicians (“coma” is an exception), but should be considered specifically defined jargon. The definitions of these terms use the aforementioned three parameters, but most psychiatrists are not well served by memorizing them; instead, they might be better off heeding the maxim, “better to describe without naming than name without describing.”

Attention Attention (and concentration) involves the ability to engage appropriate stimuli and thoughts without inappropriate distraction. Attention cannot be fully intact if the patient is not alert; however, a patient can be alert yet inattentive. Another state-dependent function, attention, influences performance on the remainder of the cognitive examination and must be assessed to ensure the latter’s subsequent validity. In most psychiatric evaluations, it might be sufficient to note that the patient is not distracted by extraneous stimuli and remains on topic during the

interview. The “gold standard” by which attention is formally screened in the office or at the bedside is forward digit span. Forward digit span is conducted by reciting a progressively longer list of numbers for the patient at a pace of one digit per second; the patient then repeats the numbers back to the examiner. Forward digit span is not cumulative (i.e., incorrect: “1” – “1, 2” – “1-2-3”; correct: “1” – “2, 5” – “9, 3, 7”). A forward digit span of 7 is normal in nongeriatric adults; 5 is normal in geriatric populations. Backward recitation of over-learned information (e.g., days of the week, months of the year) is sometimes used to assess attention. This practice is generally fine because the information (so long as accurately recited forward first) is very easily accessible to most patients. However, it should be noted that these tasks also recruit working memory , which entails not only the ability to hold information in consciousness, but also the ability to perform cognitive “work” on it. That work involves executive function (see the discussion on this later in this chapter), and working memory is generally considered, cortically, to be associated with the dorsolateral prefrontal cortex (DLPFC). Attention, also cortically, localizes to the DLPFC but additionally involves the parietal lobes, the cholinergic system, and the monoaminergic systems, particularly dopamine and norepinephrine. Interestingly, a recent study seemed to demonstrate that the “Months of the Year Backward” (MOTYB) test was a highly-sensitive screening tool for delirium in older inpatients. Subsequent work has cast some doubt on this seemingly too-good-to-be-true solution to a well-known diagnostic detection problem. Still, with attentional impairment being one of the cardinal features of delirium, MOTYB at least demonstrates a component of neuropsychiatric exam– diagnosis linkage, and at most may yet prove to be a simpler screening tool than others, such as the Confusion Assessment Method (CAM ).

Motivation Although objective assessment of motivation is a prized goal of neuropsychological testing, it currently remains a matter for the astute clinician’s observational and interactional skills. Many patients, if asked, will openly admit that they are not trying. This situation might stem from genuine disinterest, other priorities, apathy or abulia (themselves neuropsychiatric entities), depressive illness, disdain, deception, face-saving, or the so-called “catastrophic reaction,” in which patients experience marked distress as their performance on cognitive screening results in a collision between who they thought they were and who

they are being revealed to be. Patients undergoing catastrophic reactions notoriously become angered by the exam and demand its cessation; many continue to engage but with rising irritation or even fear.

Language Fluency and comprehension of language are usually apparent from the interview alone. For the patient whose minimalist or “yes/no” responses and ambiguous responses to commands leave comprehension in question, absurdity can be useful (e.g., including “shoe factory” in a list of orientation options; asking, “Do helicopters in Panama eat their young?”), as the uncomprehending (or profoundly and diffusely confused) patient might not recognize it. Recall that patients with Wernicke’s aphasia might speak fluently but non-sensically; so, fluency is not equated with comprehensibility. It might seem that language impairment is self-evident, but it is still occasionally missed by clinicians whose concerns about “paranoia” in a hospitalized patient might reflect the uncomprehending, suspicious state of a patient with Wernicke’s aphasia. Repetition and naming are next assessed. Repetition is most difficult for short words and connector words; hence, “no ifs, ands, or buts.” Tongue twisters should be avoided because they elicit dysarthria more than repetition ability. All of the language screening discussed up to this point involves the peri-sylvian language areas (Broca’s anteriorly, Wernicke’s posteriorly, and the arcuate fasciculus that connects them). Naming is generally lumped in with language screening, though in some cognitive neurological schemes, it would be considered an aspect of object identification. Patients might have rather selective deficits of naming—and knowing—such that anomias and agnosias can specifically involve, for instance, tools, faces, or furniture. Note that anomias and agnosias are not the same; a patient who cannot name an object, yet can use it appropriately, has an anomia, not an agnosia. One should not expect to assess naming and object identification in a global manner, but the usual two-item identification task in the mini–mental state exam (discussed in the section “Structured Instruments” later in the chapter) can at least be supplemented by having the patient name components of the objects in question. Also, occasionally discussed separately from language, prosody involves the conveyance and appreciation of affect in communication. A right hemisphere dominant function in the majority of patients, the localization of “expressive and receptive” prosody loosely parallels that of word-based language on the left.

Aprosodias can manifest as poor social skills due to inability to take cues, inability to “give the floor” in conversation, “pressured” and jargon-laden speech, or seemingly “blunted” affect. Prosody can be screened by asking the patient to say or interpret the examiner’s output of the same sentence with varying emotional flavor (e.g., “Get out of here” in an angry and humorous way). Note that the lesions that accompany deficits revealed through the aformentioned exam might not correlate as closely with the Broca-Wernicke scheme as medical school lectures led us to believe. Recent research on the network neuroanatomy of language is revealing it to more closely resemble that of more complex cognitive-behavioral functions. This work might help explain the subtle receptive deficits in patients with Broca’s area lesions, and the expressive deficits seen in patients with Wernicke’s area lesions, at least when there is significant associated white matter involvement.

Praxis Praxis—the ability to carry out a voluntary act—is sometimes presumed intact at the examiner’s (and patient’s) peril. By definition, the apraxic patient has the requisite motor, sensory, language, and skill sets necessary to execute the acts in question, so the failure to perform written or other aspects of the cognitive exam can seem baffling, or, worse yet, feigned. Apraxias, of which there are several types, involve lesions of parietal lobe and/or its connections to frontal motor areas. Dressing and constructional apraxias are debatable as to their status as true apraxias and are associated with right-sided lesions. Ideomotor apraxia—the inability to carry out voluntary acts on command—is sometimes used synonymously with apraxia and is usually associated with left-sided lesions. It is tested, sometimes unwittingly, by asking the patient to perform a directed task; when purposely screened, the task is often pantomimed, as when a patient is asked to simulate brushing his or her teeth. Even if the patient can perform the task spontaneously without command, you can imagine the difficulties that ideomotor apraxia can introduce into common medical situations, such as post-stroke rehabilitation. Ideational apraxia is usually produced by left-sided lesions and is marked by a patient’s inability to execute a complex, sequential motor act, despite being able to perform each individual component.

Visuo–spatial Although the ability to draw/copy a cube, intersecting pentagons, or a

symmetric daisy are seldom called upon in life, problems in performance of these construction tasks are illustrative of larger problems of visuo–spatial skill. Both parietal lobes participate in visuo–spatial processing, but lesions to the “non-dominant” (usually right) hemisphere produce the most profound deficits. In a complex figure (such as the Rey-Ostereith ) the right hemisphere gets the “big picture,” whereas the left is more involved with the details; detailorientation also engages frontal lobe functioning. Double simultaneous sensory stimulation, in which patients are unable to appreciate right-sided touch when touched bilaterally while eyes are closed, is a particularly sensitive screen for right parietal dysfunction. Parietal lobes are affected early in Alzheimer’s disease and probably account for the “wandering” noted at this stage, which is unlikely to be a memory problem.

Memory The heterogeneity of memory both complicates and increases the yield of screening it. With regard to content, declarative or explicit memory is intentional, conscious, and recalls information and experiences. It is sub-divided into semantic—memory for facts—and episodic—autobiographical memory— types, though for the most part this distinction is of little diagnostic utility in adults. Non-declarative or implicit memory is generally not addressed in bedside or office-based cognitive screening, and includes classical and operant conditioning, habituation and sensitization, priming, and procedural memory. After they are consolidated, declarative memories are “stored” diffusely, likely in connection patterns between ensembles of cortical neurons. These remote memories thus tend to be quite resilient because the destruction of no single structure or group of cells will efface them. Temporally, remote declarative memory exists on a scale of days to years, whereas recent memory operates on a scale of minutes to days. Immediate and working memory are more usefully thought of in association with attention and executive function (discussed further later in this chapter) than memory per se . Because there can be confusion between various time-based terms for memory (see Table 39-1), the clinician performing cognitive screening might be better off considering anterograde memory—the learning of new information, a hippocampal function—and retrograde memory—the recall of consolidated information from distributed stores. Table 39-1: Terminologies for Temporal Aspects of Declarative Memory*

Psychiatric Neurologic Neuropsychological Time Critical Terms Terms Terms Scale Anatomy N.B. Attention and Immediate working memory memory

Short-term memory

Seconds to minutes

Dorsolateral prefrontal portex

Short-term memory

Recent memory Long-term memory

Minutes to days

Hippocampal Anterograde memory might formation reduce confusion.

Long-term memory

Remote memory

Days to Neocortical indefinite networks

Remote memory

No recall involved when information is externally derived.

Retrograde memory might reduce confusion

* Note: Table reflects the author’s impressions of common usages. It is meant to illustrate variability and to help with cross-referencing.

When engaged in the screening of anterograde memory via three-item recall screens and the like, be aware that deficits in encoding, consolidation, and retrieval will all produce poor recall, but actually represent different pathologies. Before resorting to prompts, first see if the patient can “just try to think of one” item, rather than all at once; many patients will then exert more effort and give a better impression of their capabilities. Improved recall with categorical or multiple-choice prompts suggests a retrieval (“search engine”) rather than consolidation (“writing”) deficit, and thus might point the examiner toward frontal sub-cortical rather than hippocampal-parahippocampal-thalamic pathology. Further, note that encoding information requires somewhat intact attention, and the forgetfulness complained of by many patients reflects a problem with attention rather than with memory proper. Finally, common questions about “orientation” are actually screens of memory proceeding along a gradient from anterograde/recent (e.g., floor, date) to retrograde/remote (e.g., state, year), so long as the answers cannot be gleaned by deduction, in which case executive function is being employed.

Executive Function Executive functions are sub-served by dorsolateral prefrontal cortex and its sub-cortical connections, underlie response selection, and are manifest in planning, sequencing, inhibiting distractors, monitoring errors, and appropriately shifting and sustaining cognitive focus. Common, but vague and limited screening questions that address reasoning and abstraction (e.g., proverbs) address executive function. During the interview itself, the examiner should note possible perseveration (i.e., inability to shift cognitive set), and distinguish it from persistence (i.e.,

normal, voluntary adherence to a topic of importance to the patient). Formal screening tools for executive dysfunction include alternating figures (Figure 391), the Luria hand maneuvers, the go/no-go task, and clock-drawing. Often thought of (partially accurately) as a construction task, the clock actually yields more “frontal” information, as when patients fail to appropriately plan the spacing of numbers, perseverate on a particular number, or misplace the hands. If language and education are not in question, then one-minute word-list generation (e.g., animals, cities and towns, fruits and vegetables named in a minute) and cognitive estimations (e.g., how tall in feet is the tallest building in town?) can also be employed.

Figure 39-1: Alternating figures (top) and sequencing/perseverative error on reproduction/extension. Frontal lobe dysfunction can also manifest as amotivated and disinhibited states of various severities. These are usually observed rather than specifically screened by the clinician. Another behavioral state to be alert to is environmental dependency . During the interview, examiners suspicious of prefrontal pathology might exaggerate their gestures and watch for imitation behavior by the patient, or casually leave a pen or other utile object near the patient and watch for utilization behavior .

Structured Instruments The term “screening” has been used for the aforementioned cognitive techniques so as to distinguish it from the more formal “testing” work done by neuropsychologists. However, some structured instruments, most notably, the Mini-Mental State Examination (MMSE ) and the Montreal Cognitive Assessment (MoCA ) are commonly used in routine exams by psychiatrists. It is important to point out that these two instruments are each a composite of screens of several different cognitive domains. As such, interpretation of error profiles, rather than pure numeric score totals, are key to their useful implementation.

Physical Examinations and Diagnostic Test Selection

Space and practicality preclude a review of physical examination aspects of neuropsychiatric assessment. Largely psychodynamically-derived taboos against psychiatrists touching their patients certainly have no place in neuropsychiatric evaluations. Systemic illness, by definition can strike any organ system, and a targeted physical examination is always a consideration. A competent neurological examination in particular can be quite useful, though examiners should bear in mind that relative to the cognitive screening described earlier, routine motor, sensory, cranial nerve, gait and coordination examinations actually cover a fairly small area of cortex and can be quite normal even in profoundly neuropsychiatrically ill patients. Nonetheless, such an exam can offer added information and credibility to psychiatrists’ recommendations for diagnostic imaging, electroencephalography (EEG), or other testing. Returning to the topic of “focality” introduced at the outset of this chapter, requests for structural or functional neuroimaging should come with ideas about what is being searched for. More important than clear etiologic impressions, domains of dysfunction on examination lead to educated speculation about anatomic lesions being sought. Anatomic speculation is especially important when deficits cluster around one or a few channeldependent functions or abulia; more diffuse pathology, and a greater likelihood of EEG abnormalities might be expected with profound state-dependent function impairment, especially of alertness or attention.

Suggested Reading 1. Jefferson Al, Cosentino SA, Ball SK, et al: Errors produced on the Minimental State Examination and neuropsychological test performance in Alzheimer’s disease, ischemic vascular dementia, and Parkinson’s disease. J Neuropsychiatry Clin Neurosci . 2002; 14: 311–320. 2. Malloy PF, Richardson ED: Assessment of frontal lobe functions. J Neuropsychiatry Clin Neurosci . 1994; 6: 399–410. 3. Nasreddine ZA, Phillips NA, Bedirian V, et al: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc . 2005; 53: 695-699. 4. Royall DR, Cordes JA, Polk M: CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry . 1998; 64: 588-594. 5. Squire LR: Mechanisms of memory. Science. 1986; 232:1612-1319.

6. Voyer P, Champoux N, Desrosiers J, et al: Assessment of inattention in the context of delirium screening: one size does not fit all. Int Psychogeriatr . 2016; 23: 1–9.

CHAPTER Clinical Neurophysiology and 40 Electroencephalography RANI SARKIS MD, MSC; SHAHRAM KHOSHBIN, MD; AND ZEINA CHEMALI, MD, MPH

KEY POINTS Overview The electroencephalogram (EEG) allows the assessment of brain activity in real time using scalp electrodes and it aids in the diagnosis of epilepsy, epileptic and non-epileptic seizures, and in the assessment of patients with transient neurologic spells and altered mental status. Evoked potentials enable the assessment of the integrity of nerves, muscles, and neuro-muscular junctions and provide objective measures of their function. Theoretical Basis Scalp electrodes can measure the summation of electrical activity that arises from brain regions. The origin of this activity is likely from the contribution of neurons, glia, and the extracellular space. Evoked potential studies rely on repeated exposure to a sensory stimulus (visual, auditory, somatosensory) and measurement of the velocity of transmission across different central nervous system pathways. The electromyogram (EMG) allows for the assessment of the integrity of muscles and the nerves that control them. Indications The EEG is a useful test for the assessment of any patient with an altered mental status or transient neurologic symptoms (including loss of consciousness). In a patient with suspected epileptic seizures, inter-ictal abnormalities can point the physician toward the correct diagnosis. Evoked potentials and the EMG are useful when objective measures are

required to confirm the integrity of visual, auditory, or somatosensory pathway systems, as well as muscles, motor neurons, and neuromuscular junctions. Clinical Applications EEG studies can consist of a limited (20 to 40 minutes) assessment of brain activity or more prolonged studies (hours to days) that can be performed in the hospital or at home. The EEG can also be combined with video to correctly analyze a specific behavior and rule-out epileptic seizures or psychogenic non-epileptic seizures. In a patient with an altered mental status, the EEG can provide an assessment of the level of encephalopathy, whereas serial EEGs may aid in revealing improvement or worsening. In patients with functional blindness, deafness, or somatosensory and neuromuscular complaints the evoked potentials and EMG aid in refining the differential diagnosis. An EMG can also be used to confirm neuromuscular compromise from medications (e.g., from a toxic myopathy).

Overview Activity in the brain and peripheral nerves can be depicted by neurophysiological discharges. In pathological cases, changes in the velocity, frequency, and amplitude of these discharges are evident. Although the precise nature of this electrical activity remains unknown, in the case of electroencephalogram recordings, it is most likely attributed to contributions from neurons, glia, and the extracellular space.

The Electroencephalogram Characteristics of Recordings The electroencephalogram (EEG) records low-voltage electrical activity produced by the brain. Recordings are often characteristic of certain ages and states of consciousness; in addition, it is possible to recognize generalized malfunctions of the brain, as well as localized or paroxysmal abnormalities. Ordinarily, the EEG is recorded from the scalp with small surface electrodes. Electrical activity is recorded from a variety of standard sites on the scalp, according to the international electrode placement system. The placement of the

electrodes relies on anatomic landmarks on the head that include the nasion, inion, and pre-auricular areas. For clinical purposes, 19 to 21 electrodes are often used. However, additional surface electrodes or more invasive electrodes (e.g., sphenoidal, foramen ovale) can be added. Recording electrical activity requires the measurement of the voltage between two electrodes. Because it is impossible to record from all pairs of electrodes at the same time, a series of electrode pairs are evaluated. Two different styles of recording exist. In the referential (or monopolar) method, a series of different electrodes are referred to the same reference electrode, which is presumed to be relatively electrically inactive. Commonly used references points are the ears, the vertex, the average of all electrodes, or a non-cephalic reference. In another method, the bipolar method, electrodes placed in a line are recorded serially as successive pairs; the first recording would be from the first and second electrodes, the second recording would be from the second and third electrodes, and so on. Creation of different montages gives various views of the electrical activity at different parts of the brain. The electrical activity from any electrode pair can be described in terms of amplitude and frequency. Amplitude ranges from 5 μV to 200 μV. The frequency of EEG activity ranges from 0 Hz to about 20 Hz. The frequencies are described by Greek letters: delta (0–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (more than 13 Hz).

The Normal EEG In the normal awake adult (with eyes closed), an alpha rhythm is seen predominantly in the posterior part of the head. The amplitude of the alpha waves falls off anteriorly and it is often replaced by low-voltage beta activity. The alpha rhythm disappears (or is blocked) when the eyes are open and reappears when they close again. The EEG is dynamic and changes with state. When a normal adult becomes drowsy, the alpha rhythm gradually disappears, and fronto-central-temporal theta activity becomes predominant. Drowsiness is stage I sleep. As sleep becomes deeper, high-voltage single or complex theta or delta waves, called vertex sharp waves, appear centrally. Stage II sleep is characterized by centrally predominant runs of sinusoidal 12 to 14 Hz activity, called sleep spindles, and the appearance of large waves over the vertex region (the K complex). Deeper sleep (slow wave sleep) is characterized by progressively more and higher-voltage theta and delta activity. REM (rapid eye movement) sleep looks similar to the awake EEG, but has the presence of rapid

eye movements and motor paralysis (documented with an el ectromyogram [EMG] electrode). In routine EEG studies, some “activations” (e.g., 3 minutes of hyperventilation and a flashing strobe light at different frequencies) are employed to try to bring out abnormalities not apparent in the record without the activations.

EEG Abnormalities EEG abnormalities can be divided into slowing and epileptiform abnormalities. Their localization can either be focal (involving only one area of the brain) or generalized (involving the whole brain). Focal lesions in the brain tend to cause focal abnormalities on the EEG, whereas more generalized disturbances, e.g., toxic or metabolic, cause generalized abnormalities. Additionally, abnormalities are either continuous or intermittent. As a general rule, the EEG is a sensitive test for abnormalities, but it is not specific (see Figure 40-1).

Figure 40-1: Sample of a normal inter-ictal EEG of an adult during resting wakefulness with eye opening and eye closure. A bipolar montage is used to link the electrodes. F: frontal; Fp: frontopolar; C: Central; P: parietal; T: temporal; O : occipital. Z subscript indicates a central lead. Odd subscripts are on the left and even sub-scripts are placed on the right hemisphere. After eye closure, there is the appearance of an alpha rhythm in the posterior electrodes. Information on frequency (number of waves per second [Hz]) and amplitude (height of the waves [μV]) can be obtained.

In the adult EEG during wakefulness, the presence of theta or delta slowing is abnormal. Generalized slowing is a sign of encephalopathy, with most severe encephalopathies characterized by more delta slowing. Although a specific type of focal slowing termed poly morphic delta activity (PDA) indicates an underlying focal lesion that disrupts the white-matter tracts, there is another type of delta activity called fron tal intermittent rhythmic delta activity (FIRDA); it is non-specific and can be a sign of raised intracranial pressure or encephalopathy. Epileptiform abnormalities are divided into spikes or sharp waves. They indicate abnormal hypersynchronous neuronal firing. A spike is a single wave that stands out from the background activity and lasts less than 70 ms. A sharp wave is similar but it has duration of 70 to 200 ms. A spike or sharp wave is often followed by a slow wave, and spikes–slow waves can alternate at frequencies from 1.5 to 5 Hz.

EEG Limitations The EEG has a number of technical limitations , and it is very susceptible to artifacts. Eye movements, tongue movements, muscle movements, the elec trocardiogram (EKG), ventilators, intravenous (IV) drips, dialysis machines, among others can easily create EEG artifacts that can be misinterpreted as epileptiform abnormalities. Because recordings rely on scalp electrodes, only around one-third of the surface of the brain’s electrical activity is detected, whereas activity in deeper areas at the bottom of sulci or deep-brain regions (cingulate, oribtofrontal cortex, mesial temporal cortex) can be missed. For example, an epileptiform abnormality in the hippocampus must spread to the temporal neocortex for it to be detected on the scalp. In addition, approximately 6 cm2 of cortex must synchronize for the activity to be detected on the scalp.

The EEG in Clinical Practice A routine EEG usually takes 20 to 40 minutes and often involves activation procedures (e.g., photic stimulation, hyperventilation). An EEG is of higher yield if stage II sleep is captured; thus, some centers advocate sleep deprivation prior to the routine EEG. The presence of REM sleep on a routine 20- to 40minute EEG is unusual because REM sleep usually occurs more than 60 minutes after sleep onset. Early-onset REM noted on the routine EEG should raise the possibility of narcolepsy, sleep deprivation, psychotropic medication effects, or medication/alcohol withdrawal. In the outpatient setting, repeated EEGs could be requested to increase the yield of diagnosing an epileptiform abnormality. A 1- to 7-day continuous

ambulatory EEG is another viable alternative because the capture of sleep is guaranteed. In the acute inpatient setting, a bedside long-term EEG can be performed, often with accompanying video monitoring. Finally, in hospitals with epilepsy centers, elective epilepsy monitoring unit admissions with continuous video-EEG are scheduled to rule-out epilepsy. The duration of the EEG study needed depends on the resources available and the clinical question being asked. For the EEG to be useful, the patient’s age and clinical data needs to be considered. There is also some inter-rater disagreement in the interpretation of EEGs, and at times direct communication with the EEG reader is required. Findings of interest on a routine EEG are predominantly going to be inter-ictal (i.e., in between seizures) given the short sampling period, whereas more prolonged EEGs increase the likelihood of capturing an ictal event (seizure). Studies assessing the yield of a single EEG quote a detection rate for epileptiform abnormalities of 30% to 55%, and this increases to 80% to 90% with repeated or more prolonged EEGs in patients with a diagnosis of epilepsy. In the patient who is awake but with an altered mental status of unexplained etiology, a 24-hour EEG is recommended because it increases the yield of detecting seizures. Meanwhile, if the goal of the EEG is to capture a specific event or behavior, a continuous EEG with video monitoring is required. The presence of inter-ictal epileptiform abnormalities on the EEG does not immediately implicate epilepsy as the underlying diagnosis. Some individuals with these findings are asymptomatic, and the EEG finding might indicate a lower seizure threshold in general. For example, siblings of patients with generalized epilepsy can have generalized epileptiform abnormalities on the EEG with photic stimulation, and patients with blindness can have occipital sharp waves even if they have never had a seizure in their lifetime. Populationbased studies have documented a prevalence of 0.5% to 3% of epileptiform abnormalities in asymptomatic children and adults. In contrast, a normal EEG does not rule-out epilepsy, given its limitations and the fact that patients cannot be monitored indefinitely. This emphasizes the importance of interpreting EEG findings in light of the clinical data.

The EEG in Psychiatry The EEG is a useful diagnostic tool in the work-up of the patient with unexplained delirium /encephalopathy, fluctuating mentation, transient recurrent behavioral changes, or alterations in awareness.

In general, toxic and metabolic derangements cause diffuse changes on the EEG and slowing of the background. Certain psychotropics can have more profound effects; clozapine can cause epileptiform abnormalities (especially at toxic doses), and it lowers the seizure threshold. Lithium, at toxic doses, can also cause an encephalopathy, trigger seizures, or increase the frequency of epileptiform abnormalities. Periodic epileptiform abnormalities have also been described with toxic doses of ketamine, phencyclidine, tric yclic antidepressants (TCAs), and baclofen. Sedative-hypnotic medications, such as benzodiazepines and barbiturates, increase the beta activity on the EEG; the presence of beta activity might be an indication that the patient is on one of these drugs. The EEG shows slower frequencies during alcohol intoxication, with more pronounced slowing being associated with higher alcohol levels. During alcohol withdrawal, epileptiform abnormalities can be seen with photic stimulation (photoparoxysmal response); alternatively, twitching of the anterior head muscles (photomyogenic response) can be seen. With chronic alcoholism, patients tend to have a lower-voltage EEG. Metabolic derangements also cause EEG changes, especially if there is a rapid change in serum levels. For example, changes in glucose, calcium, thyroid, and osmolytes can cause slowing or epileptiform abnormalities on the EEG, which are reversible if the derangements are addressed. In the setting of renal or hepatic failure generalized waves on the EEG can appear with three phases, termed triphasic waves . Although initially thought to be benign, triphasic waves might represent a seizure pattern, and only a response to a benzodiazepine or an antiseizure medication can confirm this. Another important use of the EEG is in the detection of non-c onvulsive status epileptics (NCSE). NCSE is defined as persistent and prolonged (usually longer than 30 minutes) seizure activity in the absence of convulsive activity. Clinically, patients with NCSE can present with abrupt confusion, psychosis, or subtle automatisms (e.g., lip smacking, hand automatisms). Prompt treatment of NCSE is essential and an EEG is required to confirm the diagnosis. The EEG is also useful in the setting of autoimmune and infectious encephalitides, as certain diseases have been associated with specific patterns. In herpes encephalitis, lateralized periodic epileptiform discharges are noted in the temporal lobe due to the virus’ predilection for that region, whereas in the latter stages of Creutzfeld-Jakob disease (CJD) a pattern of 1 Hz generalized periodic discharges is seen that has a sensitivity of 86% and a specificity of 67%. In subacute sclerosing panencephalitis (SSPE) due to longstanding measles, a

characteristic pattern of large-voltage discharges every 4 to 15 seconds is seen, and in patients with NMDA encephalitis that can present as new-onset psychosis, approximately one-third have an EEG pattern termed extreme delta brush that is characterized by rhythmic delta activity with over-riding beta activity. Psyc hogenic non-epileptic seizures (PNES), a form of conversion disorder, are always on the differential when epilepsy is being considered. The “gold standard” for the diagnosis of PNES is a video EEG because a spell can be analyzed using video and a simultaneous EEG to rule-out an underlying seizure pattern. In the setting of PNES, the EEG is normal; this allows for confirmation of the diagnosis. The co-occurrence of epilepsy and PNES is common, and the goal of the video EEG is to capture all the spells the patient is complaining of to categorize them correctly.

Evoked Potentials A sensory stimulus in any modality (e.g., visual, auditory, somatosensory) will produce a change in the EEG. The change is usually small compared to the background EEG; the exact configuration of the change depends on the nature of the stimulus and the site of recording on the scalp. The evoked potential is the change in the EEG that is dependent on, and timelocked to, the stimulus; to see it, the stimulus must be repeated many times and the EEG averaged. Evoked potentials can be used to test the integrity of a pathway in the central nervous system (CNS). The most common use of evoked potentials is to test the speed of conduction in a particular pathway, and to provide objective measures that show disruption of these pathways in patients with sensory, visual, or auditory complaints. In clinical practice, they are most often used when a demyelinating disease is suspected. Because multiple sclerosis is a disease of central myelin, when myelin is damaged, conduction is slowed and the evoked potentials will be delayed. Although many multiple sclerosis plaques are clinically silent they show themselves with this electrical test. Hence, evoked potentials are quite useful in making the diagnosis of multiple sclerosis.

Visual Evoked Potentials Visu al evoked potentials (VEPs ) were the first of this type to become popular. They are ordinarily obtained with a checkerboard stimulus that alternates black and white squares. Each eye is stimulated individually and then responses are measured from the occipital area of the scalp. The major wave measured is a

large positive wave at a latency of about 100 ms. In multiple sclerosis or optic neuritis, the wave is delayed. Delayed or absent VEPs can be seen in many other conditions, including ocular conditions (e.g., glaucoma), compressive lesions of the optic nerve (e.g., pituitary lesions), and pathological conditions of the optic radiations or the occipital cortex. Alternatively, VEPs can be used to confirm the integrity of the visual pathway in the setting of psychogenic blindness.

Auditory Evoked Potentials Auditory stimulation produces complex waveforms. Stimulation with brief clicks produces six small waves in the first 10 ms. Surprisingly, the sources of this electrical activity are in serial ascending structures in the brain stem. It becomes possible to study the integrity of the brain stem with these waves, and the test has also been used to assess “brain stem death” in cases suspected of “brain death.”

Somatosensory Evoked Potentials Soma tosensory evoked potentials (SEPs ) are the averaged electrical responses in the CNS to somatosensory stimulation. Like sensory action potentials (SAPs) in the peripheral nervous system, most components of SEPs represent activity carried in the large sensory fibers of the dorsal column (medial lemniscus primary sensorimotor cortex pathway). SEPs can be used to test the integrity of the pathway and to test the speed of conduction in the pathway. SEPs from the upper extremity are commonly produced by stimulation of the median nerve at the wrist. The cerebral SEP to median nerve stimulation is best recorded from a site approximately 2 cm posterior to the contra-lateral central electrode. SEPs from the lower extremity are produced by stimulation of the posterior tibial nerve at the ankle or the peroneal nerve at the fibular head. It is possible to localize a lesion in the somatosensory pathway by using shortlatency SEPs from sub-cortical structures. Several systems of electrode placement can be used, but the one, which seems to produce potentials of greatest amplitude, is where the active electrode is placed over the cervical spine and referred to an “inactive” site. By stimulating nerves in the leg, it is possible to obtain evoked potentials at all levels of the neuraxis, including over the spinal cord.

EMG and Nerve Conduction

The EMG and nerve conduction studies are another set of neurophysiological tools available to test the activity of muscles and nerves. They provide objective evidence of muscle or nerve injury in patients with motor or sensory complaints, and can be useful tools to rule-out an underlying somatic symptom disorder. Myopathies (muscle damage) can be seen in the setting of alcohol abuse, use of atypical antipsychotics, and exposure to a wide variety of medications and toxins. Neuropathies (nerve damage) can be seen also with chronic alcohol abuse, vitamin deficiencies, and use of a wide variety of medications and toxins.

Nerve Conduction Sensory Nerve Conduction The cell bodies of sensory neurons are located in the dorsal root ganglia. Each neuron has a central process entering the spinal cord through the dorsal horn, and a peripheral process connecting to a sensory receptor in the skin or deep tissues of the limb. The receptors transduce somatosensory stimuli into electrical potentials, which eventually give rise to action potentials in the axons that are transmitted along the peripheral process to the central process. There are a variety of sensory neurons, each with a characteristic spectrum of axonal diameters. Some neurons are myelinated, whereas some are unmyelinated; in routine studies, the unmyelinated fibers cannot be measured. Many sensory axons with differing function and size run together with motor axons. The goals of sensory nerve conduction studies include: assessment of the number of functioning axons and assessment of the state of the myelin of these axons. Nerve conduction studies assess the integrity of peripheral nerves by measuring the speed and amplitude of the response. In the usual sensory nerve conduction study, all of the axons in a sensory nerve are activated with a pulse of electric current. Action potentials travel along the nerve, and the electric field produced by these action potentials is recorded at a site distant from the site of stimulation. Each axon contributes to the magnitude of the electrical field and thus the amplitude of the recorded sensory action potential is a measure of the number of functioning axons. Utilizing the distance between the site of stimulation and the site of recording and the time between stimulation and the arrival of the action potentials at the recording site, it is possible to calculate a conduction velocity that reflects the quality of the myelination of axons.

In axonal degeneration neuropathies, the primary feature is reduced sensory action potential amplitudes. The conduction velocity can be slightly slowed, but only to the extent that the normally largest axons are gone and the measured conduction velocity reflects the velocity of the largest remaining axons. In demyelinating neuropathies, the primary feature is slowing of conduction. In radiculopathies, sensory action potential amplitudes and conduction velocities are fully normal. This is because the lesion is virtually always proximal to the dorsal root ganglion, and the cell body and its peripheral process remain normal. Sensory action potential similarly remains normal with lesions of the CNS.

Motor Nerve Conduction There are significant differences between sensory and motor nerve conduction that depend in large part on the differences of their anatomy. Motor neurons have cell bodies in the anterior horn of the spinal cord, and they send their axons to innervate muscle fibers. Motor axons are always intertwined with sensory axons; there are no nerves that are pure motor nerves. Hence, the electrically-stimulated compound action potential of any nerve with motor fibers in it is a mixed nerve action potential. Consequently, it is not possible to deduce the number of functioning motor axons simply by looking at the amplitude of a nerve action potential. It is possible to study motor nerve axons separately from sensory axons by electrically stimulating a nerve and by recording from the muscle fibers innervated by the motor axons in that nerve. Because each motor axon typically innervates hundreds of muscle fibers the compound muscle action potential is very much larger than the nerve action potential. The number of axons can be diminished and the action potential normal if the process of collateral reinnervation by the remaining axons has been complete. The number of axons can be normal and the action potential diminished if there is a neuromuscular junction deficit or if there is loss of muscle fibers. As a neuropathy progresses and collateral reinnervation fails to keep pace, the muscle action potential will decline. The time interval between delivery of the electrical stimulus and the onset of the muscle action potential can be difficult to interpret. This period is composed of the time it takes for the motor nerve action potential to travel down the terminal branches of the axon, the time for the release of acetylcholine into the neuromuscular junction, the time for the acetylcholine to produce an end-plate potential, the time for generation of a muscle action potential, and, depending on

the position of the recording electrodes, the time for the muscle action potential to propagate to the recording electrodes. Calculation of a conduction velocity for these neurons is not as straightforward as it for the sensory nerve. The time itself, if obtained under standard conditions, can be a useful measure of the conduction time in the terminal part of the axon; it is called the distal motor latency . The conduction velocity of motor axons can be determined for parts of the axon proximal to the distal portion. If the nerve is stimulated supra-maximally in two places, virtually identical muscle action potentials will result; the major difference will be the different latencies from the time of stimulation. The difference in the latencies is due to the difference in the distances from the sites of stimulation to the muscle. Dividing the difference in the distances by the difference in the times produces a conduction velocity for the segment of nerve between the two sites of stimulation. Similar to the measurement of the sensory action potential, measurements of the muscle action potential are ordinarily made to the time of onset; hence, the calculated conduction velocity refers to the fastest (and largest) axons in the nerve. In axonal degeneration neuropathies, motor nerve conduction studies are not significantly abnormal until the process is moderately advanced. Total reliance on motor nerve conduction would result in failure to detect many significant neuropathies. Typically, there will be a slight slowing of conduction velocity and prolongation of the distal motor latency because the largest axons are lost. There can be loss of action potential amplitude when the process is advanced. In demyelinating neuropathies, there will be slowing of conduction velocity and prolongation of distal motor latency. A focal lesion of a nerve will lead to slowing of conduction and to a decrement of amplitude across the segment, including the area of the lesion, but studies of the nerve distal to the lesion will be fully normal. Studies of nerve segments proximal to the lesion will show normal conduction velocity with unchanging and reduced action potential amplitude. Quite dramatic nerve conduction findings are seen with a focal, total lesion. The nerve is fully normal below the lesion but electrical stimulation proximal to the lesion produces no response (similar to the patient’s attempts to activate the muscle). In radiculopathy, motor nerve conduction studies will ordinarily be normal. There can be slight slowing of conduction velocity in direct relation to the amount of loss of large fibers. In CNS disease, there will ordinarily be no change in motor nerve conduction unless there is involvement of anterior horn cells.

Late Responses Studying the most proximal segments of nerves is difficult because they are deep and not easily accessible as they leave the spinal column. However, it is useful to study the proximal segments of nerves, given that processes (such as radiculopathies from disc protrusion and certain neuropathies [e.g., GuillainBarré]) affect this segment predominantly. The so-called late responses (the Ereflex and the F-response ), provide a relatively easy technique for study of the proximal segments of nerves that are not accessible to peripheral stimulation. These responses are produced in certain circumstances after an electrical stimulus to a peripheral nerve, and are late with respect to the muscle response (the M-response) produced by the orthodromic volley of action potentials traveling to the muscle directly from the electrical stimulus. The H-reflex is a monosynaptic reflex response similar in its pathway to that of the tendon jerk. The electrical stimulus activates the I-a afferents (coming from the muscle spindles) and action potentials travel ortho-dromically to the spinal cord. In the cord, the I-a afferents make excitatory monosynaptic connections to the alpha motor neurons; a volley of action potentials is set up in the motor nerve that runs orthodromically the entire length of the nerve from the cell bodies to the muscle. Hence, action potentials travel through the proximal segment of the nerve twice during the production of the H-reflex (once in the sensory portion of the nerve, and once in the motor portion). Obtaining an H-reflex depends on the ability to stimulate the I-a afferents. If a motor axon is electrically stimulated, an action potential will travel along the axon anti-dromically toward the spinal cord as well as ortho-dromically toward the muscle. The anti-dromic action potential will collide either in the proximal motor axon or in cell body with the developing H-reflex in that axon and nullify it. In routine clinical practice, it is possible to get this differential stimulation and to produce E-reflexes only in the posterior tibial division of the sciatic nerve while recording from the triceps surae. The F-response or F-wave has an advantage over the H-reflex in that it can be found in most muscles. It is a manifestation of recurrent firing of an anterior horn cell after it has been invaded by an anti-dromic action potential. After a motor nerve is stimulated, an action potential runs anti-dromically as well as ortho-dromically; a small percentage of anterior horn cells that have been invaded anti-dromically will produce an ortho-dromic action potential that is responsible for the F-response. Thus, to produce an F-response, action potentials must travel twice through the proximal segment of the motor nerve.

The EMG The EMG measures muscle fibers electrical activity in bundles (collectively) or individually (single recording). The EMG aids in differentiating a neurogenic process from a myopathic one, while defining normal processes, as well.

The Physiology Underlying the EMG Understanding the concept of the motor unit is central to the understanding of the physiology of electromyography. A motor unit is composed of all the muscle fibers innervated by a single anterior horn cell. In most proximal limb muscles, there are hundreds of fibers in each motor unit. In the normal situation, the muscle fibers from the same unit are not clumped together, but are intermingled with fibers from other motor units. When a motor axon fires, each muscle fiber in its motor unit is activated in a constant time relationship to the other fibers in the unit. EMG activity is ordinarily recorded with a needle placed into the muscle. Because the muscle fibers of a single motor unit are not packed closely together, the EMG needle records from only about 10 fibers from each motor unit. The amplitude, duration, and configuration of the electrical activity recorded from a motor unit vary as the needle changes its orientation to the muscle fibers. Despite its variability, it is possible to specify a normal range for the amplitude, duration, and configuration of m otor unit action potentials (MUAPs) for each muscle and each age. When an EMG needle is placed in a normal muscle at rest, there is no electrical activity. With weak effort, first one and then several motor units are activated. At this low level of activation, it is possible to see the individual MUAPs and evaluate their parameters. With maximal effort so many units are brought into action that individual MUAPs cannot be discerned; all that can be seen is a dense electrical pattern, called an interference pattern, which can be characterized by its density and peak-to-peak amplitude. The normal density would be either “full,” if there are no gaps, or “highly mixed,” if there are a few, short gaps. Some people are not willing or able to exert a maximal effort and the pattern will be less dense as a result. Hence, the degree of effort has to be taken into account when assessing the interference pattern.

Findings on the EMG Acute partial injury, e.g., a partial laceration of a nerve: motor axons that are injured undergo Wallerian degeneration over the course of about 5 days, leaving

muscle fibers previously innervated by those axons in a denervated state. Within approximately 10 to 14 days, denervated muscle fiber action potentials are recorded by the EMG needle as fibrillations and positive sharp waves. There is nothing different about fibrillations and positive sharp waves other than a slight difference in the particulars of the recording; both are simply small, diphasic potentials beginning with a positive phase. The motor units that can be activated will be normal; it will not be possible to activate voluntarily the denervated muscle fibers. Descriptive terminology for these patterns is “high mixed,” “mixed,” low mixed,” and single unit,” in order of decreasing density.

Chronic Partial Injury After weeks to months there will be collateral sprouting from surviving motor axons to innervate denervated muscle fibers. Spontaneous activity will cease. Motor units will now contain more muscle fibers than normal; hence, MUAPs will be long in duration, high in amplitude, and more complex in shape or be polyphasic. The interference pattern might improve in density, but probably it will remain less than full, although the amplitude will increase.

Complete Injury In this circumstance, no voluntarily initiated motor nerve action potentials can reach the muscle due to a focal demyelinating injury. Muscle fibers will not be denervated, so they will not fibrillate. The EMG examination will reveal no spontaneous activity, no MUAPs, and no interference pattern. This is not different from the first few days of a total injury; after these first days when the denervated muscle fibers begin to fibrillate.

Myopathy The simple model of myopathy is characterized by dropout of individual muscle fibers from their motor units. In active myopathies, especially polymyositis, there can be some segmental muscle necrosis. This process divides a muscle fiber into an innervated segment and an uninnervated segment. The uninnervated segment might fibrillate and, hence, result in active myopathies, some fibrillation, and positive sharp waves; most commonly spontaneous activity is lacking.

Suggested References General

1. Aminoff MJ, ed.: Electrodiagnosis in Clinical Neurology . Philadelphia, PA: Saunders; 2012.

EMG and Nerve Conduction 1. Pease WL, Lew HL, Johnson EW, eds.: Practical Electromyography . Philadelphia, PA: Lippincott Williams & Wilkins Co.; 2007.

Electroencephalography 1. Ebersole JS, ed.: Current Practice of Clinical Electroencephalography . Philadelphia, PA: Wolters Kleuwer Health; 2014. 2. Holschneider DP, Leuchter AF: Clinical neurophysiology using electroencephalography in geriatric psychiatry: Neurobiologic implications and clinical utility. J Geriatric Psychiatry Neurol . 1999; 12(3): 150–164. 3. Kaplan PW: The EEG in metabolic encephalopathy and coma. J Clin Neurophysiology . 2004; 21(5): 307–318. 4. Yamada T, Meng E., eds.: Practical Guide for Clinical Neurophysiologic Testing . Philadelphia, PA: Lippincott Williams & Wilkins Co.; 2010

Evoked Potentials 1. Howard JE, Dorfman LJ: Evoked potentials in hysteria and malingering. J Clin Neurophysiology . 1986; 3(1): 39–49. 2. Khoshbin S, Hallet M: Multi-modality evoked potentials and blink reflex in multiple sclerosis. Neurology (Ny). 1981; 31: 138–144. 3. Pogarell O, Mulert C, Hegerl U: Event-related potentials in psychiatry. Clin EEG Neuroscience . 2007; 38(1): 25–34. 4. Shahrokhi F, Chiappa K, Young R: Pattern shift visual evoked responses. Arch Neurol . 1978; 35: 65–71. 5. Shibaski H, Yamashita Y, Tsuji S: Somatosensory evoked potentials: Diagnostic criteria and abnormalities in cerebral lesions. J Neurol Sci . 1977; 34: 427–439. 6. Starrr A, Joseph A: Auditory brain responses in neurologic disease. Arch Neurol . 1979; 29: 827–834.

7. Robinsono J, Rudge P: Abnormalities of auditory evoked potentials in patients with multiple sclerosis. Brain . 1977; 100: 19–40.

CHAPTER Seizure Disorders 41 RANI SARKIS MD, MSC; ZEINA CHEMALI, MD, MPH; AND SHAHRAM KHOSHBIN, MD

KEY POINTS Overview Psychiatrists need to be familiar with seizure disorders because they are highly prevalent, frequently have behavioral co-morbidities, and can mimic unusual and bizarre behaviors. Differentiating between epileptic seizures, psychogenic non-epileptic seizures, and conversion disorders, is a common clinical dilemma. Epidemiology The cumulative life-time incidence of seizures is up to 10%, whereas the cumulative risk of epilepsy is 2% to 3%. Clinical Features Seizures consist of transient stereotyped neurologic symptoms that can include subjective sensations (auras), loss of awareness with hand and mouth automatisms, and generalized tonic and clonic movements. Seizures that affect the level of consciousness are followed by a post-ictal period characterized by confusion that lasts minutes to hours. Etiology Seizures can be the result from several etiologies, including cortical lesions, sudden metabolic derangements, alcohol withdrawal, medication effects, and fevers. Up to one-third of seizures have no clearly defined etiology. Differential Diagnosis The most common mimics of seizure include syncopal spells and psychogenic

non-epileptic seizures. Migraines, transient ischemic attacks, movement disorders, and sleep disorders should also be considered in the differential diagnosis. Approaches to Evaluation Meticulous history-taking is crucial to make the diagnosis, identify triggers, and localize the area of the brain involved. Laboratory investigations looking for metabolic derangements and toxins are required as is neuroimaging to rule-out structural lesions. An electroencephalogram is also an essential part of the diagnostic work-up. Treatment Provoked seizures with a clear cause are treated by addressing the underlying trigger. Several anti-seizure medications are available for the treatment of epilepsy; they target various ion channels to lower neuronal excitation or increase inhibition. Each medication can have its own positive or negative effect on mood, cognition, and anxiety. Medications with a particularly favorable mood profile include carbamazepine, oxcarbazepine, lamotrigine, and valproic acid. Non-pharmacologic treatments of epilepsy also include dietary treatments, neuromodulation, and epilepsy surgery.

Overview Psychiatrists should be familiar with the diagnosis and management of seizure disorders given their high prevalence, elevated behavioral co-morbidities in patients with epilepsy, and similarity to psychogenic non-epileptic seizures (PNES ). An epileptic seizure as defined by the International League Against Epilepsy (ILAE ) is a “transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.” Epileptic seizures are categorized as provoked if they are caused by a temporary or reversible factor (e.g., a fever, alcohol withdrawal, hypoglycemia); otherwise, they are considered un-provoked. Epilepsy is diagnosed in the setting of two un-provoked seizures, a

single unprovoked seizure with a risk of recurrence assessed as greater than 60%, or an underlying epilepsy syndrome. The cumulative life-time incidence of seizures is up to 10%, whereas the cumulative risk of epilepsy is 2% to 3%. Both in terms of its physical and psychological effects, epilepsy can be disabling (e.g., seizures can prevent a person with epilepsy from driving a car or piloting an aircraft) and present special problems during pregnancy, both to the mother and the fetus. Its medical and psychosocial aspects extend beyond concrete outcomes (e.g., seizure-freedom), and comprise psychiatric comorbidities, poor school performance, unemployment, social stigmatization, and burden on families and caregivers. Management is often challenging because an individual might require different types of treatment at different times, and because inappropriate therapy can worsen the patient’s condition. Given these patients’ complex needs, a multi-disciplinary team approach is often recommended.

Seizure Classification The International Classification of Epilepsy The classification of epilepsy has been through several iterations since the first international classification was published in 1960; the latest updated version was released in 2010. The classification system and schema is being continuously upgraded due to emerging neuroimaging techniques, genomic technologies, and findings from molecular biology. According to the 2010 classification (Table 411), epileptic seizures are considered either focal or generalized . Focal seizures originate in networks limited to one hemisphere, whereas generalized seizures involve bilateral distributed networks. Table 41-1: Classification of Epileptic Seizures Generalized Seizures Tonic-clonic Absence seizures Typical Atypical Absence with special features Myoclonic absence Eyelid myoclonia

Myoclonic Myoclonic Myoclonic atonic Myoclonic tonic Clonic Tonic Atonic

Focal seizures Descriptors: With/without impairment of consciousness or awareness (previously “complex partial” and “simple partial,” respectively) With observable motor components With observable autonomic components Involving subjective sensory or psychic phenomena only Evolving to bilateral, convulsive seizure (previously called secondary generalized)

In persons with focal epileptic seizures, neuroimaging techniques, such as magnetic resonance imaging (MRI), have made it relatively easy to detect brain lesions (e.g., tumors, strokes, vascular malformations, malformations of cortical development) that were previously detected only on biopsy. In contrast, findings on neuroimaging in patients with generalized seizures are usually unremarkable.

Generalized Seizures According to the 2010 classification, there are six distinct types of generalized seizures: Tonic–clonic (previously “grand-mal”) Absence Myoclonic Clonic Tonic Atonic

Tonic–Clonic Seizures

Tonic–clonic seizures are the most common type of generalized seizure; they also occur when a focal seizure evolves into a generalized seizure. In a generalized tonic–clonic seizure the first component is loss of consciousness; the patient will be unaware of what has happened. The second phase is the tonic stage, characterized by sustained contraction of the skeletal muscles, extension of the axial musculature, upward deviation of the eyes, and paralysis of the respiratory muscles due to thoraco-abdominal contractions. This stage is brief, ranging from only about 3 seconds to a maximum of 30 seconds, although it can seem longer because of its dramatic appearance. The most striking feature is extension of the upper and lower extremities. Sudden spasm of the respiratory muscles results in forced exhalation that can sound like a scream (the so-called epileptic cry). Although contraction of the respiratory muscles causes the patient to stop breathing, it is not a cause for concern, given that the tonic stage lasts only a few seconds. As the muscles of mastication go into spasm the patient might bite down hard. Contrary to popular belief, the patient will not swallow his or her tongue, so objects (such as a spoon or a tongue depressor) should not be inserted forcefully into the patient’s mouth. In the young patient, this action could also dislodge a loose tooth, which could later be aspirated. Eye movements that occur during the tonic stage of a generalized seizure are typically described as an upward deviation. This contrasts with eye movements made during a focal seizure where the eyes deviate either to the right or to the left. These eye movements are sustained, forced, and conjugate and are followed by a rotation of the head and/or trunk to the same side (versive seizure). Even inexperienced observers tend to notice whether the patient’s eyes moved straight up or to one side. The best approach to the tonic stage is to observe the patient and to take any necessary measures to prevent inadvertent injury. Patients should be placed on their side to prevent aspiration. After the tonic stage ends, the patient enters the clonic stage, which is characterized by rhythmic jerking movements. Clonic movements have a high amplitude and low frequency, unlike myoclonic movements, which are very brief, have a low amplitude, and a high frequency. In a generalized seizure, clonic movements are symmetrical with the arms and legs moving in unison. Clonic arm movements generally have greater amplitude than clonic leg movements, and the trunk is usually not involved. The clonic stage generally lasts between 1 and 2 minutes, on average, after which time the patient is usually conscious but confused.

Generalized tonic–clonic seizures are also characterized by symptoms (some of which can alarm the inexperienced physician) that involve the autonomic nervous system. Hippus, in which the pupils alternately contract and dilate in a rhythmic pattern, is common, but occasionally the pupils might either contract or dilate. It is often useful to examine the pupils during a seizure, even in a patient on a respirator, because hippus can be a sign of seizures. Other common autonomic signs include: changes in facial color (to either pallid or flushed), though typically, skin color remains unchanged and an excessive pallor should entertain the possibility of a vascular event such as syncope; excessive salivation (to the point of drooling); increased heart rate and blood pressure; and relaxation of the urinary and anal sphincters (resulting in incontinence or defecation). A generalized tonic–clonic seizure is followed by a post-ictal period that lasts minutes to hours during which the patient is disoriented and confused. Due to sustained muscle contractions patients might also complain of muscle pains and bite the lateral aspect of their tongue. If the seizure happens while the patient is asleep and it is unwitnessed, patients might complain of waking up the next morning feeling sore, having an unexplained tongue bite, or unexplained incontinence. Physicians rarely see their epileptic patients in the throes of a tonic-clonic seizure because the 1- to 2-minute event is usually over by the time they arrive. Because the event ends naturally within a few minutes, it might not be necessary to administer medications unless the patient has repeated seizures or is in status epilepticus (i.e., seizures lasting for more than 5 minutes or two or more sequential seizures without full recovery of consciousness between seizures).

Absence Seizures Absence seizures (termed by some as “petit-mal”) occur mainly during childhood and are rare after puberty. They are characterized by the arrest or suspension of consciousness for 5 to 10 seconds. These seizures can be missed easily, and teachers might label a child as “inattentive.” Without treatment, absence seizures can occur about 70 to 100 times a day, and such frequent blackouts can seriously impair a child’s school performance. If absence epilepsy is suspected, the physician can usually confirm the diagnosis by asking the child to hyperventilate, which will precipitate an attack. Other signs include rhythmic blinking (at a rate of three blinks per second) and rudimentary oral motor behaviors called automatisms, which also occur in adult temporal lobe epilepsy. Absence epilepsy is the easiest seizure disorder to diagnose because of its

pathognomonic electroencephalogram (EEG) (a spike-and-wave pattern that occurs at three cycles per second), especially when the child hyperventilates.

Other Generalized Seizures The other most common types of generalized seizures are myoclonic and akinetic seizures. Although these seizures usually occur in childhood, adults can also experience them. Myoclonic seizures are characterized by sudden, brief, muscular contractions that can occur singly or repetitively. The contractions can involve the arms/legs or the axial musculature. Myoclonic seizures can be seen in the setting of specific epilepsy syndromes (juvenile myoclonic epilepsy), end-stage dementia, progressive early-onset neurodegenerative diseases, after cardiac arrest, and with other conditions. Due to their brief nature, myoclonic seizures can be missed and instead attributed to “clumsiness.” A corresponding EEG rhythm is required to confirm that the myoclonus is due to an electrical discharge. Epileptic myoclonus must be differentiated from hypnic myoclonus, which is a benign myoclonus that occurs during sleep. Unlike myoclonic seizures, atonic seizures are characterized by a loss of muscle tone. The appearance depends on the muscles affected. “Head bobbing” occurs if the neck loses muscle tone, “bending seizures” occur if the upper extremities are affected, and “drop attacks” occur if the lower extremities are involved. These seizures usually occur in patients with epileptic encephalopathies characterized by developmental delay and multiple seizure types. The seizures can result in significant injuries, and patients will often wear a helmet to protect themselves from head trauma. Although not diagnostic, the EEG is often helpful in identifying atonic seizures. A typical pattern consists of slow spikes and waves (or polyspikes and waves), which can be seen even during the periods between seizures. In contrast, patients with syncope have a normal EEG.

Focal Seizures Focal seizures originate within neural networks limited to one hemisphere and can be associated with brain lesions. These disorders can be accompanied by an impairment of consciousness or awareness.

Focal Seizures Without Impairment of Consciousness When a seizure is restricted to a single hemisphere and does not spread to the contralateral hemisphere or the sub-cortical arousal centers, the patient might

maintain consciousness during the episode. Seizures can affect any part of the cortex, and the symptoms will depend on the function of the cortex being irritated. Because much of the motor cortex is devoted to controlling the face and hands, focal seizures with observable motor components (“focal motor”) most commonly affect these body parts. Motor movements can spread, usually starting in the hands and then affecting other areas (such as the face and the upper half of the body). This is known as the Jacksonian march . (There is almost never movement of the hip or trunk.) In what is sometimes called a fencing seizure, the arm also flexes ipsilateral to the focus and extends contralateral to the focus. These signs indicate involvement of the supplementary motor area in the medial frontal lobes. Seizures spreading to the frontal eye fields will cause contralateral deviation of the eyes. Somatosensory seizures are usually described as a tingling feeling (paresthesia) or by a sensation of heat or water running over the affected area; this sensation can spread rapidly from one body part to another. Rarely, a patient will report pain or a burning sensation as well as various auras. When a somatosensory seizure causes tingling of the hands and face the physician may attribute this finding to a transient ischemic attack (TIA) involving the middle cerebral artery. Unlike TIAs that can start abruptly but end gradually, somatosensory seizures both begin and end abruptly. Although the differential diagnosis of tingling of the hands and face should also include migraines (which begin gradually, and spread slowly to other parts of the body), these symptoms differ from those of somatosensory seizures, in which the spread is rapid. Auditory seizures are produced by discharges in the anterior transverse temporal gyrus (Heschel’s convolution) and the superior temporal convolution. The patient typically reports tinnitus in the form of hissing, buzzing, or roaring sounds. Visual seizures, produced by discharges from the occipital focus, take the form of flickering lights or flashing colors, usually red or white and are distinct from the “zig-zag” pattern of light sometimes reported by patients experiencing a migraine. Involvement of the temporo-occipital region can involve more complex visual hallucinations. The perception that objects are getting bigger (macropsia) or smaller (micropsia) might also be reported. The British mathematician and author Lewis Carroll had temporal lobe epilepsy (TLE). In a sense, Carroll’s Alice in Wonderland might be considered a long description of visual phenomena such as those experienced in TLE: objects and people shrinking and growing, passing through mirrors, and so forth.

It is worth noting that a number of epileptic patients have migraines headaches and many migraine sufferers have non-specific abnormalities (e.g., slowing) on the EEG. Good history-taking is often key, to elucidate a family history of migraines, and to determine triggers and the duration of the spell. Focal seizures affecting the limbic system can cause transient fear that can be misdiagnosed as panic attacks. Similarly, temporal lobe seizures causing abdominal auras usually described as a rising epigastric sensation can be misdiagnosed as a gastrointestinal disorder. Other symptoms, include the feeling of familiarity known as déjà vu (French for “already seen”), and, more the feeling of unfamiliarity, referred to as jamais vu (French for “never seen”). Pleasant ictal feelings can also occur, but they are very rare. Some women experience orgasms during limbic seizures: the only corresponding feeling in the male genitalia is an uncomfortable penile sensation. As a general rule, seizures tend to be abrupt and stereotyped because they involve the same brain regions repeatedly. A high clinical suspicion is key, and neuroimaging and an EEG is often required.

Focal Seizures with Impairment of Consciousness or Awareness Focal seizures with impairment of consciousness or awareness are the most common types of seizures seen in adult medicine. They are characterized by an alteration of consciousness as well as by other complex manifestations; they are also the most difficult to diagnose and to treat. They were previously termed “complex partial seizures,” but the current terminology of “focal dyscognitive” seizures is favored. The loss of consciousness can be isolated or accompanied by a number of behaviors. Psychomotor symptoms or “automatisms” can take the form of simple vegetative movements or complex actions, such as disrobing. The most common automatisms are oral and buccal movements (e.g., lip-smacking, licking, or chewing), and the picking behavior sometimes seen in patients with dementia. Walking is one of the most interesting automatisms that can occur. The physician should not attempt to prevent such behavior during a seizure because the patient might become violent if restrained. When questioned about their behavior, patients often say they have the urge to leave their present location and some might drive off or go to the bus station or airport out of a desire to travel. Psychomotor symptomatology also includes staring behavior similar to that seen in absence epilepsy. However, unlike absence seizures, which last only about 6

seconds, staring episodes in focal seizures with loss of awareness typically last about 1 to 3 minutes. Although rage reactions and aggression are sometimes reported in TLE, these behaviors are extremely rare. Aggressive behavior generally occurs late in a seizure and is usually un-directed. For instance, a patient might punch into the air, but he is unlikely to attack a person.

Evaluation of Seizure Disorders Obtaining a Description of the Seizure Meticulous history-taking is key to determining whether a spell, behavior, or abnormal movement in question is due to an epileptic seizure. Common seizure mimics include PNES , syncope, certain movement disorders, and behavioral changes. Eliciting a history of auras is important because patients might not consider them as epileptic phenomena. It is not unusual to elicit a history of nonspecific auras though the occurrence of epileptic auras in a stereotyped fashion is highly suggestive of epilepsy. Epileptic seizures last on average less than 2 minutes and may have triggers (such as sleep deprivation, use of alcohol, photic stimulation), and the loss of awareness; if/when it happens, it is usually followed by a period of post-ictal confusion. Patients can also sustain injuries, lateral tongue bites, and incontinence. PNES are a form of conversion disorder listed as a somatic symptom disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and likely share a common pathophysiology with other somatoform disorders. Patients with PNES frequently report and exhibit multiple functional motor symptoms. Consequently, there is increasing recognition that patients with PNES carry a neuropsychiatric diagnosis. Although epileptologists are the main caregivers for patients with PNES, the prognosis of the disorder depends highly on treating the neuropsychiatric co-morbidities and integrating the multidisciplinary treatment efforts of psychiatrists and social workers, and other practitioners. Patients with PNES can constitute up to 30% of patients seen in the epilepsy clinic, and it is also common for patients to have both epileptic and non-epileptic seizures. Features that might suggest PNES as an underlying diagnosis include: eye closure/fluttering, side-to-side head movements, preserved awareness, pelvic thrusting, opisthotonic posturing, influence by bystanders, and prolonged duration.

If an epileptic seizure is suspected, the goal of the history-taking is to also determine whether the epileptic seizure was focal or generalized in origin because this affects counseling and the management plan. Focal seizures are sometimes preceded by an aura; in TLE common auras include: affective (e.g., fear, euphoria); experiential (e.g., déjà vu , jamais vu ); abdominal (e.g., rising epigastric sensations); olfactory (e.g., usually a burnt smell); and gustatory (e.g., a metallic taste) auras. To correctly classify seizure disorder, the physician should carefully question the patient or a witness about the state of consciousness at the time of the seizure. If the patient remains conscious during the episode, the seizure is classified as focal without impairment of consciousness ; if the patient loses consciousness, the seizure is either generalized or focal with impairment of consciousness. The history should focus on identifying any clear triggers, given that the seizure can be a manifestation of several different systemic and central nervou s system (CNS) disorders. Because patients often have preconceived notions about the type of epilepsy they have, the physician should always ask for a detailed description of the seizures rather than accepting the patient’s reported “diagnosis” or accepting it at face value. Patients often mistakenly assume that “petit mal” simply means a relatively minor seizure and that “grand mal” means a major seizure. However, the distinction between the different types of epilepsy is considerably more complex. Nearly half of all adult patients will claim they have petit mal epilepsy (when they mean focal seizures with impaired consciousness). “Petit mal” seizures are a condition usually occurring in children between the ages of 2 and 9 years and they are rarely seen in adults. The physical exam following a seizure is also useful, looking for subtle focal signs that might indicate a focal seizure. Patients can experience a form of transient paralysis on one side, termed Todd’s paralysis , which is reversible and noted directly after the seizure. Although the physical examination is almost always normal, a few signs can provide clues to the diagnosis. Because some patients with epilepsy often have a history of brain lesions at an early age, the physician should look for evidence of hemi-atrophy. For example, if a patient is asked to place his hands palm to palm, you might find that one hand is smaller than the other. In focal seizures, the physical expression of an emotional response can be asymmetrical; for example, a smile can be one-sided. In about 80% of patients with asymmetrical emotional responses or reflexes, the responsible brain lesion is in the hemisphere opposite the weaker side of the body.

In the setting of new-onset seizures, a patient should receive a thorough workup with vital signs, blood work, urine toxicology, and some form of neuroimaging to rule-out any lesions or reversible etiologies, which need to be addressed. Provoked seizures do not require anti-seizure medications and are prevented by addressing the underlying trigger. For example, a patient with a seizure due to hypoglycemia would only need the glucose level corrected.

Obtaining an EEG Physicians should obtain an EEG if they suspect a seizure disorder. It is often possible to increase the yield of an EEG by asking the patient which events or stimuli seem to trigger a seizure and then trying to reproduce these in a controlled setting. For instance, if a patient says he has seizures after a sleepless night, you might ask him or her to remain awake overnight and then come in for an EEG the following day. In other patients, you might be able to induce abnormal brain activity by asking them to hyperventilate or by exposing them to a flashing light. Video EEG recordings involve the continuous EEG monitoring in a controlled inpatient setting with concomitant video recording, usually for 5 to 7 days or until a seizure that corresponds to the description of the patient is captured. The “gold standard” of diagnosing PNES is to capture a typical spell on video with a corresponding normal EEG to confirm the diagnosis. The history alone is not enough in most cases, and certain frontal-lobe seizures can look bizarre and can be mislabeled as PNES. Any spell that occurs out of sleep is concerning and deserves further investigation. Patients with new-onset seizures should receive some form of neuroimaging. MRI is better than computed tomography (CT), in which bone artifact can obscure the temporal lobe. However, in developing countries, where the prevalence of neurocysticercosis is high, a CT scan can be more effective at picking up to 61% of calcified lesions in a patient presenting with focal seizures. The initial MRI work-up should include contrast to rule-out enhancing lesions. In adults, because TLE is the most common type, higher-resolution MRIs, and coronal sections allow better assessments of the hippocampus to document atrophy or hyperintensity. If both are present this is suggestive of mesial temporal lobe sclerosis, one of the most common etiologies of epilepsy. Around one-third of the time, the MRI might be completely normal even if the epilepsy is focal.

Behavioral Changes in Epilepsy

Inter-Ictal Personality Changes Geschwind and colleagues described the following five types of personality changes associated with partial complex epilepsy: Hypergraphia Hyper-religiosity Hyposexuality Aggressiveness Viscosity The Russian author Fyodor Dostoyevsky is perhaps the best-known example of an epileptic with hypergraphia, which is the tendency to write prolifically. Some patients with epilepsy are deeply interested in religion, although not necessarily one of the world’s major religions. In some adult patients, the onset of seizures coincides with a sudden loss of interest in sex. Because patients rarely volunteer this information, the physician should make a point of asking whether the patient noticed any change in his or her sexual desire. Some patients with TLE also report a change in their sexual preference. Aggressiveness is distinct from the automatic aggressive behavior occasionally seen during seizures. Again, patients often do not volunteer information about this type of personality change. If patients are asked about their temper, they might become defensive or evasive. Upon further questioning, you might learn that they engage in aggressive behavior (such as breaking dishes or throwing objects out of a window). Finally, some epileptic patients develop a personality trait Geschwind called viscosity, meaning that the patients tend to be “sticky.” For example, some patients with TLE might call you every night, and once they start talking, they won’t stop. These five characteristic personality disturbances provide evidence that brain lesions can cause long-term changes in behavior.

Neuropsychiatric Manifestations Epilepsy is associated with a significant number of co-morbidities, whether stemming directly from the seizure disorder or indirectly from the psychosocial burden of living with the disease. Its neuropsychiatric manifestations are common, but under-diagnosed. In general, it is useful to categorize the symptoms as ictal (during the seizure), post-ictal (hours to days following the

seizure), and inter-ictal. Post-ictal symptoms might require brief interventions, whereas inter-ictal symptoms might require daily therapy. The prevalence of depression in epilepsy is reported to be as high as 55% and persists despite adequate seizure control. Its etiology is multi-factorial, including genetic, neurological, and iatrogenic factors. Interestingly, there is also a bidirectional relationship between epilepsy and mood disorders as patients with a history of mood disorders have a higher incidence of epilepsy suggesting possible common pathophysiological links. Depression significantly impoverishes the quality of life of patients with epilepsy and puts them at risk for suicide, and for worse outcomes after epilepsy surgery. There is also the described entity of inter-ictal dysphoric disorder, with prominent irritability, depressive moods, anergia, insomnia, atypical pains, anxiety, fears, and euphoric moods. An anxiety disorder is diagnosed in 25% of people with epilepsy, outside of the ictal manifestation of fear that can occur as part of a focal seizure. Psychotic symptoms are also seen, usually in the setting of chronic refractory epilepsy; the symptoms can be post-ictal and last a few days to weeks, or can be chronic. Moreover, many anti-epileptic medications exacerbate an underlying depression and suicidality, which should be always assessed in patients with epilepsy who appear depressed. Appropriate treatment should be instituted when depression or another psychiatric diagnosis is made. Bupropion should be avoided in patients with epilepsy, if possible; there is data that the immediate-release formulation above 450 mg/day lowers the seizure threshold. Other medications, such as lithium and clozapine, can also lower the seizure threshold and should be monitored closely. The data is not as strong for other antipsychotics, antidepressants, or stimulants. When psychosis occurs with epilepsy, it is most frequently a post-ictal phenomenon, although inter-ictal psychosis occurs, as well. Criteria for the diagnosis of post-ictal psychosis include the occurrence within 7 days of a seizure or a cluster of seizures (with a duration of 15 hours to less than 2 months) and a mental state characterized by delirium/delusions or hallucinations. An EEG is needed to rule-out that the behavior is ictal, and other possible etiologies, such as medication effects, head trauma, alcohol withdrawal, need to be ruled-out. Patients often develop a lucid period after their seizures prior to the emergence of the psychosis. Inter-ictal psychosis occurs in 3% to 7% of patients with epilepsy especially those with TLE. Psychosis could also be drug-induced and may last up to one

week. Common symptoms in inter-ictal psychosis and post-ictal psychosis include ideas of reference, delusions of persecution, auditory and visual hallucinations, grandiosity, religiosity, and logorrhea.

Therapy of Seizure Disorders The treatment of chronic epilepsy involves a multi-disciplinary approach including seizure control, the treatment of co-morbid neuropsychological and psychiatric manifestations, and the initiation of a pre-surgical evaluation (if an underlying brain lesion is identified, such as in the case of focal epilepsy). Nonmedication options include a ketogenic diet, neuromodulation with a vagal nerve stimulator or invasive electrodes, and epilepsy surgery. Ketogenic diets mimic aspects of starvation by forcing the body to burn fats rather than carbohydrates . Such a diet is high in fat, has adequate protein, and low-carbohydrate intake. It is used commonly to treat refractory epilepsy in children because they tend to tolerate the diet better. The treatment of an acute seizure requires another approach and a different set of treatment options. Finally, interventions that improve prognosis (such as maintaining a healthy diet, having an exercise routine, paying attention to better sleep hygiene, and engaging in more meaningful social support) should always be highlighted. In addition, spending meaningful time with a non-compliant patient to understand the psychosocial factors behind his or her resistance to treatment could avert an emergency department visit or a hospital admission for a breakthrough seizure. As a general rule, doses of anti-seizure medications used for mood stabilization are usually lower than those required for treating epilepsy, and dosing is usually twice a day (if an extended-release formulation is not used). Most medications also come in liquid formulation and extended-release formulation that can be tailored to the individual patient (see Table 41-2). Several seizure medications also can cause a life-threatening rash, such as Stevens-Johnson syndrome , and patients should be instructed to inform their physicians if any rash develops. A complete blood count and liver enzymes should be documented at least once after the initiation of a new treatment. Table 41-2: Anti-Seizure Medications Dose Range (mg) Carbamazepine 400–1,600

Liver Frequency* Enzymes

Mood Effects

BID/TID

+

Inducer

Anxiolytic Effects

Phenobarbital

50–200

BID

Inducer

Phenytoin

200–400

BID/TID

Inducer

Primidone

500–1,500

BID

Inducer

–

Sodium valproate

500–2,500

BID

Inhibitor

+

Eslicarbazepine 800–1,200

QD

Inducer**

Felbamate

1800–3,600

BID

Gabapentin

900–3,600

TID

Lacosamide

100–400

BID

Lamotrigine

100–300

BID

+

Levetiracetam

1,000–4,000

BID

–

Oxcarbazepine 600–2,400

BID

Perampanel

8–12

QD

Pregabalin

150–600

BID

Topiramate

100–400

BID

Vigabatrin

1,000–3,000

BID

Zonisamide

200–400

QD

–

+

– +

Inducer

+ – +

Inducer•

+/–

+/–

Older generation and newer generation antiseizure medications. Frequency is based on the immediate-release formulation of the medications. Dosing range should not be considered fixed, but should be adjusted based on levels depending on the medication. * QD = once daily; BID = two times daily; TID = three times daily ** Eslicarbazepine and topiramate (at high doses) are mild enzyme inducers.

Lorazepam Benzodiazepines , and especially lorazepam , are often preferred for treatment of an acute seizure and when patients have a compromised consciousness. Lorazepam can be easily used rectally or intravenously. The IV dose is usually 2 mg, to be repeated up to 8 mg (see Table 41-3 for management of acute seizures). Lorazepam can cause respiratory depression and drowsiness. Given its short half-life, lorazepam should not be used for the treatment of chronic epilepsy. Table 41-3: Management of Status Epilepticus Immediate: Assess airway, breathing and circulation

Establish continuous EKG and monitor blood pressure frequently Sample venous blood for glucose, electrolytes. BUN, and levels of anticonvulsant drugs Measure arterial pO2 , pCO2 , and pH

Within 5 minutes: Administer normal saline and thiamine IV Administer 50 ml of 50% normal glucose Administer an IV benzodiazepine Lorazepam (2 mg/min. max = 8 mg) OR diazepam (2 mg/min. max = 10 mg), Start phenytoin (20 mg/kg) IV in normal saline, no faster than 50 mg/min OR fosphenytoin (20 mg/kg) no faster than 150 mg/min OR levetiracetam (50 mg/kg) OR valproic acid (30 mg/kg) OR phenobarbital (20 mg/kg)

Within 30 minutes If seizures have not stopped: Add a second IV anticonvulsant (phenytoin, phenobarbital, levetiracetam, valproic acid)

After 30 minutes If seizures have not stopped: Intubate and start an anesthetic agent.

Phenytoin Oral and IV phenytoin has been a mainstay of epilepsy treatment since it was first used in the 1930s by two Boston physicians, Houston Merritt and Hillary Putnam. The United States Food and Drug Administration (FDA) first approved its use in epilepsy in 1953. Although the usual oral dosage for adults is 100 mg three times a day, the dose prescribed should be based on serum levels, which should be in the range of 10 to 20 μg/ml which is easy to achieve with the oral form. It is used to treat both acute breakthrough seizures and chronic epilepsy. If phenytoin is given intravenously, it must be delivered in a normal saline solution: if a 5% dextrose solution is used, the drug will precipitate and be ineffective. Also, when administered intravenously, the rate of administration should not exceed 50 mg/minute because this can cause fatal hypotension and cardiovascular collapse. Clinicians can determine when the drug has reached therapeutic levels by measuring the serum concentration. If the concentration reaches toxic levels, ataxia will develop.

The main side effect of phenytoin is drowsiness, which can be a major concern to many patients. To ensure compliance, the physician should warn patients about this potential effect and assure them that it is only temporary. Phenytoin is generally not prescribed during adolescence because it can induce hirsutism, acne, and gingival hyperplasia. Some patients might develop important medical complications, including megaloblastic anemia and osteopenia. In general, anemia develops quickly and it should be treated with vitamin B12 and folate. Osteopenia can develop over a long period in women and can lead to pathologic fractures. Some patients are allergic to phenytoin and develop erythema multi-forme and Stevens–Johnson syndrome up to 2 months after the start of therapy. It is important to inform patents about t he manifestations of Stevens–Johnson syndrome and emphasize that they should seek immediate medical attention at the first sign of this potentially fatal condition.

Carbamazepine The anti-convulsant carbamazepine is in general used for focal epilepsy. It should not be used in absence seizures because it exacerbates the disorder. The typical dosage for adults using the immediate-release formulation is 200 mg three times a day, with serum levels in the range of 4 to 12 mcg/ml. The major side effects of this agent are bone marrow suppression and hepatic toxicity. Like the related drug imipramine, carbamazepine has as an antidepressant-mood stabilizing effect.

Valproate Although valproate is considered the drug of choice for generalized genetic seizures. The usual adult dosage is 250 mg three times a day of the immediaterelease formulation with serum levels in the range of 50 to 100 μg/ml. The most significant side effects of valproate are alopecia, weight gain, and hepatotoxicity. Valproate should be absolutely avoided in pregnancy due to severe malformations, neural tube defects, elevated autism risks, and lower IQ scores in children who were exposed during pregnancy. Supplementing with folate does not provide complete coverage against valproate’s teratogenic effects. Every woman of child-bearing age should discuss with her health-care providers at length her use of anti-seizure medications, their benefits, and side effects (before pregnancy, during pregnancy, and post-partum). Other risks include liver failure,

lower platelet counts, and pancreatitis. Positive effects of the medication include mood stabilization and migraine prophylaxis.

Phenobarbital Phenobarbital is one of the first-generation anti-seizure medications and is still commonly used, especially in children. It is effective for focal and generalized epilepsy. Its main mechanism of action is on γ -amino butyric acid (GABA) receptors. Because it has a very long half-life, it is dosed daily and carries a low risk of withdrawal seizures. It is also a liver enzyme-inducer; thus, drug–drug interactions should be monitored. Serum levels should be monitored and the therapeutic range for adults is 15 to 40 µg/ml. Side-effects include sedation, hypersalivation, aggression, and connective tissue contractures with long-term use.

Treatment of Newly Diagnosed and Refractory Epilepsy: The Use of Second-Generation Anti-Seizure Medications A host of newer generation anti- epileptic drugs (AEDs) are available for the treatment of epilepsy and they are used increasingly. They provide a better sideeffect profile compared to the older medications, but they are not more efficacious. Drug–drug interactions are also less common given that some of the older anti-seizure medications (e.g., carbamazepine, phenobarbital, phenytoin) induce liver enzymes or inhibit them (e.g., valproic acid). FDA-approval for newer drugs is often as an adjunctive treatment in patients already on antiseizure medications for refractory epilepsy. Approval for monotherapy (in refractory or new-onset epilepsy) is sometimes sought, but not always present, and physicians may use these medications off-label as monotherapy.

Lamotrigine (Lamictal) Lamotrigine is widely used in psychiatry as a mood-stabilizer. It is also used to treat focal seizures, primary and secondary generalized seizures, as well as the Lennox-Gastaut syndrome. It is a member of the sodium-channel blocking class of medications. Lamotrigine has a “black-box warning” for the development of the Stevens–Johnson syndrome and other life-threatening dermatologic conditions. Roughly 5% to 10% patients develop a rash on lamotrigene. Only 1 in 1,000 develop a serious rash, and 1 in 50,000 die following the onset of a rash.

Starting low and ramping up slowly generally prevents development of this serious side effect. The incidence of life-threatening rashes has decreased now that slower titration regimens have been implemented. Other side effects include hepatotoxicity, tremor, loss of balance, double vision, difficulty with sleep, vivid dreams, nightmares, and thoughts of suicide. The main drug–drug interaction of note is that its levels drop almost by half when oral contraceptives are added. It has the safest profile during pregnancy, and also has mood-stabilizing effects.

Topiramate (Topamax) Topiramate can be used as monotherapy or as an adjunctive therapy in both focal and generalized epilepsy. It has also been used as a prophylactic agent for migraines. It is also used when weight loss is desired. Acute glaucoma, cognitive dulling, renal calculi, and thoughts of suicide are some of its side effects. Some patients complain of a tingling sensation in the arms; this is usually transient and lasts a few weeks upon initiation. It is sometimes used as a mood-stabilizer, but can also aggravate an underlying depression. At high doses, it is a mild liver enzyme-inducer.

Levetiracetam (Keppra) Levetiracetam is shown to decrease seizure frequency in both newly diagnosed focal and generalized epilepsy, and it has been used both as monotherapy and as an adjunctive therapy. It is highly effective when rapid control of seizure activity is needed. It can result in somnolence and dizziness. It should be used with caution in patients with psychiatric disturbances because it is known to contribute to agitation, anger outbursts, and depression.

Oxcarbazepine (Trileptal) Oxcarbazepine is FDA-approved as monotherapy in new-onset epilepsy and is used as add-on in refractory focal epilepsies. Its side effects are similar to those of carbamazepine and it can cause blood dyscrasias, hyponatremia, and excessive drowsiness. It is also a liver enzyme-inducer. It can also be used as a mood-stabilizer.

Pregabalin (Lyrica) Pregabalin remains an add-on drug for epilepsy treatment. It was FDAapproved for the treatment of epilepsy in 2004. It also targets neuropathic pain, fibromyalgia, and may have anxiolytic properties. Pregabalin can cause CNS depression, and lower extremity edema.

Zonisamide (Zonegran) Zonisamide is used to treat focal and generalized seizures in adults. It is often used as an add-on drug to other AEDs. Common side effects include drowsiness, headache, dizziness, loss of appetite, irritability, and agitation. Similar to topiramate, it also carries the risk of nephrolithiasis.

Vigabatrin (Sabril) The FDA-approved (2009) vigabatrin is used for the treatment of infantile spasms and for un-controlled focal seizures in adults. Its most serious adverse effects include vision loss and the onset of tunneled vision. As a result, it is not commonly used in adults. The need for vigabatrin should be continuously reassessed.

Lacosamide (Vimpat) Lacosamide was FDA-approved (2009) as an adjunctive treatment in focal epilepsy, and in conversion to monotherapy for refractory epilepsy. It is also used to treat peripheral diabetic neuropathy. Lacosamide can increase the PR interval; therefore, an EKG is recommended prior to its initial administration. Cognitive and behavioral side effects are minimal.

Felbamate (Felbatol) Felbamate is used to treat certain seizures in adults and children with epilepsy when the seizures are refractory to all other antiseizure medications. It was first marketed for treatment of Lennox-Gastaut syndrome/infantile spams in young infants and children. Felbamate use has been linked to cases of fatal aplastic anemia. When used, it should be closely monitored.

Eslicarbazepine (Aptiom) One of the newer AEDs, eslicarbazepine is chemically linked to carbamazepine and oxcarbazepine. Current FDA-approval is for add-on treatment, and conversion to monotherapy in refractory epilepsy. Side effects include dizziness, somnolence, diplopia, and hyponatremia. It is unclear whether it has any moodstabilizing properties.

Perampanel (Fycompa) Perampanel has a novel mechanism of action because it targets AMPA receptors. It is FDA-approved as an add-on for refractory seizures, and in the treatment of primary generalized tonic-clonic seizures. Common side effects

include dizziness and fatigue. Most important, it has an FDA-warning about its neuropsychiatric side effect risk, including suicidal and violent behavior.

AEDs and Suicidal Ideation: Black Box Warning AEDs have been linked with thoughts of suicide and depression . Among older AEDs, barbiturates were linked with higher rates of depression in adults with epilepsy as well as with higher rates of suicide in children with epilepsy. Major depression was noted in 40% of children receiving phenobarbital as compared with 4% of those receiving carbamazepine. The FDA issued a warning in 2008 about an increased risk of suicide for 11 AEDs (carbamazepine, felbamate, gabapentin, lamotrigine, leviteracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide), following a meta-analysis that found a 1.8-fold increased risk for suicidal thinking for all AEDs. Many argued that this meta-analysis was flawed and that the data from different AEDs were grouped together despite each of them having a different mechanism of action, and prior psychiatric history was not always accounted for. A Danish study found that phenobarbital, clonazepam, valproate, and lamotrigine, increased the risk of suicide shortly after the initiation of therapy (with odds ratios of 1.96, 2.01, 2.08, and 3.15, respectively). It is important to recognize that depression and suicidality are increased in the setting of epilepsy, and should be routinely screened for and treated on a caseby-case basis. Failing to screen for and to treat co-morbidities increases disease burden (e.g., premature death and/or decreased functionality) and adds to the costs for antidepressant use and for psychiatric hospitalizations.

Surgery for Refractory Epilepsy The most challenging and rate-determining step in the care of any epilepsy patient referred to surgery is the accurate localization of his or her epileptogenic zone, defined as the culprit area of the cortex where seizures arise. For this reason, a pre-surgical assessment might include tests that aim to identify this area. These include MRI, video EEG, singl e-photon emission computerized tomography (SPECT) scan, positron emission tomography (PET) scan, magnetoencephalography (MEG), and neuropsychological testing. Video EEG can be useful especially when epilepsy surgery is contemplated to better define the epileptic lesion. Intra-cranial recordings are sometimes warranted and involve

the surgical placement of sensory grids directly on the surface of the brain or use of intraparenchymal electrodes. In addition, the Wada test might be used in some centers to identify language and memory dominance, whereas other centers rely on functional MRI scans. Anterior temporal lobectomy is the most common epilepsy surgery and has the highest rates of seizure freedom. Because surgery can be curative, medically refractory patients should be referred to epilepsy centers for a pre-surgical evaluation. Patients, who do not achieve post-surgical seizure-freedom, have higher rates of post-surgical anxiety, depression, low self-esteem, and worse selfreported health and quality of life.

Vagal Nerve Stimulation The vagal nerve stimulator is a neuromodulatory option for the treatment of epilepsy. Its mechanism of action is unclear, but, similar to other neuromodulatory interventions, it takes months to years for its effect to take hold. It should not be viewed as a curative option; rather, it might help to decrease seizure frequency in approximately half of patients in whom it was used. It is especially useful in patients with epileptic encephalopathies and atonic seizures. It can also have positive effects on mood. The complications of vagal nerve stimulation (VNS ) can be related to the surgery itself (e.g., injury to the vagus nerve or carotid sheath) resulting in hoarseness, cough, dysphonia, and paraesthesias, or can involve longer-term complications (including infections, heart rate changes).

Suggested References Epilepsy General 1. Berg AT, Berkovic SF, Brodie MJ, et al: Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010; 51(4): 676–685. 2. Perucca E, Tomson T: The pharmacological treatment of epilepsy in adults. The Lancet. Neurology . 2011; 10(5): 446–456. 3. Wyllie E, Cascino GD, Gidal B, et al: Wyllie’s treatment of Epilepsy: Principles and Practice. 6th Ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015.

Psychiatric Aspects of Epilepsy 1. Adachi N, Kanemoto K, de Toffol B, et al: Basic treatment principles for psychotic disorders in patients with epilepsy. Epilepsia. 2013; 54(Suppl 1): 19–33. 2. Fiest KM, Dykeman J, Patten SB, et al: Depression in epilepsy: A systematic review and meta-analysis. Neurology . 2013; 80(6): 590–599. 3. Geschwind N: Behavioral change in temporal lobe epilepsy. Arch Neurology . 1977; 34: 453. 4. Holmes G, Schachter SC, Kasteleijn-Nolst Trenite: Behavioral Aspects of Epilepsy: Principles and Practice . New York: Demos Medical Publishing; 2008. 5. Kanner A, Schachter SC: Psychiatric Controversies in Epilepsy . Amsterdam: Elsevier/Academic Press, 2008. 6. Kanner AM: Management of psychiatric and neurological co-morbidities in epilepsy. Nature Reviews . Neurology . 2016; 12(2): 106–116. 7. Khoshbin S: Van Gogh’s malady and other cases of Geschwind’s Syndrome. Neurology . 1986; 36(Suppl): 213–214. 8. Logsdail SJ, Toone BK: Post-ictal psychoses. A clinical and phenomenological description. Br J Psychiatry . 1988; 152: 246–252. 9. Lyketsos CG, Kozauer N, Rabins PV: Psychiatric manifestations of neurologic disease: Where are we headed? Dialogues in Clin Neurosci . 2007; 9(2): 111–124. 10. Perez DL, Dworetzky BA, Dickerson BC, et al: An integrative neurocircuit perspective on psychogenic non-epileptic seizures and functional movement disorders: Neural functional unawareness. Clin EEG and Neurosci . 2015; 46(1): 4–15. 11. Trimble MR, Schmitz B: The Neuropsychiatry of Epilepsy . 2nd ed. Cambridge, UK: Cambridge University Press; 2011.

CHAPTER Headache 42 SHAMIM H. NEJAD, MD; JOHN DENNINGER, MD, PHD; EDWARD R. NORRIS, MD; AND MARTIN A. SAMUELS, MD

KEY POINTS Overview Headache is one of the most frequent complaints heard in medical practice and is the most common reason for referral to a specialist. Headache is so common that virtually everyone has had at least one headache, and 90% of Americans have headaches occasionally. The majority of these are migraine, tension, or cluster headaches. Epidemiology Up to 90% of all benign headaches fall under a few categories: migraine, tension-type, cluster, and chronic daily headache. Episodic tension-type headache is the most frequent headache type. Migraine is the most common diagnosis in patients presenting to primary care physicians with headache. Migraine prevalence in women is estimated at 20%; the ratio of females to males is 3:2. There is a family history of migraines in 90% of those who suffer from migraines. Cluster headache typically leads to significant disability and most of these patients will come to medical attention. Cluster headaches are not associated with a family history. Their prevalence is estimated less than 0.4%. The maleto-female ratio of cluster headaches is 5:1. Clinical Features Migraines: Individual migraine symptoms are usually stereotypic and recurrent for every patient. Migraine headaches present with a unilateral pulsating headache, often in the fronto-temporal region. Sensory hypersensitivity (including photophobia and phonophobia) are common features. Autonomic dysfunction and disability often accompany the migraine and can cause

nausea, vomiting, and slow gastric emptying. Cluster headaches: Cluster headaches (that are often sharp and retro-orbital) peak in 5 to 10 minutes and can last up to three hours; they occur in clusters (of one to eight times daily for several weeks). Autonomic dysfunction is present with injected conjunctiva, nasal blockage, profuse sweating, facial flushing, ptosis, or miosis. Onset is usually in middle-age and can have a cyclical pattern that occurs in the spring. Tension-type headaches: These are often precipitated by stress and result in band-like pain around the head; this pain can be generalized or located in the frontal, occipital, or cervical areas. It is not associated with photophobia or phonophobia. The onset is usually brief and the pain is worse during the day. Secondary headaches: These headaches often do not follow a characteristic pattern of migraine, tension-type, or cluster headache. Structural causes should be suspected with an abnormal neurological examination or when the headache is acute or progressive. Differential Diagnosis The patient’s history is the primary diagnostic tool. There can be overlap in symptoms, particularly between migraine and tension-type headache and between migraine and some secondary causes of headache, such as sinus disease. Abnormal physical examination or neurological findings should raise the suspicion for a secondary headache, and, if indicated, further evaluation should be pursued to evaluate for potential emergent conditions. Approaches to Evaluation The examination of a headache patient must include a neurological examination, a fundoscopic examination (searching for papilledema), and a physical examination of the head (observing and palpating for tenderness or masses, along with listening over the temples and eyes for bruits). The neurological examination is aimed at excluding lateralized or focal findings (especially on visual field confrontation and testing of strength and gait). Further testing and work-up is required when the history suggests a specific diagnosis (e.g., epilepsy or tumor); the headaches develop a new quality or become intractable; the history is atypical (e.g., trigeminal neuralgia that may suggest multiple sclerosis in a young patient); or when the neurological examination is abnormal.

Treatment Migraines: Reduction of aggravating factors (e.g., caffeine intake, alcohol [especially red wine], chocolate, peanuts) can reduce headache frequency. Abortive treatment is effective for patients who have infrequent headaches. Effective treatments for mild to moderate headaches include analgesics, NSAIDs, or caffeine adjuvant combinations. For more severe headaches, ergotamine and dihydroergotamine, the selective 5-HT1 antagonists are the most effective. Cluster headaches: Treatments to abort headaches include use of 100% oxygen (by mask for 15 minutes), or vasoconstrictive medications and sumatriptan. Prophylactic treatment includes use of calcium-channel blockers (e.g., verapamil) or lithium carbonate. Tension type headaches: Tension type headache can be precipitated by stress. Exercising, jogging, having a neck massage, taking a hot bath, or engaging in other stress relieving activities often ameliorate symptoms. Effective pharmacological treatments include use of NSAIDs, and simple analgesics (with and without caffeine and NSAIDs); however, these medications should be limited to use for fewer than three or four days per week to prevent medication over-use headache. Secondary headaches: the treatment of secondary headaches largely depends on the cause of the headache, and may necessitate acute intervention.

Introduction Headache is one of the most frequent complaints heard in medical practice and it is the most common reason for referral to a specialist. Headache is so common that virtually everyone has had at least one headache, and 90% of Americans have headaches occasionally. The majority of these are migraine, tension, or cluster headaches. Although most who experience headache treat themselves, those who see a doctor almost always experience pain and are worried about a serious underlying disease (such has a brain tumor, aneurysm, or stroke).

Evaluation of the Patient with a Headache Medical History Obtaining a thorough headache history is the most important step in the assessment of the patient. Typically, with the information derived from the history and the physical examination, a diagnosis can be made.

The optimal history begins by asking open-ended questions in a supportive manner. The history must identify the severity and character of the headache, the onset and duration of the headache, precipitating and ameliorating factors, the effect of medications, and other associated symptoms. Acute or steadily progressive headaches are often signs of life-threatening diseases of the brain (including temporal arteritis, intracranial mass lesions, pseudotumor cerebri, meningitis, and subarachnoid hemorrhage).

Examination The examination of a headache patient must include a neurological examination, a funduscopic examination, and a physical examination of the head. The neurological examination is aimed at excluding lateralized or focal findings (especially on visual field confrontation, and testing of strength and gait). A funduscopic examination should search for papilledema. A physical examination of the head should include observing and palpating for tenderness or masses, along with listening over the temples and eyes for bruits.

Ancillary Tests It is unusual for any test to demonstrate an abnormality not suggested by the history and the physical examination. A test is indicated when the history suggests a specific diagnosis (e.g., epilepsy or tumor), the headaches develop a new quality or become intractable, the history is atypical (e.g., trigeminal neuralgia that might suggest multiple sclerosis in a young patient), or when the neurological examination is abnormal. Imaging with a non-contrast computerized tomographic (CT) scan of the head has almost no risk and will pick up all important causes of headache; however, magnetic resonance imaging (MRI) scans of the head are more sensitive but more expensive. A lumbar puncture is indicated when increased intracranial pressure or infection is suspected. An elevated erythrocyte sedimentation rate (e.g., > 70 mm/hr) suggests giant cell arteritis in an elderly person with newonset headache. An electroencephalogram (EEG), evoked responses, and an angiogram are rarely indicated in the evaluation of headache.

Headache Syndromes Migraine

Migraine headaches are a type of vascular headache. The term vascular headache is somewhat of a misnomer because the name implies that the cause is entirely related to blood vessels; most evidence indicates that the cause is an abnormality in neurotransmitters (e.g., substance P) that deal with pain perceptions associated with inconsistent secondary vascular phenomena. The term vascular is meant to emphasize the pulsatile nature of the pain. The frequency and severity of vascular headaches occur on a spectrum (from infrequent brief pains to daily severe migraine headaches). Migraine headaches are common and their prevalence in females is estimated at 20%. The ratio of females to males is 3:2. There is a family history of migraines in 90% of those who suffer from them. Individual migraine symptoms are usually stereotypic and recurrent for every patient. Migraine headaches present with a unilateral pulsating headache, often in the fronto-temporal region. Sensory hypersensitivity (including photophobia and phonophobia) are common features. Autonomic dysfunction and disability often accompany the migraine and can cause nausea, vomiting, and slow gastric emptying. Although rare, personality changes can also occur. Migraine patients usually have a life-long history that varies with age. The history often starts in infancy (with colic and episodic abdominal pain). Headaches can begin in puberty and wax and wane throughout the lifespan with long headache-free intervals. Vascular headaches often improve in middle age. Headaches can last from seconds to days, but usually last between 4 and 24 hours. Patients are usually the best informants on what precipitates their headaches. Many foods (such as aged cheese, red wine, chocolate, and peanuts) can precipitate migraines. Skipping meals, having too little or too much sleep, and being faced by other psychological stresses can also aggravate vascular headaches. Birth control pills can make headache better or worse, whereas pregnancy often ameliorates vascular headaches. Common migraines (migraine without aura) are more frequent, however, migraine headaches can be preceded by an aura (migraine with aura). Auras, which usually persist for about 20 minutes, can be moving visual lights but can include visual field cuts (scotoma) and flashing zig-zag lines (scintillations), and may consist of any particular transient alteration in any neurological function. There is a range of treatments available for the migraine patient. Reduction of aggravating factors (e.g., caffeine intake, alcohol [especially red wine], chocolate, peanuts) can reduce headache frequency.

Abortive treatment is effective for patients who have infrequent headaches. It is important to treat early (at the onset of headache or aura). The most common reason for poor efficacy of treatment is a delay between when the headache begins and when the patient takes the medication. Effective treatments for mild to moderate headaches include analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), or caffeine adjuvant combinations. For more severe headaches, ergotamine and dihydroergotamine, or the selective 5-HT1 antagonists (e.g., sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan) are the most effective. Suppositories, nasal sprays, and injections can be used when oral medication is ineffective or contraindicated because of nausea and emesis. Adjunctive anti-emetic and prokinetic medications (e.g., metoclopramide) can be used to increase gastric absorption of oral medications and to minimize nausea and vomiting. Prophylactic treatment might be necessary for a patient with frequent headaches. Beta-blockers, calcium-channel blockers, antidepressants, serotonin antagonists, anti-epileptic medications, and NSAIDs have all been used effectively for preventative migraine treatment. Lipophilic beta-blockers are the most effective (e.g. propranolol, atenolol, nadolol). The calcium-channel blocker verapamil can be useful in patients who cannot tolerate a beta-blocker, but it is generally more effective for cluster-like headaches. Valproic acid has also demonstrated efficacy. Cyproheptadine, a weak serotonergic-blocking drug, is effective in many cases, and anticholinergic tricyclics (e.g., amitriptyline) are used effectively. Status migrainosis is diagnosed when a migraine lasts longer than 72 hours. Steroids in a rapid taper can abort longer migraine headaches. When this is ineffective intravenous barbiturates can be used to induce coma.

Cluster Headaches Unlike migraine headaches, cluster headaches are not associated with a family history. Their prevalence is estimated at less than 0.4%. The male-to-female ratio of cluster headaches is 5:1. The aptly named cluster headaches occur in clusters (of one to eight times daily for several weeks). Cluster headache pain is often sharp and retro-orbital. Autonomic dysfunction is present with injected conjunctiva, nasal blockage, profuse sweating, facial flushing, ptosis, or miosis. Symptom severity has been associated with increased suicidality in patients suffering from cluster headaches.

Their onset is usually in middle-age and can have a cyclical pattern that occurs in the spring. The cluster headache pain peaks in 5 to 10 minutes and can last up to three hours. Persons with cluster headaches are sensitive to alcohol. Cluster headaches often occur several hours after going to sleep and are not relieved by sleep. Tobaccosmoking can also precipitate headache. Treatments to abort headaches include use of 100% oxygen (by mask for 15 minutes), or vasoconstrictive medications and sumatriptan. Prophylactic treatment includes use of calcium-channel blockers (e.g., verapamil) or lithium carbonate (aimed at achieving a blood level of 0.6 to 1.0 mmol/L).

Tension-Type Headaches Tension-type headaches (TTHs ) have not been associated with increased pericranial muscle contraction; instead, the mechanism is thought to be related to increased pain sensitivity. A family history is common and their prevalence is higher in women than in men. The pain is band-like around the head. It can be generalized or located in the frontal, occipital, or cervical areas. It is not associated with photophobia or phonophobia. The onset is usually brief and the pain is worse during the day. Tension type headaches can be precipitated by stress. They are often relieved by alcohol. Exercising, jogging, having a neck massage, taking a hot bath, or engaging in other stress-relieving activities often ameliorate symptoms. Many non-medical treatments (including biofeedback, relaxation techniques, physical therapy, stress reduction) are effective. Patients should avoid expensive or potentially-harmful strategies. Benzodiazepines and narcotics, although effective, should be avoided. Effective pharmacological treatments include use of simple analgesics (with and without caffeine and NSAIDs); however, these medications should be limited to use for fewer than three or four days per week to prevent medication overuse headache.

Secondary Headaches These headaches often do not follow a characteristic pattern of migraine, tension-type, or cluster headache. Structural causes should be suspected with an abnormal neurological examination or when the headache is acute or progressive.

Post-Traumatic Headache

Up to half of all people with concussions have headaches for two months after the incident. Acceleration and deceleration forces of the injury can cause shear injuries of neurons. The extent of the contribution of psychosocial and medical– legal factors to this syndrome is unclear and this should be explored cautiously in the evaluation. Post-traumatic headaches usually occur within 14 days of a head injury and they resemble migraine or tension headaches. Nausea, vomiting, dizziness, vertigo, and mood symptoms can also occur. Treatment is similar to that of tension and migraine headaches, as previously described. Likewise, benzodiazepines and narcotics should be avoided.

Sub-Arachnoid Hemorrhage The cause of sub-arachnoid hemorrhage is rupture of a cerebral artery, usually from the circle of Willis or from rupture of a vascular malformation. Head trauma and a bleeding diathesis (e.g., thrombocytopenia or a factor deficiency) can also result in a sub-arachnoid hemorrhage. Hypertensive crises caused by ingestion of tyramine by patients on monoamine oxidase inhibitors (MAOIs) or the use of cocaine can also cause sub-arachnoid hemorrhage. A severe headache with nuchal rigidity is the most common symptom. A sentinel bleed or leak with milder headache can occur during exercise, with straining, or during sexual intercourse. Diagnosis is made by performing a lumbar puncture or by neuroimaging. Treatment is the repair of the leaking or ruptured blood vessel. Intravenous (IV) phentolamine, an alpha-adrenergic blocking agent, should be used in patients with MAOI-related hypertensive headaches.

Giant Cell (Temporal) Arteritis Patients with temporal arteritis are usually older than 55 years. Although the etiology is unknown, histology reveals a focal granulomatous arteritis containing giant cells. The erythrocyte sedimentation rate (ESR) is usually greater than 40 mm/hr. The pain is typically a dull, continuous headache in the temples, and in advanced stages, the temporal arteries appear inflamed. The headache can be accompanied by dysphoric mood, pain, joint stiffness, fever, weight loss, night sweats, and visual loss (including amaurosis fugax). Chewing can precipitate the pain (jaw claudication). Treatment with high-dose steroids is standard; untreated arteries can occlude, causing blindness or stroke.

Idiopathic Intra-Cranial Hypertension (Pseudotumor Cerebri) These headaches usually occur in young obese women, sometimes with menstrual abnormalities. Although the pathophysiology is unknown, interstitial brain edema and decreased cerebrospinal fluid (CSF) absorption at the arachnoid villi are the hypothesized mechanisms. The headache is a dull, generalized pain. Papilledema is usually present. Unlike the mass-lesion headache, there is no alteration in personality or cognitive function. Treatment includes serial lumbar punctures to relieve symptoms. Diuretics are helpful, as is a steroid taper. Dieting can also reduce headache severity. Surgical placement of a shunt can be used in refractory cases.

Low CSF Pressure Headaches Post-lumbar puncture headaches are the most common of this type, but headaches can occur following trauma, an operation, or with an idiopathic CSF leak. Pain is bilateral, and nausea, blurred vision, photophobia, and postural syncope are often present. Symptoms usually last several days and rarely persist for weeks. The pain is worse within 15 minutes of the patients sitting or standing and is worsened by cough, strain, or head movement. It is relieved within 30 minutes of lying flat. Remaining flat in bed and taking analgesics are the most effective treatments. Injection of sterile autologous blood (blood patch) in the epidural space can seal the leak.

Headaches Secondary to Infections Acute meningitis is usually caused by meningococcus or pneumococcus and often occurs in small epidemics in confined areas. Acute meningitis is associated with a rapid onset of a severe headache with photophobia, fever, nuchal rigidity, and malaise. Chronic meningitis occurs most frequently in people with a compromised immune system, especially in those with AIDS, those on steroids, or the elderly. Chronic meningitis is associated with a continuous dull headache with symptoms of systemic illness and cognitive decline. Herpes simplex encephalitis has a predilection for the inferior surface of the frontal and temporal lobes. It causes fever, somnolence, delirium, and complex partial seizures with amnesia.

Diagnosis is facilitated by performing a lumbar puncture and neuroimaging. Treatment with appropriate antibiotics is the cure.

Intra-Cranial Mass Lesions Headaches from mass lesions are caused by an increase in intracranial pressure. The pain is often bilateral, dull, and mild. Papilledema is often absent. Subtle personality and cognitive changes are usually present. Lateralized neurological signs often occur within weeks of the onset of symptoms. An increase in intracranial pressure by bending or coughing can worsen headaches. Treatment is the removal of the mass-causing lesion.

Headaches Due to Substances and/or their Withdrawal Iatrogenic headaches are caused by use of medicines. The addition or withdrawal of a medication or substance can precipitate them. People who have migraines or other headaches and who use medications to treat their original headache encounter these headaches. The diagnosis is confirmed after exclusion of other causes. These headaches are not usually associated with nausea, a throbbing sensation, or hypersensitivity. They can mirror the symptoms of tension headaches. The onset occurs after the discontinuation or the addition of a substance. This type of headache can last many weeks without treatment. These headaches are precipitated by the addition of nitroglycerin or isosorbide. The withdrawal of external substances, including caffeine, can cause headaches. The withdrawal of any substance used to treat headaches (including aspirin, acetaminophen, NSAIDs, and narcotics), can precipitate headaches. Discontinuation of the causative substance or re-introduction of the substance that was withdrawn effectively stops the headache. A brief course and taper of steroids (e.g., prednisone 30 mg/d, 20 mg/d, 10 mg/d) can help break the cycle.

Trigeminal Neuralgia (Tic Douloureux) This type of headache is common in patients over the age of 60 years. The usual cause is compression of the trigeminal nerve root by a cerebral blood vessel at it origin from the brainstem. Occurrence in young people may suggest multiple sclerosis with a plaque involving the trigeminal nerve root. Trigeminal neuralgia is manifested by brief (20 to 30 seconds) jabs of sharp pain that extend along the three divisions of the fifth cranial nerve. The pain usually subsides at night. Unlike other headaches, stimulation of affected areas by touch, eating, or drinking cold liquids results in a sharp pain.

Injection of an anesthetic in the nerve root can stop the pain. Use of carbamazepine is often helpful. In refractory cases, surgical placement of a barrier between the vessel and the trigeminal nerve may be necessary.

Conclusions Headache is common, with 90% of Americans having had an occasional headache. Patients who are seen for evaluation of headache are typically in pain and worried about a serious underlying disease. Evaluation of headache involves taking a careful history with identification of the severity and character of the pain, the onset and duration of the pain, the precipitating and ameliorating factors, the effect of medications, and associated symptoms. Examination of the patient must include a neurological examination (focused on excluding lateralized or focal findings), a funduscopic examination, and a physical examination of the head. Migraine, cluster, and tension-type headaches account for the majority of headache syndromes. Patients with headaches that do not follow a characteristic pattern or who have an abnormal neurological examination require a thorough work-up for possible underlying etiologies.

Suggested Readings 1. Buse DC, Silberstein SD, Manack AN, et al: Psychiatric co-morbidities of episodic and chronic migraine. J Neurol . 2013 Aug; 260(8): 1960–1969. 2. Freitag FG, Schloemer F: Medical management of adult headache. Otolaryngol Clin North Am . 2014 Apr; 47(2): 221–237. 3. Ghadiri-Sani M, Silver N: Headache (chronic tension-type). Systematic review 1205. BMJ Clinical Evidence . 2016 February. 4. Holland S, Silberstein SD, Freitag F, et al: Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology . 2012 Apr 24; 78(17): 1346–1353. 5. Kaufman DM, Millstein MJ: Kaufman’s Clinical Neurology for Psychiatrists . 7th ed. New York: W.B. Saunders Company; 2013: pp. 181– 200.

6. Nicolson SE: Headache. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Saunders/Elsevier, 2016; pp. 839–851. 7. Samuels MA: Video Textbook of Neurology for the Practicing Physician . Boston: Butterworth-Heinemann; 1999. 8. Silberstein SD, Holland S, Freitag F, et al: Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology . 2012 Apr 24; 78(17): 1337–1345. 9. Silberstein SD, Lipton RB, Goadsby PJ: Headache in Clinical Practices . London: Martin Dunitz Ltd; 2002.

CHAPTER 43 Pain SHAMIM H. NEJAD, MD AND MENEKSE ALPAY, MD

KEY POINTS Overview Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience arising from the actual or potential tissue damage or described in terms of such damage.” An individual’s previous physical conditioning, affective state, and individual/endogenous system of analgesia, all affect the pain experience. A multi-disciplinary approach is not only effective but usually required in controlling pain and restoring function. To manage pain effectively, it is important to have an understanding of the underlying pathophysiology, pain categories, and treatment therapies available. Epidemiology Pain symptoms affect more than 100 million people in the United States and accounts for 20% of outpatient visits, 12% of all prescriptions, and more than $100 billion in direct and indirect expenses. Pain-related costs (direct and lost wages) for the United States exceed those for cancer, heart disease, and diabetes combined. Chronic pain is among the most common reasons for seeking medical attention and is reported by 20% to 50% of patients seen in primary care. Although pain is one of the most common presenting symptoms to the primary care setting, only a small percentage of patients ultimately develop a chronic pain syndrome. In a study based on a survey of representative population in the United States from 1999 to 2002, chronic pain (defined as more than 3 months of pain) was related to: chronic regional pain 11.1%; back pain 10.1%; leg/foot pain 7.1%; arm/hand pain 4.1%; widespread pain 3.6%; and headache 3.5%. The majority of patients who report chronic pain have more than one type of pain. Clinical Features

Pain is often categorized as being either nociceptive or neuropathic. Other pain schemas define additional categories (psychogenic or muscle pain). Distinguishing between nociceptive and neuropathic pain has implications for evaluation and treatment. Nociceptive pain is the perception of input, usually due to tissue damage (e.g., post-operative pain). It is further sub-divided into somatic and visceral pain. Somatic pain arises from injury to body tissues. It is well localized but variable in description and experience. Visceral pain arises from the viscera mediated by stretch receptors. It is poorly localized, deep, dull, and cramping (e.g., pain associated with appendicitis, cholecystitis, or pleurisy). Neuropathic pain arises from abnormal neural activity secondary to disease, injury, or dysfunction of the nervous system. Neuropathic pain is further subdivided sympathetically-mediated pain, peripheral neuropathic pain, and central pain. Sympathetically-mediated pain arises from a peripheral nerve lesion and is associated with autonomic changes (e.g., complex regional pain syndrome I and II, and causalgia). Peripheral neuropathic pain is secondary to damage to a peripheral nerve without autonomic change (e.g., post-herpetic neuralgia). Central pain arises from abnormal central nervous system activity (e.g., phantom limb pain, spinal cord injuries, and post-stroke pain). Etiology Pain can be divided into one of four categories, which are not mutually exclusive: neuropathic pain, musculoskeletal pain, inflammatory pain, and visceral pain. Approaches to Evaluation A thorough history is mandatory in the evaluation of the patient with chronic pain. The history should review all components of a usual medical history, in addition to specific items related to pain. A detailed history related to the circumstances surrounding the onset of pain and potential mechanisms of injury should be obtained. Open-ended questions, at least initially, should be used to ascertain the nature of the pain. Descriptors (such as sharp, dull, squeezing, throbbing, colicky) can be offered if the patient cannot fully describe his or her symptoms.

Patients should be questioned about the impact of pain on function (social and physical) and overall quality of life. Areas of impact include: social and recreational functioning; relationships; occupation; mood, affect, and anxiety; sleep; and exercise. The impact of pain on activities of daily living should be assessed along with activities that are required to live independently (instrumental activities of daily living). Treatment Pharmacologic approaches are the most widely used therapeutic options to ameliorate persistent pain. For many patients, an approach that combines drugs that target different pathways can result in improved analgesia and fewer side effects. Co-morbidities should be evaluated and treated. This includes, major depression and chronic pain, which frequently co-exist, and both conditions must be addressed to maximize the treatment response for either disorder. The major categories of pharmacologic options for pain management include non-opioid analgesic medications, opioids, and adjuvants. These include: nonopioid analgesic agents (e.g., aspirin , acetaminophen , non-steroidal antiinflammatory drugs); opioids; alpha-2 adrenergic agonists; antidepressants (tricyclics and serotonin-norepinephrine re-uptake inhibitors); antiepileptic drugs (gabapentin , pregabalin , and other anticonvulsants); muscle relaxants, N -methyl-d-aspartate receptor antagonists; and topical analgesic agents. Non-pharmacologic interventions include: behavioral medicine approaches; cognitive-behavioral therapy; biofeedback; relaxation therapy; psychotherapy and individual or group counseling; exercise; acupuncture; physical and occupational therapy; osteopathic manipulation; ultrasonic stimulation; electrical neuromodulation; transcutaneous electrical nerve stimulation; spinal cord stimulation; thermal applications (heat/cold); interventional approaches; botulinum toxin injections; nerve blocks; trigger point injections; epidural steroid injections; and surgical approaches.

Introduction Pain is a common, yet complex and challenging symptom. It is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience arising from the actual or potential tissue damage or described in terms of such damage.” This definition recognizes the fact that pain has both an acute nociceptive aspect and an underlying psychological dimension.

An individual’s affective state, previous conditioning, and endogenous system of analgesia, all affect the experience of pain. Frequently, a multi-disciplinary approach is not only effective but required in controlling pain and restoring function. To manage pain effectively, it is important to understand the underlying pathophysiology, categories, and treatments available.

Pathophysiology of Pain Nociception Nociception is the neural mechanism of detection of noxious stimuli; however, it should not be viewed as being synonymous with pain. Differentiation of somatic pain, involving activation of nociceptors in peripheral tissues, and visceral pain, which involves activation of nociceptors in bodily organs, can be difficult. Somatic pain is usually well localized, attributable to certain anatomical structures or areas, and is typically characterized as stabbing, aching, or throbbing. Visceral pain is typically poorly localized, not necessarily attributable to the involved organ (i.e., referred pain), and can be described as dull and crampy.

Peripheral Conduction of Nociception Pain originating from the skin is often used as the model for nociception. Nociceptors in the skin transduce mechanical, thermal, and chemical stimuli into action potentials. When tissue is injured, nociceptors are stimulated by the liberation of prostaglandins, arachidonic acid, histamine, and bradykinin. Aspirin, acetaminophen, steroids, and non-steroidal anti-inflammatory agents (NSAIDs) act at this stage of the pain pathway. Subsequently, axons transmit the pain to the spinal cord (to cell bodies in the dorsal root ganglia). Three different types of axons are involved in transmission of painful stimuli from skin to the dorsal horn. They are classified by their diameters; their velocity being directly proportional to the diameter and thickness of the myelin sheath. A-β fibers are the largest and most heavily myelinated fibers that transmit awareness of light touch. A-D fibers and C fibers are the primary nociceptive afferents. A-D fibers are 2 to 5 micrometers in diameter and are thinly myelinated. They conduct immediate, rapid, sharp, and brief pain (first pain) with a velocity of 20 m/second. C fibers are 0.2 to 1.5 micrometers in diameter and are unmyelinated. They conduct prolonged, burning, and unpleasant pain (second pain) at a speed of 0.5 m/second. A-D and C fibers enter the dorsal root and ascend or descend one to three segments before

synapsing with neurons in the lateral spinothalamic tract (substantia gelatinosa in the gray matter).

Central Conduction of Nociception A-D and C fibers enter the dorsal root and ascend or descend one to three segments before synapsing with neurons in the lateral spinothalamic tract (laminae I, II, and V of the substantia gelatinosa in the gray matter). Substance P, an 11–amino acid polypeptide that is the major pain neurotransmitter, is released from the fibers at many of these synapses. Capsaicin, which is extracted from red, hot peppers, inhibits nociception by inhibiting substance P. Stimulation of the A-D fibers not only excites some neurons but also inhibits others. This inhibition of nociception has significant functional importance, as A-D fiber stimulation might explain effects of acupuncture and t rans-cutaneous electrical nerve stimulation (TENS).

Spinothalamic Tract The lateral spinothalamic tract crosses the mid-line and ascends toward the thalamus. At the level of the brainstem, more than half of this tract synapses in the reticular activating system (in the spinoreticular tract), in the limbic system, and in other brainstem regions. The close relationship of pain, affect, and sleep might be explained by these synapses. Another site of projections is the p eriaqueductal gray (PAG), which plays an important role in the brain’s endogenous analgesia system. The lateral spinothalamic tract has two parts: the neospinothalamic and the paleospinothalamic tracts. The neospinothalamic tract, which serves to localize pain, is phylogenetically recent in evolutionary terms; it ends in the v entroposterolateral (VPL) and ventroposteromedial (VPM) nuclei of the thalamus. These nuclei project to the primary somatic sensory cortex in the parietal lobe. The paleospinothalamic tract is a phylogenetically older pain system, which projects to the intra-laminar nucleus of the thalamus, which has widespread cortical projections. These projections, which are involved in the affective nature of pain, serve to alert, rather than to localize pain.

Cortex After synapsing in the thalamic nuclei, pain fibers project to the somatosensory cortex, located posterior to the Sylvian fissure in the parietal lobe (Brodmann areas 1, 2, and 3).

Endogenous Analgesic System Overview Endogenous analgesic systems involve at least 18 endogenous peptides with opiate-like activity in the c entral nervous system (CNS). For the most part, they are the products of three precursor proteins: pro-opiomelanocortin is the precursor of β -endorphin and adrenocorticotropic hormone; pro-enkephalin is the precursor of met-enkephalin and leu-enkephalin; pro-dynorphin is the precursor of dynorphin and related peptides.

Central Opiate Receptors Mu (m )-receptors are involved in the regulation of analgesia, respiratory depression, constipation, and miosis. Mu receptors (located in the PAG, rostral ventral medulla, medial thalamus, and dorsal horn of the spinal cord) are the receptors that are mainly responsible for supra-spinal analgesia. Kappa (k )-receptors are involved in spinal analgesia, sedation, and miosis. They are located in the dorsal horn (spinal analgesia), deep cortical areas, and other locations; pentazocine preferentially acts on these receptors. Delta (D )-receptors, like k -receptors, mediate spinal analgesia, hypotension, and miosis. Enkephalins have a higher affinity for these receptors than do opiates. They are located in the limbic system, the dorsal horn, and other locations unrelated to pain. D -receptors also mediate psychotomimetic effects (i.e., psychosis) in the CNS. Their effects are not reversed by naloxone, an opiate antagonist.

Descending Analgesic Pain Pathway The descending analgesic pain pathway starts in the PAG (which is rich in endogenous opiates), projects to the rostral ventral medulla, and from there descends through the dorsolateral funiculus of the spinal cord to the dorsal horn. The neurons in the rostral ventral medulla use serotonin to activate endogenous analgesics (enkephalins) in the dorsal horn. This effect inhibits nociception at the level of the dorsal horn because neurons that contain enkephalins synapse with spinothalamic neurons. Additionally, there are noradrenergic neurons that project from the lo cus coeruleus (LC) (the main noradrenergic center in the CNS) to the dorsal horn and inhibit the response of dorsal horn neurons to nociceptive stimuli. The effect of tr icyclic antidepressants (TCAs) and serotonin-norepinephrine re-uptake

inhibitors (SNRIs) is thought to be related to an increase in serotonin and norepinephrine that inhibits nociception at the level of the dorsal horn.

Categories of Pain Acute Pain Acute pain is usually related to an identifiable injury or to a disease; it is selflimited, and resolves over hours to days or in a time frame that is associated with healing. Acute pain is usually associated with objective autonomic features (e.g., tachycardia, hypertension, diaphoresis, mydriasis, pallor).

Chronic Pain Chronic pain (i.e., pain that persists beyond the normal time of healing or lasts longer than 6 months) might have a neurologic origin, involving lowered firing thresholds for spinal cord cells that modulate pain (triggering pain more easily); anatomic plasticity and recruitment of a wide range of cells in the spinal cord (so that touch or movement causes pain); convergence of cutaneous, vascular, muscle, and joint inputs (where one tissue refers pain to another); or aberrant connections (electric short-circuits between the sympathetic and sensory nerves that produce causalgia). Muscle pains often add to the pain experience. Vascular and other visceral mechanisms share features with neurologic mechanisms; however, these mechanisms involved are not mutually exclusive. Characteristic features include vague descriptions of pain and an inability to describe the pain’s timing and localization. Unlike acute pain, chronic pain lacks signs of heightened sympathetic activity. Depression, anxiety, and pre-morbid personality problems are common in this patient population. Usually the major issue is a lack of motivation and incentive to improve. It is usually helpful to determine the presence of a dermatomal pattern, determine the presence of neuropathic pain, and assess pain behavior.

Continuous (or Basal) Pain Continuous pain tends to originate from well-defined tissue damage, for example due to terminal illness (e.g., cancer) or to severe trauma with extensive injuries. It is a variant of nociceptive pain. Stress, sleep deprivation, pre-morbid psychiatric illness, substance use disorder, and personality problems can exacerbate this pain.

Neuropathic Pain

Neuropathic pain is caused by an injured or dysfunctional central or peripheral nervous system; it is manifest by spontaneous, sharp, shooting, or burning pain that is usually distributed along dermatomes. Neuropathic pain is often observed in deafferentation pain, co mplex regional pain syndrome (CPRS), diabetic neuropathy, central pain syndrome, trigeminal neuralgia, or post-herpetic neuralgia. Terms commonly used to describe neuropathic pain include: hyperalgesia (an increased response to stimuli that are normally painful); hyperesthesia (an exaggerated pain response to noxious stimuli [pressor or heat]); allodynia (pain with a stimulus not normally painful [e.g., light touch or cool air]); and hyperpathia (pain from painful stimuli with a delay and a persistence that is distributed beyond the area of stimulation).

Phantom Limb Pain Phantom limb pain refers to severe and excruciating pain in the body part that is no longer present following amputation. The amputation of a limb is commonly followed by sensations that the deafferented body part is still present. These non-painful phantom sensations can include specific positions, shape, or movement, sensations of warmth or cold, itching, tingling, or electric sensations, and other paraesthesias. However, pain can also be present, and it occurs in 50% to 80% of all amputees. Although this condition is most common after amputations of limbs, it can also occur after the surgical removal of other body parts (such as the breast, rectum, penis, testicle, eye, tongue, or teeth). The pathophysiology of this pain is poorly understood; however, is likely secondary to CNS and peripheral (e.g., nociceptive input from the residual limb) factors, with psychological factors influencing the course and severity of the pain. Consistent with the impact of the psyche on pain, one study showed that it is possible to induce pain in an amputee with hypnotic suggestion.

Myofasical Pain Myofascial pain can arise from one or several of the following problems: hypertonic muscles, myofascial trigger points, arthralgias, and fatigue with muscle weakness. Myofascial pain is generally used to describe muscle and connective tissue sources of pain. Myofascial pain can be a primary diagnosis (e.g., fibromyalgia) or, as is more often the case, a co-morbid diagnosis (e.g., with vascular headache or with a psychiatric diagnosis). Psychiatric symptoms are common in patients with muscle pain; other symptoms often involve decreased energy, impaired sleep, and changes in psychomotor activity.

Myofascial pain syndromes can involve muscle trigger points, hypersensitive skin, a subjective sense of swelling and numbness, somatoform pain disorder, affective and anxiety disorders, non-restorative sleep, as well as pain of the head and neck. The diagnosis should be considered if there are multiple muscle trigger points (in the temporalis, sternocleidomastoid, rhomboids, or trapezius muscles); if the person cannot get at least 5 hours of uninterrupted sleep; and if there is chronic fatigue. Deficient stage 4 sleep is thought to underlie the lack of deep muscle relaxation, aching muscles, arthralgias, and general malaise.

Complex Regional Pain Syndrome CRPS , formerly known as reflex sympathetic dystrophy, is a syndrome of sympathetically-maintained pain, or pain (mediated by sympathetic overactivity) in an extremity. The syndrome is usually caused by injury; however, the cause is unknown in approximately 10% of cases. Either micro-trauma or macrotrauma such as a sprain, a fracture, or a contusion can cause it; iatrogenic causes include amputation, lesion resection, myelography, and in tramuscular (IM) injections. CRPS can be disease-related (e.g., due to myocardial infarction, shoulder-hand syndrome, herpes zoster, cerebrovascular accidents, diabetic neuropathy, disc herniation, degenerative disc disease, neuraxial tumors or metastases, multiple sclerosis, or poliomyelitis). CRPS is divided into two types. In type I CRPS, which typically develops after minor trauma or fracture, no overt nerve lesion is detectable. In type II CRPS, a definable nerve injury is present. Per diagnostic criteria set forth by the In ternational Association for the Study of Pain (IASP), the diagnosis of CRPS can be made if the following criteria are met: There is a preceding noxious event without (CRPS I) or with an obvious nerve lesion (CRPS II) There is spontaneous pain or hyperalgesia/hyperesthesia that is disproportionate to the inciting event and it is not limited to a single nerve territory There is edema, skin blood flow (temperature) or sudomotor abnormalities, motor symptoms or trophic changes on the affected limb (in particular at distal sites) Other diagnoses are excluded.

The clinical course (which can last up to 6 months) begins with an acute phase that involves pain, edema, and warm skin. Subsequently dystrophic changes dominate the picture, with cold skin and trophic changes (3–6 months after the onset of the untreated acute phase). Irreversible atrophic changes (atrophy and contractures) eventually occur. There can be symptom improvement with inhibition of sympathetic output; sympathetic blockade can be both diagnostic and therapeutic.

Idiopathic Pain Idiopathic pain , previously referred to as “psychogenic pain,” is poorly understood. The presence of pain does not imply or exclude a psychological component. Typically, there is no evidence of an associated organic etiology or an anatomical pattern consistent with symptoms. Symptoms are often grossly out-of-proportion to an identifiable organic pathology. Jurisigenic pain results from perceived physical or emotional damage related to medical, personal, work, or product injury. Patients with this pain syndrome usually maintain the sick role for as long as possible to maximize financial return. It is important to recognize the existence of a conflict and to educate patients and attorneys; maintenance of a helping and neutral posture is critical.

Psychopathology of Pain Interviewing the patient with pain, particularly chronic pain, demands close attention to both what was said and to the unspoken elements of the interview. A detailed history of when and how the pain began, inquiring about the various treatments received, and the patient’s relationships with other physicians are also important in the evaluation. Throughout the history, one should look for fluctuations in the course of the pain. Why did it improve? Did the medication help, or was it some other factor that proved palliative? In addition, one should explore the patient’s past and present mental state and consider the family history and sociocultural beliefs. Open-ended questions can also be beneficial, garnering helpful data with regard to the patient’s narrative of possible suffering and possible neurovegetative symptoms that might compromise function. The psychiatrist plays an important role in the treatment of the pain by his or her ability to recognize psychiatric conditions that can either present with pain or possibly complicate pain symptoms and recovery. Several important changes have been made in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) from Diagnostic and

Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IVTR), including the discontinuation of the diagnosis of pain disorder. Patients are now classified with somatic symptom disorder (SSD) with predominant pain. SSD is characterized by somatic symptoms that are either very distressing or result in significant disruption of functioning as well as excessive and disproportionate thoughts, feelings, and behaviors regarding those symptoms. To be diagnosed with SSD, the individual must be persistently symptomatic (typically at least for 6 months). Initial DSM-5 field trial seems to suggest the potential of over-inclusiveness for this diagnosis in those with medical illness. As validity and safety data are lacking for this diagnosis, studies will need to examine this in more detail.

Mood Disorders Major depressive illness can be diagnosed by DSM-5 or similar research criteria in approximately 25% of patients who suffer from chronic pain. Recurrent affective illness, a family history of depression, and psychiatric comorbidity (with anxiety and substance use) are often present. More often than not, depression predates the pain; overall, 60% to 100% of pain patients have depressive symptoms, with major depressive disorder (MDD) present in 8% to 50% of pain patients and dysthymia seen in more than 75% of patients with chronic pain. Although some depressive syndromes are secondary to pain itself (e.g., adjustment disorder with affective symptoms), many patients have MDD masked by denial or by medications that promote sleepiness.

Anxiety Disorders Anxiety disorders occur in approximately 30% of patients with intractable pain (usually in the form of generalized anxiety or panic disorder). More than 50% of patients with anxiety disorders also have a current or past history of MDD or another psychiatric disorder. Alcohol and substance use are the most common co-morbid diagnoses; consequently, recognition and treatment of co-morbid depression and substance use disorders (SUDs) are critical to long-term treatment outcome.

Somatoform Disorders SSDs occur in 5% to 15% of treated chronic pain patients, and somatizers account for roughly one-third (36%) of all cases of psychiatric disability, as well as nearly half (48%) of all sick-leave occasions.

Among those with a history of somatic complaints, pain in the head or neck, epigastrium, and limbs predominates. Visceral pain from the esophagus, abdomen, and pelvis associated with psychiatric co-morbidity, especially somatoform disorders, can be challenging to diagnose. Missed ovarian cancers, central pain following inflammatory disorders, and referred pain are often overlooked because of the non-specific presentations of visceral pain. Moreover, in one study, nearly two-thirds (64%) of women with chronic pelvic pain reported a history of sexual abuse. Sufferers from somatoform disorders often have painful physical complaints and excessive anxiety about their physical illness. Most of their pain complaints to physicians do not have a well-defined cause, and a psychiatric diagnosis is often particularly difficult to establish.

Other Psychiatric States Factitious Disorder Factitious disorder with physical symptoms involves the intentional production or feigning of physical symptoms. Renal colic, orofacial pain, and abdominal pain are three of the common presenting gambits in factitious disorder; of these, abdominal pain and a scarred belly herald the diagnosis most often. Pain can be described as occurring anywhere in the body, and the patient often uses elaborate technical detail to intrigue the listener with pseudologia fantastica .

Malingering In malingering , the patient fakes a complaint, even though no pain is felt, because of an external incentive (such as obtaining money, drugs, privilege, or the avoidance of work). The conscious manipulation by malingerers precludes much diagnostic help from amytal interviews or hypnosis because of the willful withholding of information by the patient. The mnemonic for suspicion of the diagnosis is WASTE (W ithholding of information; A ntisocial personality; S omatic examination is inconclusive and changeable; T reatment is erratic with non-compliance and vagueness; E xternal incentives exist, such as occur in a medico-legal context). The psychiatrist’s familiarity with the neurologic examination is always useful, but it is of critical importance for the diagnosis of malingering when non-anatomic findings arise. After an organic etiology has been ruled-out, careful scrutiny of old records and calls to previous physicians might unearth evidence of similar behavior in the past. Similar to lying, malingering tends to be a character trait used in times of stress from early adolescence to older age.

Substance Use Disorders SUDs can develop as a result of chronic pain and the misuse of opioid or analgesic medications, particularly with the use of potent mu-acting opioids (such as fentanyl) which result in significant dopamine activity in the mesolimbic reward pathway. Patients with a history of other substance or alcohol use disorder, with significant psychiatric co-morbidities, and those with a history of traumatic brain injury are at increased risk for complications with the use of short-acting opioids. Patients with neuropathic pain or MDD fare especially poorly, with a bad outcome four times more likely than a good outcome. Even when patients are carefully selected (i.e., lacking a previous addiction or gross personality disorder), one-third of patients can develop addiction and SUDs over a 3-year period. The minimization of short-acting opioids, with a preference for longer-acting medications and better yet, non-opioid analgesics, in addition to nonpharmacological interventions should be employed, if feasible.

Analgesic Therapies Overview Judicious and effective use of medicine in patients with pain rests on the concise evaluation of the four main components of the pain complaint: nociceptive pain, CNS mechanisms of pain, suffering, and pain behavior. In its most basic form, the medical management of these four components employs non-opioid analgesics, opioids, and pharmacological and non-pharmacological interventions. The initiation of analgesic therapy typically involves a multi-factorial decision process. At times, analgesia might be delayed until psychopathology can be identified and managed. Furthermore, the efficacy of analgesia needs to be closely monitored, with function helping to guide treatment.

Acute Pain Acute pain is usually managed medically via treatment of the underlying disorder. The World Health Organization (WHO) has established a three-step guideline for pain treatment (Figure 43-1). Step 1 involves the use of NSAIDs or acetaminophen. Step 2 adds codeine, or another weak opioid, to the NSAID/acetaminophen, with other adjuvants (e.g., TCAs, other antidepressants, anti-epileptics, stimulants). Step 3 employs opioids with adjunctive agents. Conceived for cancer pain, and with a reported efficacy of 90% in cancer

patients, the three steps are a useful template for many kinds of acute pain, adjusted for the particular pain mechanism being treated. NSAIDs/acetaminophen are useful for acute and chronic pain (such as inflammation, muscle pain, vascular pain, and post-traumatic pain), or when the physician wants to use a non-opioid analgesic (Table 43-1). Opioids can be delivered by patient-controlled analgesia (PCA) or by an epidural route either with or without local anesthetics (Table 43-2).

Figure 43-1: The World Health Organization’s analgesic ladder. Table 43-1: Non-Steroidal Anti-Inflammatory Drugs Drug

Dose (mg)

Half-Life Dosage Interval Peak Effect (Hours) (Hours) Daily Dose (mg) (Hours)

Diclofenac

25–75

6–8

200

2

1–2

Etodolac acid

200–400

6–8

1,200

1–2

7

Fenoprofen

200

4–6

3,200

1–2

2–3

Flurbiprofen

50–100

6–8

300

1.5–3

3–4

Ibuprofen

200–400

6–8

3,200

1-2

2

Indomethacin

25–75

6–8

200

0.5–1

2–3

Ketoprofen

25–75

6–8

300

1–2

1.5–2

Oral

10

6–8

40

0.5–1

6

Parenteral

60 load, then 30

6–8

120

Meclofenamic acid 500 load, then 275 6–8

400

Mefenamic acid

500 load, then 250 6

1,250

2–4

3–4

Nabumetone

1,000–2,000

2,000

3–5

22–30

Naproxen

500 load, then 250 6–8

1,250

2–4

3–4

Naproxen sodium

550 load, 275

6–8

1,375

1–2

13

Oxaprozin

60–1200

Every day

1,800

2

3–3.5

Phenybutazone

100

6–8

400

2

50–100

Piroxicam

40 load, then 20

24

20

2–4

36–45

Sulindac

150–200

12

400

1–2

7–18

Tolmetin

200–400

8

1,800

4–6

2

Ketorolaca

12–24

Source: Borsook D, Lebel AA, McPeek B: MGH handbook of pain management . Boston, MA: Little, Brown; 1995. a Use no longer than 5 days.

Table 43-2: Pharmacological Treatment of Acute Pain with Opiates

Drug

Approximate Approximate Equianalgesic Oral Equianalgesic Dose Parenteral Dose

Recommended Starting Dose (>50 kg Body Weight) Oral Parenteral

Morphine

30 mg q 3–4 h

10 mg q 3–4 h

30 mg q 3–4 h

10 mg q 3–4 h

Codeine

130 mg q 3–4 h

75 mg q 3–4 h

60 mg q 3–4 h

60 mg q 2 h

Hydromorphone 7.5 mg q 3–4 h

1.5 mg q 3–4 h

6 mg q 3–4 h

1.5 mg q3–4 h

Levorphanol

4 mg q 6–8 h

2 mg q 6–8 h

4 mg q 6–8 h

2 mg q 6–8 h

Meperidine

300 mg q 2–3 h

100 mg q 3 h

Not recommended

100 mg q 3 h

Methadone

5 mg q 6–8 h

2.5 mg q 6–8 h

5 mg q 6–8 h

2.5 mg q 6–8 h

Oxycodone

30 mg q 3–4 h

Not available

10 mg q 3–4 h

Not available

Oxymorphone

Not available

1 mg q 3–4 h

Not available

1 mg q 3–4 h

Note: Published tables vary in the suggested doses with regard to equianalgesia to morphine. Clinical titration must be applied for each patient. Note: Recommended adjustments necessary to apply to patients with renal or hepatic insufficiency or other conditions that may alter drug metabolism and kinetics. Caution: Methadone conversion varies with daily oral morphine dose. When changing to methadone from higher doses of morphine the ratio of methadone: morphine changes. Chronic dosing of methadone advised. Reference to other sources advised if clinician wishes to convert to methadone for acute dosing.

Chronic Pain Chronic pain is usually treated with a multi-disciplinary approach given that long-standing pain has far-reaching effects on many physical and psychological systems. Neuropathic pain is typically treated with anti-epileptic drugs (e.g., gabapentin, carbamazepine, valproate, clonazepam), antiarrhythmics (e.g., lidocaine, mexiletine), or antidepressants (e.g., SNRIs, TCAs). Response can also be seen with other analgesics (such as opioids or NSAIDs); however, efficacy, particularly with opioid medication, tends to be limited. Nerve blockade and nerve transection rarely offer persistent relief. Initial treatment for chronic regional pain syndrome involves conservative therapy, usually mild analgesics and physical therapy. Sympathetic interruption may be both diagnostic and therapeutic. Direct sympatholysis usually involves lumbar sympathetic or a stellate ganglion block or a systemic drug challenge with a sympatholytic agent (e.g., phentolamine, phenoxybenzamine). Idiopathic pain or pain that fails conventional therapy requires a multidisciplinary approach that includes consultation from psychiatry, physical medicine and rehabilitation, physical therapy, and social work. Invasive interventions are of unclear value and should be considered after a likely etiology is defined delineating appropriate treatment. Some severe cases can lead to use of chronic opioids whereby function can be improved; however, these cases should be followed by a specialist (with attempts made to enhance adherence to treatment guidelines and protocols).

Opioid Medications The use of opioid medications is the “gold standard” for severe or unremitting pain due to trauma, acute physical injuries, or cancer pain. The basic principles

of opioid use should follow the guidelines put forth by the WHO’s analgesic ladder. Physicians should explain to patients that opioids are not curative, can cause both physiological and psychological dependence, and have no prophylactic value. When used chronically, function rather than pain, should be followed. Opioids are equally efficacious when used in equi-analgesic dosages; however, for unknown reasons, one individual might respond better to one agent than to another. Analgesia can be potentiated by other drugs (e.g., NSAIDs, antihistamines, clonidine, neuroleptics, TCAs), and this can be utilized to help the likelihood of better pain control, in addition to minimizing the amount of short-acting opioid medication used. For longer-term use of opioid medications, longer-acting analgesics are generally preferred as compared to PRN dosing of shorter-acting opioids.

Adverse Effects Adverse effects are not uncommon and often limit the use of a medication. Such effects are usually idiosyncratic, and it is unclear why some patients are more sensitive than others. Predictors as to which patients will experience which side effects and which opioids will produce them are lacking. Thus, one should expect side effects and take preventive actions. Tolerance to the adverse effects of opioids, except constipation, occurs. The most common side effect of opioids is constipation, which requires use of a daily stimulating cathartic. Respiratory depression, is the most potentially serious complication; however, when used in appropriate doses, this is a rare event. Furthermore, tolerance occurs early in chronic therapy. If respiratory compromise develops, reversal with naloxone should be initiated, with close monitoring of other physiological parameters. Severe nausea and emesis caused by opioids generally is rare and symptoms usually mild. Pruritus, which probably occurs through a central mechanism, is more common with spinal and epidural opioids but can be seen during the initiation state, particularly with shorter-acting opioid medications. Symptoms are generally treated with antihistamines, such as diphenhydramine (IV or PO), along with hydroxyzine.

Opioid Use for Chronic Pain Opioids for chronic non-malignant pain are highly controversial but might have a role in certain well-selected cases. Such management has been avoided owing to high misuse potential, tolerance, dependence, and other adverse effects. However, opioids can be a reasonable option for patients with chronic non-

malignant pain who have failed other reasonable conventional non-opioid interventions, and in whom opioids can improve function without substantial medication loss or aberrant dose escalations. Guidelines for using opioids in chronic non-malignant pain are provided in Table 43-3. Table 43-3: Guidelines for Using Opioids in Chronic Non-Malignant Pain Individualize therapy with opioids. Use a single opioid agent, if possible. Use a long-acting preparation. Mix a single short-acting agent and a single long-acting agent. Document the efficacy of opioid analgesia; remember, function is of greater interest than analgesia. Use opioid contracts and provide informed consent. Discuss side effects and risks of addiction, physiologic dependence, tolerance, cognitive impairment, fetal dependency in pregnancy, rules of usage and prescribing, and consequences of breaking the contract. Designate a single prescriber for all opioids. Designate a single pharmacy for distribution of all opioids. Maintain a symptom diary. Do not provide over-the-phone appointments resulting in prescriptions. Maintain close follow-up. Maintain a high level of suspicion of toxicity and addictive tendencies (e.g., watch for evidence of drug hoarding, acquisition of opioids by multiple physicians, uncontrolled dose escalations, or other aberrant behaviors). Follow usage guidelines. Consult with an addictions specialist for any concerns or questions. Periodically review the case with a multi-disciplinary team. Be aware of the relative contraindications (e.g., a history of a SUD, a severe character disorder, an inability to follow rules, and for those with a substance use history, the relative nature of these contraindications must yield to compassionate use of opioids for pharmacologic treatment).

Analgesic Adjuvants A variety of agents (including stimulants, tricyclic monoaminergic agents, benzodiazepines, anti-epileptic agents, antihistamines, peptides, and prostaglandin inhibitors) also have roles as non-opioid pain treatment adjuvants. Use of adjuvants (such as TCAs, SNRIs, and antiepileptic drugs) have

independent analgesic properties and are commonly used in pain patients, particularly in patients with neuropathic or chronic pain symptoms.

Anti-Depressants The pain relief obtained from anti-depressants is often independent of their effects on mood or the alleviation of MDD. In fact, the greatest response to antidepressants in patients with pain can occur in those who are not depressed.

Tricyclic Anti-Depressants The mechanisms of action of TCAs are multiple and probably co-modulate the pain-relieving effect. TCAs have an effect in augmenting the descending periaqueductal spinal inhibitory control of pain mediated by serotonin and norepinephrine. In addition, they potentiate naturally-occurring or administered opiates. TCAs supported as analgesics by controlled studies include amitriptyline, nortriptyline, desipramine, imipramine, and maprotiline. TCAs that are supported as analgesics by anecdotal reports include doxepin, trazodone, and clomipramine. Complete analgesia is rare and side effects are common with the use of TCAs, so, typically, the patient must accept mild side effects in exchange for analgesia. TCAs are particularly compelling when pain is accompanied by co-morbid depression or by insomnia. Reasonable goals of therapy include decreasing pain intensity by 10% to 50% or by decreasing pain from unbearable to bearable levels. Analgesic TCA dosages can be lower than anti-depressant dosages; some patients require higher dosages.

Serotonin-Norepinephrine Re-Uptake Inhibitors Duloxetine , an SNRI, has become the first antidepressant to have a specific pain indication for the treatment of painful diabetic neuropathy. Duloxetine has also been studied in a number of large studies for the treatment of fibromyalgia and has been found to be efficacious not only in pain reduction, but also in reduction of tender points and stiffness scores, while also increasing the tenderpoint pain threshold when compared with placebo. These results have also been reproduced by other SNRIs, with milnacipran and venlafaxine also having been shown to be efficacious for the treatment of pain associated with fibromyalgia.

Anti-Epilepetic Drugs Blocking abnormally high-frequency and spontaneous firing in afferent neurons, in the dorsal horn and in the thalamus, are the putative mechanisms for

the efficacy of anticonvulsants with regard to pain. Carbamazepine, valproic acid (VPA), and benzodiazepines, along with some of the newer antiepileptic drugs (AEDs), including gabapentin, pregabalin, lamotrigine, topiramate, and oxcarbazepine, are agents used to treat pain. These drugs have a number of shared cellular effects, which include antagonism of excitatory amino acids, g amino butyric acid (GABA)-receptor agonism, sodium and calcium pump stabilization, along with antagonism of adenosine. Indirectly, they all antagonize the effects of excitatory amino acids, which are believed to kindle hyperexcitability of CNS neurons.

Non-Pharmacological Approaches Invasive Techniques Nerve blocks and implantable devices, including trigger-point injections, epidural injections, selective nerve root injections, stellate ganglion and lumbar sympathetic nerve blockade, are often utilized to achieve symptomatic pain control. Placement of an intra-thecal pump, which typically delivers an opioid, but can administer baclofen (for spasticity) or a local anesthetic is also used for active chronic pain symptoms. A spinal cord stimulator (dorsal column stimulator) is a catheter device placed in the epidural space that electrically stimulates the spinal cord. It is used in neuropathic pain and in sympathetically maintained pain states. Ablative therapy, including radio-frequency lesions are used in peripheral pain (e.g., trigeminal and glossopharyngeal neuralgia), along with ganglionectomy (with ablation of the dorsal ganglia), dorsal rhizotomy (with sensory loss in lesioned distribution), are also possible treatment options. Central techniques include mesencephalotomy (for lesions of mid-brain spinothalamic and secondary trigeminal tracts—for unilateral head and neck pain), thalamotomy (which is sometimes used with bilateral analgesia), and cingulotomy (for diffuse chronic pain associated with affective disorders) are also utilized for severe cases.

Non-Invasive Techniques Non-pharmacological approaches to pain treatment (e.g., physical therapy, trans-cutaneous electrical stimulation [TENS], acupuncture, massage, cognitivebehavioral therapy [CBT], hypnosis) can also be incorporated, particularly when

medications are not effective, result in unwanted side effects, or if they do not produce concomitant improvements in physical and emotional functioning.

Cognitive-Behavioral Therapy In a meta-analysis of 25 psychosocial treatment interventions, the utility of psychoeducational treatment, particularly CBT emphasizing relaxation, support groups, and education for patients with cancer-related pain, was demonstrated. The efficacy of CBT in treating various pain disorder has been shown in numerous studies and reviewed in multiple meta-analyses.

Hypnosis The use of hypnosis in chronic pain syndromes is well known. Self-hypnosis is particularly helpful, but only about one in four subjects are able to achieve a state of concentration of sufficient magnitude for lasting pain control. Hypnosis is a method worth considering, provided that the physician knows its limitations and how to apply it to the individual patient’s needs.

Multi-Disciplinary Approach Goals of the multi-disciplinary approach include improving coping, planning a focus on function rather than on analgesia, and decreasing addictive behaviors (including detoxification). This approach offers alternatives to drugs, injections, or surgery for pain control and improves overall physical and psychological well-being. It strives to decrease behaviors that negatively impact on pain and function, improve social supports, decrease social isolation, and decrease dependence on the health-care system. Multi-disciplinary team meetings include practitioners from Medicine, Neurology, Pediatrics, Physical Medicine and Rehabilitation, Psychiatry, Surgery, Anesthesia, Neurosurgery, and Physical Therapy.

Suggested Readings 1. American Pain Society (APS): Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain , 6th ed. Glenview, IL; 2008. 2. Bair MJ, Robinson RL, Katon W, et al: Depression and pain co-morbidity: a literature review. Arch Intern Med . 2003; 163: 2433–2445. 3. Breitbart W: Psychotropic adjuvant analgesics for pain in cancer and AIDS.

4. 5.

6.

7. 8.

9.

10.

11.

12.

13.

14.

Psychooncology . 1998; 7: 333–345. Breivik H, Borchgrevink PC, Allen SM, et al: Assessment of pain. Br J Anaesth . 2008; 101: 17–24. Cheadle MD, Wasser T, Foster C, et al: Prevalence of suicidal ideation in patients with chronic non-cancer pain referred to a behaviorally based pain program. Pain Physician . 2014; 17: E359–367. Demyttenaere K, Reed C, Quail D, et al: Presence and predictors of pain in depression: results from the FINDER study. J Affect Disord . 2010; 125(1– 3): 53–60. Devine EC: Meta-analysis of the effect of psychoeducational interventions on pain in adults with cancer. Oncol Nurs Forum . 2003; 30: 75–89. Finnerup NP, Attal N, Haroutounian S, et al: Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol . 2015; 162–173. Harada E, Tokuoka H, Fujikoshi S, et al: Is duloxetine’s effect on painful physical symptoms in depression an indirect result of improvement of depressive symptoms? Pooled analyses of three randomized controlled trials. Pain . 2016; 157(3): 577–584. Hyman SH, Cassem NH: Pain. In: Rubenstein E, Federman DD, eds.: Scientific American Medicine: Current Topics in Medicine. Subsection II . New York: Scientific American; 1989: pp. 1–7. IASP: Subcommittee on Taxonomy: Pain terms: a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain. 1979; 6: 249–252. Lang E, Liebig K, Kastner S, et al: Multi-disciplinary rehabilitation versus usual care for chronic low back pain in the community: effects on quality of life. Spine J . 2003; 3: 270–276. Nejad SH, Alpay M: Pain patients. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010; pp. 211–236. Ohayon MM, Schatzberg AF: Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry . 2003; 60: 39– 47.

15. Russell IJ, Mease PJ, Smith TR, et al: Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebocontrolled, fixed-dose trial. Pain . 2008; 136: 432–444. 16. Turk DC, Swanson KS, Tunks ER: Psychological approaches in the treatment of chronic pain patients—when pills, scalpels, and needles are not enough. Can J Psychiatry . 2008; 53: 213–223. 17. Wall PD, Melzack R, eds.: Textbook of Pain . 3rd ed. New York: ChurchillLivingstone; 1995. 18. Webster LR: Chronic pain and the opioid conundrum. Anesthesiology Clin . 2016; 34: 341–355.

CHAPTER Stroke 44 JAMES A. JENKINS, MD; SCOTT R. BEACH, MD; AND ALICE W. FLAHERTY, MD, PHD

KEY POINTS Overview Strokes can present with a variety of signs and symptoms that mimic psychiatric illness. It is imperative that psychiatrists have the diagnostic skills to identify stroke and to rapidly refer for treatment. In the setting of stroke, time is brain tissue. The post-stroke recovery period is one of increased prevalence of psychiatric illness and, if left untreated, this can impede recovery, increase morbidity, and increase mortality associated with the initial stroke. Epidemiology Strokes are the fourth leading cause of morbidity and mortality in the United States with an incidence of 130,000 new cases each year. Definitions Stroke is defined as the rapid onset of a neurologic deficit with identifiable tissue damage on imaging studies (especially magnetic resonance imaging). Transient ischemic attacks, in contrast, are transient neurological deficits without evidence of tissue damage. Classification and Pathophysiology Ischemic The most common neurologic deficits observed in ischemic strokes are motor weakness (especially facial weakness and pronator drift), sensory disturbances, and speech difficulty. 85% of strokes are ischemic. Of the ischemic strokes, the breakdown of causes are: atherosclerosis (50%), embolic (20%), hypertension and lipohyalinosis

(20%), and other (10%). Re-combinant intravenous tissue plasminogen activator (rt-PA), a thrombolytic, is the treatment of choice for stroke. There is a 3- to 4.5-hour window from the onset of symptoms, or when the patient was last witnessed at baseline, to qualify for this treatment. Hemorrhagic Hemorrhagic stroke typically presents with progressive deficits, crossing vascular territories, possibly accompanied by a thunderclap headache, vomiting, meningeal signs, or seizures. Hemorrhagic strokes are classified as either non-traumatic or traumatic. The most common etiologies for non-traumatic hemorrhagic strokes are hypertension, amyloid angiopathy, and aneurysm rupture. Treatment includes reversing any causes of bleeding and applying aggressive blood pressure control. Stroke Syndromes Anterior cerebral artery strokes involve contralateral leg weakness, grasp reflex, frontal signs (including apathy or disinhibition), depression, poor judgment, shuffling gait, perseveration, and urinary incontinence. Middle cerebral artery strokes involve contralateral arm and face weakness with sensory loss with or without aphasia. Posterior circulation strokes involve altered consciousness, cerebellar signs, lower cranial nerve deficits, and crossed (e.g., right face and left body) or bilateral deficits. Lacunar strokes involve pure motor or sensory findings without cortical signs. Psychiatric Sequela Changes in speech, affect, and cognition are the most common observations on the mental status exam in patients with stroke. Speech changes, like aphasia and prosody changes, can be mistaken for symptoms of mood or thought disorders. Post-stroke depression is the most common psychiatric disorder following stroke, affecting 25% to 30% of patients in the first 6 months after stroke. Pseudobulbar affect, catastrophic reactions, and post-stroke mania are other potential manifestations of psychiatric illness in the post-stroke period. Psychosis is a rare, but possible, result of stroke. Cognitive changes in the post-stroke period can overlap with those seen with

vascular dementia and include problems with processing speed, memory, and executive functioning. Treatment for psychiatric illness in the post-stroke period is not different from treatment of a primary psychiatric disorder with the caveat that, if possible, psychiatrists should avoid using antipsychotics in the first several days after stroke.

Introduction Strokes kill approximately 130,000 Americans each year, making it fourth leading cause of morbidity and mortality in the United States according to the Center for Disease Control’s and Prevention (CDC). Although recent advances in acute stroke management have led to a decrease in mortality over the past 10 years, these benefits are contingent on rapid diagnosis and referral. Many strokes present with, or are followed by, neuropsychiatric symptoms, and knowledge about stroke is thus important in the differential diagnosis of mood disorders, delirium, dementia, and other psychiatric disorders. This chapter summarizes the classification and pathophysiology of stroke, reviews specific stroke syndromes, and summarizes the neuropsychiatric sequelae of stroke.

Stroke Classification and Pathophysiology Stroke is the rapid onset of a neurological deficit caused by cerebrovascular disease, either ischemic or hemorrhagic. Neurologists usually use the word “stroke” to mean ischemic stroke, and speak of hemorrhages using different terms. Transient ischemic attack (TIA ), in contrast, is defined as a transient episode of neurologic dysfunction cause by focal brain, spinal cord, or retinal hypoperfusion, without permanent tissue damage visible on magnetic resonance imaging (MRI) scans. In the past TIAs were defined clinically by the temporary nature (less than 24 hours) of neurologic dysfunction they induced; however, research has shown that there is no reliable time frame to distinguish TIAs from strokes, and a tissue-based diagnosis was adopted in the 2009 guidelines. In practice, most TIAs are symptomatic for no more than 5 minutes. Despite the transient nature of TIA symptoms, 4% to 10% of those with TIAs will go on to have an ischemic stroke within 48 hours of their TIA. TIAs should thus be investigated as seriously as strokes, and clinicians should be aware that because the deficits associated with TIAs have resolved by the time most patients are

evaluated, careful history is crucial. Language is important too because many patients will say that their arm felt “numb” to describe one that was in fact paralyzed, a much more ominous symptom.

Ischemic Stroke The sudden painless onset of a focal neurologic deficit is typical of an ischemic stroke, accounting for 85% of all strokes. The most common neurologic deficits observed in ischemic strokes are motor weakness (especially facial weakness and pronator drift), sensory disturbances, and speech difficulty. Headache or alterations in consciousness usually suggests a hemorrhagic rather than an ischemic stroke. About 50% of ischemic strokes are caused by atherosclerosis and by gradual narrowing of the carotids, the vertebrals, or the circle of Willis. Roughly 20% of ischemic strokes come from cardiac or artery-to-artery emboli. Atrial fibrillation, a patent foramen ovale, and a low ejection fraction can increase a patient’s embolic risk. An additional 20% of strokes, termed lacunar strokes, result from lipohyalinosis and narrowing of tiny end-arteries that supply blood flow to the deep, white-matter structures of the brain. These types of stroke are strongly associated with hypertension and smoking. The remaining 10% of ischemic strokes include rarer causes like arterial dissection (usually resulting from head or neck injury), various hypercoagulability disorders (e.g., pregnancy, use of oral contraceptives, anti-phospholipid antibody syndrome, sickle-cell disease), venous sinus thrombosis, and systemic hypoperfusion. In evaluating for stroke, the clinician should place a special emphasis on determining the time course and onset of symptoms because this is the most important factor in determining eligibility for treatment from thrombolytics. A full neurologic exam should be performed and most neurologists also use standardized instruments, like the National Institutes of Health Stroke Scale (NIHSS ), to rapidly assess the severity of stroke and estimate prognosis. The initial management should also include stabilization of vital signs and evaluation for other diagnoses on the differential, like seizure or hypoglycemia. Labs commonly checked in the acute setting include: serum glucose; platelets; cardiac enzymes; serum electrolytes; renal function tests; and coagulation studies. After the patient is stabilized, imaging studies are performed to confirm the diagnosis and to evaluate the extent of disease burden. Computed tomography (CT ) scans are useful only to rule-out bleeds or to detect large old strokes. Diffusion-weighted MRI (DWI ); however, can detect ischemic strokes within 30 minutes of their onset. Comparing diffusion and perfusion imaging on MRI

might allow detection of reversibly impaired tissue, known as the stroke penumbra. CT angiograms, MR angiograms, and vascular ultrasounds all help assess arterial stenosis and often determine whether intra-arterial clot lysis or disruption can be attempted. No imaging studies should be performed that will delay treatment past the window for appropriate intervention (> 4.5 hours from onset of symptoms). This is particularly relevant for a situation in which a patient would need to be transferred to an acute stroke center to receive necessary intervention. The mainstay of acute, ischemic, stroke treatment is re-combinant intravenous tissue plasminogen activator (rt-PA ). rt-PA may be used as thrombolytic therapy if given within 3-4.5 hours of the onset of symptoms, or when a patient was last witnessed at baseline, assuming that there are no contraindications to its use. Patients who receive rt-PA will need careful monitoring of blood pressure to reduce the risk of hemorrhagic conversion; however, aggressive lowering of blood pressure in the acute phase of a stroke (> 15% in first 24 hours) is not recommended. Lowering blood pressure too much may lead to worsened hypoperfusion and tissue ischemia. Neuroleptics, benzodiazepines, and alphaantagonists should be avoided in the acute phase, as there is evidence to suggest that these can be neurotoxic during this phase. Within the first 48 hours of stroke, but not necessarily in the acute phase, lipidlowering drugs and anti-platelet agents are usually started as secondary prevention. Appropriate treatment of hypertension is also important, as blood pressure is the most important modifiable risk factor for future stroke. Routine anti-coagulation is no longer recommended except for prophylaxis of deep vein thromboses (DVTs ) and in patients with atrial fibrillation. Nearly all patients with atrial fibrillation should be on warfarin even if they have never had a stroke. It is important to keep in mind that warfarin use increases the risk of bleeding following falls, and that the metabolism of warfarin can be affected by certain psychotropics, including some selective serotonin re-uptake inhibitors (SSRIs). Early aggressive physical therapy and use of SSRIs in the post-stroke rehabilitative period can help with motor recovery and functional outcomes.

Hemorrhagic Stroke Unlike ischemic strokes for which neurologic deficits are maximal at the onset, hemorrhagic strokes cause progressive deficits that are less focal and can cross vascular territories. Hemorrhagic stroke can also be accompanied by a

thunderclap headache, vomiting, meningeal signs, and seizures. The causes for hemorrhagic stroke can be divided into traumatic and non-traumatic causes. Of the non-traumatic causes, the most common include: hypertension, cerebral amyloid angiopathy, vascular malformations, brain tumors, CNS infections, bleeding disorders, and vasculitis. Hypertensive vasculopathy is the most common cause of non-traumatic intracerebral hemorrhage. Basal ganglia and intraventricular bleeds are often associated with hypertension. Lobar or cerebellar bleeds, in contrast, are often due to amyloid angiopathy, the second most common cause of non-traumatic bleeding. Arteriovenous malformations can cause both lobar and sub-arachnoid bleeding and are more likely to present with seizures or focal deficits than other intracranial hemorrhages. Another common cause of hemorrhagic stroke is sub-arachnoid hemorrhage. Spontaneous subarachnoid bleeds are much more dangerous than are traumatic ones because they often indicate the presence of a Berry (saccular) aneurysm that has a high likelihood of re-bleeding. Ruptured aneurysms are associated with a 30% mortality rate. Aneurysms are usually found around the circle of Willis; they sometimes press on cranial nerves and cause chronic focal deficits. They can be repaired by neurosurgical clipping and intra-arterial coiling or, if less than 5 mm, can be monitored by MR or CT angiography. Sub-dural and epi-dural hematomas usually stem from trauma and are not generally called strokes except by patients. Epi-dural hematomas are neurosurgical emergencies. Chronic sub-dural hematomas are common in the elderly. They are often discovered incidentally and might not require treatment. Sometimes, they cause headache, focal neurological signs, or altered consciousness. A CT scan is generally sufficient to make the diagnosis of hemorrhagic stroke, except in the setting of very small posterior fossa bleeds. In sub-arachnoid hemorrhage, a sentinel bleed might not appear on CT and in some cases is identified only through evidence of elevated red blood cell counts or xanthochromia in the cerebrospinal fluid (CSF) on lumbar puncture. MRI with iron susceptibility sequencing gives evidence about prior bleeds. A neurosurgeon should be consulted immediately for all sub-arachnoid and epidural bleeds, and for intracerebral and subdural bleeds for which there is altered consciousness, progressive deterioration, hydrocephalus, blood in the ventricles, or a posterior fossa clot greater than 3 cm wide. In the acute period, the chief concerns with all hemorrhagic strokes are continued bleeding and mass effect.

Patients’ systolic blood pressure should be kept below 150 mm Hg and vitamin K should be given to patients on warfarin. Following the 2010 guidelines, the routine use of prophylactic anti-epileptic medications are not recommended. Management of hypertension and reducing future bleeding risk are the primary means of secondary prevention. Although a patient’s deficits from an intracerebral hemmorhage are initially worse than those from an ischemic stroke of the same size, patients will eventually have a greater recovery, given that much of the initial deficit is due to mass effect rather than to cell death.

Stroke Syndromes Of the many stroke syndromes , only those that affect management will be discussed here. Syndromes are organized by vascular territory. Left (dominant) hemisphere strokes are more disabling, primarily because of language deficits and depression. The distinction between anterior (carotid) and posterior (basilar) circulation strokes is crucial. The latter are generally more dangerous, although there is less danger of secondary bleeding and thus a longer time window for invasive treatment.

Anterior Circulation Strokes Anterior circulation strokes may arise from internal carotid artery (ICA) syndromes or syndromes affecting any of the three branches of the ICA (anterior cerebral artery [ACA], middle cerebral artery [MCA], and the ophthalmic arteries). With ICA syndromes, clinical manifestations vary with the efficacy of collateral vessels. A complete infarct destroys the entire anterior two-thirds of that cerebral hemisphere and can be fatal due to secondary swelling. Occlusion of the ICA can present with some or all of the clinical symptoms that occur after occlusion of its three branches. ACA syndromes cause contralateral leg weakness, a grasp reflex, frontal signs (including apathy or disinhibition), depression, poor judgment, shuffling gait, perseveration, and urinary incontinence. Leg weakness may be bilateral because some right and left ACAs have a common origin. MCA syndromes are sub-divided by superior and inferior divisions. Superior division strokes cause contralateral arm and face weakness with sensory loss. Severe leg weakness is not common and implies a full ICA syndrome or a lacunar pure motor stroke. Dominant hemisphere strokes of the superior MCA cause a Broca’s (expressive) aphasia, with non-fluent speech and relatively

retained comprehension. Of note, many aphasias appear global, without comprehension or expression during the first few hours after the stroke. It is important to distinguish this muteness (in which gestural imitation might be preserved) from delirium (altered attention, dreamy nonsense speech), dementia, and psychiatric language disorders. Non-dominant superior MCA strokes can cause monotone speech without emotional inflection (expressive aprosodia), left-sided neglect, and indifference to one’s disability. Inferior MCA strokes cause mild or transient sensorimotor deficit. Dominant hemisphere lesions usually cause Wernicke’s (receptive) aphasia, with fluent, content-less speech. Non-dominant lesions result in an inability to recognize the emotional inflections of speech (receptive aprosodia) as well as left-sided neglect. There can sometimes be a contralateral field cut. Ophthalmic artery syndrome causes transient (amaurosis fugax ) or permanent sudden monocular blindness due to optic nerve and retinal ischemia. This deficit is ipsilateral, and thus can present as left-sided blindness with a right facial droop from middle cerebral ischemia. Pressing the eyeball firmly (4 seconds on, 4 seconds off) can occasionally move the clot through the circulation. The differential diagnosis includes temporal arteritis, and patients presenting in this manner should therefore be given prednisone presumptively and have an erythrocyte sedimentation rate determined.

Posterior Circulation Strokes Evidence for posterior circulation ischemia includes altered consciousness, cerebellar signs, lower cranial nerve deficits, and crossed (e.g., right face, left body) or bilateral deficits. Most blood to the posterior circulation comes from the basilar artery, and such strokes can signal the life-threatening “top of the basilar” syndrome (see the upcoming description). Strokes in the occipital lobe usually cause a contralateral field cut (homonymous hemianopsia). Medial temporal lobe strokes can damage the hippocampus and cause anterograde amnesia. Thalamic strokes can cause amnesia as well as contralateral sensory disturbances and, sometimes, tremor. Rostral midbrain lesions can paralyze vertical eye movements. The vertebral arteries supply the medulla and the inferior cerebellum. They then fuse to form the basilar artery. The basilar artery supplies the occipital lobe, midbrain, pons, much of the cerebellar hemispheres, and the nuclei of cranial nerves III, IV, V, VI, VII, and VIII. Strokes in this territory therefore cause complicated combinations of visual loss, double-vision, nystagmus, ataxia,

hearing loss, weakness, and numbness. Top of the basilar syndrome occurs when a clot lodges at the origins of the posterior cerebral arteries (PCAs) and fragments are released over a period of hours or days. The resulting protean change in exam and focal deficits can be dismissed as conversion disorder, but this syndrome is often fatal. A complete basilar territory stroke results either in a comatose patient (due to lesions of the reticular activating system), or a conscious but paralyzed (“locked-in”) patient. Vertical eye movements and blinking are often spared in the latter. Cerebellar strokes cause severe ataxia, dysmetria, vertigo, nausea, and nystagmus. Although it is unusual for strokes to cause headache, cerebellar strokes frequently do. An older patient who presents with sudden vomiting and incoordination should be evaluated for cerebellar stroke. Large cerebellar strokes can cause rapid herniation and death if undetected. The lateral medullary syndrome (Wallenberg’s syndrome), despite its bizarre array of crossed symptoms, is relatively common. Symptoms include ipsilateral ataxia, vertigo, nystagmus, ipsilateral Horner’s syndrome (drooping lid and small pupil), ipsilateral face and contralateral body loss of pain and temperature sense, and hoarseness. Prognosis is good, although there is a risk of silent aspiration from the associated dysphagia.

Lacunar Strokes Lacunar strokes are usually sub-cortical, most often in the putamen, caudate nucleus, thalamus, internal capsule, or pons. They are typically less dangerous though also less treatable than large artery strokes. The most common kinds include pure motor and pure sensory strokes. Pure motor lacunar strokes present with face, arm, and leg weakness, but without cortical signs (such as aphasia). They are most often from lacunes in the internal capsule, the base of the pons, or the cerebral peduncle. Pure sensory lacunar strokes have face, arm, and leg numbness, but no cortical signs. Pure sensory deficits in young people are rarely secondary to stroke and should raise suspicion for conversion disorder.

Psychiatric Sequelae of Stroke Any patient with focal neurologic deficits, acute or sub-acute onset of symptoms, vascular risk factors, or an atypical presentation, warrants a careful investigation into a potential neurologic etiology of their symptoms. Strokes have been associated with depression, anxiety disorders, apathy, cognitive disorders, mania, psychosis, labile or bizarre affect, and delirium. Additionally,

individual symptoms of stroke can mislead psychiatrists in their differential diagnosis, both on the mental status exam (MSE) and the psychiatric review of systems. Changes in speech, affect, and cognition are the most common observations on the MSE in patients with stroke. Aphasia, acquired by 25% to 40% of stroke survivors, can be mistaken for a psychiatric disorder or delirium. The laconic speech of Broca’s aphasia can be misinterpreted as depression or as psychotic withdrawal. Wernicke’s aphasia, with its pressured speech and clang associations, might be misinterpreted as mania. Semantic paraphasias (“hotel” for “hospital’’) can be incorrectly taken as signs of a formal thought disorder. The change in affect associated with frontal lobe lesions overlaps significantly with mood disorders and can be challenging to distinguish. Akinetic mutism can resemble catatonia but typically lacks negativism and waxy flexibility. Orbitofrontal lesions, particularly right-sided, can cause disinhibition, indifference, and uncontrollable joking or punning (Witzelsucht ) which can be misinterpreted as signs of mania. Frontal convexity lesions cause apathy, poor sequencing, and perseveration, which can mimic depression or hypoactive delirium. Medial frontal lesions cause leg weakness or incoordination, incontinence, akinesia, and abulia; thus, they can resemble normal pressure hydrocephalus or atypical parkinsonism. There is much overlap between the cognitive changes seen in stroke and those seen in dementias. In fact, vascular or multi-infarct dementia is the second most common cause of dementia, accounting for about 25% of cases. It usually stems from multiple tiny sub-cortical strokes (periventricular white-matter disease) associated with hypertension, smoking, diabetes, and other vascular risk factors. Sub-cortical dementia has normal language, slowed but normal cognition, normal memory encoding with poor retrieval, depression or apathy, and hypophonia, bradykinesia, or a gait abnormality. Less often, multiple emboli to cortical gray matter can also produce a cortical dementia. Cortical dementia has anomia, abnormal cognition with normal processing speed, poor memory encoding but normal retrieval, normal or disinhibited affect, and no hypophonia, bradykinesia, or gait problems. Delirium can be seen (rarely) during the acute phase of strokes involving the thalamus or midbrain, or occasionally with strokes of the right temporal or parietal lobe. However, the presence of delirium is rare enough in ischemic stroke that it should be a strong clue that metabolic or toxic factors are involved.

Stroke is most closely associated with development of depression in the poststroke period. Post-stroke depression (PSD ) can be seen in 25% to 30% of patients with stroke; it is commonly defined as the onset of depressive symptoms within 6 months of a stroke. The risk factors most consistently associated with development of PSD include: location of lesion, degree of functional impairments, and degree of cognitive impairments. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), PSD is classified as a depressive disorder due to stroke. The differential diagnosis of PSD includes abulia from frontal lesions and flattened prosody from lesions in the right hemispheric equivalents of Broca’s area. There seems to be a tendency for infarctions of the left hemisphere, in particular of the left prefrontal cortex and rostral caudate, to carry the highest risk for PSD, though this lateralized association is more pronounced in depressive states occurring within days of the stroke. PSD has an average duration, if left untreated, of 12 months. However, mortality and functional impairment significantly increases in patients with untreated PSD when compared to other matched cohorts. Patients with untreated PSD have approximately three times the risk of all-cause mortality in the 10 years following their stroke. Conversely, 9-year survival rates for patients with treated versus untreated PSD are 59.2% and 34.6%, respectively. Treatment of PSD is similar to that of other types of depression. SSRIs, serotonin norepinephrine re-uptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), stimulants, and electroconvulsive therapy (ECT) have all proven efficacy in the treatment of PSD. SSRIs have also been shown to improve motor recovery at 3 months post-stroke when used in combination with physical therapy. Stimulants are also used to treat PSD and have the advantage of inducing an antidepressant response within days of treatment initiation. They are also more effective for frontal abulia than are traditional antidepressants or ECT. A catastrophic reaction, thought to be a mixed-mood variant of PSD, presents with restlessness and mood lability shortly after left hemispheric stroke. This reaction is also accompanied frequently by Broca’s aphasia. The response to the sudden experience of disability may play an important role. Antidepressants and mood stabilizers may be helpful in this setting. Post-stroke mania occurs after about 1% of strokes. The first onset of mania in an elderly patient should suggest a neurological cause until proven otherwise. Right hemisphere strokes are more likely to cause mania and hypomania than are left hemisphere ones.

Pseudobulbar affect (PBA ) can occur in the setting of stroke and is characterized by disinhibition of emotional expression without a significant underlying mood disorder. In this disorder, the threshold for affective responses, like laughter and crying, are dramatically lowered. Additionally, the stimulus that brings about these behaviors can be consciously incongruent with the affective display. PBA is caused by disruptions along the circuits linking the frontal lobes to the cerebellum and the brainstem, and may be accompanied by spasticity and dysphagia. Use of baclofen or antidepressants may help. Additionally, a drug combination, dextromethorphan and quinidine, was recently approved by the United States Food and Drug Administration (FDA) for treatment of this disorder. If not considered, PBA will often be misdiagnosed as either depression, mania, or psychosis. Psychotic symptoms related to stroke are rare, but can occasionally occur. When they occur, they typically involve hallucinations and delusions rather than formal thought disorder or ideas of reference. Simple auditory hallucinations (i.e., sounds rather than voices), without confusion, have been described after temporal lobe and pontine lesions. Simple visual hallucinations usually stem from occipital cortex lesions. Complex hallucinatons (e.g., voices, dream-like images) typically occur with temporal lobe lesions or lesions of the cerebral peduncle causing “peduncular hallucinosis.” The types of delusions observed after stroke correlate loosely with anatomic location of the stroke. Lesions involving the right parietal lobe can lead to paranoia or persecutory delusions, whereas bifrontal or right frontal lesions can cause delusional misidentification syndromes. The latter category includes Capgras syndrome, in which the patient believes family members have been replaced by impostors, and reduplicative paramnesia, in which patients believe that a place simultaneously exists in two or more physical locations.

Suggested Readings 1. Birkett PB, ed.: The Psychiatry of Stroke. Washington, DC: American Psychiatric Press; 1996. 2. Flaherty AW, Rost N: The Massachusetts General Handbook of Neurology, Second Edition. Philadelphia, PA: Wolters Kluwer; 2007. 3. Easton JD, Saver JL, Albers MJ, et al: Definition and evaluation of transient ischemic attack: A scientific statement for healthcare professionals

from the AHA/ASA. Stroke . 2009; 40(6): 2276. 4. Hemphill JC, Greenber SM, Anderson CS, et al: Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for healthcare professionals from the AHA/ASA. Stroke. 2015; 46: 1–30. 5. Robinson RG, Jorge RE: Post-stroke depression: A review. Am J Psychiatry. 2016; 173:221–231. 6. Hackett ML, Kohler S, O’Brien HT, Mead GE: Neuropsychiatric outcomes of stroke. Lancet Neurol. 2014; 13: 525–534.

CHAPTER Movement Disorders 45 FRANKLIN KING IV, MD; SCOTT R. BEACH, MD; AND ALICE W. FLAHERTY, MD, PHD

KEY POINTS Overview Movement disorders are commonly found in patients with psychiatric disease. They are almost exclusively diagnosed based on the history and examination. Pathophysiology “True” movement disorders have origins in the basal ganglia and can be hyperkinetic, hypokinetic, or both. Clinicians should differentiate movement disorders based on their motor system abnormalities (e.g., damage to the pyramidal motor tracts or cerebellum). Parkinson’s Disease and Parkinson’s “Plus” Syndromes These conditions are characterized by the triad of tremor, bradykinesia, and rigidity. Treatment includes use of levodopa, dopamine agonists, and amantadine (an N -methyl d-aspartate antagonist). Roughly 30% of patients with idiopathic Parkinson’s disease suffer from major depression, and a similar proportion eventually will exhibit a cognitive disorder. Psychosis can be common in the late stages of treatment, or due to dopaminergic therapy at any point in the course of the illness. Parkinson’s “plus” syndromes include multiple systems atrophy, progressive supranuclear palsy, and dementia with Lewy bodies; dopamine replacement is ineffective in multiple system atrophy. Other Disorders

Chronic traumatic encephalopathy may present with motor, affective, behavioral, or cognitive symptoms; the disorder is progressive despite an absence of continued injury. Huntington’s disease is a genetic disorder and it exhibits the phenomenon of anticipation (earlier and more severe with successive generations). Depression, suicide, and psychosis are common. Wilson’s disease is a disorder of copper metabolism that usually presents in childhood or adolescence, with a movement disorder, cognitive decline, and psychiatric (psychosis, disordered mood) symptoms. Tourette’s syndrome is a tic disorder arising before the age of 18 years and it is commonly associated with attention deficit hyperactivity disorder and obsessive-compulsive disorder. Treatment includes use of α 2 agonists (clonidine, guanfacine), haloperidol, and aripiprazole. Drug-Induced Movement Disorders Akathisia is the most common of these disorders and is caused by many psychiatric medications other than neuroleptics; propranolol is first-line treatment. Acute dystonia can be life threatening, and treatment is with intravenous anticholinergics. Parkinsonism is caused by dopamine antagonists and is treated by addition of an anticholinergic or by discontinuation of the offending drug. Tremor is commonly seen with use of lithium and valproate and it can be treated with dose reduction or addition of propranolol or primidone. Tardive dyskinesia has a high incidence with chronic, typical neuroleptic treatment. Treatment usually includes switching to clozapine or olanzapine, or a reduction in dose. Psychogenic Movement Disorders Movement disorders are a common form of conversion disorder. Abrupt onset, normal imaging, varying body distribution, and other atypical signs should suggest inclusion of a psychogenic disorder in the differential.

Introduction Movement disorders are particularly important for psychiatry because they often cause, are co-morbid with, or are caused by major psychiatric diseases.

Abnormalities of movement are frequent and sometimes devastating side effects of psychotropic medications. Nearly all movement disorders are diagnosed by exam and history, rather than by laboratory tests or neuroimaging. Textbook knowledge helps little in distinguishing a patient’s facial tics associated with Tourette’s syndrome from his pimozide-induced tardive dyskinesia (TD); observing real patients or video are crucial to learning this crucial distinction. When evaluating a patient, clinicians should ask about difficulties with daily tasks, falls, drug use, memory loss, hallucinations, and incontinence. Examiners should watch for involuntary movements and excessive “normal” gestures, weakness, muscle tone, movement speed, postural reflexes, festination, freezing, and ataxia.

Pathophysiology Although movement disorders are usually classified as hypokinetic (too little movement) and hyperkinetic (too much) most contain complicated combinations of the two. For instance, a person with Parkinson’s disease can have bradykinesia and a tremor simultaneously. By convention, most neurologists consider conditions as being a movement disorder only when symptoms are presumed to originate in the basal ganglia, which includes the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, parts of the thalamus, and the subthalamic nucleus. Hypokinetic disorders usually stem from damage to the direct pathway through the internal globus pallidus; hyperkinetic movements from damage to the indirect pathway through the external globus pallidus and sub-thalamic nucleus. These pathways control affect and cognition as well as movement, and, as a result, patients suffering from movement disorders frequently exhibit psychiatric symptoms. “Extrapyramidal symptoms” (EPS) is an anatomically inaccurate term for problems related to the basal ganglia, but it is entrenched in clinical usage. Paralysis (complete inability to voluntarily use a muscle), paresis (partial paralysis), fasciculations, and ataxia are not, by convention, movement disorders, because they stem from damage to motor neurons or to the cerebellum. However, we cover them briefly in this chapter because they are often an important part of the differential diagnosis.

Hypokinetic Signs

Akinesia is the tendency not to move, and bradykinesia is the presence of abnormally slow movements. Both are characteristic of parkinsonism, whether idiopathic, drug-induced, or from other causes. Balance is often impaired in both akinesia and bradykinesia. Freezing is the sudden inability to move, often triggered by doorways or rising from a chair. It is also seen in parkinsonism and is a major risk factor for falls in this disease. Rigidity is increased tone in a muscle group and can contribute to akinesia. In classic rigidity, there is constant “lead pipe” resistance to movement along the entire range of the joint. “Cogwheel rigidity” is simply a tremor superimposed on rigidity, although the tremor is not always apparent. Both rigidity and cogwheeling are characteristic of parkinsonism . The differential diagnosis of rigidity includes spasticity, paratonia, and give-way weakness. Spasticity is a jerky “clasp-knife” rigidity seen following stroke or other upper motor neuron lesions. The presence of hyper-reflexia and spasms helps distinguish this entity from rigidity. Spasticity is often treated with baclofen, a γ -amino butyric acid sub-unit B (GABAB ) antagonist, or tizanidine, an α 2 noradrenergic agonist. Paratonia (gegenhalten ) is a progressive resistance to the examiner’s force; the harder the examiner pushes, the more the limb resists, despite all efforts of the patient to relax. This is common in prefrontal damage as occurs with dementia or some strokes, and it is also seen in catatonia. “Give-way weakness,” jerky lapses of tone in testing the strength of a supposedly paretic limb, is most often a sign of a patient who is feigning weakness. However, it is also often present in patients who are elaborating real weakness, in those with proprioceptive deficits, and in those with multiple sclerosis. Paralysis and paresis stem not from basal ganglia damage but from interruption of the corticospinal (pyramidal) motor system. This includes upper motor neurons, such as the giant Betz pyramidal cells in layer V of the primary motor cortex (as in stroke) and lateral corticospinal tracts, lower motor neurons (as in amyotrophic lateral sclerosis [ALS] or Lou Gehrig’s disease), or peripheral nerve injury (as in severe alcoholic neuropathy). Upper and lower motor neuron lesions can be distinguished by spasticity in the former and flaccidity in the latter. ALS is unique in usually having both.

Hyperkinetic Signs Chorea and athetosis are two ends of a spectrum , differing only in speed of movement. Both are involuntary and dance-like, but chorea is jerky, whereas athetosis more writhing. Both result from basal ganglia injury. Causes include

use of neuroleptics as well as lupus, chorea from pregnancy or from oral contraceptives, Huntington’s disease, and Wilson’s disease. Choreoathetosis is best treated with typical neuroleptics such as haloperidol, though these can cause a tardive worsening of the syndrome. Dyskinesia looks very similar to chorea; the distinction is to a large extent convention. The two major types are TD, from long-term exposure to dopamine antagonists, and parkinsonian dyskinesia, from long-term exposure to dopamine agonists. Akathisia is motor fidgetiness. It is of lower amplitude than chorea or dyskinesia, more natural looking, and, importantly, accompanied by an often severe, inner sense of restlessness and a desire to move. Restless legs syndrome is akathisia triggered by relaxation, seen predominantly in the legs. It is sometimes associated with Parkinson’s disease, iron-deficiency anemia, pregnancy, or use of certain medications. Dystonia involves slow, tonic muscle contractions. It is the slowest end of the spectrum including chorea and athetosis, and is on the border between hyperkinetic and hypokinetic movements. Focal dystonias are best treated with botulinum toxin injections; acute or generalized dystonias are managed with anticholinergic agents. Acute dystonia is usually drug induced. Torticollis (cervical dystonia) affects the neck and is the most common form of dystonia. Meige’s syndrome (orofacial dystonia) involves tonic and clonic grimacing. Though usually idiopathic, it is sometimes a side effect of dopaminergic medications. Blepharospasm resembles Meige’s syndrome but it affects only the muscles around the eyes. Writer’s cramp and other occupational cramps are task specific. They are not psychogenic despite being associated with sometimes odd limitations, such as not being able to write despite being able to play the piano. The onset of idiopathic dystonia is frequently preceded by a psychiatric illness. Progressive generalized dystonia is usually congenital from the DYT-1 and other genetic mutations, but it can be from medications as in tardive dystonia. Myoclonus consists of quick, non-rhythmic jerks. Asterixis is negative myoclonus, involving sudden lapses of tone; although most readily identified at the wrists, it can be seen in other joints of the upper and lower extremities, as well. Both myoclonus and asterixis can be seen in encephalopathy, drug intoxication (especially from opiates) and neurodegenerative diseases. Myoclonus during sleep is normal. Unlike tics, myoclonus is completely involuntary. Clonazepam or levetiracetam are often the first choices for the treatment of myoclonus (unless it is caused by encephalopathy). For patients with a mood disorder, valproate might be a better choice than levetiracetam.

Tics are brief, multi-focal, but repetitive and stereotyped muscle contractions. They are classified as simple versus complex, and motor versus vocal. They most often affect the face, giving rise to blinking, sniffing, facial grimacing, or coughing. Most tics can be distinguished from myoclonus by their heightened complexity and by the patient’s report of a premonitory urge to perform the tic as well as an ability to temporarily suppress the movement. Tics are common in children between the ages of 5 and 10 years and they typically disappear over time. Tourette’s syndrome (see the section later in the chapter) is a sub-type of tic disorder. Stereotypies are seemingly purposeless, repetitive movements that can be confused with complex tics, but are longer lasting and more continuously expressed. Examples include rocking, head banging, hand flapping, and repeated, stereotyped vocalizations. They can be associated with self-injurious behaviors. Stereotypic movement disorders arise in the early developmental period and they are frequently associated with intellectual disability and autism spectrum disorders. Tremor is an involuntary oscillatory movement. The differential diagnosis includes focal seizures, frequent segmental myoclonus or tics, chorea, and dysmetria. Resting tremors, including Parkinsonian tremor and rubral tremor, are worse when then patient relaxes—but, like all tremors, they disappear with sleep. Parkinsonian tremors typically improve with action, and they are often asymmetric. It is classically a 3 to 5 Hz large-amplitude “pill-rolling” hand movement. There can be a smaller action component. It is associated with tiny handwriting (micrographia). Rubral tremor, an uncommon tremor deriving from lesions in the cerebellar outflow tract, is alternating and rhythmic when the patient is relaxed; it can lead to ataxia on goal-directed action. Action tremors can cause significant disability, even if they are apparently minor during office visits. They are typically 8 to 15 Hz, and cause large, sloppy handwriting. It is important to distinguish them from cerebellar dysmetria. Enhanced physiological tremors are caused by catecholamine release during anxiety, illnesses (such as hyperthyroidism), or with stimulants (such as caffeine or cocaine). Physiologic action tremors are typically treated with propranolol. Familial essential tremors are often treated with primidone. Festination involves tiny, accelerating steps with difficulty stopping, and it can cause the patient to run into a wall. It is characteristic of parkinsonism. Hemiballism involves sudden flinging movements of a limb, usually caused by injury to the sub-thalamic nucleus.

Ataxia and dysmetria are of cerebellar origin and result from dysfunctional coordination of muscle groups. They cause difficulty reaching targets, often with wild oscillations. The patient’s gait might demonstrate remarkable swaying without falls. Cerebellar deficits are common in alcoholism. Fasciculations are tiny twitches of the skin surface caused by spontaneous activation of motor units. They are of neuromuscular, not basal ganglia, origin, and are often due to exercise, anxiety, or drugs (such as opiates). However, lower motor neuron disease can also cause fasciculations.

Movement Disorders with Psychiatric Symptoms Parkinsonism Parkinsonism involves a set of symptoms that can be caused by several disorders. Classically, idiopathic Parkinson’s disease (IPD ) is characterized by a triad of tremor, bradykinesia, and rigidity. Additional symptoms, such as poor levodopa response, early falling, early dementia, or early autonomic signs, suggest one of the “Parkinson’s Plus” syndromes. Secondary causes of parkinsonism are many and include use of medications, heavy metal toxicity, and repetitive cranial trauma. Extreme caution should be exercised when prescribing dopamine antagonists to any patient with parkinsonism. Clozapine and quetiapine are generally the only dopamine-blocking agents recommended for use in this population. Anti-emetics with dopamine blockade, typical antipsychotics, and many atypical antipsychotics (e.g., olanzapine, risperidone, and ziprasidone) should be avoided. These drugs will greatly worsen the patient’s motor symptoms, sometimes for many days. IPD affects 3% of the population older than 65, and is sometimes diagnosed before age 40. It results from dopaminergic cell death in the substantia nigra. Levodopa is the treatment of choice in older patients because it has the fewest side effects. Long-acting formulations of dopamine agonists, such as pramipexole ER and ropinirole XL, are helpful for motor fluctuations, but are more likely to cause sedation, nausea, hallucinations, and compulsions. Amantadine, an antagonist at the N -methyl d-aspartate (NMDA) receptor, can suppress dyskinesias. Electrical stimulation in the sub-thalamic nucleus or globus pallidus is an increasingly popular treatment. About 30% of Parkinson’s patients meet criteria for major depression. Treatment of depression with Parkinson’s disease is similar to that for the treatment of depression in the general population. Earlier claims that selective

serotonin re-uptake inhibitors (SSRIs) worsened motor symptoms have not been substantiated. A head-to-head trial comparing nortriptyline to paroxetine showed antidepressant benefit from nortriptyline but not from paroxetine. Bupropion can be particularly helpful for parkinsonian fatigue, mirtazapine might reduce tremor, and selegiline might be neuroprotective. When using a sedating antidepressant, clinicians should consider the high fall risk in this population. Use of modafinil or stimulants can reduce fatigue from both the disease itself and from dopamine agonists. Electroconvulsive therapy (ECT) can improve both parkinsonian motor symptoms and depression. Thirty percent of patients with Parkinson’s disease eventually develop a cognitive disorder, usually a sub-cortical dementia, with bradyphrenia (slowed responses) paralleling the bradykinesia. Frontal and executive deficits are also present. Acetylcholinesterase inhibitors, such as donepezil and rivastigmine, as well as the NMDA antagonist memantine and levodopa can help cognitive performance. In some cases, concomitant Alzheimer’s disease is found on autopsy. Early or severe dementia is evidence against IPD. In advanced Parkinson’s disease, levodopa wears off precipitously, and some patients alternate in two- or three-hour blocks between being immobile and being wildly dyskinetic. During their off phases, they might have panic attacks; benzodiazepines can be helpful in combating these symptoms. On-phase dyskinesia can be associated with mania or psychosis. Amantidine can greatly help dyskinesias but sometimes worsens psychosis. If giving smaller, more frequent doses of levodopa does not help, psychosis might lessen with use of very low doses of quetiapine or clozapine. Pimavanserin, a serotonin2A inverse agonist, is currently being evaluated specifically for treatment of psychosis due to Parkinson’s disease.

“Parkinson’s Plus” Syndromes Dementia with Lewy bodies (DLB) usually presents with dementia, followed by parkinsonism. It is the second leading cause of neurodegenerative (nonvascular) dementia after Alzheimer’s disease. Hallucinations, commonly visual, occur in more than 20% of patients, with the hallucinatory content often impressively well-formed and complex. Fluctuating levels of cognition are also characteristic. Dopamine agonists can exacerbate hallucinations, creating a more mobile but also more psychotic patient who is more likely to injure himself. As with all forms of parkinsonism, dopamine antagonists other than clozapine and quetiapine should be avoided.

Progressive supranuclear palsy (PSP ) presents with early downgaze palsy and falls as well as with parkinsonism. Dementia and pseudobulbar affect, marked by involuntary or uncontrollable laughter or crying, soon follow. Levodopa is not useful and treatment is largely supportive. Multiple system atrophy (MSA ) is a rapidly progressive condition, with an age of onset earlier than it is in IPD. It is now classified by the predominating features, as either with parkinsonian features or with cerebellar ataxia. The term Shy-Drager syndrome is sometimes still used to denote predominant autonomic features. Early signs of dysautonomia (e.g., orthostatic hypotension, bladder dysfunction), cerebellar dysfunction, and spasticity can be present in addition to parkinsonism. In contrast to IPD and other Parkinson’s “plus” syndromes, cognition is relatively spared in MSA. Levodopa helps little. Recent evidence suggests that prion infection might cause some MSA.

Chronic Traumatic Encephalopathy Chronic traumatic encephalopathy (CTE ) results from repeated head injuries. Presentation is variable, with one or more predominating symptom clusters, including motor, affective, behavioral (impulsivity, aggression), and cognitive. Parkinonsism might be found; when present, it is less levodopa-responsive than is IPD. Though once considered to be a rare syndrome restricted to boxers (dementia pugilistica), CTE is being diagnosed with greater frequency in former professional athletes such as football and hockey players as well as in combat veterans. Patients with dementia from CTE appear to be at significantly higher risk for depression and suicide. The disorder is progressive, worsening despite the absence of continued brain injury.

Normal Pressure Hydrocephalus Symptoms involve the triad of frontal gait (feet stuck to floor, falling backward), frontal or abulic dementia, and incontinence. Computed tomography (CT) shows ventricular dilation out of proportion to gyral atrophy. If largevolume lumbar puncture relieves gait symptoms, a ventriculoperitoneal shunt should be considered as treatment.

Huntington’s Disease Huntington’s disease (HD) is an autosomal dominant disorder characterized by chorea, as well as by psychiatric and cognitive changes. It affects about 8 in 100,000 people. Psychiatric symptoms are often the presenting symptom; dementia is a late phenomenon. Cell death is prominent in the striatum and

cortex. The Huntington’s gene defect is a CAG triplet repeat expansion. As in other neuropsychiatric genetic disorders, such as fragile X syndrome and some spinocerebellar ataxias, a longer expansion results in earlier and more severe symptoms; this process occurs as the defective gene is passed down in a process known as anticipation. The average age of onset is 40 years, and children of patients with HD have a 50% chance of developing the disease. The risk of suicide in patients with HD is thought to be 5 to 10 times that of the general population. Psychosis is also commonly seen in later stages. Treatment of the psychiatric disturbances is symptomatic, using typical antipsychotics (which also help the chorea) and antidepressant drugs. Tetrabenazine, which depletes presynpatic dopamine, is sometimes used for motor symptoms. It is the only FDAapproved medication for chorea, though it carries a risk of worsening depression.

Wilson’s Disease Wilson’s disease is an autosomal recessive disorder causing copper deposition. Typical age of onset is childhood or adolescence, though diagnosis can be made as late as the fifth decade. Symptoms are related to dysfunction of the liver and brain. Neuropsychiatric symptoms include dystonia, chorea, ataxia, tremor, mood disorder, psychosis, and intellectual decline. Although Wilson’s disease is rare, affecting only 1 in 400,000 people, clinicians should have a high index of suspicion, because it is highly treatable with chelation therapy (e.g., Dpenicillamine) and dietary copper restriction. Diagnosis is suggested by detection of low serum ceruloplasmin, followed by finding a high 24-hour urinary copper excretion. Definitive diagnosis is by liver biopsy. Slit-lamp ophthalmic examination for Kayser-Fleischer rings can also be useful in making the diagnosis.

Tourette’s Syndrome Tourette’s syndrome is defined by multiple motor tics and at least one vocal tic, lasting more than a year, starting before the age of 18 years. Its prevalence is 70 per 100,000 people, with men affected four times more frequently than women. There is a waxing and waning course, but not a progressive deterioration. Spontaneous remissions can last as long as two decades. Tourettes’s is very frequently co-morbid with obsessive-compulsive disorder (OCD) and attention deficit and hyperactivity disorder (ADHD). Depression, learning disability, and impulse control disorders are also common. Tics should be treated only if they are significantly bothersome to the patient. Behavioral therapy is often effective

in suppressing tics. Alpha2 -receptor agonists (clonidine, guanfacine) are often the first-line agents because they have few side effects, but they are only moderately effective. Low doses of haloperidol, pimozide, and, recently, aripiprazole, are the only medications approved by the United States Food and Drug Administration (FDA) to treat Tourette’s syndrome. Antipsychotic-induced TD can be mistaken for exacerbation of tics. Withdrawal of dopamine-blocking agents can also worsen tics and should therefore be done slowly. Tetrabenazine and the anticonvulsant topiramate, are occasionally used, as well. SSRIs effectively treat co-morbid OCD as well as social phobia that often develops due to concerns about experiencing tics in public. Stimulants may help co-morbid ADHD but can sometimes worsen tics. Deep brain stimulation (DBS) has been used but only in extreme cases, and evidence about its efficacy remains mixed.

Basal Ganglia Calcifications Basal ganglia calcifications are usually incidental. In hypopararathyroidism and Fahr’s disease , they can be associated with movement disorders and psychiatric disorders.

Drug-Induced Movement Disorders Acute Drug Reactions Neuroleptic malignant syndrome (NMS) is a serious psychiatric drug reaction that is described further in Chapter 31 . NMS can be caused not only by dopamine antagonists but also by the withdrawal of dopamine agonists in parkinsonian patients. Akathisia is the most common psychiatric drug reaction and is caused by a variety of drugs, including neuroleptics, SSRIs, tricyclic antidepresasants (TCAs), and lithium. Relatively high doses of propranolol are the first-line treatment. Benzodiazepines and selegiline can sometimes help, as well. Restless legs syndrome, a form of akathisia, can also be caused by use of medications. Dopamine agonists, such as ropinirole, are the main treatment for restless legs syndrome; clonazepam, low-dose opiates, levodopa, and, increasingly, gabapentin and pregabalin are also used. Acute dystonia is experienced by 10% of patients treated with typical neuroleptic agents within the first hours and days of treatment. Dystonias are less common with atypical antipsychotics. Common forms of acute dystonia include torticollis (cervical dystonia), opisthotonos (involving axial muscles around spinal column), and oculogyric crisis (involving ocular muscles). Acute

dystonias respond quickly to intravenous anticholinergic drugs, such as diphenhydramine or benztropine. Oral medications are not recommended in the setting of acute dystonia due to the possibility of laryngospasm but can be started concurrently with typical neuroleptics to prevent acute dystonic reactions. Anticholinergic agents should be used with caution in patients at risk for delirium, cardiac arrhythmia, glaucoma, ileus, urinary retention, or prostatic hypertrophy. Ataxia is seen during initiation of therapy or in the setting of supra-therapeutic blood levels of many drugs. It is especially common with mood stabilizers, such as carbamazepine, though it can sometimes be produced simply by the sedative effects of some neuroleptics or antidepressants. Ataxia can cause dangerous falls in the elderly. Treatment for medication-induced ataxia is typically discontinuation or reduction of the offending agent. Parkinsonism can begin 5 to 30 days after starting a dopamine antagonist and is dose-dependent. Treatment with dopamine agonists risks worsening the symptoms for which the antagonist was prescribed, and it is usually ineffective. Thus, anticholinergic agents are the mainstay of treatment. It is controversial whether drug-induced parkinsonism always resolves after the offending medication is stopped—in some cases the parkinsonism appears to persist indefinitely. Drug-induced action tremor , of which lithium and valproic acid are the most common offenders, must be distinguished from the rest tremor of drug-induced parkinsonism because the treatment is different. Drug-induced action tremors typically occur at supratherapeutic drug levels, though they can be seen even with therapeutic levels. Reduction of the dose is often sufficient to resolve the tremor. Substitution of an alternative mood stabilizer for lithium or valproate can also be helpful. If such interventions are ineffective or not feasible, propranolol or primidone are generally considered effective. Because patients often use caffeine to combat the sedation from mood stabilizers, replacing caffeine with modafinil can further help reduce tremor.

Delayed Drug Reactions TD and tardive dystonia are most often caused by long-term administration of dopamine blockers but can occur with use of other drugs, as well. TD most often affects the mouth and tongue, presenting as lip smacking, sucking, or facial grimacing. It can also cause limb or truncal choreoathetosis or dystonia. TD often develops rapidly before stabilizing. Because the movements decrease

during voluntary actions, they usually do not interfere with tasks of daily living and are primarily aesthetic. TD is seen in 10% to 20% of patients treated with a typical antipsychotic for more than one year but can be seen after only three months of exposure. After the first year, the risk appears to be about 5% per patient per year. With atypical antipsychotics, the risk is thought to be substantially reduced, though TD might still occur. Patient groups at highest risk for TD appear to be mood-disordered patients, those with structural brain lesions, elderly women, children, and non-Caucasian patients. Frequent starting and stopping of antipsychotic medication and use of anticholinergic agents and lithium in conjunction with antipsychotic agents are also thought to elevate the risk. TD-like symptoms are seen in some never-medicated patients with schizophrenia, suggesting co-morbidity with a chronic thought disorder. The differential diagnosis for TD includes other causes of chorea, as well as withdrawal dyskinesia. The latter can be particularly difficult to distinguish from TD because both can present in the setting of a reduction of antipsychotic agents. Increased sensitivity to dopamine receptors might underlie the pathophysiology of TD. Documentation of movement disorders should include use of scales such as the Abnormal Involuntary Movement Scale (AIMS). Management includes a gradual dose reduction of the dopamine receptor blocker. Abrupt discontinuation of the drug might cause severe transient worsening of symptoms. Increasing the dose of the current dopamine antagonist might help in the short term, but can worsen TD in the long term. Switching to clozapine or olanzapine might also be a useful strategy because these medications are thought to be least likely to induce TD. Switching to quetiapine usually does not help significantly. Tetrabenazine can suppress TD, but it carries a risk of depression. Studies are currently underway examining its pro-drug, valbenazine. Other treatment strategies with some evidence for efficacy include vitamin B6 , vitamin E, ginkgo biloba , benzodiazepines, baclofen, and amantadine. Anticholinergic agents might also be useful for management of tardive dystonia. Severely disabling TD has been treated with DBS to the internal globus pallidus.

Psychogenic Movement Disorders The diagnosis of psychogenic (functional) movement disorder is very difficult to make because many movement disorders thought to be purely neurological have odd features. For example, a boy with DYT-1 hereditary dystonia might not show signs of dystonia while tap-dancing, or a patient with Parkinson’s disease

might remain frozen unless a pencil is placed on the ground for her to step over. Further, many patients have both neurological illness and psychogenic symptoms. Nonetheless, movement disorders are a very common form of conversion disorder, though they are less commonly seen in malingering or factitious disorder. Clues to the presence of a psychogenic movement disorder include: abrupt onset; normal neuroimaging; varying body distribution; atypical movement disorder phenotype; movements disappearing with distraction; response to placebo; paroxysmal symptoms; excessive startle; and lack of real falls or self-injury. Unfortunately, however, all of these are sometimes seen in basal ganglia movement disorders. More recent imaging and neurophysiological studies have indicated abnormalities in limbic regions as well as in regions involved in motor preparation, suggesting that concepts of intentionality and volition in these disorders are more complex than previously thought. Hysterical paralysis can be distinguished from true paralysis by several tests, although in practice these tests are often used inaccurately to dismiss patients with complex motor disorders. The Babinski’s plantar reflex is the classic test that was used to distinguish corticospinal injury from shell-shock conversion disorder in World War I. Firmly stroking the outer edge of the sole toward the toes causes the big toe to dorsiflex in corticospinal injuries; in normal or hysterical subjects, all toes will curl. The face-drop test is performed by lifting the patient’s flaccid hand above his face and dropping it. In hysterical paralysis, the hand will drop next to the face, rather than on it. Patients with hysterical leg weakness will often drag the leg semi-uselessly, in distinction to the circumduction of upper motor neuron damage or the foot drop of lower motor neuron damage. Finally, the Hoover’s Sign is elicited by placing the examiner’s hands under each of the heels of the reclining patient and asking the patient to raise the affected leg. If patients are truly making an effort, there should be a compensatory downward pressure of the good leg. Hysterical tremors tend to be low frequency, high amplitude, and paroxysmal, in part because they require significant energy to sustain for long periods. “Distractibility,” or a tremor that moves to another body part if the originally affected limb is restrained are not typically reliable signs of hysterical tremor.

Suggested Readings 1. Aquino CC, Lang AE: Tardive dyskinesia syndromes: current concepts. Parkinsonism Relat Disord . 2014; 20: S113–117.

2. Czarnecki K, Hallett M: Functional (psychogenic) movement disorders. Current Opin Neurol . 2012; 25: 507–512. 3. Daroff RB, et al, eds.: Neurology in Clinical Practice . 7th ed. Philadelphia, PA: Elsevier; 2016. 4. Flaherty AW, Rost NS: The Massachusetts General Hospital Handbook of Neurology . Philadelphia, PA: Lippincott Williams and Wilkins; 2007. 5. Meehan W 3rd, et al: Chronic traumatic encephalopathy and athletes. Neurology. 2015; 27: 1504–1511. 6. Weintraub D, Burn MD: Parkinson’s disease: the quintessential neuropsychiatric disorder. Mov Disord . 2011; 26: 1022–1031.

Treatment Approaches

S E C T I O N F O U R

CHAPTER 46

Basic Psychopharmacology SHARMIN GHAZNAVI, MD, PHD AND JAMES A. JENKINS, MD

KEY POINTS Basic Principles of Neuronal Anatomy and Functioning The neuron is the primary cell in the central nervous system (CNS), and consists of a cell body, axon, and dendrites. The synapse is the space between two neurons where neurotransmitters communicate information from one neuron to the next. Synapses can be axodendritic (between axon and dendrites), axo-somatic (between axon and cell body), or axo-axonal (between the axons of two neurons). Neurotransmitters interact with several different types of membrane-bound protein receptors on both the pre-synaptic and post-synaptic neuron to induce changes in electrochemical characteristics of neurons, and in turn gene and protein expression in the cell body. The two main types of receptors involved in psychopharmacology are fast, ionotropic receptors, which open to allow influx or efflux or ions, and slow Gprotein-coupled receptors (GPCRs), which are linked to intra-cellular signaling cascades that regulate gene and protein expression. Neuronal Circuitry Organization The CNS can be organized anatomically, functionally, and by neurotransmitter circuitry. The seven main neurotransmitters in the brain can be grouped by their distribution in the following manner: diffuse (γ -amino butyric acid [GABA]-ergic and glutaminergic), or, circumscribed with long projections (serotonergic, noradrenergic, dopaminergic, histaminergic, and cholinergic). Neurotransmitters Glutamate is the primary excitatory neurotransmitter in the brain and it interacts with ionotropic NMDA and AMPA receptors that are important for mood and cognition. These receptors have been implicated in the glutamate

hypothesis of schizophrenia and are emerging as novel targets for rapid-acting antidepressants. GABA is the primary inhibitory neurotransmitter in the brain with important implications for mood and anxiety. Traditional anxiolytics interact with these receptors. Serotonin is a complex neurotransmitter system including at least six different families of GPRCs. This system is involved in mood and anxiety disorders, both the positive and negative symptoms of schizophrenia, and in modulating dopamine in the basal ganglia. Atypical antipsychotics modulate these receptors. Norepinephrine is the primary neurotransmitter involved in arousal, positive affect, and anxiety in the brain. Numerous antidepressants act to modulate noradrenergic activity. Dopamine regulates reward and movement pathways via two families of dopaminergic GPCRs. Typical antipsychotics and antiparkinsonian medications provide examples of the impact of dopamine modulation in the CNS. Histamine GPCRs are involved in regulation of sleep and appetite. Side effects, like sedation and weight gain, from psychotropics are mediated through agonism of these receptors. Acetylcholine has a role in memory, cognition, level of arousal, and modulation of dopaminergic neurons in the basal ganglia. Effects on acetylcholine account for some side effects observed in patients on antipsychotics; acetylcholine is targeted in the treatment of Alzheimer’s dementia. Emerging neurotransmitters of interest include melatonin and orexin.

Introduction Psychopharmacology is the art and science of using psychotropic medications to modulate human brain functions to treat psychiatric symptoms. It requires a fundamental understanding of how the brain functions both at the level of neurons (since much of the activity we are modulating happens in and around the synapse of two neurons), and at the level of neural circuits or systems (which underlie symptoms and behavior). Here we review both aspects of brain function and provide an overview of the main neurotransmitter systems involved in psychiatric management.

Basic Principles of Neuronal Anatomy and Functioning A basic understanding of the anatomy of a neuron and how neurons function is essential to understanding psychopharmacology since psychotropic medications modulate neuronal function. Although there are many different types of neurons, they all have three components in common: a cell body, an axon, and dendrites. The cell body which contains the cell nucleus, is the location of protein and neurotransmitter synthesis, and is essential to neuronal function because it integrates the inputs it receives from dendrites. Dendrites are branched cytoplasmic projections from a neuron’s cell body that receive electrochemical information from other neurons and transmit them to the cell body. These inputs are converted into chemical cascades that bring about effects by affecting protein synthesis within the cell nucleus. Finally, the axon is the output station of the neuron. At the place where the cell body and axon meet, the axon hillock, electrical signals are integrated. When they reach a certain threshold, an action potential is generated and it travels down the axon to the nerve terminal, where it stimulates the release of neurotransmitters, allowing communication with another neuron. The point where the nerve terminal of one neuron meets a neighboring neuron is called a synapse. Synapses can be axo-dendritic (between axon and dendrites), axo-somatic (between axon and cell body), or axo-axonal (between the axons of two neurons). A synapse is composed of a pre-synaptic neuron (the neuron sending the signal) and a post-synaptic neuron (the neuron receiving the signal). All co mmunication across a synapse is chemical. The pre-synaptic neuron releases neurotransmitters that bind to receptors on the post-synaptic cell, activating a signal transduction cascade in the post-synaptic neuron. There are four different types of signal transduction cascades corresponding to four different classes of receptors: G-protein-coupled (metabotropic), ionotropic, hormone-linked, and neurotrophin-linked. Of these, the most important in psychopharmacology are the ionotropic and G-protein-coupled receptors (GPCRs). The ionotropic receptors are fast-acting, Class I receptors. A neurotransmitter binds to the receptor protein and within milliseconds a change in the permeability of the associated ion channel occurs, allowing the influx of ions, such as Ca++ , Na+ , K+ , or Cl– . The entry of such ions affects the electrical threshold of the neuron resulting in either excitation or inhibition of the neuron, making it either more or less likely that signals are further propagated.

Ionotropic receptors have both the immediate effects of the influx of ions, as well as effects further downstream at the level of gene expression. Downstream effects result from activation of signal transduction cascades in which Ca++ acts as a second messenger interacting with a protein known as calmodulin that then activates certain kinases (calcium-calmodulin-dependent protein kinases) that act on the cell nucleus by transferring a phosphate group to a substrate protein involved in gene expression. Many anxiolytics and hypnotics act directly on ionotropic receptors and the immediate effects of the influx of ions, which decrease excitability, are thought to help explain the immediate effects of some anxiolytics and hypnotics. In contrast, the tolerance that develops with prolonged exposure to an anxiolytic is thought to be the result of the change in levels of ionotropic receptor gene expression via secondary messenger signaling cascades. GPCRs are slow-acting, Class II receptors. A neurotransmitter binds to the GPCR on the extra-cellular side, changes the protein’s conformation, and results in the exchange of an inactive g uanidine diphosphate molecule (GDP) for the active g uanidine triphosphate molecule (GTP), thereby activating the G-protein complex inside the neuron. Activated G-proteins facilitate the opening of neighboring ion channels, or the synthesis of second messengers, such as c yclic AMP (cAMP). Second messengers (Ca++ , cAMP) in turn regulate the activity of protein kinases and phosphatases involved in gene expression and protein synthesis pathways. As just demonstrated, the goal of a signal transduction cascade is to influence gene expression and protein production or function in neurons. Gene expression is regulated by transcription factors that bind to specific sequences of the DNA in the nucleus. Gene expression produces proteins; since proteins assemble the neuron and determine neuronal properties, gene expression regulates neuronal function. Many psychopharmacological agents (e.g., antidepressants, antipsychotics) with delayed therapeutic effects are thought to produce their therapeutic benefits through modulation of gene expression. The pre-synaptic neuron also expresses two proteins that can fine-tune synaptic communication. One is a membrane-bound receptor that binds the intrinsic neurotransmitter (autoreceptor) or transmitters of neighboring neurons (heteroreceptors) and affects the cell via intra-cellular messengers. One effect of such binding is the modulation of neurotransmitter release from the pre-synaptic neuron. The other protein is a membrane-bound re-uptake transporter that pumps the released neurotransmitter back into the pre-synaptic neuron, decreasing its availability in the synapse, and thus its ability to bind receptors.

Psychotropic medications function either directly on ionotropic and GPRCs or indirectly through the neurotransmitter transporters. The two types of neurotransmitter transporters include pre-synaptic re-uptake transporters and vesicular transporters. S elective serotonin re-uptake inhibitors (SSRIs), for example, block the re-uptake of serotonin, leaving higher concentrations available in the synaptic cleft to then bind serotonin GPRCs. Vesicular transporters package neurotransmitters into vesicles for release into the synaptic cleft. Amphetamine and methylphenidate are examples of medications that increase release of these vesicles resulting in the increase of available monoamines in the synaptic cleft. Understanding the difference between the type of receptor being activated (fast ionotropic versus slow metabotropic) and whether a medication has direct or indirect mechanism of action on neurotransmitters, helps to better understand the time course of clinical observations with psychotropics.

Neuronal Circuitry How are neurons arranged to process information? There are about 1011 neurons in the c entral nervous system (CNS) and each neuron establishes about 103 to 104 connections to other neurons. Given that one of the goals of psychopharmacology is to target specific symptoms and behaviors, a basic understanding of functional neuroanatomy and the major circuits involved in psychopharmacology can prove invaluable. The key brain areas that are most relevant to our understanding of psychopharmacology are the prefrontal cortex, basal forebrain, striatum, nucleus accumbens, thalamus, hypothalamus, amygdala, hippocampus, brainstem, spinal cord, and cerebellum. Five groups of densely-packed neurons provide diffuse projections to all areas of the brain to modulate their functions: cholinergic neurons in the basal forebrain and brainstem, dopaminergic neurons in the substantia nigra and v entral tegmental area (VTA), noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the raphe nuclei, and histaminergic neurons in the hypothalamus. Although there are many more neurotransmitter systems in the brain, in clinical psychopharmacology there are seven main systems: the glutamatergic, the γ -amino butyric acid (GABA)-ergic, cholinergic, serotonergic, noradrenergic, dopaminergic, and histaminergic systems. These seven systems can be divided into two groups based on their anatomical characteristics.

The first group includes the glutamatergic and GABA-ergic systems. Their neurons are by far the two most prevalent and most widely distributed types in the human brain. The widespread distribution of these three neurotransmitter systems has functional implications: the modulation of glutamatergic and GABA-ergic neurotransmission affects many neural systems. The second group of neurotransmitter systems comprises the cholinergic, serotonergic, noradrenergic, dopaminergic neurons, and histaminergic systems. These five systems project to their target areas typically by long-ranging projection fibers. Among these, the cholinergic, serotonergic, noradrenergic, and dopaminergic neurons have neurotransmitter-specific projection systems that reach selected neural systems, so their modulation leads to more circumscribed effects.

Neurotransmitter Systems Glutamatergic Glutamate (Glu ) is a neurotransmitter that is also an amino acid. It is the most abundant neurotransmitter in the brain and can act on virtually every neuron. However, the most important glutamatergic pathways are the cortico-cortical projections, the cortico-thalamic as well as thalamo-cortical, the cortico-striatal (extrapyramidal), and the cortical brainstem pathway (pyramidal tract). Glutamate is synthesized from glutamine in glial cells by the enzyme glutaminase. It is stored in vesicles and released by a Ca++ -dependent mechanism. Glutamate is an excitatory neurotransmitter that acts at various receptors. These include a pre-synaptic re-uptake pump, a vesicular transporter, and three different types of ionotropic receptors and a family of G-proteincoupled (metabotropic) receptors. The ionotropic glutamate receptors include N -methyl-D-aspartate (NMDA), alpha-amino-3-hydoxy-5-methyl-4-isoxazole-propionic acid (AMPA), and kainate receptors. Binding of glutamate to the ionotropic receptor opens an ion channel allowing the influx of Na+ and Ca++ into the cell. Binding of glutamate on AMPA and kainate receptors allow the influx of sodium, whereas binding of glutamate on NMDA receptors allow the influx of the calcium. Interestingly, ketamine, a short-acting, non-competitive antagonist of the NMDA receptor, has been shown to rapidly relieve depression within two hours of a single dose administration with effects lasting up to two weeks. Dosing is kept below the threshold for anesthetic and psychotomimetic effects in these trials. Although the exact mechanism is not yet understood, it is thought that transient, low-level NMDA receptor blockade results in a de-suppression of

transcription factors that control dendritic growth. The result is a burst of synaptic plasticity, which is thought to correspond to symptom reduction. Most of the current research into novel antidepressant medications is focusing on the glutaminergic system, specifically in modulating the NMDA receptor. The metabotropic glutamate receptor family includes at least eight different types of GPRCs. They are linked to different second-messenger systems and lead to the increase of intra-cellular Ca++ or the decrease of cAMP. Changing the availability of these intra-cellular molecules modulates the function of other receptors and amount of glutamate released to protect neurons from the toxic effects of excessive excitation. Drugs that selectively target these receptors remain in the experimental phase of development. Glutamate is removed from the synapse by high-affinity re-uptake; two transporter proteins are expressed in glial cells and one in neurons. Glutamate is relevant to a number of psychiatric disorders (e.g., schizophrenia, bipolar disorder, Alzheimer’s disease) and the medications we currently use to treat them. Memantine, an NMDA antagonist, is used in Alzheimer’s disease to slow the progression of the disease. Some anticonvulsants (e.g., gabapentin) and mood stabilizers (e.g., lamotrigine, riluzole) are thought to act by inhibiting glutamate as glutamate hyperactivity is thought to be one of the problems in bipolar disorder. Finally, the current NMDA hypothesis of schizophrenia proposes that cortico-brainstem glutamate neurons that tonically inhibit the mesolimbic dopamine pathway are hypoactive in schizophrenia. In fact, phencyclidine (PCP), which is an NMDA antagonist, mimics the positive and negative symptoms of schizophrenia. There is currently a significant push to develop new drugs for schizophrenia that target glutamate systems.

GABA-Ergic GABA is the primary inhibitory neurotransmitter in the brain and spinal cord. It too is synthesized from glutamate, but by the enzyme glu tamic acid decarboxylase (GAD). GABA-ergic neurons can be divided into two groups: short-ranging neurons (inter-neurons and local circuit neurons) in the cortex, thalamus, striatum, cerebellum, and spinal cord; and, medium to long-ranging neurons that travel between regions (such as the septo-hippocampal neurons). There are three types of GABA receptors: two ionotropic and one metabotropic (GPRC). The two ionotropic receptors are GABAA and GABAC . Binding of GABA to GABAA and GABAC receptors leads to opening of ion channels that allows an influx of Cl– ions, resulting in inhibition of the neuron. GABAA

receptors are targets of benzodiazepines, barbiturates, and alcohol. These receptors are composed of a number of classes of sub-units (six variants of α , three variants of β , three variants of γ , one variant of δ , ε , θ , π , and three variants of ρ ); the sensitivity of the receptor to a certain compound is dependent on the composition of its subunits. For example, benzodiazepine-sensitive GABAA receptors must have 2 β sub-units, 1 γ subunit, and 2 α sub-units. The function of GABAC receptors is still not known, but it is known that they are not sensitive to benzodiazepines. The GABAB receptor is a GPRC. The GABAB receptor is linked to Gi (decreasing cAMP and opening of K+ channels) and Go (closing Ca++ channels). The net effect is prolonged inhibition of the cell. GABAB receptors are thought to be important in pain, mood, and memory. Termination of GABA activity is by removal of GABA from the synapse by a sodium-dependent pre-synaptic GABA uptake transporter.

Serotonergic Serotonin , or 5-hydroxytryptamine (5-HT), is a monoamine widely distributed in many cells of the body, with about 1% to 2% of its entire body content present in the CNS. Serotonergic neurons are found in several clusters along the mid-line of the brainstem. The rostral group of nuclei contains the dorsal and medial raphe as well as the nucleus linearis and raphe pontis. These neurons project to the thalamus, hypothalamus, amygdala, striatum, and cortex, and regulate a wide range of functions (including mood, anxiety, and sleep). The caudal group consists of the raphe magnus, raphe pallidus, and raphe obscurus and project to other brainstem neurons, the cerebellum, and the spinal cord. These serotonergic projections are believed to be important for the regulation of pain. Serotonin is synthesized by the enzyme amino acid de carboxylase (AAD), from 5-hydroxy-tryptophan, which itself is derived from tryptophan via tryptophan hydroxylase. The rate-limiting step of the pathway is the production of 5-hydroxy-tryptophan by tryptophan hydroxylase. Serotonin acts at two different types of receptors, one ligand-gated ion channel (5-HT3 ) and six different families of GPRCs. Of the six families of metabotropic serotonin receptors, the most represented in psychopharmacology are the 5-HT1 and 5-HT2 receptors. The 5-HT1 receptors are coupled to Gi/Go and, when stimulated, decrease levels of cAMP. This family of receptors has a net inhibitory effect on neurons.

There are two pre-synaptic 5-HT1 receptors. The pre-synaptic 5-HT1B/1D autoreceptor blocks 5-HT release and the pre-synaptic 5-HT1A auto-receptor slows neuronal impulse through the pre-synaptic neuron. The 5-HT1A post-synaptic neuron stimulates dopamine (DA) release, especially in the medial prefrontal cortex and striatum. Medications that produce 5-HT1A agonism reduce anxiety and depression and are thought to improve the negative symptoms of schizophrenia. Partial agonism of this receptor is also hypothesized to account for the reduced incidence of extrapyramidal symptoms (EPS) associated with the atypical antipsychotics. Buspirone is an example of a 5-HT1A agonist. The 5-HT2 receptors are coupled to phospholipase C and lead primarily to depolarization of the post-synaptic cell. Hallucinogens, like lysergic acid diethylamide (LSD) and mescaline, are potent agonists of 5-HT2A receptors. Conversely, antagonism of 5-HT2A is hypothesized to be the mechanism by which atypical antipsychotics reduce the positive symptoms of schizophrenia. The 5-HT3 receptor is the only monoamine receptor coupled to an ion channel, probably a Ca++ channel. It is found in the cortex, hippocampus, and area postrema (a medullary structure that regulates emesis). It is typically localized pre-synaptically and regulates neurotransmitter release. Well-known antagonists are odansetron and granisetron, which are used as anti-emetic agents. Mirtazapine also acts at the 5-HT3 receptor. The action of serotonin is terminated by its removal from the synapse at a highaffinity serotonin re-uptake site (SERT) and break down by monoamine oxidase (MAO). SSRIs, as well as tricyclic antidepressants (TCAs), work by blocking reuptake of serotonin. MAO inhibitors (MAOIs) function by blocking the activity of the MAO enzyme.

Noradrenergic Norepinephrine (NE ) is a catecholamine. This neurotransmitter is produced in neurons located in the LC and the lateral tegmental region of the brainstem. The noradrenergic neurons in the LC provide extensive projections to the cortex, hippocampus, thalamus, cerebellum, and spinal cord. The tegmental noradrenergic neurons project predominantly to the hypothalamus, basal forebrain, and spinal cord. NE is involved in the regulation of sleep cycles, appetite, mood, and cognition. Excessive NE output from the LC is thought to underlie anxiety, particularly the symptoms of hyperarousal, nightmares,

flashbacks, and panic attacks. Reduced NE is thought to underlie reduced positive affect and apathy observed in major depression. NE is synthesized from dopamine by the enzyme dopamine-β-hydroxylase (DBH). The pathway’s rate-limiting step is the production of dopa by tyrosine hydroxylase, which can be activated through phosphorylation. NE is stored in vesicles in noradrenergic neurons. In fact, amphetamine works by facilitating release of NE from its vesicles. NE binds with varying affinities to the G-protein-coupled, noradrenergic receptors α 1, α 2, β 1, and β 2, all of which are located in the CNS. Of these, α 1 and α 2 are of the most clinical significance. Pre-synaptic α 2 receptors are autoreceptors that attenuate the release of NE when an agonist binds. Clonidine and guanfacine are potent agonists and yohimbine is an antagonist of α 2 receptors. The α 1 receptors are primarily located post-synaptically. Prazosin is an α 1 receptor antagonist, used to treat nightmares and hypervigilance associated with post-traumatic stress disorder (PTSD), both of which are thought to be the result of excess adrenergic tone. Adrenergic β receptors are mostly located post-synaptically and are found throughout the body as part of the sympathetic nervous system. Those found in the CNS are usually β 1 adrenergic receptors and are believed to regulate synaptic plasticity. The action of NE is terminated by its breakdown by two enzymes, catechol-Ome thytransferase (COMT) and MAO, and by its re-uptake via a NE transport pump (NET). The NET is Na+ /CI– -dependent neurotransmitter transporter that removes NE from the synapse. Desipramine’s and atomoxetine’s mechanism of action involves blocking NET.

Dopaminergic Dopamine (DA ) is not only a neurotransmitter, it is an intermediate of NE, as discussed above. DA neurons are located in the VTA of the brainstem, substantia nigra of the brainstem, the hypothalamus, and the thalamus. There are five major dopamine pathways in the brain. The mesolimbic pathway which originates in the VTA of the brainstem and projects to the nucleus accumbens in the ventral striatum. It is thought to mediate delusions and hallucinations. It is also believed to be involved in reward behavior and in the development of addiction. The mesocortical pathway arises from the same neurons in the brainstem and projects to the prefrontal cortex and is thought to mediate cognitive function, in particular executive function. The nigrostriatal pathway orginates in the substantia nigra of

the brainstem and projects to the basal ganglia and striatum. It mediates motor movements and is part of the extrapyramidal system. The tubero-infundibular pathway originates form dopaminergic neurons in the hypothalamus and project to the anterior pituitary that inhibits prolactin release. Antipsychotics that block DA result in hyperprolactinemia through their effects on the tubero-infundibular pathway. Finally, there is one other pathway, the thalamic pathway, which originates in DA neurons at a number of sites that project to the thalamus. This pathways function is relatively undescribed, but it is not believed to have a role in psychosis. DA is synthesized by the enzyme L-aromatic amino acid decarboxylase from dopa (which is produced from tyrosine via tyrosine hydr oxylase [TH]). The turnover rate of dopa is extremely high and DA levels can be elevated if extra dopa is supplied to the brain. L-Dopa, which is used in Parkinson’s disease, provides increased numbers of precursors for the formation of DA. DA is released into the synapse from vesicles. Both amphetamine and methylphenidate facilitate release of DA from its vesicles. There are numerous types of DA receptors, all G-protein-coupled, however two families of receptors are most relevant for our purposes: the D1 receptor family and the D2 receptor family. The D1 receptor family includes the D1 and D5 receptors, which are coupled to Gs and lead to an increase in cAMP. D1 receptors are found in the striatum, cortex, substantia nigra, and olfactory tubercule. D5 receptors are found primarily in the hippocampus and hypothalamus. The D2 receptor family includes the D2 , D3 , and D4 receptors, which are linked to Gi and lead to a decrease in cAMP. D2 receptors are found in the striatum, substantia nigra, pituitary gland, retina, and olfactory tubercule. Only D2 receptors are autoreceptors that can also function to decrease the release of DA. D3 receptors are found in the nucleus accumbens. D4 receptors are found on the GABA-ergic neurons in the cortex, thalamus, hippocampus, and substantia nigra. The D2 family of receptors plays a pivotal role in the treatment of psychosis. In general, agonism of D2 receptors increases the amount of available DA in the synaptic cleft, whereas antagonism results in a decrease. Typical antipsychotics, like haloperidol, exert their effects through antagonism of the D2 -like receptors. Medications that target this family of receptors are relatively non-selective between D2 , D3 , and D4 , which helps explain some of the side effects produced by their administration, like anhedonia and EPS with antipsychotics. Anti-

parkinsonism drugs, like bromocriptine, work as agonists on the D2 receptor family. The activity of DA is terminated either by its removal from the synapse by reuptake via a pre-synaptic dopamine tran sporter (DAT), transport by NET, or by its breakdown by COMT or MAO. The DAT is a Na+ /Cl– -dependent neurotransmitter transporter that transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by several drugs (e.g., cocaine, amphetamine, bupropion, benztropine, nomifensine).

Histaminergic Histamine is one of the critical neurotransmitters in the regulation of sleep and wakefulness. In addition to its role in regulating wakefulness, histamine is also believed to have a role in regulating cognition in the dorsolateral prefrontal cortex. Histamine is produced in the tubero-mamillary nucleus of the hypothalamus and it has projections throughout the brain. It is synthesized from the amino acid histidine by the enzyme histidine decarboxylase. There are three different types of histamine receptors: two are GPRCs, and one is an auto-receptor. H1 and H2 receptors are G-protein-coupled. H1 receptors activate phosphatidyl inositol and a transcription factor cFOS, to modulate wakefulness, when activated by histamine. Antihistamines function by blocking histamine and causing sedation or sleep. H2 receptors are prevalent in the gut, but can also be found in the brain. However, the function of the H2 receptors in the brain is unknown, but they do not appear to promote wakefulness. H3 receptors are auto-receptors that stop the release of histamine. The action of histamine is thought to be terminated by its diffusion away from the synapse and breakdown by a number of enzymes including histamine N methyl-transferase and MAOB that work in concert to convert histamine into an inactive form.

Cholinergic Acetylcholine (ACh ) is a neurotransmitter that operates at several sites in the CNS and the peripheral nervous system. Cholinergic neurons are found in the brainstem neurotransmitter center and in the basal forebrain. Cholinergic neurons in the basal forebrain (septum, diagonal band, nucleus basalis of Meynert) project to the entire cortex, the hippocampus, and the amygdala. Neurons located in the brainstem project predominantly to the thalamus and are

thought to be important for regulating wakefulness/sleep. Cholinergic interneurons in the striatum modulate the activity of GABA-ergic striatal neurons. Increased cholinergic tone in Parkinson’s disease and decreased cholinergic tone in patients treated with neuroleptics are examples where there is an imbalance of the cholinergic and dopaminergic neurons in the striatum. In the peripheral nervous system, acetylcholine operates at the autonomic ganglia, the parasympathetic post-ganglionic synapse, and the neuromuscular junction. ACh is synthesized from two precursors, acetyl-coenzyme A and choline, by the enzyme choline acety ltransferase (ChAT). Acetylcholine is produced in the mitochondria from glucose and choline is derived from diet and intra-neuronal sources. High-affinity and low-affinity transporters pump choline, the ratelimiting factor in the synthesis of ACh, into the cell. Acetylcholine has two different types of receptors, one inotropic and one metabotropic. The metabotropic (G-protein-coupled) receptors are muscarinic receptors, which can be excitatory or inhibitory, and are relatively abundant in the CNS. There are many sub-types of muscarinic receptors, but three are particularly important. The M1 sub-type is a post-synaptic receptor that appears to be important in memory function. The M2 sub-type is a pre-synaptic autoreceptor that blocks the further release of ACh. The M3 sub-type is found on pancreatic β cells—binding of acetylcholine leads to release of insulin. Certain atypical antipsychotics, such as olanzapine and clozapine, block M3 receptors and reduce insulin release, which might explain some of the metabolic side effects of these medications. When activated, the final effect of most of the muscarinic receptors is to open or close channels for K+ , Ca++ , or Cl– . The ionotropic receptors are nicotinic receptors that are less abundant than the muscarinic type in the CNS. They are excitatory receptors that allow influx of Na+ , K+ , or Ca++ into the cell. While there are several sub-types of nicotinic receptors, the most important are those in the nucleus accumbens that are thought to be the target of nicotine, and those located in the prefrontal cortex, which are believed to regulate cognition. The action of ACh is terminated by its hydrolysis into acetyl-CoA and choline by the enzyme acetylcholinest erase (AChE). Removing ACh from the synapse can be blocked irreversibly by organophosphate compounds and in a reversible fashion by drugs (such as physostigmine). Alzheimer’s disease and anticholinergic delirium are examples of illnesses arising from deficits in ACh. Donepezil is an example of a medication that

inhibits the metabolism of ACh by AChE with the goal of improving cognitive function in patients with Alzheimer’s disease.

Other Neurotransmitters Although the previously mentioned neurotransmitter systems are the best understood and most widely modulated in psychopharmacology, there are other neurotransmitter systems in the brain that are of increasing interest in the development of future psychotropics; two examples are melatonin and orexin . Melatonin is a hormone produced by the pineal gland in response to darkness. There are three melatonin GPRCs found in the CNS that contribute to the regulation of mood and circadian rhythms. Ramelteon, a melatonin receptor agonist, is one example of a novel agent recently approved to promote sleep. It has been demonstrated to be particularly helpful in people with sleep–wake cycle disturbance. Agomelatine, another melatonin receptor agonist, is a novel antidepressant currently used in Europe. Orexin is a neuropeptide produced in the hypothalamus that regulates wakefulness and appetite. The loss of this neuropeptide has been implicated in the pathophysiology of narcolepsy. Orexin exerts its effects through two GPRCs. Novel wakefulness promoting agents and appetite suppressants are in development that agonize these receptors. Additionally, an antagonist, suvorexant, was recently approved in the United States for the treatment of insomnia.

Suggested Readings 1. Brisbare-Roch C, Dingemanse J, Koberstein R, et al: Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nature Medicine . 2007; 13(2): 150–155. 2. Catena-Dell’Osso M, Marazziti D, Rotella F, et al: Emerging targets for the pharmacological treatment of depression: focus on melatonergic system. Current Medicinal Chemistry . 2012; 19(3): 4 28–437. 3. Kandel ER, Schwartz J, Jessel T: Principles of Neural Science . 4th ed. New York: Elsevier; 2012. 4. Singh SP, Singh V, Kar N: Efficacy of agomelatine in major depressive disorder: meta-analysis and appraisal. Int J Neuropsychopharmacol , 2011; 23:1–12.

5. Stahl SM: Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications . New York: Cambridge University Press; 2014.

CHAPTER Treatment of Anxiety 47 Disorders ERIC BUI, MD, PHD; BRIAN J. SCHULMAN, MD; DAN V. IOSIFESCU, MD, MSC; AND MARK H. POLLACK, MD

KEY POINTS Overview Anxiety disorders tend to be chronic and to fluctuate. First-line treatments of anxiety disorders include cognitive-behavioral therapy (CBT) and selective serotonin re-uptake inhibitors (SSRIs)/serotonin norepinephrine re-uptake inhibitors (SNRIs). SSRIs/SNRIs doses required to achieve treatment response in anxiety disorders are usually higher than in major depressive disorder, and require slow titration with a low starting dose. Use of concomitant benzodiazepines might alter the efficacy of CBT. Panic Disorder Evidence-based pharmacological treatments include use of tricyclic antidepressants, benzodiazepines, and SSRIs/SNRIs. SSRIs/SNRIs are usually considered first-line pharmacological treatments due to their safety, side effect profile, and broad-spectrum efficacy for co-morbid psychiatric conditions. FDA-approved medications include paroxetine, sertraline, fluoxetine, venlafaxine, alprazolam, and clonazepam. CBT is the first-line psychosocial treatment. It aims to eliminate the catastrophic misinterpretations and fear of somatic sensations as well as avoidance behaviors. Generalized Anxiety Disorder Evidence-based pharmacological treatments include SSRIs/SNRIs, benzodiazepines, and pregabalin. SSRIs/SNRIs are usually considered first-line pharmacological treatments due

to their safety, side effect profile, and broad-spectrum efficacy for co-morbid psychiatric conditions. United States Food and Drug Administration (FDA)–approved medications include paroxetine, escitalopram, duloxetine, venlafaxine, alprazolam, and buspirone. CBT is the first-line psychosocial treatment. It aims to identify maladaptive cognitions and the process of worrying as a primary cause of anxiety. Social Anxiety Disorder Evidence-based pharmacological treatments include SSRIs/SNRIs, benzodiazepines, monoamine oxidase inhibitors, gabapentin, and beta-blockers (for the performance-only type). SSRIs/SNRIs are usually considered first-line pharmacological treatments due to their safety, side effect profile, and broad-spectrum efficacy for co-morbid psychiatric conditions. FDA-approved medications include paroxetine, sertraline, and venlafaxine. CBT is the first-line psychosocial treatment. It aims to decrease the fear of critical evaluation by others in social interactions and the resulting avoidance behaviors. Specific Phobia Exposure-based interventions are the basis of psychosocial treatments. Pharmacological treatments may include benzodiazepine on a prn basis. Obsessive-Compulsive Disorder Evidence-based pharmacological treatments include tricyclic antidepressants and SSRIs/SNRIs. SSRIs/SNRIs are usually considered first-line pharmacological treatments due to their safety, side effect profile, and broad-spectrum efficacy for co-morbid psychiatric conditions. FDA-approved medications include clomipramine, fluvoxamine, sertraline, fluoxetine, and paroxetine. CBT is the first-line psychosocial treatment, and aims to interrupt the chronic cycles of intrusive concerns and the compulsive rituals used by patients to ameliorate their obsessions. Post-Traumatic Stress Disorder

Evidence-based pharmacological treatments include SSRIs/SNRIs. SSRIs/SNRIs are usually considered first-line pharmacological treatments due to their safety, side effect profile, and broad-spectrum efficacy for co-morbid psychiatric conditions. FDA-approved medications include sertraline and paroxetine. Cognitive and behavioral therapies include Prolonged Exposure Therapy, Cognitive Processing Therapy, and Eye Movement Desensitization and Reprocessing.

Introduction Anxiety disorders tend to be chronic, and to fluctuate. Although they are associated with considerable morbidity and impairment, they respond well to pharmacological and cognitive-behavioral treatments.

Panic Disorder Panic disorder (PD ) is characterized by fear of recurrent unexpected panic attacks and by a persistent concern related to the autonomic arousal, which accompanies such attacks. Traditionally, treatment of PD has focused on blocking panic attacks, diminishing anticipatory anxiety, and reversing phobic avoidance. At the same time, co-morbid conditions, including depression and alcohol abuse, also need to be addressed.

Pharmacotherapy The pharmacotherapy of PD aims to reduce the patient’s distress and impairment to the point of remission, or to the point where the patient can participate in other forms of therapy (e.g., cognitive-behavioral therapy [CBT]). (See Table 47-1 for recommended dosages of the most commonly prescribed medications.) Historically, the first medications shown to be effective in PD were the tricyclic antidepressants (TCAs). Subsequently, benzodiazepines also demonstrated efficacy in this condition. More recently, the broad class of serotonin re-uptake inhibitors (SRIs), which include both selective serotonin re-uptake inhibitors (SSRIs) and serotonin norepinephrine re-uptake inhibitors (SNRIs), have been shown to be effective. Of note, to date, there is no evidence for the superiority of one of these three classes (TCAs, benzodiazepines, and SRIs) in the treatment of PD. As such, the decision as to which medication to choose for PD involves

considerations of side effects and drug interactions, cost, prior treatment history, and the presence of co-morbid medical and psychiatric conditions (see Table 471). Table 47-1: Recommended Dosage of Most Commonly Prescribed Antianxiety Medications Drug

FDA-Approved Indications for Daily Dose Anxiety Disorders Range (mg)

Initial Dose (mg/day)

Dosing Schedule

PD, GAD, SAD, OCD, PTSD PD, GAD, SAD, OCD, PTSD PD, SAD, PTSD, OCD OCD PD, OCD — GAD

10–50 12.5–50 25–200 50–300 10–80 20–40 10–30

10 12.5 25 25 10 10 5–10

QD QD QD QD QD QD QD

PD, SAD, GAD GAD

75–300 60–120

37.5 20–30

QD QD

— OCD —

100–300 100–250 100–300

10-25 12.5–25 10–25

QD QD QD

60–90 30–60

15 10

BID BID

300–600 100–450 15–45

50 50–100 7.5–15

BID BID–TID QD

SSRIs Paroxetine (Paxil) Paroxetine CR (Paxil CR) Sertraline (Zoloft) Fluvoxamine (Luvox) Fluoxetine (Prozac) Citalopram (Celexa) Escitalopram (Lexapro) SNRIs Venlafaxine (Effexor XR) Duloxetine (Cymbalta) TCAs Imipramine (Tofranil) Clomipramine (Anafranil) Amitriptyline (Elavil) MAOIs Phenelzine — (Nardil) — Tranylcypromine (Parnate) Atypical antidepressants Nefazodone (Serzone) Bupropion

— — —

(Wellbutrin) Mirtazapine (Remeron) Vilazodone (Viibryd)

—

40

40

QD

PD, “anxiety” (GAD) PD “Anxiety disorders” “Anxiety disorders”

2–10 1–5 5–40 3–16

0.25–0.5 0.25 2.5 1.0

QID BID BID TID–QID

“anxiety” (GAD)

15–60

5

BID–TID

—

10–60

10–20

BID

— — —

500–2000 300–5400 150–600

250 300 50

BID BID–TID BID–TID

Benzodiazepines Alprazolam (Xanax) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan) Azapirones Buspirone (Buspar) Beta-blockers Propranolol (Inderal) Anticonvulsants Valproate (Depakote) Gabapentin (Neurontin) Pregabalin (Lyrica)

SRIs are considered first-line pharmacotherapy for the treatment of PD, largely due to their safety and a side effect profile as well as broad-spectrum efficacy for co-morbid psychiatric conditions. Within the class, there is currently United States Food and Drug Administration (FDA)–approval for the SSRIs, paroxetine ([Paxil] and [Paxil CR]), sertraline (Zoloft), and fluoxetine (Prozac), as well as the SNRI venlafaxine (Effexor XR). Nonetheless, other SSRIs, such as fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro), have also demonstrated anti-panic efficacy, both in double-blind and open trials. The SNRI, duloxetine (Cymbalta), has preliminary support for efficacy via an openlabel study. To date, direct comparisons among different SRIs in the treatment of PD are scarce with no compelling evidence suggesting the superiority of one agent over another. One of the primary disadvantages of SRIs is a delayed onset of action (3–6 weeks). Moreover, despite being generally well tolerated, SRIs are associated

with sexual dysfunction as well as side effects (including restlessness, “jitteriness,” increased anxiety) at the outset of treatment. Given the side effects when first prescribed, and the fact that patients with PD are particularly sensitive to somatic sensations, the starting doses should be low (e.g., paroxetine 10 mg/day, paroxetine CR 12.5 mg/day, sertraline 25 mg/day, fluoxetine 10 mg/day, venlafaxine 37.5 mg/day, fluvoxamine 50 mg/day, citalopram 10 mg/day, and escitalopram 5 mg/day). SRI doses can then be titrated up, based on clinical response and side effects. The average effective doses of SRIs will be in the typical antidepressant range, and sometimes higher (e.g., paroxetine 20–40 mg/day, paroxetine CR 25–50 mg/day, sertraline 100– 200 mg/day, fluoxetine 20–40 mg/day, venlafaxine 150–225 mg/day, fluvoxamine 100–200 mg/day, citalopram 20–40 mg/day, and escitalopram 10– 20 mg/day). The TCAs were the first pharmacological agents shown to be efficacious in PD, reducing the frequency of panic attacks and the severity of anticipatory anxiety. These older agents appear as effective as the more recently developed SRIs. However, their widespread use is limited by their unfavorable side effect profile, so they are no longer considered as a first-line strategy. In terms of specific drugs, imipramine (Tofranil) and clomipramine (Anafranil) have considerable empirical support. Advantages of TCAs include their well-studied efficacy and their lower direct cost when compared to SRIs. (However, evidence suggests that the total cost of care might be higher than that associated with SRIs due to the need for more frequent visits, and for monitoring of serum levels and cardiac conduction.) Disadvantages of TCAs include: wide-ranging adverse effects (with anticholinergic effects, orthostatic hypotension, effects on the cardiac conduction system, weight gain, sexual dysfunction, restlessness, “jitteriness”); heightened anxiety on initial dosing; a delayed onset of action (3–6 weeks); cardiotoxicity in overdose; and the fact that TCAs are not effective for social phobia that is frequently co-morbid with PD. The side-effect profile of TCAs accounts for the high dropout rate (30%–70%) noted in published studies. Treatment should be initiated with lower doses (e.g., 10 mg/day for imipramine) to minimize the “activation syndrome” (restlessness, “jitteriness,” palpitations, and increased anxiety) noted at the outset of treatment. Typical antidepressant doses (e.g., 100–300 mg/day for imipramine) can ultimately be used to control the symptoms of PD. Blood levels of TCAs, especially for imipramine, nortriptyline (Pamelor), and desipramine (Norpramin), can be

checked after a steady state (about 5 days after a dose change) is achieved and can be useful in cases of poor response. Benzodiazepines are frequently used in the treatment of PD due to their efficacy, their rapid onset of action, and their relatively favorable side effect profile. Common side effects noted at the initiation of treatment include sedation and ataxia, which can be minimized by beginning treatment with low doses and by gradually titrating the dose upward. In addition to those common initial side effects, disadvantages of benzodiazepines include their association with withdrawal syndromes, potential for abuse, increased sedation in the elderly, interactions with alcohol, short-term memory impairment, and lack of efficacy for co-morbid conditions (such as depression). Both clonazepam (Klonopin) and alprazolam (Xanax) are FDA-approved for the treatment of PD, but non-FDA-approved agents, such as diazepam (Valium) and lorazepam (Ativan), also have documented efficacy. In terms of dosing, scheduled administration of benzodiazepines is preferred as dosing on an asneeded basis is rarely indicated for PD, and might serve to worsen the disorder. Treatment with alprazolam should begin with 0.25 to 0.5 mg BID-TID, and then be gradually increased to maintenance doses (0.5–3 mg QID). However, alprazolam’s short half-life might lead to inter-dose rebound anxiety and withdrawal symptoms. The need to treat interdose anxiety with extra medication might foster a cognitive dependence on the medication. Therefore, a longeracting, high-potency benzodiazepine, such as clonazepam, might be preferred. Clonazepam is usually administered with an initial bedtime dose of 0.25 to 0.5 mg, which is gradually titrated up to 1 to 3 mg/day, given in BID doses. Lowerpotency benzodiazepines can be as effective for PD at equivalent doses (e.g., 40 mg/day of diazepam). Despite concern over the potential development of therapeutic tolerance (i.e., loss of therapeutic efficacy) with benzodiazepines, the evidence suggests that they appear to remain effective over time without significant dose escalation in the clear majority of patients. When indicated, discontinuation of benzodiazepines should be done gradually, (e.g., 0.5 mg/week of alprazolam or clonazepam), sometimes over as long as several months. The taper should be slower near its end. Rapid taper of benzodiazepines or abrupt discontinuation is frequently associated with a withdrawal syndrome, associated with rebound anxiety, weakness, and insomnia. The withdrawal syndrome, which has been seen after using benzodiazepines for as little as 3 to 4 weeks, can be severe enough to cause seizures, confusion, and psychotic symptoms, and is more

intense following discontinuation with shorter-lasting agents. One strategy to minimize withdrawal is to switch from use of shorter-lasting agents to longerlasting benzodiazepines (e.g., clonazepam) prior to initiating the taper. Symptoms that persist more than two weeks after discontinuation are more likely to be interpreted as a return of the underlying anxiety disorder. Clinicians should consider the potential for abuse and dependence before prescribing benzodiazepines , especially in patients with a history of alcohol and substance abuse. A history of substance abuse is not an absolute contraindication to benzodiazepine treatment, but it should warrant caution. Of note, benzodiazepines should be used cautiously in the elderly , who metabolize drugs less efficiently, and who can be more sensitive to sedation, ataxia, and memory impairment, as well as being at greater risk for falls. The elderly also experience paradoxical agitation on benzodiazepines more often than do younger patients (see Table 47-2). Table 47-2: Characteristics of Commonly Used Benzodiazepines Dose HalfEquivalent Life (h) (mg)

Onset of Significant Action Metabolites

Typical Route of Administration

0.5

Intermediate- No Fast

PO

Chlordiazepoxide 5–30 (Librium)

10

Intermediate

Yes

PO, IV

Clonazepam (Klonopin)

15–30

0.25

Intermediate

No

PO

Clorazepate (Tranxene)

30–200

7.5

Fast

Yes

PO

Diazepam (Valium)

20–100

5.0

Fast

Yes

PO, IV

Flurazepam (Dalmane)

40

5.0

Fast

Yes

PO

Lorazepam (Ativan)

10–20

1.0

Intermediate

No

PO, IM, IV

Oxazepam (Serax)

5–15

15

Slow

No

PO

Drug Alprazolam (Xanax)

12–15

The monoamine oxidase inhibitors (MAOIs) are an older class of antidepressants that has been investigated for anxiety disorders. MAOIs are

anecdotally regarded as effective for PD, but there have been virtually no controlled studies in this population, except for a single study of phenelzine (Nardil) finding it to be effective. Disadvantages of MAOIs include side effects (e.g., orthostatic hypotension, weight gain, sexual dysfunction), the need for dietary restrictions (to prevent hypertensive crisis or serotonin syndrome), drug interactions, and their toxicity in overdose. Due to the danger associated with consumption of tyramine-containing foods while taking a MAOI, with drug interactions, and with toxicity in overdose, MAOIs are usually reserved for patients with PD who remain symptomatic after treatment with safer and better tolerated agents. Optimal doses for phenelzine range between 60 and 90 mg/day, whereas doses of tranylcypromine (Parnate), generally range between 30 and 60 mg/day. In terms of other antidepressants, there is some evidence to suggest that nefazodone (Serzone), bupropion (Wellbutrin), and mirtazapine (Remeron) might have some efficacy for PD. Nefazodone, a 5-HT2 antagonist, has not demonstrated robust efficacy; there are a few small uncontrolled studies showing benefits. Dosing is usually based on typical antidepressant doses (300–600 mg/day). Its use has been limited by concerns about life-threatening hepatic failure; monitoring of liver function tests has been advised during treatment with nefazodone. Studies of bupropion (Wellbutrin-SR), a norepinephrine-dopamine re-uptake inhibitor, have yielded conflicting results in PD with both negative and positive open-label trials. Treatment is typically initiated at low doses (i.e., 50– 100 mg/day) to minimize early activation, with a usual target dose of 100 to 200 mg BID. A few open-label studies support the potential efficacy of mirtazapine, an alpha2 antagonist, in PD, typically dosed at 15 to 45 mg/day. Buspirone (Buspar), a 5-HT1A partial agonist, has antianxiety properties, but it does not appear to be effective in PD. Beta-blockers are not useful as primary treatment of PD, but they can reduce some somatic symptoms of autonomic arousal and be used as adjuvants. Results of open-label studies, and a couple of randomized trials indicate that some anticonvulsants (valproate [Depakote], gabapentin [Neurontin], levitiracetam [Keppra]) can have efficacy in subsets of patients, such as treatment-resistant PD. There is limited positive evidence for second-generation antipsychotics in PD. Data from open-label studies suggest the potential efficacy of olanzapine (Zyprexa), aripiprazole (Abilify), and risperidone (Risperdal); however, two

randomized trials failed to demonstrate efficacy of risperidone in PD co-morbid with affective disorders. Finally, a recent randomized controlled trial (RCT) showed efficacy of long-acting quetiapine (Seroquel XR). In summary, there are many classes of medications to choose from in PD, with SRIs, TCAs, and benzodiazepines yielding comparable efficacy. Although TCAs might not be indicated as a first-line treatment because of the side effect profile, SRIs and benzodiazepines can be considered as equally reasonable first-line choices, and the choice between these classes should be dictated by cost, potential side effects, drug interactions, treatment history, and co-occurring medical and psychiatric conditions. For example, benzodiazepines might be favored in patients for whom the rapid control of the symptoms is critical. On the other hand, SRIs should be the first choice if the patient exhibits co-morbid depression, operates machines at work, or has a history of substance abuse and dependence. Of note, there is evidence that initiating combined treatment with benzodiazepines and antidepressants, followed by a benzodiazepine taper after a few weeks, might provide early benefit while avoiding the potential adverse consequences of long-term combination therapy. Empirical data does not support the use of anticonvulsants and second-generation antipsychotics as first-line agents for PD. Recommendations for the duration of the treatment in PD are at least 12 to 18 months given that studies showed long-term therapeutic gains through maintaining pharmacotherapy. This allows patients sufficient time to experience potential triggers, learn safety, and return to previously avoided situations, and can decrease the risk of relapse with medication discontinuation. Regardless, slow medication discontinuation over weeks to months when possible is preferable and can decrease the likelihood of triggering a return of symptoms or intolerance of medication discontinuation due to medication withdrawal symptoms.

Psychosocial Treatment In terms of psychosocial interventions, CBT is a well-established, first-line treatment in PD, focusing on the maladaptive cognitions and behavioral reactions associated with the panic response. The initial panic typically emerges at a time of intense stress, which activates the firing of the fight-or-flight alarm system. In vulnerable individuals, the somatic sensations experienced during the initial panic episodes become associated with intense stress and danger. Subsequently, catastrophic misinterpretations of the meaning of somatic sensations (e.g., “I’m going to have a heart attack”) can trigger similar reactions,

even in the absence of danger. The misinterpretations trigger intense anxiety, which further intensifies somatic sensations (a positive feedback loop), resulting in a dramatic increase of anxiety and the development of panic. Later during PD, the alarm reactions (panic attacks) can become the focus of fear. CBT of PD aims to eliminate catastrophic misinterpretations and the conditioned fear of somatic sensations as well as to eliminate avoidance behavior. CBT for PD typically lasts 12 to 15 sessions, and includes four components: psychoeducation, cognitive re-structuring, exposure interventions, and anxiety management skills. Psychoeducational informational interventions (i.e., explanations about the nature of the disorder) aim to demystify the somatic sensations experienced during panic attacks and to instruct patients about self-perpetuating patterns that maintain the disorder. Cognitive re-structuring aims to de-catastrophize beliefs about the meaning and the consequences of somatic symptoms. The catastrophic misinterpretations often distort the meaning of somatic sensations (e.g., “I’m going to have a heart attack”), or overestimate the probability or the severity of feared outcomes (e.g., “I’m going to lose control”). Patients with panic attacks are asked to record their thoughts in panic diaries and to analyze these thoughts. The goal is to help patients reduce catastrophic interpretations and bring their thoughts in accordance with actual consequences. Exposure interventions attempt to extinguish the conditioned response (fear) to certain somatic sensations or external situations associated with panic (i.e., agoraphobia). Interoceptive exposure is designed to induce somatic sensations usually associated with panic (e.g., running up the stairs to induce tachycardia). In-vivo exposure targets the suffering of those with agoraphobic avoidance, by exposing them to the avoided situations. Exposure methods are utilized in a gradual manner. Anxiety-management skills (e.g., slow breathing techniques, muscle relaxation training) provide patients with skills for prevention of anxious responses to initial sensations of anxiety. CBT has been shown efficacious as an initial treatment for PD with treatment gains maintained over time. Moreover, CBT also effectively reduces the rates and severity of co-morbid conditions. There is little evidence in PD, however, that combining CBT and pharmacotherapy is superior to either modality alone. Thus, one clinical strategy is to use CBT for patients who have failed to respond to pharmacotherapy or who wish to discontinue it.

Another psychosocial treatment that has an emerging evidence-base in PD is psychodynamic psychotherapy, which focuses on the underlying psychological meaning of panic symptoms and on current social and emotional functioning. Panic-focused psychodynamic psychotherapy, is a twice-weekly, 12-week manualized treatment program that has been shown to be effective in one RCT.

Generalized Anxiety Disorder Generalized anxiety disorder (GAD) is characterized by unrealistic or excessive worry about life circumstances and is accompanied by chronic symptoms of autonomic arousal.

Pharmacotherapy In terms of pharmacotherapy , most pharmacological agents used in PD are also effective in GAD, with some distinctions. Similarly, to PD treatment, SRIs are first-line treatments for GAD. FDA-approved for GAD are the SSRIs, paroxetine (Paxil) and escitalopram (Lexapro), and the SNRIs, venlafaxine (Effexor XR) and duloxetine (Cymbalta). Considerations in the use of these antidepressants for GAD are similar to those for PD. Benzodiazepines have been a mainstay of treatment for GAD; however, most current guidelines suggest the use of an antidepressant that can treat the symptoms of both anxiety and depression. Nevertheless, benzodiazepines remain widely prescribed either as co-therapy or monotherapy for GAD because of their anxiolytic effect, rapidity of therapeutic onset, and favorable side effect profile. There is no evidence that any benzodiazepine is more effective than any other for GAD. However, longer-lasting benzodiazepines (e.g., clonazepam, diazepam) are generally preferred for maintenance therapy, given the risk for rebound anxiety associated with short-lasting benzodiazepines (e.g., alprazolam). The principles of treatment with benzodiazepines discussed for PD also apply for GAD; however, because benzodiazepines are not effective in the treatment depression that is frequently co-morbid with GAD, they are usually not recommended as first-line treatment for GAD. Early data suggest that buspirone , a 5-HT1A partial agonist, can be useful in the treatment of GAD, with a gradual onset of action and a generally favorable sideeffect profile. However, a recent literature review of treatment trials with azapirones (including buspirone), found no evidence for their superiority over antidepressants, and they should thus not be considered as first-line treatments.

The starting dose is usually 5 mg BID, which is then gradually increased to the average therapeutic dose of 10 to 30 mg BID (20–60 mg/day). In terms of other classes of antidepressants, TCAs have been less studied in GAD than in other anxiety disorders, and there are no placebo-controlled trials of MAOIs to support their use in GAD. Among the TCAs, there is evidence from an RCT to suggest that imipramine is effective, although its success was somewhat hampered by higher reported rates of adverse effects compared to diazepam. The principles of treatment with imipramine for PD also apply for GAD. Among the newer antidepressants, bupropion and nefazodone have limited evidence supporting their use in GAD. Finally, results of a recent RCT supports the efficacy of a SSRI and a 5-HT1A receptor partial agonist, vilazodone (Viibryd), at 40 mg/day in GAD. Among anticonvulsants, pregabalin (Lyrica) has the greatest amount of randomized controlled support for its use in GAD. (Although not approved by the FDA for use in GAD, it does have approval for this indication in Europe.) It has a relatively favorable side effect profile and current treatment guidelines suggest a dose range of 150 to 450 mg/day. Controlled data for the use of second-generation antipsychotics in GAD has been limited for risperidone (Risperdal), aripiprazole (Abilify), and ziprasidone (Geodon). Recent randomized controlled data provided support for the efficacy of quetiapine (50 mg–300 mg) monotherapy in the treatment of GAD; however, the risk–benefit ratio for these antipsychotics agents in general remains a concern, due to their association with metabolic side effects, their use might be more limited to treatment-refractory cases.

Psychosocial Treatment In terms of psychosocial treatments for GAD, CBT approaches have the most support. Many of the same components of CBT discussed for PD (i.e., psychoeducation, cognitive re-structuring, exposure, and anxiety management) also apply to GAD. Informational interventions in GAD identify maladaptive cognitions and the process of worrying as a primary cause of anxiety. Cognitive re-structuring in GAD comprises patients’ self-monitoring of their maladaptive cognitions as they occur in high-anxiety situations. Later, they analyze these thoughts. As patients become better at evaluating the content of their thoughts, specific “worry times” can be assigned to help them gain control over the constant tendency to worry. Exposure interventions include imaginal exposure to

catastrophic images while preventing overly-cautious response behaviors. Anxiety-management skills include the use of relaxation training (e.g., slowbreathing techniques, muscle relaxation training) to decrease the arousal that accompanies worry and to provide patients with tools to cope with anxietyprovoking situations. Recent data suggests that mind-body approaches including Mindfulness-Based Stress Reduction group intervention might also be helpful for individuals with GAD.

Social Anxiety Disorder or Social Phobia Patients with social phobia are primarily concerned about humiliation, embarrassment, or a negative evaluation by others.

Pharmacotherapy An increasing number of studies have examined the efficacy of pharmacological agents for the treatment of social phobia. Medications with demonstrated efficacy include SRIs, benzodiazepines, MAOIs, beta-blockers, and the anticonvulsant gabapentin. As with other anxiety disorders, SRIs are considered first-line agents. Multiple trials support the use of various SSRIs as well as the SNRI for social phobia at typical antidepressant doses. Although empirical data suggests the efficacy of the SSRIs fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro) in SAD, to date, only paroxetine (Paxil), sertraline (Zoloft) as well as the SNRI venlafaxine (Effexor XR) are FDA-approved for this indication. High-potency benzodiazepines, including alprazolam (Xanax) and clonazepam (Klonopin), are thought to be effective in social anxiety disorder (SAD); however, prn dosing of benzodiazepines alone is generally not recommended for SAD, unless the disorder is limited to performance situations alone. In terms of older antidepressant classes, MAOIs have proven efficacy in social phobia, whereas TCAs are generally ineffective. In particular, the MAOI phenelzine (Nardil) has proven effective in multiple double-blind studies in social phobia. Doses used are similar to those used for depression and for PD. The newer antidepressant mirtazapine has limited support for its use in social phobia from an open trial and a single RCT that was restricted to use in women. Beta-blockers have been used with mixed results in the treatment of social phobia. Propranolol (10–40 mg/day) and atenolol (50–150 mg/day) have been

shown to benefit patients with performance anxiety, but beta-blockers are not effective for the non-“performance-only” SAD. Among anticonvulsants , RCTs have demonstrated efficacy for the use of gabapentin (Neurontin) (dose range, 300–3600 mg/day) and high-dose (600 mg) pregabalin. Second-generation antipsychotics have been investigated in a limited number of studies of social phobia with mixed results.

Psychosocial Treatment CBT is the mainstay of psychosocial treatment for social phobia. It targets the central fear in social phobia of critical evaluation by others in social interactions, which motivates avoidance of social situations and ultimately prevents the acquisition of social confidence and skills. CBT for social phobia includes psychoeducation, cognitive restructuring, exposure, and social skills training. Informational interventions are designed to clarify for the patient the anxiogenic nature of their thoughts and the role of avoidance in heightening phobic patterns. Cognitive re-structuring is designed to modify the maladaptive cognitions that detract from competent social performance. Typical cognitive distortions include negative expectations of social performance (“I will not know what to say”), distorted evaluations of the self (“Everyone can do it but me”), and distorted anticipation of the reaction of others (“They will think I’m stupid”). Patients are taught to self-monitor their cognitive distortions and to analyze them logically. Exposure interventions aim to provide patients with the ability to practice in social situations and to evaluate their cognitions in that context. Patients rehearse feared interactions in group and homework assignments. Social skills training includes instructions and programmed practice in a role-playing format. In recent years, a few RCTs have examined the efficacy of psychodynamic therapies for SAD with promising results; however, the heterogeneity of interventions falling under this umbrella available in the community prevents us from formulating any strong recommendation.

Specific Phobia Patients with specific phobia are fearful of circumscribed situations or objects (e.g., heights, blood, animals); those fears lead to significant distress and disability. Exposure-based interventions, a form of CBT, are the mainstay of the treatment for specific phobia. Adding medications to these interventions appears to bring no additional benefit. However, benzodiazepine treatment can be used to help an

individual cope with an occasionally encountered feared event (e.g., flying in an airplane). The exposure-based treatment consists of systematic desensitization and participant modeling. The systematic desensitization involves relaxation training combined with gradual exposure (frequently imaginary) to the feared stimulus. In participant modeling, the therapist enacts a behavior and then encourages the patient to repeat that behavior.

Obsessive-Compulsive Disorder (OCD) Obsessive-compulsive disorder (OCD) is characterized by recurrent, intrusive, unwanted thoughts (i.e., obsessions, such as fears of contamination) and compulsive behaviors or rituals intended to reduce the anxiety caused by obsessive thoughts.

Pharmacotherapy Psychotropic agents that inhibit serotonin re-uptake are the pharmacological treatments of choice for OCD. Clomipramine , a TCA with potent serotonin reuptake inhibition, has been studied for more than 25 years and has been proven efficacious in the treatment of OCD. (It is the only TCA with FDA-approval for OCD.) The effective doses tend to be high, up to 250 mg/day. More recently, several SSRIs (e.g., fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram) have been shown to provide safe and effective treatment for OCD. Fluvoxamine, sertraline, fluoxetine, and paroxetine have been FDAapproved for the treatment of OCD. SSRIs are generally effective in OCD at doses that are higher than antidepressant doses: fluvoxamine (up to 300 mg/day), fluoxetine (up to 80 mg/day), sertraline (up to 200 mg/day), and paroxetine (up to 60 mg/day). Few patients with OCD become symptom-free with serotonergic agents alone; partial relief from obsessional thinking is more typical. In these patients, their subjective experience of anxiety and their use of compulsive behaviors are often reduced but not eliminated. Despite the recognized efficacy of clomipramine, clinical guidelines generally recommend SSRIs as first-line in OCD due to the balance between efficacy and tolerability. Response to SSRI therapy may require 8 to 10 weeks of treatment. Failure to respond to SSRI therapy may reflect inadequate dosing or inadequate duration of treatment. If a patient does not respond to an SSRI at a high dose, use of an alternative SSRI may be successful.

Benzodiazepines (e.g., clonazepam) have been used successfully to treat comorbid anxiety in the OCD patient. However, benzodiazepines are ineffective when used alone in the treatment of OCD. Some benzodiazepines (e.g., diazepam, alprazolam) are reported to have increased plasma levels when used in combination with SSRIs, such as fluvoxamine. Other agents, (e.g., gabapentin, mirtazapine, buspirone, and risperidone [an antipsychotic]), have sometimes proven effective as adjuvants to SSRIs for the treatment of OCD.

Psychosocial Treatment As in other anxiety disorders, CBT is the mainstay for the psychosocial treatment of OCD. The goal of CBT for OCD patients is to interrupt the chronic cycles of intrusive concerns and the compulsive rituals used by patients to ameliorate their obsessions. CBT is very effective in OCD, especially in combination with pharmacotherapy. CBT for OCD involves exposure and cognitive interventions. Exposure and response prevention is a typical CBT intervention for OCD. The exposure consists of gradually confronting the patient with situations that are likely to trigger obsessive thoughts and compulsive rituals. For example, patients who fear contamination might be given a “dirty” hand towel and encouraged to hold the “contaminated” towel for an hour or longer. The response prevention used at the time of exposure requires patients to resist performing their compulsive rituals, such as hand washing, for a progressively longer period of time. The repeated exposure without performing the compulsive rituals gradually decreases anxiety. Cognitive interventions in OCD provide patients with additional skills for breaking the link between intrusive thoughts and compulsive responses.

Post-Traumatic Stress Disorder Patients with post-traumatic stress disorder (PTSD) have experienced an event that involved the threat of death, injury, or severe harm to themselves or others. The severe trauma disrupts the patient’s sense of safety to the extent that the patient avoids situations that remind him or her of the trauma; he or she can become emotionally numb, irritable, hypervigilant, or have difficulties with sleep and concentration. Patients with PTSD frequently re-experience the traumatic event in the form of nightmares and flashbacks, or have marked arousal when exposed to situations reminiscent of the event.

Pharmacotherapy The role of pharmacotherapy in PTSD has traditionally been to relieve symptoms and to facilitate the onset of trauma-focused psychotherapy. However, SSRIs have recently been shown to reduce the symptoms of PTSD. As in other anxiety disorders, SRIs are considered first-line in PTSD. Sertraline and paroxetine are the only pharmacological agents that have received FDA approval for PTSD, but other agents have efficacy in controlled studies (e.g., fluoxetine, venlafaxine). TCAs (e.g., amitriptyline, imipramine), and MAOIs (e.g., phenelzine) have reduced PTSD symptoms in double-blind studies. Nefazodone has also been shown to have some efficacy in PTSD. The drugs are used in doses similar to those listed in Table 47-1. In a preliminary open trial, buspirone has been reported to reduce the anxiety and the increased arousal in PTSD patients at doses of 30 to 60 mg/day. When used, it is typically co-administered with an antidepressant. A small pilot study did find the anticonvulsant, lamotrigine, to be helpful and the anticonvulsant, topiramate, has some indication of efficacy, but with mixed results across studies. Beta-blockers (e.g., propranolol) can be useful in some patients with PTSD in decreasing persistent symptoms of autonomic hyperarousal; there is some evidence that it prevents the development of PTSD in the acute aftermath of a traumatic event. Clonidine , at doses of 0.2 to 0.6 mg/day might also be beneficial. Prazosin , an alpha-blocker, might also be useful in reducing nightmares. No large RCTs support the use of benzodiazepines in PTSD. Although potentially beneficial as adjuncts to reduce anxiety and improve sleep, benzodiazepines might in fact have negative effects (including disinhibition, irritability, and forestalling recovery) and interfere with successful exposurebased psychotherapy. Second-generation antipsychotics can reduce psychosis or impulsivity and have been reported as having some efficacy against the hypervigilance associated with PTSD; however, this is still an area of active research, and the role of antipsychotics in PTSD is still uncertain because augmentation with these agents has yielded mixed results.

Psychosocial Treatment Psychological interventions are important in the treatment of PTSD. General support, educating patients about the time-limited nature of many post-traumatic

symptoms (such as sleep disturbance), providing symptomatic relief, and making patients aware of the availability of mental health resources are reasonable management strategies for most individuals exposed to trauma. Accruing evidence suggests that broadly applied “Critical Incidence Stress Debriefing ” in the aftermath of a trauma might not be beneficial for most patients and might actually increase the likelihood of developing PTSD. For the chronic PTSD patient, exposure-based therapies, such as CBT, appear to be the most successful and have become first-line treatments. CBT interventions aim to disrupt the link between trauma-related cues and the severe anxiety responses and hypervigilance that characterize PTSD. Components of CBT for PTSD include psychoeducation, cognitive restructuring, exposure, and relaxation training. Informational interventions aim to help patients understand their symptoms. Discussion of dissociation and flashbacks might normalize and decrease the fear triggered by these symptoms. Cognitive re-structuring (i.e., cognitive processing therapy) aims to help patients identify distortions in their thoughts that may have been generated by trauma (e.g., “The world is an unsafe place” or “I am helpless”). Exposure intervention (prolonged exposure) aims to help patients control their emotional reactions associated to situations and objects reminiscent of the trauma. Patients with PTSD associate objects and situations that are only remotely linked to the trauma. With repeated exposure, patients learn to differentiate between the diffuse, exaggerated fears generated by trauma and the actual safety of current situations. The intensity of exposure therapy can vary. Implosive therapy, an intense form of exposure therapy, is effective but depends on the ability of the patient to tolerate intense levels of arousal. Systematic desensitization implies a more gradual exposure and can be beneficial in overcoming the phobic avoidance related to the trauma. Relaxation training can be used as in other anxiety disorders to provide patients with skills for preventing anxious responses to the initial stages of exposure. Another psychological intervention found to be effective in PTSD and with elements of exposure therapy is Eye Movement Desensitization and Reprocessing (EMDR ). It aims to promote increased adaptive coping by systematically reprocessing distressing memories and decreasing their influence on current functioning. EMDR incorporates elements of CBT, psychodynamic, interpersonal and body-oriented therapies and its focus on eye movements is theoretically linked to the notion of stimulating both hemispheres of the brain.

Conclusions

Anxiety disorders benefit from a range of pharmacologic and psychotherapeutic interventions. For some patients, a combination of treatment modalities is the most effective solution, although this issue requires further study. Most treatments have been studied for short periods, generally up to 6 months. However, a large number of patients (20%–50%) experience a recurrence of anxiety when the treatment is interrupted. For many patients, maintenance pharmacotherapy (more than 12 months) is warranted.

Suggested References 1. Baldwin DS, Anderson IM, Nutt DJ, et al: Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessivecompulsive disorder: a revision of the 2005 Guidelines from the British Association for Psychopharmacology. J Psychopharmacol . 2014 May; 28(5): 403 –439. 2. Bui E, Pollack MH, Kinrys G, et al: The Pharmacotherapy of Anxiety Disorders. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd Ed.: Philadelphia, PA, Elsevier; 2016. 3. Freire RC, Machado S, Arias-Carrión O, et al: Current pharmacological interventions in panic disorder. CNS Neurol Disord Drug Targets . 2014; 13(6): 1057–1065. 4. Labbate LA, Fava M, Rosenbaum JF, et al: Handbook of Psychiatric Drug Therapy . 6th ed., Philadelphia, PA: Lippincott Williams & Wilkins; 2010. 5. Otto MW, Reilly-Harrington NA, Harrington JA: Cognitive-behavioral therapy. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Primary Care Psychiatry . 2nd ed. New York: McGraw-Hill; 2004. 6. Pollack MH, Smoller JW, Lee DK: The anxious patient. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Primary Care Psychiatry. 2nd ed. New York: McGraw-Hill; 2004: pp. 137–152. 7. Ravindran LN, Stein MS: Anxiety disorders: somatic treatment. In: Sadock BJ, Sadock VA, Ruiz P, eds.: Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009: pp. 1906–1914.

CHAPTER Antipsychotic Drugs 48 ABIGAIL L. DONOVAN, MD; DAVID C. HENDERSON, MD; AND OLIVER FREUDENREICH, MD

KEY POINTS Overview Antipsychotic drugs are the foundation of treatment for schizophrenia and psychotic disorders. Antipsychotics effectively treat psychosis acutely and prevent psychotic relapses in the maintenance phase. Increasingly, second-generation antipsychotics (SGAs) are used in the management of patients with serious mood disorders. All antipsychotic medications block dopamine D2 receptors, but with different binding affinity and selectivity for this receptor. First-generation antipsychotics (FGAs) have high affinity for the D2 receptor, whereas SGAs share combined serotonin 5-HT2 and dopamine D2 blockade. A third group is characterized by only partial dopamine receptor antagonism. Antipsychotics have comparable efficacy for patients with non-refractory schizophrenia, but different side-effect profiles and tolerability. First-Generation Antipsychotics FGAs are high-affinity dopamine D2 receptor antagonists that can be subdivided into low-, medium-, and high-potency agents. Extrapyramidal symptoms (EPS), such as dystonia, akathisia, and parkinsonism, are more commonly associated with high-potency FGAs than with low-potency agents, although they can occur with any antipsychotic. Tardive dyskinesia (TD) and neuroleptic malignant syndrome (NMS) may occur with all D2 antagonists, unrelated to their neuroleptic potency. Second-Generation Antipsychotics

SGAs are dopamine D2 receptor antagonists combined with high-affinity serotonin (5-HT2 ) antagonists. They offer reduced rates of EPS and TD compared to most FGAs, although several are associated with increased rates of weight gain, dyslipidemias, and the development of diabetes. Treatment-Resistance Patients with a poor response to treatment must have their previous medication trials, diagnosis, and adherence critically re-assessed. All patients with two failed trials of an antipsychotic should be offered a timelimited trial of clozapine. Clozapine has superior efficacy to all other antipsychotic agents, and it can be life-saving; it requires registry-based prescribing due to the risk of granulocytopenia. Some patients may also benefit from thoughtful adjunctive medication use to target residual symptoms.

Introduction Antipsychotic drugs are the foundation of treatment for schizophrenia and psychotic disorders. All antipsychotic medications block dopamine D2 receptors, but with different binding affinity and selectivity for this receptor. Firstgeneration antipsychotics (FGAs ) have high affinity for the D2 receptor, whereas second-generation antipsychotics (SGAs ) share combined serotonin 5-HT2 and dopamine D2 blockade. A third group, with aripiprazole as the prototype, is characterized by only partial dopamine receptor antagonism. All antipsychotics (with the exception of clozapine and possibly olanzapine) have comparable efficacy but different side-effect profiles and tolerability. Even though this chapter discusses FGAs and SGAs as if they were distinct classes, there is much side effect overlap between them and this historical distinction has little clinical utility. Antipsychotic medications offer significant benefit for the treatment of positive symptoms (such as delusions and hallucinations), agitation in the setting of acute psychosis, and prevention of psychotic relapse. They are broadly ineffective for the treatment of cognitive problems associated with schizophrenia and negative symptoms (such as alogia and flat affect). This chapter reviews the different

antipsychotics agents, particularly their side effects, dosing schedules, and drug interactions, as well as approaches to the treatment-resistant patient.

Antipsychotic Agents FGAs FGAs , also known as typical or conventional antipsychotics or “neuroleptics,” were developed in the 1950s. All of them are high-affinity dopamine D2 receptor antagonists that can produce extrapyramidal symptoms (EPS), tardive dyskinesia (TD ), and prolactin elevation . FGAs can be sub-divided into low-, medium-, and high-potency agents. Low-potency antipsychotics, such as chlorpromazine, have less selectivity for the dopamine D2 receptor, and additional antagonism at histamine, acetylcholine, and adrenergic receptors (causing sedation, anticholinergic side effects, and orthostatic hypotension, respectively). Highpotency agents, such as haloperidol, have higher selectivity for the dopamine D2 receptor and more motor system side effects, particularly at higher doses. Medium-potency agents, such as perphenazine, fall in between the two categories for both potency and selectivity. All FGAs have comparable efficacy. Antipsychotic efficacy occurs when approximately 65% of D2 receptors are blocked. For tightly-bound agents like the FGAs, increasing the dose significantly beyond this point will not lead to increased efficacy, but only to increased risk of EPS (which occurs at 80% receptor-binding). The dose at which EPS emerge, called the “neuroleptic threshold,” signals that the maximal antipsychotic effect has been reached: giving more antipsychotic will lead to more motor side effects but not to more antipsychotic efficacy. Dosing for individual FGA agents can be guided by chlorpromazine equivalents (CPZ-Eq) (see Table 48-1). Table 48-1: First-Generation Antipsychotic Agents CPZ- Acute Therapy* Eq (mg/day)

Maintenance Therapy* (mg/day)

Class

Haloperidol (Haldol)

2

6–20

6–12

Butyrophenone

Trifluoperazine (Stelazine)

5

15–50

15–30

PhenothiazineC

Fluphenazine (Prolixin)

2

6–20

6–12

PhenothiazineC

Agent High-potency

Thiothixene (Navane) 5

15–50

15–30

Thioxanthenes

Mid-potency Perphenazine (Trilafon)

10

12–64

12–40

PhenothiazineC

Loxapine (Loxitane)

10

30–100

30–60

Dibenzapine

Chlorpromazine (Thorazine)

100

300–1000

300–600

PhenothiazineA

Thioridazine (Mellaril)

100

300–800

300–600

PhenothiazineB

Low-potency

*Based on PORT Guidelines (Buchanan et al, 2010) A = aliphatic phenothiazine; B = piperidine phenothiazine; C = piperazine phenothiazine.

Side Effects of FGAs Extrapyramidal symptoms (EPS), such as dystonia , akathisia, and parkinsonism, are more commonly associated with high-potency, selective FGAs than with low-potency agents, although they can occur with any antipsychotic. The less selective low-potency agents tend to produce sedation, hypotension, weight gain, and anticholinergic symptoms (e.g., dry mouth, urinary retention, constipation, blurred vision). TD and neuroleptic malignant syndrome (NMS ) can occur with all D2 antagonists, unrelated to their neuroleptic potency. Hyperprolactinemia is common and variable among agents. Other potential side effects include impaired heat regulation (i.e., poikilothermia with hyper- or hypothermia); pigmentary retinopathy (with thioridazine at doses > 800 mg/d) and electrocardiographic (EKG) changes (especially with pimozide, chlorpromazine, and thioridazine and its metabolite, mesoridazine).

Extrapyramidal Symptoms Dystonia Dystonia is an involuntary , sustained muscle contraction that can involve any muscle, but frequently involves the tongue, neck, back, and eyes. It is extremely uncomfortable and can jeopardize compliance with antipsychotics. It can be lifethreatening if laryngeal spasms occur. In general, it occurs within the first 4 days of antipsychotic treatment or following an increase in the antipsychotic dose.

Risk factors include youth (age less than 40 years), male sex, prior dystonic reactions, recent use of cocaine, and the use of high-potency antipsychotics. High-risk patients started on high-potency FGAs should receive prophylaxis with benztropine (1–2 mg twice daily for 10 days), followed by a taper. Often, benztropine is initiated for prophylaxis and continued needlessly for weeks, months, or years. Treatments for acute dystonia include benztropine (1–2 mg intramuscularly [IM] or orally [PO]), diphenhydramine (25–50 mg IM or PO), or diazepam (5 mg, slow IV push). After the initial dystonic reaction has resolved, a standing dose of benztropine or another anticholinergic agent is recommended. Even if the antipsychotic is not going to be continued, patients should continue to take an anticholinergic agent for several days because the dystonia can return without ongoing treatment and prophylaxis. Dystonias are less common with SGAs than with FGAs; they rarely if ever occur with clozapine. “Tardive dystonia” is a variant of TD that appears to respond well to SGAs, particularly clozapine. In severe cases of tardive dystonia, Botox injections or deep brain stimulation have been used.

Akathisia Akathisia is the extremely uncomfortable (at times unbearable) sensation of intense motor restlessness, which is most prominent in the lower extremities. Akathisia results in foot or leg jiggling, the inability to sit still for more than a few minutes, or near-constant pacing. It is most commonly associated with highpotency agents, and it is dose-related. Akathisia can be mistaken for agitation, which can lead to a dose increase of the antipsychotic and an unfortunate worsening of akathisia. Possible treatments include: lowering the antipsychotic dose; switching to a SGA; adding a beta-blocker (e.g., propranolol 20 mg BID–QID) or a benzodiazepine (e.g., lorazepam 0.5 mg TID).

Parkinsonian Symptoms Antipsychotic-induced parkinsonism resembles idiopathic Parkinson’s disease, with the triad of rigidity, tremor, and bradykinesia. In milder forms, bradykinesia can be mistaken for negative symptoms or depression. Parkinsonian side effects tend to be associated with the use of high-potency agents, and they are doserelated. Possible treatments include lowering the antipsychotic dose, switching to a SGA, or adding an anticholinergic agent (benztropine 1–2 mg BID; in the

elderly, start with 0.25 mg) or amantadine (100–200 mg BID). The elderly are most sensitive to anticholinergic agents; therefore, long-term use of these agents should be avoided in this population.

Tardive Dyskinesia TD is a late-developing, potentially irreversible, involuntary, choreiform movement disorder, most commonly of the mouth, tongue, or upper extremities. The risk for developing TD is approximately 4% to 5% per year of FGA exposure, although that risk is even higher for the elderly. By contrast, the risk of TD with SGAs is several-fold lower, with possible differences between SGAs; with clozapine, the risk is close to zero. Risk factors for TD include old age, affective illness, female sex, antipsychotic exposure for more than 6 months, high-dose antipsychotic exposure, history of parkinsonian side effects, and diabetes. Given the severity and possible irreversibility of TD, it is prudent to document a discussion of TD risk with every patient prior to the initiation of any antipsychotic medication. In addition, a careful baseline neurological examination should note the presence of preexisting motor abnormalities (or their absence). The Abnormal Involuntary Movement Scale (AIMS) should be performed at least yearly, and more often in high-risk clinical situations, to monitor for TD. The best treatment of TD is preventing its development. Antipsychotics (and other dopamine-blocking agents, like metoclopramide, which is used for nausea) should be used only when there is clear benefit. Clinicians should use the lowest possible effective dose, particularly with FGAs. If TD does develop, the need for ongoing antipsychotic treatment should be critically reassessed. If discontinuation is not possible, consideration should be given to decreasing the antipsychotic dose or switching to a SGA, particularly clozapine, which is associated with improvement in TD symptoms. Of note, a “withdrawal dyskinesia” can occur when the antipsychotic dose is decreased or when a switch is made to a SGA. This type of dyskinesia usually resolves within 6 weeks. Early use of vitamin E (1,600 IU/day) can prevent worsening of symptoms, although late use has no established benefit. Tetrabenazine can offer some benefit for severe cases.

QTc Prolongation QTc prolongation is a risk factor for the development of torsades de pointes (TdP), a malignant ventricular arrhythmia. Although thioridazine, mesoridazine,

and ziprasidone might have the most pronounced effects on the QTc interval, other antipsychotic agents, including haloperidol (particularly IV haloperidol), can also lead to QTc prolongation. Patients with multiple risk factors, including old age, cardiac disease, low magnesium levels, and concurrent treatment with other QTc -prolonging agents, can benefit from monitoring with EKGs.

Hyperprolactinemia FGAs are particularly associated with hyperprolactinemia , as are risperidone, paliperidone, and, to a lesser extent, some other SGAs (e.g., high-dose olanzapine, lurasidone). These agents all block dopamine D2 receptors, leading to the loss of dopamine’s inhibition of prolactin, and as a result, prolactin levels rise. High prolactin levels can be associated with decreased libido, erectile dysfunction, menstrual irregularity or amenorrhea (through hypoestrogenemia), infertility, and galactorrhea. Long-term, hypoestrogenemia can lead to osteoporosis, and some women might benefit from hormone replacement with oral contraceptive pills. Dose, duration of treatment, potency, female sex, and age (pre-menopausal and adolescence) are all associated with more severe hyperprolactinemia. Prolactin levels should be checked in any patient with symptoms of hyperprolactinemia. Decreasing the medication dose or switching to a prolactin-sparing agent (such as aripiprazole) should be considered as initial interventions for the patient with symptomatic drug-induced hyperprolactinemia. Partial agonists like aripiprazole can lower prolactin levels in patients with antipsychotic-induced hyperprolactinemia.

Neuroleptic Malignant Syndrome NMS is a rare, potentially lethal complication of antipsychotic treatment characterized by the triad of fever, rigidity, and altered mental status. NMS is also typically associated with autonomic instability, diaphoresis, and elevated creatine phosphokinase (CPK) levels. The symptoms usually occur within one month of initiating an antipsychotic medication and can be triggered by all antipsychotics, including clozapine. The symptoms can evolve over time (hours to days), starting with mental status changes and culminating with fever and elevated CPK. NMS represents a medical emergency and hospital-based treatment should begin immediately. Treatment includes immediate discontinuation of the antipsychotic, hydration, temperature control, and possibly bromocriptine or dantrolene (although it is unclear whether these agents

facilitate recovery). At least two weeks should pass before restarting an antipsychotic agent.

Second-Generation Antipsychotics SGAs are dopamine D2 receptor antagonists combined with high-affinity serotonin (5-HT2 ) antagonists. They offer reduced rates of EPS and TD compared to most FGAs, although they are significantly associated with increased rates of weight gain, dyslipidemias, and the development of diabetes. Clozapine was the first atypical antipsychotic developed and it served as the prototype for subsequent drug development with regard to lack of motor side effects (motor side effects were thought to be “typical” and intricately linked with antipsychotic efficacy). A third group (comprising aripiprazole, brexpiprazole, and cariprazine) are partial dopamine D2 receptor agonists/antagonists. Table 48-2 lists the SGAs and their dosing schedules. Table 48-2: Second -Generation Antipsychotic Agents Agent

Starting Dose Dose Range (mglday)

Clozapine (Clozaril)

12.5 mg/day

25–900

Olanzapine (Zyprexa)

2.5–10 mg/day

5–20

Quetiapine (Seroquel)

25–50 mg/day BID 25–750

Ziprasidone (Geodon)

20–40 mg BID

40–160

Aripiprazole (Abilify)

10–15 mg/day

10–30

Brexpiprazole (Rexulti) 1 mg/day

2–4

Cariprazine (Vraylar)

1.5mg/day

3–6

Asenapine (Saphris)

5 mg BID

10–20

Risperidone (Risperdal) 1–2 mg/day

0.5–16

Iloperidone (Fanapt)

1 mg BID

12–24

Lurasidone (Latuda)

40 mg/day

40–160

Clozapine Clozapine (Clozaril) is the single most effective antipsychotic agent available, especially for treatment-resistant patients. Clozapine leads to symptomatic improvement in 30% of previously treatment-resistant patients within 6 weeks, and in 60% of treatment-resistant patients at 6 months. In addition, clozapine

appears to stabilize moods, improve polydipsia and hyponatremia, reduce hostility and aggression, and it might reduce the risk of suicide. Clozapine can also reduce cigarette smoking and substance abuse in individuals with schizophrenia. Clozapine is a weak D2 antagonist, with relatively greater D1 and D4 antagonism. Clozapine also has significant interactions with other neurotransmitter systems; it is an alpha adrenergic antagonist, a histaminergic (H1 ) antagonist, a serotonin (5-HT2 ) antagonist, and it is highly anticholinergic. It also influences glutaminergic NMDA-receptor sensitivity and the release of brain-derived neurotrophic factor (BDNF). Clozapine produces many side effects, including sedation, tachycardia, sialorrhea, dizziness, constipation, orthostatic hypotension, and weight gain. Serious side effects include agranulocytosis, seizures, diabetes, pulmonary embolus, and myocarditis. The risk for agranulocytosis (granulocytes < 500/mm3 ) is highest during the first year of treatment (0.8%), and the maximum risk appears to be between 4 and 18 weeks (the time frame when 77% of cases occur). However, agranulocytosis can occur at any point in treatment, and strict monitoring is required. Registry-based prescribing, which has been mandatory since the introduction of clozapine, involving weekly (for the first 6 months), then bi-weekly (for the next 6 months), and then monthly (for the duration of treatment) complete blood counts, has reduced the incidence of clozapineinduced agranulocytosis in the United States. Risk factors can include Ashkenazi Jew heritage (with blood markers of HLA B38, DR4, and DQw3) or Finnish heritage. When agranulocytosis occurs, typically other cell lines (i.e., platelets, red blood cells) are preserved. Patients usually recover within 14 days if clozapine is stopped. There appears to be no cross-sensitivity with other drugs. However, carbamazepine, captopril, sulfonamides, and propylthiouracil (PTU) should be avoided in clozapine-treated patients. Before starting clozapine, patients, prescribers, and pharmacists must be registered with the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program (go to https://www.clozapinerems.com for full details). To initiate clozapine, the patient’s absolute neutrophil count (ANC) must be above 1,500/mm3 . Individuals from certain ethnic groups, including those of African descent or some Middle East ethnicities, might have benign ethnic neutropenia (BEN ) with lower baseline ANC counts (and without increased susceptibility to infection). These individuals can be prescribed clozapine with clear documentation of stable BEN status and ANC above 1,000/mm3 . For all patients

(except patients with BEN for which different cut-offs apply), if neutropenia develops during treatment, the guidelines are as follows: For mild neutropenia (ANC between 1,000 and 1,499/mm3 ), continue treatment and check the ANC three times weekly until it is at least 1,500/mm3 . For moderate neutropenia (ANC between 500 and 999/mm3 ), interrupt treatment and check the ANC daily until it is at least 1,000/mm3 , then three times weekly until it is at least 1,500/mm3 , then weekly for four weeks, before returning to the patient’s last monitoring interval. Clozapine can be resumed when the ANC is at least 1,000/mm3 . For severe neutropenia (ANC less than 500/mm3 ), stop clozapine and check the ANC daily until it is at least 1,000/mm3 , and then three times weekly until it is at least 1,500/mm3 . The patient should not be rechallenged with clozapine, unless the benefits clearly outweigh the risks. Clozapine is usually started at 12.5 to 25 mg at bedtime. The dose is then increased by 25 mg/day (on inpatient units) or 25 mg/week (in outpatient settings) as tolerated. It is best to overlap with the previous antipsychotic agent (and to watch for additive side effects) and then to taper it when the clozapine dose reaches 100 mg/day. Clozapine dosing should be based on the serum level (of clozapine alone), with an initial target range of 200 to 300 ng/ml. For patients with insufficient response, the dose can be increased to achieve levels of at least 450 ng/ml. The maximum clozapine dose is 900 mg/day. Clozapine is predominantly metabolized by the cytochrome P450 1A2 and 3A4 systems. Agents that affect these enzymes can alter clozapine metabolism (see Table 48-3). Often, to prevent seizures, an anticonvulsant (such as valproate, but not carbamazepine, which can cause bone marrow depression and reduces clozapine blood levels) is added when patients are at higher risk for seizures (e.g., “organic” brain damage, previous history of seizures). Therapeutic drug monitoring can greatly reduce the risk of dangerously high clozapine blood levels. Table 48-3: Drug Interactions with Antipsychotic Agents (Most Metabolized by Cytochrome P450 2D6) Agent

Interaction

Alcohol

Addictive sedation; incoordination; increased alcohol levels

Antacids

Impair absorption of chlorpromazine

Antiarrhythmics (class I)

Additive conduction impairment

Anticonvulsants (except valproate) Lower antipsychotic blood levels

Antihypertensives Guanethidine

Reverses the antihypertensive effect

Methyldopa

Hypotension and confusion

Propranolol

Increases levels of chlorpromazine and thioridazine

Buspirone

Increases haloperidol levels

Disulfiram

Lowers chlorpromazine levels

Erythromycin

Increases clozapine levels (3A4)

Fluvoxamine

Increases clozapine levels

Ketoconazole

Increases clozapine levels (3A4)

Lithium

May increase chlorpromazine levels

SSRIs

Increase antipsychotic levels and worsen EPS

Tricyclic antidepressants

Levels increased; increase antipsychotic blood levels

Tobacco

Lowers antipsychotic blood levels

Risperidone Risperidone (Risperdal) is a SGA with 5-HT2 and D2 antagonism. Risperidone also antagonizes D4 , noradrenergic, and histaminergic receptors. Like other SGAs, risperidone has a lower incidence of EPS, but this risk increases at doses above 6 mg/day. Unlike some other SGAs, risperidone causes a sustained increase in prolactin levels in many patients. Side effects of risperidone include dizziness, hypotension (particularly after the first few doses), headache, nausea, vomiting, anxiety, hyperprolactinemia, weight gain, and mild QT interval prolongation. The mean optimal dose of risperidone for patients with chronic, serious mental illness is 4 to 6 mg/day. The usual starting dose is 1 to 2 mg/day. Treatmentnaïve patients might require only 2 to 4 mg/day. Elderly patients should be started at very low doses (0.5 mg/day), with a dose range of 0.5 to 2.0 mg/day. Risperidone is metabolized by cytochrome P450 2D6 isoenzymes, and it has a half-life of 24 hours. It can be given once daily.

Paliperidone Paliperidone (Invega) is 9-hydroxyrisperidone, the active metabolite of risperidone. It is equipotent to risperidone and it shares a similar side effect profile. It has the highest propensity for hyperprolactinemia among all the

antipsychotics. As the end-product of metabolism, it is not metabolized any further by the liver, but it is renally excreted. The dose range is 3 to 6 mg/day.

Olanzapine Olanzapine (Zyprexa) is a SGA with a high 5-HT2 /D2 ratio that resembles clozapine structurally. Olanzapine possesses anticholinergic activity, as well as histaminergic and alpha adrenergic antagonism. Olanzapine had the highest efficacy in the CATIE study, and it might be effective for patients who have failed trials of other antipsychotics. Olanzapine also appears to have a substantial antidepressant and antimanic effects when compared to placebo. Side effects of olanzapine include somnolence, dizziness (without hypotension), constipation, dry mouth, elevation of s erum glutamic-pyruvic transaminase (SGPT) (without evidence of hepatotoxicity), and weight gain. Together with clozapine, olanzapine is associated with the highest risk of obesity, hyperlipidemia, insulin resistance, new-onset diabetes, and diabetic ketoacidosis (DKA). Olanzapine is also associated with mild QTc interval prolongation. Starting doses of olanzapine are usually 5 to 10 mg and the optimal dose is 10 to 20 mg/day for adults. Although doses greater than 20 mg/day are above FDA recommendations, some patients might continue to improve with doses up to 40 mg/day. Elderly patients should be started at lower doses (2.5 mg/day). Olanzapine is metabolized by cytochrome P450 1A2 and 3A4 isoenzymes; it has a half-life of approximately 20 hours and it is usually given once daily.

Quetiapine Quetiapine (Seroquel) is a SGA with a high D2 /5-HT2 ratio (it can be effective with < 60% D2 blockade). Quetiapine also exhibits alpha adrenergic and histaminergic antagonism. Side effects include postural hypotension, somnolence, elevation of liver function tests (LFTs) (reversible), headache, weight gain, decreased serum T3 and T4 levels, and cataracts (in beagles; the risk in humans has not been established, so eye examinations are not recommended every year). Quetiapine has a low incidence of EPS and is prolactin-sparing. It is associated with mild to moderate QTc interval prolongation. The starting dose is 25 mg twice daily (12.5 mg daily in the elderly). The clinically effective dose range is from 250 to 750 mg/day. Doses should be titrated with care to reduce the risk of postural hypotension, particularly in the elderly. Quetiapine has a half-life of approximately 6 hours and is often given

twice daily or three times daily. An extended-release formulation (Seroquel XR) can be given once daily, with a dose range from 300 to 800mg/day. Quetiapine is metabolized by the cytochrome P450 2D6 isoenzyme system.

Ziprasidone Ziprasidone (Geodon) is a SGA with a high 5-HT/D2 ratio. Ziprasidone is also a moderate inhibitor of serotonin and norepinephrine re-uptake. Side effects include nausea, sedation/activation, restlessness or akathisia, and dizziness/hypotension. Ziprasidone is associated with a mean QTc increase of 16 to 21 milliseconds, although the incidence of QTc prolongation greater than 500 milliseconds is rare and ziprasidone is not associated with an increased risk of clinically meaningful endpoints (e.g., death from arrhythmias). Nevertheless, ziprasidone should be used cautiously in patients with risk factors for QTc prolongation (e.g., use of other QTc -prolonging medications, cardiac disease, electrolyte disturbances). Ziprasidone causes the least weight gain of all antipsychotics. It causes less sedation, less EPS, and it is prolactin-sparing. The starting dose for ziprasidone is 20 to 40 mg BID. Clinically effective doses range from 80 to 160 mg/day, and ziprasidone should be administered twice daily with meals (because of better absorption).

Aripiprazole Aripiprazole (Abilify) is a potent (high-affinity) partial agonist at D2 and 5HT1A receptors, and it is a potent antagonist at 5-HT2A receptors. Because of its partial agonist properties, aripiprazole is hypothesized to stabilize the dopamine system by binding to D2 receptors and increasing activation in hypodopaminergic states, and displacing dopamine in hyper-dopaminergic states, thereby decreasing activation of D2 receptors. Aripiprazole can also act as a stabilizer of serotonergic neural pathways and, therefore, function as a dopamine-serotonin system stabilizer. Side effects include nausea, vomiting, anxiety, headache, somnolence, insomnia, akathisia, and agitation. It can cause less weight gain than some other SGAs, but it should not be viewed as being “weight neutral.” It is unlikely to cause EPS with the exception of akathisia, and it is prolactin-sparing. It has negligible impact on the QT interval. The recommended starting dose for adults is 10 to 15 mg once daily, and the effective dose range is 15 to 30 mg/day. Aripiprazole is metabolized by P450

2D6 and 3A4 isoenzymes.

Brexpiprazole Brexpiprazole (Rexulti) is a more-recently-marketed antipsychotic that is structurally similar to aripiprazole, with which it shares partial agonist activities at dopamine receptors. It is also a partial agonist at D2,3 and 5-HT1A receptors, an antagonist of 5-HT2A and α 1 receptors, with low affinity for histamine and muscarinic receptors. Brexpiprazole is associated with mild weight gain in the short run (1 kg/6 weeks), although its long-term tolerability remains to be established. Side effects reported in initial tolerability studies include akathisia, restlessness, insomnia, and anxiety. It is associated with small increases in prolactin and negligible QT c interval prolongation. The recommended dosing schedule is 1 mg daily for four days, followed by an increase (based on clinical response and tolerability) to 2 mg daily for three days, and then 4 mg daily on day 8. The maximum daily dose is 4 mg. Brexpiprazole is metabolized by P450 2D6 and 3A4 isoenzymes.

Cariprazine Cariprazine (Vraylar) is the most recently approved partial dopamine agonist/antagonist. It is a D2 /D3 receptor partial agonist, with preferential binding for the D3 receptor, the clinical relevance of which is uncertain. It is also a partial agonist for the 5-HT1A receptor. Side effects include akathisia, insomnia, restlessness, and EPS. There does not appear to be any effect on the QTc interval. Weight gain appears to be mild, but long-term tolerability remains to be established. The recommended starting dose is 1.5 mg once daily. The dose can be increased, as tolerated, to 3 mg on day 2. Further adjustments in increments of 1.5 mg or 3 mg can be made as indicated, up to a maximum dose of 6 mg. Cariprazine is metabolized by CYP3A4, and to a lesser extent, by CYP2D6. The half-life of cariprazine is 2 to 4 days; it’s active and equipotent metabolites (DCAR and DDCAR) have long half-lives, as well, which means that it takes several weeks to reach steady state.

Asenapine Asenapine (Saphris) is a sub-lingual SGA. It has high affinity for dopamine receptors D1-4 , 5-HT2A,B,C and alpha adrenergic receptors. It has poor

gastrointestinal absorption (< 2% bioavailability) and must be taken sublingually, without any subsequent ingestions for 10 minutes. Side effects include severe akathisia, oral hypoesthesia, EPS, somnolence, dizziness, weight gain, headache, insomnia, and sedation. Asenapine can also increase prolactin levels mildly and is associated with mild QTc interval prolongation. The starting dose is 5 mg twice daily, which can be increased to 10 mg twice daily if needed. Asenapine is metabolized by uridine diphosphate glucuronyl transferase (UGT1A4) and cytochrome P450 isoenzymes (predominantly by CYP1A2, and to lesser extent by CYP3A4 and CYP2D6).

Iloperidone Iloperidone (Fanapt) is a SGA with high affinity for D 2 /5-HT 1A receptors, as well as dopamine D 3 and noradrenergic α 1,2c receptors. Side effects include orthostatic hypotension, dizziness, somnolence, weight gain, dysphagia, QTc prolongation, and arrhythmias. Iloperidone is also associated with mild increases in prolactin. Iloperidone must be titrated slowly from a low starting dose of 1 mg twice daily to avoid orthostatic hypotension. The dose can be increased by 2 mg twice daily each day, as clinically indicated, to a maximum of 12 mg twice daily. Iloperidone is metabolized by P450 3A4 and 2D6 isoenzymes.

Lurasidone Lurasidone (Latuda) has high affinity for dopamine D2 , 5-HT2A and 5-HT7 receptors. It has more moderate binding at adrenergic receptors. It does not have significant activity at histaminergic or muscarinic receptors. Side effects include insomnia, somnolence, EPS, akathisia, hyperprolactinemia, and agitation. Lurasidone might be less likely to cause weight gain than some other SGAs. It is prolactin-sparing and causes minimal QTc interval prolongation. The recommended starting dose, which is also clinically effective, is 40 mg once daily (no titration is required). The maximum recommended dose is 160 mg daily. Lurasidone must be taken with food for adequate absorption. Lurasidone is metabolized by the P450 3A4 isoenzyme.

Side Effects of Second-Generation Antipsychotics

Metabolic Side Effects SGAs are not immune to the variety of side effects seen with FGAs, including sedation, hyper-prolactinemia, dystonias, and QTc prolongation. Although all antipsychotic medications can cause weight gain, several of the SGAs are associated with more significant metabolic side effects, including significant weight gain, impaired glucose metabolism, diabetes mellitus (DM), high blood pressure, and dyslipidemias. Olanzapine and clozapine are associated with the highest amounts of weight gain, whereas ziprasidone, lurasidone, and aripiprazole are associated with less weight gain (although they are not necessarily weight neutral, particularly in antipsychotic-naive patients). For all patients, baseline body mass index (BMI), waist circumference, fasting glucose (or HbA1c), lipid profile, and blood pressure should be documented. BMI should then be measured at every visit for 6 months and then quarterly thereafter. Fasting glucose (or HbA1c) and a lipid profile should be rechecked at 3 months and then yearly or more often in high-risk situations. Blood pressure should be checked at 3 and 6 months and then yearly. In addition to monitoring, intervening for abnormalities is also important. Good nutrition and regular exercise are critical. Patients might benefit from referral to a nutritionist and should be encouraged to participate in a regular exercise program. Hypertension and dyslipidemias should be actively managed by, or in concert with, the primary-care physician (PCP). Some patients might also benefit from treatment or prevention of antipsychotic-induced weight gain with metformin.

Increased Mortality in the Elderly In 2005, the FDA issued a black-box warning for SGAs regarding increased mortality in the elderly with dementia-related psychosis. The relative risk of mortality was 1.6 to 1.7 times the risk compared to placebo, and the causes of death were largely cardiovascular and infectious (pneumonia). In 2008, this black-box warning was expanded to include FGAs, as well. These warnings apply specifically to the use of antipsychotic medications in treating dementiarelated psychosis and agitation (for which they are not FDA-approved) and not generally to the treatment of all psychotic disorders in this population. However, the increased risks of using antipsychotic medications in the elderly, regardless of indication, should be a part of individual risk–benefit analysis and informed consent.

Long-Acting Injectable Antipsychotics Long-acting injectable antipsychotics (LAIs ) are under-used for the treatment of psychotic disorders. LAIs can be particularly helpful in patients for whom adherence is problematic or in question, for those who prefer an injection to daily pills, in patients for whom there is frequent conflict with caregivers over taking medications, for those who refuse oral medications when actively using substances, and others. Patients with first-episode psychosis and patients with legal problems related to being psychotic might benefit specifically from medications with a very long half-life to prevent relapse. Both FGAs (e.g., fluphenazine decanoate, haloperidol decanoate) and SGAs (e.g., risperidone, paliperidone, olanzapine, and aripiprazole) have long-acting injectable formulations. Long-acting injectables, depending on the agent, are given as frequently as every two weeks and as infrequently as every 3 months. For all agents, tolerability with the oral preparation must be established before initiating the long-acting injectable. For most agents, conversion to a LAI must be initially supplemented with the oral agent until a steady-state blood level is achieved from the injectable. For some agents, a loading dose strategy can be used to shorten the time until steady-state blood levels are reached and to reduce the reliance on oral supplementation. A conservative (i.e., careful) dosing approach is prudent since an injectable cannot be taken back once given. Side effects with long-acting injectable antipsychotics are consistent with their oral formulations. Olanzapine pamoate (Relprevv) can rarely cause a postinjection delirium/sedation syndrome, characterized by confusion, sedation, or even coma. For this reason, patients must be observed for three hours after receiving each injection.

Antipsychotic Dosing Dosing Schedules In general , one should use a fixed therapeutic dose of an antipsychotic agent for an adequate period (approximately 4 to 6 weeks) to determine individual efficacy before switching to another agent (see Tables 48-1 and 48-2). Patients having their first episode of schizophrenia are generally more responsive to medication and more sensitive to side effects, so they require lower doses of antipsychotic medications. Immediate initiation of medication when psychosis is apparent is critical in this population, as a shorter duration of untreated psychosis (DUP) is associated with improved clinical and functional outcomes. Chronic

patients typically require higher doses in general, although all patients should be maintained on the lowest effective dose to provide clinical efficacy and longterm stability.

Blood Levels Therapeutic drug monitoring (TDM ) is best established for clozapine where TDM can be used to avoid insufficient or dangerously high clozapine blood levels. Although some have considered there to be a “therapeutic window” (5–15 ng/ml) for haloperidol, the data are inconsistent and blood levels should not substitute for titration of doses based on clinical response. For risperidone, the active moiety (risperidone with its equipotent, active metabolite, paliperidone) needs to be used for dosing estimates (target level of 20–60 ng/mL). Blood levels can be most useful in cases of non-response, non-compliance, or when drug interactions are suspected. Blood levels are also a reflection of the individual’s drug metabolism. Some patients are intermediate or poor metabolizers (due to low levels of P450 2D6) and might develop toxic levels even at low doses. Other patients might be rapid metabolizers and have low antipsychotic levels despite adequate dosing and compliance.

Drug Interactions Drug interactions range from relatively benign to dangerous (see Table 48-3). In general, antipsychotics have a wide therapeutic window, and pharmacokinetic drug interactions, although they can occur, are rarely life-threatening. For example, the addition of fluoxetine can elevate haloperidol blood levels, which could lead to EPS. However, a more serious interaction can occur when fluvoxamine is added to clozapine: the resulting clozapine toxicity has led to several deaths. Combining drugs with dose-dependent QTc interval prolongation could also be potentially dangerous. Smoking (not nicotine) increases the metabolism of drugs metabolized via P450 1A2, which can result in insufficient blood levels if smoking increases (or resumes after a hospitalization).

Treatment-Resistance A patient should not be considered treatment-resistant unless there is clear documentation of multiple failed antipsychotic trials that were sufficient for both dose (therapeutic dosages) and duration (at least 4–6 weeks).

Alternative Diagnoses

Patients with a poor response to treatment must have their diagnosis reassessed. Alternative diagnoses include neurological disorders (e.g., complex partial seizures), psychotic depression, drug toxicity/delirium (e.g., steroid psychosis, anticholinergic delirium), dissociative disorders, hysteria, and posttraumatic stress disorder. In addition, substance use disorders can not only cause psychosis, but also impair treatment response in patients with a primary psychotic disorder. Side effects can be mistaken for worsening psychosis. For example, an agitated patient might be experiencing akathisia from escalating doses of antipsychotics, administered to treat increasing agitation.

Adherence An assessment of adherence is critical before considering a patient treatmentresistant. Even partial non-adherence can have a serious impact on efficacy. Blood levels can be helpful in determining adherence. If there is any question about adherence, clinicians should consider a time-limited trial of a LAI. Of note, some patients might have lower-than-expected blood levels because of unusual metabolism.

Dose Adjustment Adjustment of the antipsychotic dose may be required. A time-limited trial at a higher dose is often indicated, if tolerated. Alternatively, if a patient is already taking moderate to high doses, a dose reduction might provide side effect relief and subsequent symptomatic improvement due to better tolerability.

Clozapine Trial All patients with two failed trials of an antipsychotic should be offered a timelimited trial of clozapine. Clozapine has superior efficacy to all other antipsychotic agents, and it can be life-saving. Although not every patient will agree, all patients deserve the opportunity to consider a clozapine trial.

Add-On Strategies The complete remission of all symptoms is often not achievable with antipsychotics alone. As noted earlier, antipsychotics are most effective for psychosis and hostility, and to prevent psychotic relapse; they are not effective for residual symptoms, particularly cognitive and negative symptoms. Clinicians therefore need to strike a balance between using medications adjunctively to target residual symptoms and unhelpful polypharmacy.

Risperidone Risperidone (or aripiprazole or perphenzaine) added to clozapine for clozapine partial-responders, may improve positive symptoms. Use of this strategy can allow the dose of clozapine to be reduced, which minimizes side effects.

Lithium Lithium (with blood levels of 0.8–1.2 mEq/L) can be effective, particularly if affective symptoms are present or if a cyclic variation in psychotic symptoms is observed. Drug interactions with some antihypertensive agents and non-steroidal anti-inflammatory drugs (NSAIDs) can develop.

Electroconvulsive Therapy Electroconvulsive therapy (ECT), which is helpful for catatonia and for affective symptoms, is most effective early in the course of illness. Its long-term efficacy is unclear, although it can be beneficial as augmentation in clozapineresistant schizophrenia.

Antidepressants Antidepressants should be avoided during the acute psychotic episode (because they are frequently unnecessary-depressive symptoms often resolve when the acute psychosis is treated), but they may be helpful to treat a depressive syndrome, dysphoria, or suicidal ideation during the post-psychotic and maintenance phases of illness.

Benzodiazepines Benzodiazepines can decrease agitation, psychotic symptoms, and social withdrawal. Disinhibition and misuse need to be monitored.

Anticonvulsants Anticonvulsants can decrease agitation, manic symptoms, and stabilize electroencephalographic (EEG) abnormalities. Lamotrigine can be effective for depressive syndromes, as well as chronic dysphoria or dysthymia. It is well tolerated, although an extremely slow dosing schedule must be followed to decrease the risk of Stevens-Johnson syndrome (SJS). Valproate can be helpful for decreasing irritability, aggression, and impulsivity. Valproate might be less useful in women of child-bearing age or younger, given the association with polycystic ovarian syndrome (PCOS).

Carbamazepine and oxcarbazepine are more challenging to use given drugdrug interactions. Carbamazepine in particular increases all P450 enzyme activity, and thus may lower antipsychotic blood levels.

Conclusion Antipsychotic medications are the cornerstone of treatment for psychotic disorders. The individual agents are most readily distinguished by side effect profiles because, with the exception of clozapine and possibly olanzapine, efficacy is comparable across agents. Working knowledge of the various antipsychotic agents, as well as how to manage potential side effects, is critical for the care of patients who receive antipsychotics. Increasingly, antipsychotics are used as add-ons for depression and are no longer restricted to patients with schizophrenia or other psychotic disorders.

Suggested Readings 1. Amjal A, Joffe H, Nachtigall LB: Psychotropic-induced hyperprolactinemia: a clinical review. Psychosomatics . 2014; 55: 29–36. 2. Beach SR, Celano CM, Noseworthy PA, et al: QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics . 2013; 54: 1–13. 3. Breier A, Buchanan RW, Kirkpatrick B, et al: Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry . 1994; 151: 20–26. 4. Buchanan RW, Kreyenbuhl J, Kelly DL, et al: The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophrenia Bull . 2010; 36: 71–93. 5. Carpenter WT, Buchanan RW: Expanding therapy with long acting antipsychotic medication in patients with schizophrenia. JAMA Psychiatry . 2015; 72:745–746. 6. Christison GW, Kirch DG, Wyatt RJ: When symptoms persist. Schizophrenia Bull . 1991; 17: 217–245. 7. Correll CU, Skuban A, Ouyang J, et al: Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, doubleblind, placebo-controlled trial. Am J Psychiatry . 2015;172: 870–880. 8. Farde L, Wiesel FA, Halldin C, et al: Central D2-dopamine receptor

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry . 1988; 45: 71–76. Freudenreich O, Goff DC, Henderson DC: Antipsychotic Drugs. In: Stern TA, Fava M, Wilens TA, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016: pp. 475–488. Freudenreich O, Tranulis C: A prototype approach toward antipsychotic medication adherence in schizophrenia. Harvard Rev Psychiatry . 2009; 17: 35–40. Henderson DC, Nguyen DD, Copeland PM, et al: Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry . 2005; 66: 1116–1121. Hiemke C, Baumann P, Bergemann N, et al: AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry . 2011; 44:195–235. Jarskog LF, Hamer RM, Catellier DJ, et al: Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder . Am J Psychiatry . 2013; 170 : 1032–1040. Kane JM, Zukin S, Wang Y, et al: Efficacy and safety of cariprazine in acute exacerbation of schizophrenia. J Clin Psychopharmacol . 2015; 35: 367–373. Leucht S, Cipriani A, Spineli L, et al: Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments metaanalysis. Lancet . 2013; 382: 951–962. Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med . 2005; 353: 1209–1223. Lopez LV, Kane JM: Recommendations for the monitoring of serum concentrations of antipsychotic drugs in the treatment of schizophrenia. J Clin Psychiatry . 2015; 76: 1249–1250. Meltzer HY, Alphs L, Green AI, et al: Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial (InterSePT). Arch Gen Psychiatry . 2003; 60: 82. Petrides G, Maiur C, Braga RJ, et al: Electroconvulsive therapy

augmentation in clozapine-resistant schizoprenia: a prospective, randomized study. Am J Psychiatry . 2015; 172: 52–58.

CHAPTER Antidepressants and Somatic 49 Therapies SHARMIN GHAZNAVI, MD, PHD AND MARIZIO FAVA, MD

KEY POINTS Classes of Antidepressant Medications Selective serotonin re-uptake inhibitors (SSRIs) inhibit serotonin re-uptake through inhibition of the serotonin transporter. These agents are the most widely used of all antidepressants. Serotonin norepinephrine re-uptake inhibitors inhibit both serotonin and norepinephrine re-uptake. Tricyclic antidepressants inhibit re-uptake of serotonin and norepinephrine, and block 5-HT2A and 5-HT2C receptors, leading to norepinephrine and dopamine release. Monoamine oxidase inhibitors (MAOIs) increase monoamine concentrations by blocking both MAOA and MAOB . Atypical Antidepressants Bupropion weakly inhibits dopamine and norepinephrine re-uptake and can serve as an adrenergic modulator. Mirtazapine increases serotonergic and noradrenergic activity by acting as an antagonist at inhibitory alpha2 -adrenergic auto- and hetero-receptors that results in increases in both serotonin and norepinephrine release. Trazodone inhibits serotonin re-uptake as well as antagonist of serotonin 5HT2A/C receptor and α 1 -adrenergic receptors. Nefazodone is chemically related to trazodone, but has less αl blockade. Vilazodone inhibits the serotonin transporter and is a partial agonist of serotonin 5-HT1A receptors. Vortioxetine blocks serotonin re-uptake and modulates activity at several 5-HT receptors, notably it has 5-HT3 receptor antagonism and 5-HT1A receptor agonism.

Psychostimulants affect dopamine transmission. Antipsychotic agents result in antagonism at the 5-HT2C receptors, which increase norepinephrine and dopamine, and acts through partial agonism at the 5-HT1A receptor. Special Populations Elderly patients should be started on lower-than-usual doses and proceed upwards slowly. Pregnant patients should have their depression treated during pregnancy. Options include SSRIs and electroconvulsive therapy. Patients with bipolar disorder on an antidepressant but without a mood stabilizing agent, can cycle into mania or initiate and maintain rapid cycling. Other Indications for Antidepressants Other indications for antidepressants include bulimia nervosa, obsessivecompulsive disorder, generalized anxiety disorder, panic disorder, posttraumatic stress disorder, smoking, and pain.

Introduction Antidepressants , which are the most widely used class of psychiatric medications, are robustly effective in the treatment of major depressive disorder (MDD). However, there has been some controversy regarding the superiority of antidepressants compared to placebo. This has been because rates of placebo response in antidepressant trials have progressively increased over the decades and this has markedly limited the ability to detect antidepressant signals and has also reduced the degree of difference in efficacy between antidepressants and placebo. Despite that, more than 50% of depressed patients will fully recover when an adequate dose of any antidepressant is used for an adequate amount of time (at least 6 weeks); 20% to 35% will show some improvement, and 10% to 13% will not improve substantially. The goal of treatment is full remission of depressive symptoms and relapse prevention. After a first episode of MDD, a patient should receive at least 6 months of treatment with an antidepressant at the dosage to which they respond; any tapering of the antidepressant should be done slowly to minimize the risk of relapse.

Classes of Antidepressant Medications Selective Serotonin Re-Uptake Inhibitors The most widely used class of antidepressants are the selective serotonin reuptake inhibitors (SSRIs), which include sertraline, fluoxetine, citalopram, escitalopram, paroxetine, and fluvoxamine. Their mechanism of action is inhibition of serotonin re-uptake through inhibition of the serotonin transporter (SERT). Serotonergic blockade at neuronal synaptic clefts occurs within hours of initiation of SSRI treatment. However, the typical time-to-response in depression for all antidepressant medications, including the SSRls, is 3 to 6 weeks; therefore, serotonin re-uptake inhibition on its own is not considered to account for antidepressant efficacy. One postulated mechanism of action of the SSRIs is desensitization and downregulation of pre-synaptic auto-receptors. Pre-synaptic serotonin auto-receptors usually inhibit serotonin release; thus, their desensitization and down-regulation, likely through changes in gene expression, allows for continuous release of serotonin in the synaptic cleft. Beta-adrenergic receptor down-regulation has also been postulated to be a possible mechanism, has increased neurogenesis. All currently available SSRIs are equally efficacious, but differ in their side effect profiles and half-lives. Because they are generally well tolerated and have a relatively benign side effect profile, the SSRIs have become the first-line treatment for depressive illnesses, ranging from dysthymia to severe MDD.

Side Effects Side effects of SSRIs are the result of increases in serotonin release throughout the brain and body. Some side effects are more common with some SSRIs than with others; however, side effects can also be idiosyncratic: one patient might find a particular SSRI sedating, whereas another might find the same SSRI activating. The most common side effects of the SSRIs include: nausea (mediated by serotonin receptors in the hypothalamus and brainstem); mental agitation/anxiety (mediated by stimulation of serotonin receptors in the amygdala and limbic cortex); motor symptoms, including restlessness, akathisia, and psychomotor retardation (mediated by serotonin receptors in the basal ganglia); insomnia (mediated by serotonin receptors in brainstem sleep areas); sexual dysfunction including decreased libido, impotence and anorgasmia (mediated by mesocortical and spinal cord serotonin receptors); gastrointestinal (GI) distress including bowel motility, cramps, and diarrhea (mediated by

serotonin receptors in the GI tract); and excessive sweating, headache, sedation, and dry mouth (mechanisms of action less well understood). Other side effects include prolonged bleeding time (by the serotonin effects on platelets) and weight gain with long-term treatment. Tolerance to side effects is thought to be mediated by post-synaptic serotonin receptor desensitization in regions associated with side effects. SSRIs, and in particular citalopram, are associated with QTc prolongation and should be used with caution in patients with cardiac disease and in the elderly.

Dosing and Half-Life Although dose–response curves have not been definitively established for the SSRIs, some patients who do not respond at a lower dose might benefit by having their dosage increased. SSRIs are hepatically metabolized and renally excreted; therefore, lower dosages might be required in hepaticallycompromised patients, and this is also true to a lesser degree in patients with renal failure. Half-lives vary greatly among the SSRIs. Although a drug’s half-life does not affect its treatment efficacy or its onset of action, it is significant for side effects, interactions with other agents, and discontinuation-emergent symptoms. Medications with shorter half-lives can be useful when abrupt discontinuation is desired due to intolerable side effects or to medication interactions. However, medications with shorter half-lives are more likely to cause the discontinuationemergent symptoms (e.g., tachycardia, anxiety, irritability, worsening of mood, dizziness, jitteriness, nausea). An SSRI with a longer half-life is more likely to “self-taper” and might be beneficial for a patient who is apt to miss occasional dosages.

Drug Interactions SSRIs should not be co-administered with monoamine oxidase inhibitors (MAOIs) because of the possibility of causing a potentially life-threatening serotonin syndrome, characterized by myoclonus, tremor, hypertension, diarrhea, and confusion. Alteration in the function of cytochrome P450 enzymes might cause clinically-significant pharmacokinetic drug-drug interactions via changes in drug levels. Therefore, caution is warranted when using SSRIs with other medications that rely on the P450 system, especially isoenzymes 2D6 and 3A4 because some of the SSRIs inhibit these isoenzymes.

Serotonin Norepinephrine Re-Uptake Inhibitors Another frequently-used class of antidepressants is the serotonin norepinephrine re-uptake inhibitors (SNRIs). There are four SNRIs (venlafaxine, desvenlafaxine, duloxetine, and levomilnacipram) approved for use in depression in the United States. The last of these is the levo isomer of milnacipram. Milancipram is approved for the use of depression in Europe, but only for fibromyalgia in the United States. The SNRIs function by inhibiting both serotonin and norepinephrine re-uptake. For patients who respond poorly to SSRIs, the use of SNRIs presents another mechanism for targeting their symptoms through the noradrenergic system.

Side Effects The side-effect profile of SNRIs is similar to that of the SSRIs, although there is the potential for a greater number of side effects, owing to the involvement of another neurotransmitter system. Norepinephrine is also distributed widely throughout the brain and body, so the side effects of SNRIs include those of increased norepinephrine as well as of increased serotonin (as discussed earlier). The common side effects attributable to an increase in norepinephrine include motor symptoms, particularly tremor (mediated by norepinephrine’s effects on the cerebellum and the peripheral nervous system), increased blood pressure (mediated by noradrenergic receptors in the brainstem cardiovascular centers), and anticholinergic-like side effects including dry mouth, constipation, urinary retention (mediated by reduction in sympathetic tone).

Dosing and Half-Life Venlafaxine has dose-dependent effects , with those for serotonin inhibition being more potent than norepinephrine inhibition. At even low doses (below 150 mg) venlafaxine can have potent and effective inhibition of serotonin re-uptake inhibition. However, inhibition of norepinephrine re-uptake occurs only at 225 mg/day or higher doses. The half-life of venlafaxine is 5 hours, whereas that of its metabolite O-desmethylvenlafaxine is 11 hours. Duloxetine binds selectively to both serotonin and norepinephrine transporters with high affinity, inhibiting re-uptake of both equally. The half-life of duloxetine is 10 to 15 hours. Levomilnacipram differs from other SNRIs in that it inhibits norepinephrine reuptake to a greater extent than serotonin.

Drug Interactions

Venlafaxine is hepatically metabolized by CYP 450 isoenzyme 2D6 and duloxetine is an inhibitor of 2D6. Therefore, caution should be used with other medications that are also metabolized by 2D6. Venlafaxine, duloxetine, desvenlafaxine, and levomilnacipram should not be used with MAOIs because of the risk of serotonin syndrome.

Tricyclic Antidepressants Tricyclic antidepressants (TCAs) have been used for more than 50 years. All are equally efficacious and are as effective as SSRIs and SNRIs. However, they have a more problematic side effect profile and can be lethal in overdose. The term “tricyclic” signifies a shared chemical structure made up of three rings, with two joined benzene rings. TCAs inhibit re-uptake of serotonin and norepinephrine, and block 5-HT2A and 5-HT2C receptors, leading to norepinephrine and dopamine release. They also block histamine1 , M1 muscarinic cholinergic and α 1 adrenergic receptors. There are three categories of cyclic antidepressants: tertiary amines (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine), secondary amines (desipramine, nortryptiline, amoxapine, and protriptyline), and tetracyclics (maprotiline, a tetracyclic compound of four benzene rings). The difference between the three categories is largely chemical structure: the tertiary amines differ from secondary amines in terms of the number of hydrocarbons that are on the nitrogen molecule.

Side Effects Many of the side effects of TCAs are due to the increase in serotonin and norepinephrine as well as blockade of 5-HT2 , histamine1 , M1 muscarinic cholinergic, and α 1 adrenergic receptors. The blockade of histamine receptors leads to antihistaminergic side effects, including sedation and weight gain. Secondary amine TCAs, such as desipramine and protriptyline, tend to cause less sedation than tertiary amine TCAs. Anticholinergic side effects include dry mouth, blurred vision, constipation, urinary hesitancy, and tachycardia. Bethanechol (Urecholine), a cholinergic smooth muscle stimulant, or donepezil (Aricept), a cholinesterase inhibitor, may relieve such peripheral anticholinergic signs and symptoms. Ejaculatory difficulties and other sexual dysfunction symptoms can also occur with TCAs, possibly due to anticholinergic effects. Secondary amine TCAs tend to cause fewer anticholinergic effects than tertiary amine TCAs, with the exception of protriptyline, which is extremely

anticholinergic. Antagonism of α 1 –adrenergic receptors results in orthostatic hypotension. 5-HT2A antagonism may lead to sedation. Cardiac toxicity can occur in susceptible individuals and following TCA overdose; the TCAs should be avoided in patients with bi-fascicular heart block, left bundle branch block, or a prolonged QT interval, because they can slow conduction through the AV (atrio-ventricular) node. TCAs can cause severe orthostatic hypotension in patients with congestive heart failure due to α 1 receptor blockade. TCAs should be avoided in patients with narrow angle glaucoma or prostatic hypertrophy, because symptoms related to these conditions might worsen because of anticholinergic effects. Manifestations of anticholinergic toxicity can include dilated pupils, blurred vision, dry skin, hyperpyrexia, ileus, urinary retention, confusion, delirium, and seizures. Additionally, arrhythmias, hypotension, and coma can develop. Although TCAs are highly plasmabound and are not removed by hemodialysis, they are metabolized by hepatic microsomal enzymes. Patients who have overdosed on TCAs might require alkalinization of their serum as well as pressors or ventilatory support to maintain survival. TCAs have a low threshold for toxicity; an overdose of even a 1-week supply can be lethal. Due to the lethality after overdose, it might be safer to treat acutely suicidal depressed patients with non-TCA antidepressants or to prescribe limited quantities of TCAs.

Dosing and Half-Life In general , TCAs have a linear relationship between increasing serum levels and effectiveness. Some researchers have suggested that with nortriptyline there might be an inverted U-shaped curve, with decreasing efficacy at blood levels above therapeutic range, although the evidence for this view is unconvincing due to methodological issues present in such studies. Blood levels can guide treatment with amitriptyline, imipramine, nortriptyline, desipramine, or clomipramine. The half-life of TCAs range between 24 and 72 hours.

Drug Interactions TCAs are classified as class I antiarrhythmics and must be used with great caution when used with other drugs from this class, including quinidine, procainamide, and disopyramide. TCAs can block the antihypertensive effects of clonidine, methyldopa, guanabenz, guanethadine, reserpine, and guanadrel and

can potentiate the effect of prazosin. They are metabolized by CYP 450 2D6, so care must be observed with other medications that are metabolized or affect the activity of CYP 450 enzymes. In particular, TCAs should be used with caution when used with SSRIs because certain SSRIs are inhibitors of 2D6. Coadministration of TCAs is also contraindicated with use of MAOIs because of the risk of serotonin syndrome and a hypertensive crisis.

Monoamine Oxidase Inhibitors Another class of antidepressants that have been around for a long time is the MAOIs. Monoamine oxidase (MAO) is found on the outer membrane of cellular mitochondria, where it catabolizes intra-cellular monoamines, including the monoamines of the central nervous system (CNS): dopamine, norepinephrine, serotonin, and tyramine. In the GI tract and the liver, MAO catabolizes dietary monoamines, such as dopamine, tyramine, tryptamine, and phenylethylamine. The MAOIs approved for oral use in the United States for the treatment of depression are phenelzine, tranylcypromine, and isocarboxazid, whereas selegiline is approved as a patch; they are all thought to work by increasing synaptic monoamine concentrations. All four MAOIs are active on both MAOA and MAOB and are relatively irreversible blockers of MAO activity. MAOIs have a proven efficacy for MDD. In “atypical” depression (characterized by mood reactivity plus hypersomnia, hyperphagia, extreme fatigue when depressed, and/or rejection sensitivity) and patients who have not responded to other antidepressants, MAOIs can be particularly effective.

Side Effects The side effects of MAOIs are rooted in their increase in monoamines including serotonin, norepinephrine, and dopamine. The most common side effects include postural hypotension, insomnia, agitation, sedation, and sexual dysfunction (including impotence, delayed ejaculation, and anorgasmia). Other side effects include weight change, dry mouth, constipation, and urinary hesitancy. Peripheral neuropathies also occur and can be avoided by concomitant therapy with vitamin B6 . MAOIs are contraindicated in patients with pheochromocytoma, congestive heart failure, and hepatic disease.

Dosing and Half-Life MAOIs are started at low doses with gradual increases as side effects allow. Serum levels of MAOIs are not well established. However, for phenelzine,

greater than 85% inhibition of baseline platelet MAOB activity appears to correlate with therapeutic efficacy. MAOIs should be tapered over 2 to 4 weeks, and because MAO levels do not return to normal immediately, food and drug restrictions should not be lifted for 2 or more weeks.

Food Interactions Because MAOIs block MAOB , when patients on MAOIs ingest dietary amines, rather than being catabolized in the intestines and the liver they are taken up in sympathetic nerve terminals and can cause the release of endogenous catecholamines with a resulting adrenergic crisis. This is characterized by hypertension, hyperpyrexia, and other adrenergic symptoms (e.g., tachycardia, tremulousness, cardiac arrhythmias). The amine most commonly associated with these symptoms is tyramine, but others (e.g., phenylethylalamine, dopamine) might be involved. Dietary amines can be avoided by adherence to dietary restrictions and by avoiding tyramine-containing foods. The MAOI diet must be strictly followed, but need not be as restrictive as was once thought. Patients must be instructed to avoid: all matured or aged cheese; fermented or dried meats (e.g., pepperoni, salami); fava and broad bean pods (not the beans themselves); tap beers; marmite yeast extract; sauerkraut; and soy sauce and other soy products (e.g., tofu, tempe). All meats and cheese must be fresh and must have been stored and refrigerated or frozen properly. Up to two glasses of beer can be consumed safely; this restriction includes non-alcoholic beers. Because endogenous MAO activity does not return to baseline immediately upon MAOI discontinuation, 2 weeks should elapse before discontinuing the MAOI diet after MAOI discontinuation. The selegiline patch at the lower dose does not require a dietary restriction.

Drug Interactions The MAOIs are primarily hepatically metabolized by the CYP 450 enzymes. Avoidance of toxic drug–drug interactions with MAOIs is critical. Medications with affinity for serotonergic receptors (serotonergic TCAs [e.g., clomipramine], SSRIs, SNRIs, nefazodone, and vilazodone) can result in the serotonin syndrome, with myoclonic jerks, tremor, hypertension, diarrhea, confusion, tachycardia, fever, and ocular oscillations; in its severe form, it can include hyperthermia, coma, convulsions, and death. MAOIs must be used with caution in patients with diabetes (due to possible potentiation of oral hypoglycemics and

worsened hypoglycemia). Low-dose MAOIs can increase sensitivity to insulin, and high-dose MAOIs can increase insulin resistance. Sympathomimetics, both prescribed and over-the-counter, and relatively potent norepinephrine re-uptake inhibitors such as TCAs can precipitate hypertensive crises. Sympathomimetics are most commonly found in nasal decongestants (e.g., pseudoephedrine, ephedrine, oxymetazoline [Afrin nasal spray]), and also include amphetamines and cocaine. The cough-suppressant dextromethorphan can have similar toxic effects. The hypertensive crisis is characterized by headache, stroke, pulmonary edema, and cardiac arrhythmias. Co-administration of meperidine (Demerol) is contraindicated because it is known to cause a syndrome of fever, vascular instability, delirium, neuromuscular irritability, and death. Prior to beginning an MAOI after discontinuation of a contraindicated antidepressant, the necessary drug-free time varies depending on the half-life of the previous antidepressant. At least five half-lives of the contraindicated medication are required, with two weeks required after most SSRIs and SNRIs, and five weeks required after use of fluoxetine.

Atypical Antidepressants Bupropion Bupropion’s mechanism of action remains unclear, but it seems to weakly inhibit dopamine and norepinephrine re-uptake and might serve as an adrenergic modulator, especially its metabolites that are potent inhibitors of norepinephrine re-uptake. It has a half-life of 11 to 14 hours. Bupropion is hepatically metabolized. Common side effects include agitation, insomnia, weight loss, dry mouth, headache, constipation, and tremor. It has been noted to cause seizures, at a rate of 4/1,000 in its immediate-release form. Its sustained-release (SR) form is associated with a seizure-risk comparable to that of the SSRIs. However, the risk of seizures markedly increases at doses greater than 450 mg/day in divided doses and might be more likely to induce seizures in patients with anorexia or bulimia nervosa. It is generally safe in overdose, though fatalities have been reported. Bupropion is one of the safest, if not the safest, antidepressants in patients with cardiac disease. Bupropion rarely induces sexual dysfunction or even weight gain over long-term use and can even be beneficial as an adjunct in SSRIinduced sexual dysfunction and to decrease appetite in atypical depression in which patients may have hyperphagia. Its use is contraindicated with MAOIs.

Mirtazapine Mirtazapine increases serotonergic and noradrenergic activity by acting as an antagonist at inhibitory α 2 -adrenergic auto- and hetero-receptors which results in increases in both serotonin and norepinephrine release. It is also acts as an antagonist of 5-HT2A/C receptors, which contribute to its effects as a sleep aid and anxiolytic (and why it might be less likely to cause sexual dysfunction than SSRIs and SNRIs) as well as 5-HT3 receptors, which reduces the nausea and GI distress that might otherwise be experienced with an increase in serotonin. Mirtazipine is also a relatively potent histaminergic H1 receptor antagonist, which is another reason why it makes for a good sleep aid. Common side effects include somnolence and weight gain (mediated by 5-HT2 and H1 antagonism), dizziness, dry mouth, constipation, and orthostatic hypotension. Mirtazapine demonstrates linear dose relationships in serum and has a half-life of 20 to 40 hours. It is hepatically metabolized by CYP 450 2D6 and 34. Inhibitors or inducers of these enzymes can affect serum levels of mirtazapine.

Trazodone Trazodone’s mechanism of inhibition is serotonin re-uptake as well as antagonism of serotonin 5-HT2A/C receptors. It is also an antagonist of α 1adrenergic receptors. However, for effective use as an antidepressant, trazodone must be prescribed at high doses (200–600 mg). Trazodone at low doses is most commonly used as an adjunctive medication for insomnia due to its sedating properties. Trazodone achieves peak levels in 1 to 2 hours and has a half-life of 3 to 9 hours. Trazodone is less lethal in overdose than the TCAs, though slightly more lethal than the SSRIs, as there have been some cases of fatal overdoses with trazodone. The most common side effects are sedation, orthostatic hypotension (mediated by α 1 -adrenergic antagonism), and headache. Priapism is a rare but serious side effect that requires immediate medical attention. Trazodone can induce arrhythmias in those with pre-existing heart disease. Trazodone is hepatically metabolized and can increase levels of digoxin and phenytoin.

Nefazodone Nefazodone is chemically related to trazodone, but with less α l blockade. Nefazodone is not used very much because it has been implicated in rare cases of fatal hepatic failure. Side effects are otherwise similar to trazodone, but with

less orthostatic hypotension. Nefazodone should be started at low doses and titrated up as tolerated to high doses for antidepressant effects (450–600 mg daily). It is hepatically metabolized and has a half-life of 5 hours. Nefazodone should be used with caution in patients with liver dysfunction, and monitoring of serum transaminases in patients taking nefazodone might be prudent. It is a potent inhibitor of cytochrome CYP 450 3A4 isoenzymes. Nefazodone can interact with cisapride (Propulsid), terfenadine (Seldane), or astemizole (Hismanal), and can lead to QT prolongation and torsades de pointes. There have also been reports that it has resulted in serotonin syndrome when used in conjuction with SSRIs. It is contraindicated with MAOIs.

Vilazodone Vilazodone is a molecule that combines the activity of inhibition of the serotonin transporter with that of partial agonism of serotonin 5-HT1A receptors. Side effects are otherwise similar to those of the SSRIs. It is contraindicated with MAOIs.

Vortioxetine The newest atypical antidepressant available for use in the United States is vortioxetine, which functions as a serotonin modulator and stimulator. It blocks serotonin re-uptake and modulates activity at several 5-HT receptors, notably 5HT3 receptor antagonism and 5-HT1A receptor agonism. Vortioxetine also blocks norepinephrine transport and can also effect concentrations of histamine and acetylcholine. It is contraindicated with MAOIs.

Psychostimulants Psychostimulants are thought to achieve antidepressant benefits through their effects on dopamine transmission. Although the psychostimulants dextroamphetamine, methylphenidate, and pemoline have not shown clear benefit in the long-term treatment of depression, they are frequently beneficial in apathetic geriatric patients, in medical inpatient settings for short-term use (e.g., oncology patients who are depressed), and as adjunctive medication in the treatment of refractory depression. Side effects include insomnia, tremors, appetite change, palpitations, blurred vision, dry mouth, constipation, and dizziness. Arrhythmias and tachycardia have also been reported. Pemoline has been associated with hepatic toxicity and requires monitoring of serum transaminases.

Antipsychotic Agents There is no evidence supporting the use of antipsychotic agents alone in nonpsychotic, unipolar depression; however, these agents are often beneficial in MDD with psychotic features and mixed episodes of bipolar disorder. Additionally, antipsychotics have demonstrated clear efficacy in augmentation studies when added to SSRIs and SNRIs, particularly the newer atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. The atypical antipsychotic agents are thought to exert their antidepressant effects through antagonism at the 5-HT2C receptors, which increase norepinephrine and dopamine, and through partial agonism at the 5-HT1A receptors.

Special Populations The Elderly Depression in the elderly should be treated as thoroughly as it would in any patient. It is important to begin with lower-than-usual doses. Because renal clearance and hepatic metabolism are frequently reduced in the elderly, given increased medical co-morbidity, lower dosages are often needed. Titration should also proceed slowly, to minimize adverse side effects. Particular attention should be paid to medications that have orthostatic hypotension as a side effect because there is greater morbidity and mortality associated with falls in the elderly.

Pregnant Patients Pregnancy presents a particular challenge, given the concerns of exposing the fetus to psychotropic medications that might put them at risk for fetal malformations or neurodevelopmental abnormalities. However, if depression goes untreated during pregnancy, research has shown that there are significant risks to the mother and fetus, including but not limited to poor selfcare/nutrition, low birth weight, developmental delay, as well as risk of selfharm and harm to the baby. SSRIs appear to carry no increased risk of fetal malformation. However, all the SSRIs, especially in the third trimester can lead, in rare cases, to a neonatal withdrawal syndrome and persistent pulmonary hypertension. There is little data regarding the use of TCAs, and they should generally be avoided for this reason. MAOIs should be avoided. In cases of severe depression, clinicians should consider electroconvulsive therapy (ECT), which is safe to perform during pregnancy.

Patients with Bipolar Disorder The risk of bipolar patients cycling into mania is 30% to 50% when they are treated with antidepressant medications while not on a mood-stabilizing agent. Antidepressants can even initiate and maintain rapid-cycling, particularly the TCAs.

Patients with Major Depression with Psychotic Features Major depression with psychotic features is treated with full dosages of antidepressants combined with antipsychotic agents.

Patients with Dysthymic Disorder Dysthymic disorder is a chronic, mild form of depression that is associated with a high risk of superimposed major depressive episodes (double depression). There is evidence that all antidepressant classes might be useful in the treatment of this condition, although full recovery from double depression might be less likely to occur than MDD, when seen alone.

Patients with Treatment-Refractory Depression Medical conditions, such as hypothyroidism, anemia, occult malignancy, or confounding substance abuse, must be ruled-out. Often depression is labeled “refractory” before adequate medication trials have been conducted. If a patient does not respond to antidepressant treatment of adequate duration and dose, it is reasonable to increase the dosage until benefits are seen or until side effects become problematic. Duration of medication use is equally important, with at least 6 weeks of a medication trial necessary before treatment failure can be declared. A patient who has not responded to a medication in one class might still respond to a different medication of the same class, to a switch to an antidepressant of another class, or to the addition of an antidepressant that acts on different receptors, such as the addition of bupropion, mirtazapine, or a psychostimulant to an SSRI. Other options include the addition of atypical antipsychotics, triidothyronine (T3 ), lithium, buspirone, amantadine, methylfolate, s-adenosyl-methionine, amantadine, pramipexole, and ropinerole. When a patient does not respond to robust pharmacological treatments for depression, clinicians might consider ECT or other neurotherapeutic approaches, such as transcranial magnetic stimulation (TMS).

Other Indications for Antidepressants

Chronic Pain TCAs and SNRIs are useful in many pain conditions. These include diabetic neuropathy, fibromyalgia, chronic fatigue, post-herpetic neuralgia, trigeminal neuralgia, migraine, and tension headache (for prophylaxis). Frequently, TCAs have been useful for these conditions at blood levels lower than those required to achieve antidepressant response.

Potentiation of Pain Medications Both the TCAs and psychostimulants potentiate narcotic analgesia.

Bulimia Nervosa High doses of SSRIs are effective in reducing binging/purging behaviors; MAOIs and TCAs might also be helpful, but the dietary restrictions associated with MAOI treatment might not be feasible among patients with eating-related impulsivity.

Obsessive-Compulsive Disorder Obsessive-compulsive disorder (OCD) responds to medications with serotonergic effects, specifically SSRIs, SNRIs, and the TCA, clomipramine. Obsessions respond better than do compulsions. Typically, these medications are used in dosages higher than those needed for antidepressant response and need to be used for longer periods. Trichotillomania and body dysmorphic disorder may similarly respond to SSRIs.

Generalized Anxiety Disorder and Panic Disorder SSRIs have become the first-line treatment for generalized anxiety disorder (GAD) and panic disorder. Dosing should begin at low doses, due to the jitteriness and anxiety that is frequently experienced at the beginning of treatment. MAOIs and TCAs are also effective, though their side effects, particularly at higher dosages, are less tolerable. It is not clear whether the atypical antidepressants are as effective as the other classes of antidepressants in this condition. Anticipatory anxiety and phobic avoidance might respond less well to antidepressant treatment and might benefit from the addition of cognitive-behavioral therapy (CBT).

Post-Traumatic Stress Disorder SSRIs have also become a first-line treatment for post-traumatic stress disorder (PTSD). Although SSRIs are helpful for decreasing symptoms of PTSD, they do

not eliminate them altogether and often patients benefit from augmentation with agents like prazosin (to help with nightmares) and with CBT.

Smoking Cessation Bupropion has been shown to be effective in smoking cessation when used as part of an overall smoking-cessation treatment program. Starting doses are usually lower than those used for the treatment of depression.

Suggested Readings 1. Alpert, JE: Drug-drug interactions: The interface between psychotropics and other agents. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Primary Care Psychiatry, Second Edition . New York: McGrawHill, 2004, pp. 653–670. 2. Burt VK, Suri R, Altshuler L, et al: The use of psychotropic medications during breastfeeding. Am J Psychiatry . 2001; 158(7): 1001–1009. 3. Fava M, Kendler KS: Major depressive disorder. Neuron . 2000; 28(2): 335–341. 4. Fava M, Papakostas GI: Antidepressants. In: Stern TA, Fava M, Wilens TE, et al, eds.: MGH Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier, 2016, pp. 489–505. 5. Fava M, Rosenbaum JF: Pharmacotherapy and somatic therapies. In: Beckham EE, Leber WR, eds.: Handbook of Depression . New York: Guilford Publications, 1995, pp. 280–301. 6. Fava M, Rosenbaum JF: The patient with depression. In: Stern TA, Herman JB, Slavin PL, eds.: The MGH Guide to Primary Care Psychiatry . 2nd ed. N ew York: McGraw-Hill, 2004, pp. 111–126. 7. Gardner NM, Shulman KI, Walker SE, et al: The making of a user-friendly MAOI diet. J Clin Psychiatry . 1993; 57: 99–104. 8. Papakostas GI, Shelton RC, Smith J, et al: Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry . 2007 Jun; 68(6): 826–831. 9. Pearson KH, Nonacs R, Cohen LS: Practical guide to the treatment of psychiatric disorders during pregnancy. In: Pearson KH, Sonawal1a SB,

Rosenbaum JF, eds.: Women’s Health and Psychiatry . Philadelphia, PA: Lippincott Williams, & Wilkins, 2002; pp. 115–125. 10. Rosenbaum JF, Arana GW, Hyman SE, et al: Handbook of Psychiatric Drug Therapy Fifth Edition . New York: Lippincott, Williams & Wilkins, 2005. 11. Stahl SM: Stahl’s Essential Psychopharmacology: Neuroscientific basis and practical applications . New York: Cambridge University Press, 2008.

CHAPTER Electroconvulsive Therapy 50 CARLOS FERNANDEZ-ROBLES, MD AND CHARLES A. WELCH, MD

KEY POINTS Overview Electroconvulsive therapy (ECT) has an excellent safety profile, superior efficacy, and economic benefits (due to shorter hospital stays) that make it an important part of the psychiatrist’s armamentarium against severe affective illness. Mechanism of Action Despite decades of experience with ECT, the specific mechanism of its antidepressant effect remains poorly understood. Indications for ECT Current evidence supports the use of ECT in the treatment of several neuropsychiatric illnesses: major depressive disorder; bipolar affective disorder (both manic and depressive episodes); schizophrenia (generally for acute exacerbations rather than chronic illness); and, catatonia (of either organic or affective etiology). Risk Factors and Adverse Events Adverse effects of ECT can be complicated by conditions involving the cardiovascular, cerebrovascular, and pulmonary systems. Practical Aspects of ECT A thorough pre-ECT evaluation is essential to the safety and efficacy of this procedure. As with any procedure, informed consent must be obtained from the patient

before initiation of ECT. Before starting ECT, all medications taken by the patient should be reviewed to avoid potential adverse effects and interactions. The anesthetic goals for ECT are three-fold: rapid induction with amnesia, prevention of injury from tonic–clonic seizures, and attenuation of the sympathetic response to ECT. Two standard electrode placements are currently employed for the delivery of electricity to the brain. In unilateral placement (d’Elia placement), both electrodes are placed over the same hemisphere, typically the non-dominant right side. With a bilateral placement, the electrodes are positioned symmetrically over the fronto-temporal areas. ECT devices can deliver a constant-current, brief-pulse stimulus of electricity (0.5–1 ms), an advance that has helped to minimize the degree of cognitive dysfunction. Eliciting a seizure is necessary, but not always sufficient for antidepressant effect. Complications of ECT ECT does not cause structural damage to the brain; in fact it possesses neuroprotective properties and increases hippocampal and amygdala graymatter volume. A brief (15–30 minutes) period of confusion, characterized by restlessness, disorientation, panic-like behavior, and combativeness, is seen in up to 12% of patients immediately following treatment. Additional complications include memory loss, prolonged seizures, and headaches.

Introduction Electroconvulsive therapy (ECT) has been used to treat severe psychiatric illness for more than 75 years. Currently, approximately 100,000 people receive ECT each year in the United States. Its excellent safety profile, superior efficacy, and economic benefits (due to shorter hospital stays make ECT an important part of the psychiatrist’s armamentarium against severe affective illness; knowledge of the indications, risks, techniques, and benefits of ECT remains an integral part of a complete psychiatric curriculum. Although only a small minority of

psychiatrists are involved in the actual administration of ECT, knowledge of ECT (e.g., knowing when to refer, knowing the risks and benefits) is essential for the practicing psychiatrist.

Mechanism of Action Despite decades of experience with ECT, the specific mechanism of its antidepressant effect remains poorly understood. Early theorists presumed that ECT’s effectiveness was related to the fulfillment of the need for punishment in the depressed patient, and its ability to disturb recent memory. Introduction of anesthetics and advancements in the administration of ECT have rendered these theories obsolete. Instead of trying to elucidate one mechanism of action, research has focused on examining the transformations that occur in the brain after ECT (involving neurotransmitter systems, endocrinological pathways, proinflammatory cytokines, brain connectivity, neurogenesis). ECT induces a compensatory increase in the function of the brain’s inhibitory system via alterations in the levels of γ -amino butyric acid (GABA), regulation of serotonergic receptor (notably 5-HT1A ) function, and activation of the dopamine system, including hormone release, neurotransmission, and receptor binding. ECT produces a wide swath of endocrine responses in humans (e.g., elevations of plasma concentrations of cortisol, prolactin, adrenocoricotropin, vasopressin, neuropeptide Y) and it restores abnormalities in the hypothalamic-pituitaryadrenal (HPA) axis associated with severe depression. Increased serum concentrations of the proinflammatory cytokines (e.g., interleukin 1 [IL-1] and IL-6, C-reactive protein [CRP], tumor necrosis factor [TNF]) have been documented in those with mood disorders and psychotic disorders; a single ECT session induces an immediate and transient immune activation, whereas repeated courses of ECT may down-regulate immune activation; however, current evidence is insufficient to understand ECT’s immunomodulatory role. Using functional magnetic resonance imaging (fMRI), researchers have found that ECT normalizes increased intrinsic connectivity in several neuronal networks that are implicated in depression, particularly in the frontal regions. Finally, imaging studies and post-mortem studies of patients who are severely depressed have consistently shown decreases in hippocampal volume; several animal studies have shown that electrically induced seizures increase neurotropic factors, neurogenesis, and synaptic density in the hippocampasus’ dentate gyrus,

supporting the possibility that ECT produces similar alterations in the human brain (that are crucial for its therapeutic effect).

Indications for ECT Current evidence supports the use of ECT in the treatment of several neuropsychiatric illnesses: major depressive disorder (MDD); bipolar affective disorder (both manic and depressive episodes); schizophrenia (generally for acute exacerbations rather than chronic illness); and catatonia (of either organic or affective etiology). Although most psychiatric patients initially receive a trial of medications regardless of their diagnosis, ECT should be regarded as a first-line therapy for several categories of patients, including those with: severe mood symptoms that lead to risk of malnourishment or dehydration or in those at increased risk for suicide or violence; patients with medical conditions (e.g., cardiac arrhythmias, pregnancy); an inability to take oral antidepressant medication, that precludes the use of antidepressant medication; unresponsiveness to medications during previous episodes or a positive response to ECT in the past; and excited and malignant presentations of catatonia and neuroleptic malignant syndrome. ECT has also been helpful in alleviating motor symptoms of Parkinson’s disease; behavioral disturbances associated with severe dementia, complex pain syndromes, intractable epilepsy, status epilepticus, and intra-ictal psychosis, with co-morbid depression.

Risk Factors and Adverse Events With the refinement of ECT and careful management of anesthesia, factors that were formerly considered absolute contraindications to ECT have become relative risk factors. However, careful weighing of the risks of treatment against the morbidity and lethality of presenting symptoms must occur in all situations, and a careful work-up and pre-treatment management should be undertaken. By reviewing the usual physiologic effects of ECT, two major areas of concern (cardiovascular and cerebrovascular) become clear.

Cardiovascular Conditions Autonomic hyperactivity associated with ECT leads to prominent cardiovascular effects. Parasympathetic discharge predominates initially and can cause bradycardia, premature ventricular contractions, or even several seconds of asystole. Subsequently, sympathetic outflow from the diencephalon, through

the spinal sympathetic tract, to the heart, further prolonged by a rise in the circulating catecholamines, leads to hypertension and tachycardia. After the seizure, parasympathetic tone remains strong, often causing transient bradycardia, with return to baseline function after 5 to 10 minutes. Patients with coronary artery disease, hypertension, ischemic heart disease, congestive heart failure, or cardiac arrhythmias deserve special attention. If properly managed, these conditions should not increase morbidity during ECT. Use of short-acting intravenous (IV) beta-blockers can effectively reduce the risk of complications. Patients with cardiac pacemakers are known to tolerate ECT; however, as a safety precaution a magnet should be available to convert the pacemaker from its demand mode to a fixed mode in the unlikely event of pacemaker inhibition and symptomatic bradycardia. The current recommendation for patients with an automatic implantable cardioverter defibrillator (AICD) include turning off the AICD during ECT.

Cerebrovascular Effects Changes in cerebrovascular dynamics can be equally dramatic. Cerebral oxygen consumption doubles, cerebral blood flow rises up to 400%, and as a result, increases in intracranial pressure and blood-brain barrier permeability are seen. Patients with space-occupying intracerebral lesions warrant close attention; if present, measures to reduce edema and intracranial pressure should be taken when ECT is administered. The most common intracranial risk factor is recent cerebral infarction. Retrospective reviews of ECT after recent cerebral infarction indicate that, when the treatment is properly performed, the complication rate is low. Finally, patients with a history of intracranial aneurysms are at a higher risk for complications with ECT, and tight control of cardiovascular stability (via blood pressure monitoring with an arterial line, and use of nitrates) should be targeted.

Respiratory Complications ECT is considered safe in patients with chronic obstructive pulmonary disease (COPD) and asthma; recent guidelines recommend the administration of prescribed inhalers on the morning of ECT. Risk for aspiration exists with all patients, and those with a history of gastroesophageal reflux disease are at higher risk. In general, patients should not have food for at least 6 hours prior to ECT.

ECT and Pregnancy

ECT can be safely administered during pregnancy. In preparation for the procedure, clinicians should perform a pelvic examination, discontinue nonessential anticholinergic medications, perform uterine tocodynamometry, hydrate with IV fluids, and administer adequate antacid therapy. During ECT, the pregnant woman’s right hip should be elevated, external fetal cardiac monitoring should be instituted, the patient should be intubated, and excessive hyperventilation avoided.

Clinical Efficacy Despite having being developed for the treatment of schizophrenia, ECT has been studied predominantly for the treatment of mood disorders. Although ECT remains effective for a wide variety of neuropsychiatric illnesses, the most rigorous clinical evidence exists for its use in treating MDD.

Depression A systematic meta-analysis reported the probability, in terms of odds ratios, that the positive response to ECT was approximately five times greater than with simulated ECT or placebo, and four times greater than with the antidepressant drugs. The overall response rate for ECT is approximately 75% to 90%. The severity of the mood symptoms, risk of suicide or violence, past psychotherapy, medication failures, past response to ECT, and the patient’s inability to tolerate medication trials are important considerations in the decision to move forward with ECT. Although ECT is highly effective for acute treatment of MDD, evidence shows that without active treatment, up to 84% of remitted patients relapse within 6 months after ECT, and even with continued medication treatment, patients show relapse rates as high as 60% (Sackheim et al, 2001); for this reason, the use of ECT as a maintenance treatment has been explored. One retrospective study showed that patients who received maintenance ECT along with medications had a 93% probability of surviving without relapse or recurrence at 2 years as compared to 52% for those who received only antidepressants (Gagne et al, 2000). Other suggested strategies to prevent relapse include tapering ECT over the course of several months, or starting a medication during the initial ECT treatment and following it with the addition of an augmentating agent (e.g., lithium). ECT, alone and in combination with a neuroleptic, can help patients with chronic schizophrenia, whose symptoms have persisted despite adequate medication trials. Furthermore, in young adults with intractable first-episode

schizophrenia and schizophreniform disorder, ECT was a highly efficacious treatment (Lally et al, 2016). In controlled trials, ECT has been at least as effective as lithium, in the treatment of acute mania, and an effective and safe choice for those with mixed affective states (Mukherjee et al, 1988; Palma et al, 2016). ECT has proven effective in the treatment of catatonia with response rates of 85% to 93% (Raveendranathan et al, 2012), and should be the treatment of choice for those patients who fail to achieve full resolution with pharmacotherapy. ECT is considered a definitive treatment for excited catatonia and delirious mania, and it can be a life-saving treatment in cases of malignant catatonia or neuroleptic malignant syndrome. Finally, ECT has been helpful in alleviating behavioral disturbances associated with severe dementias, motor symptoms of Parkinson’s disease, behavioral symptoms of Huntington disease, and in controlling pain syndromes in patients with co-morbid depression.

Practical Aspects of ECT Pre-Treatment Evaluation A thorough pre-ECT evaluation is essential to the safety and efficacy of this procedure. This is routinely conducted in association with an anesthesiologist; the evaluation includes a complete medical and psychiatric history, a full physical exam, a complete blood count, an electrolyte determination, an electrocardiogram (EKG), and a chest X-ray. Other tests might be indicated depending on the patient’s underlying medical condition and current medications. The goal is to stabilize the patient’s medical condition prior to ECT. This evaluation is also helpful in determining the proper setting for ECT treatments. Patients whose psychiatric symptoms preclude safe and effective management on an outpatient basis, or those who are at high risk of serious medical complications should be treated in an inpatient setting.

Informed Consent As with any procedure, informed consent must be obtained from the patient before initiation of ECT. More than just a medico-legal formality, the process of informed consent is an opportunity for the psychiatrist to fully explain the risks and benefits of the procedure, and for the patient to ask questions. Both aspects of this procedure help to allay patient anxiety, to improve the patient-doctor rapport, and to increase satisfaction with the treatment. Videotapes and

information sheets can help augment, but do not supplant, the process of informed consent.

Patient Care ECT is generally administered in the early morning hours. As with any procedure requiring general anesthesia, patients should be kept NPO for the at least six hours prior to ECT, and should avoid use of hair spray or cream (that could produce shorting of the electrical current) and nail polish (that could interfere with pulse oximetry). The patient’s mouth should be checked for foreign bodies and loose or sharp teeth; dentures should be removed unless specially indicated.

Use of Concurrent Medications Before starting ECT, all medications taken by the patient should be reviewed, to avoid potential adverse effects and interactions. The matter of discontinuing psychotropic medications has been controversial, but nowadays in the large majority of cases, these are continued or simply adjusted. Use of some specific medications (e.g., monoamine oxidase inhibitors [MAOIs], lithium, antiepileptic drugs, benzodiazepines) requires further discussion.

Monoamine Oxidase Inhibitors Historically , the recommendation had been to discontinue MAOIs prior to ECT to avoid potential drug-drug interactions during the procedure; however, a case series and reviews of the literature have concluded that use of a MAOI while undergoing ECT is a viable and safe option for patients who have benefitted from this combination, and occurrence of complications or adverse events has been rare (Dolenc and Rasmussen, 2005).

Lithium Patients taking lithium while undergoing ECT are at higher risk for developing severe cognitive disturbance, delirium, prolonged apnea, and spontaneous seizures. However, several case reviews and prospective comparative studies have challenged this notion. Overall, clinicians should carefully weigh the risks of neurotoxicity against the risks of mania and depressive relapse in patients with severe mood disorders.

Antiepileptics

Antiepileptics are not contraindicated with ECT, though they will require clinicians to use a more potent electrical stimulus to induce a therapeutic seizure. For those patients with a preexisting seizure disorder, it is probably safest to continue the medication and simply use a higher-intensity stimulus. For those receiving anticonvulsants for mood stabilization, it is reasonable to lower the dose or to discontinue anticonvulsants during a course of ECT; for those receiving maintenance ECT, withholding one or two dosages of the medication prior to the treatment is probably sufficient.

Benzodiazepines These medications also raise the seizure threshold and can increase the degree of post-ictal confusion, particularly in the elderly. Therefore, they are usually withheld during ECT. Pre-ECT anxiety or insomnia can often be managed using a small dose of a neuroleptic or a non-benzodiazepine hypnotic, such as diphenhydramine.

Anesthesia During ECT The anesthetic goals for ECT are three-fold: rapid induction with amnesia, prevention of injury from tonic–clonic seizures, and attenuation of the sympathetic response to ECT.

Rapid Induction with Amnesia Methohexital has been the agent of choice for induction of anesthesia for ECT. It is ideal for this procedure because it has a rapid onset and a short duration of action, while having little effect on the seizure threshold. The usual IV dose is between 0.5 and 1.0 mg/kg. In recent years, alternative anesthetic agents have gain some attention. Propofol has been associated with a reduction in the magnitude of hemodynamic changes accompanying ECT, and a tendency toward improved cognitive performance after anesthesia. Several case reports have documented the potential usefulness of ketamine as an anesthetic option during ECT, highlighting antidepressant benefits and attenuation of cognitive side effects; however, the evidence is still limited to fully support it’s use.

Prevention of Injury from Tonic–Clonic Seizures Although curare was the first muscle relaxant used in the modification of ECT, succinylcholine is now the most commonly used agent. Its popularity is based on its rapid onset, lack of effect on seizure threshold, and its relatively low cost. For

situations in which succinylcholine is contraindicated (i.e., pseudocholinesterase deficiency, prolonged immobilization, hypercalcemia, severe neuromuscular disease, family history of malignant hyperthermia, widespread burns), nondepolarizing muscle relaxants should be the agents of choice.

Attenuation of the Sympathetic Response to ECT In patients with pre-existing cardiovascular pathology, for whom tachycardia or hypertension might be life-threatening, pre-treatment with beta-blockers to attenuate the sympathetic response to ECT might be indicated. Labetolol (10-20 mg IV) or esmolol (100–200 mg IV) prior to induction of anesthesia have both been used for this purpose. Its use, however, should be carefully balanced because potential additive adverse effects with ECT can occur. As discussed earlier, the electrical stimulus will result in a parasympathetic response via vagus nerve stimulation; in the presence of a beta-blocker agent, bradycardia resulting from unopposed parasympathetic discharge (i.e., during sub-convulsive electrical stimulation) could transform into asystole.

Seizure Administration Electrode Placement Two standard electrode placements are currently employed for the delivery of electricity to the brain. In unilateral placement (d’Elia placement), both electrodes are placed over the same hemisphere, typically the non-dominant right side. With a bilateral placement, the electrodes are positioned symmetrically over the fronto-temporal areas.

Stimulus Intensity Current ECT devices deliver a constant-current, brief-pulse stimulus of electricity (0.5–1 ms), an advance that has helped to minimize the degree of cognitive dysfunction. The ability to elicit a seizure is necessary, but not always sufficient for antidepressant effect. The average number of ECT procedures necessary to treat MDD is between 6 and 12, administered on a three-times-perweek schedule. Patients treated with bilateral ECT should receive a stimulus 50% to 150% above the seizure threshold (1.5–2.5 times threshold), whereas patients undergoing right unilateral ECT index course, should received a markedly supra-threshold stimulation, in the range of 150% to 500% above seizure threshold (2.5–6 times the threshold) (Sackheim et al, 2000). Newer

ultra-brief pulse-width (0.3 ms) ECT, is slightly less efficacious than brief-pulse treatment, but it can greatly minimize cognitive side effects (Tor et al, 2015). Different methods are used to determine an individual’s stimulus intensity. Empirical stimulus dose-titration provides the most precise method for quantifying seizure threshold. It consists of administering an initial dosage expected to be sub-convulsive in the majority of patients, and progressively increasing the stimuli intensity until a sustained motoric or electroencephalographic manifestation of a seizure occurs. Repeated subconvulsive stimulation can result in marked bradycardia, therefore, premedication with an anticholingergic agent is required. Alternatively, others have proposed an age-based estimation method, which consists of using the patient’s age in years expressed as a percentage of 504 millicoulombs (mC). This spares patients from being exposed to repeated sub-convulsive stimulations; however, some researchers have found that it also could result in sub-optimal dosing for more than 50% of patients.

Seizure Properties To be effective, the induced seizure must generalize and be bilateral. Contrary to common belief, it is the degree to which the stimulus intensity exceeds seizure threshold, and not the absolute dose or the seizure duration, that determines the efficacy of the treatment. With the use of muscle relaxants, psychiatrists can no longer simply observe the convulsing patient to assess the characteristics of the seizure. EEG monitoring is used to determine the nature of the induced seizure. In other cases, an inflated blood pressure cuff is placed on a single extremity during the administration of succinylcholine. In this fashion, the isolated limb remains unaffected by the muscle relaxant and can be observed to convulse during the seizure.

Complications Mortality ECT is considered a safe procedure. One study on mortality related to ECT in the United States, reported with only one death that was specifically linked to ECT and four additional deaths thought to be associated with 49,048 ECT treatments (Shiwach et al, 2001). A more recent review, found no causal connection between ECT and death in 99,728 treatments (Ostergaard et al, 2014).

Cardiovascular The cardiovascular complications were discussed previously.

Cognitive The cognitive side effects of ECT have been both overdramatized by detractors as well as under-researched by clinicians. Evidence indicates that ECT does not cause any structural damage to the brain, and in fact it possesses neuroprotective properties and increases hippocampal and amygdala gray-matter volume. However, cognitive dysfunction is real and careful explanation of the major types of cognitive disturbance can help alleviate patient concerns about this dread complication.

Post-Treatment Confusion A brief (15–30 minutes) period of confusion, characterized by restlessness, disorientation, panic-like behavior, and combativeness, can be seen in up to 12% of patients immediately following treatment. Bilateral electrode placement, high stimulus intensity, inadequate oxygenation, and prolonged seizure activity are known risk factors. Older patients and those with neurological diseases are at higher risk.

Delirium Confusion associated with EEG slowing commonly causes treatment discontinuation or delay. Its specific cause is unclear, but seems to be more common in the elderly, in patients with pre-existing dementia or neurological impairment, and with the use of bilateral ECT. With cessation of ECT, delirium generally clears within days to weeks.

Memory Loss ECT is associated with both anterograde and retrograde memory impairment. As with ECT-related delirium, memory impairment is more severe with bilateral ECT.

Anterograde Amnesia During the course of ECT, the ability to learn new information is impaired, leading to anterograde-type amnesia. This difficulty persists for a short while after ECT, returning to normal between two to six months post-ECT.

Retrograde Amnesia

Loss of memory for events prior to ECT can also occur. In general, this is more severe for events closest to the time of treatment (i.e., events leading up to hospitalization) than for remote events. Usually, recall might be impaired for events during the previous six months, though memory disturbance for events occurring up to 2 years before ECT might be reported. For many patients, this is the most significant side effect of ECT.

Prolonged Seizures Prolonged seizures (i.e., seizures lasting more than 3 minutes) can result from inadequate oxygenation of the brain (increasing cognitive side effects). These events are rare and its occurrence might be linked to hyper-oxygenation, preexisting states of cerebral hyper-excitability, and medications that lower the seizure threshold. When they occur seizures should be terminated by administration of an anesthetic agent with anticonvulsant properties (e.g., propofol) or a benzodiazepine.

Other Side Effects Headache is a common side effect of ECT. It particularly affects younger patients and patients with pre-existing headache disorders. Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) provide effective treatment, and in refractory cases, patients have been successfully treated with oral sumatriptan. Myalgias related to excessive motor activity during the convulsion and the fasciculations induced by succinylcholine occur in many patients undergoing ECT. Adjusting the dose of the muscle relaxant or pre-medicating with IV ketorolac is often helpful in preventing this side effect. Finally, nausea and vomiting can occur in up to 20% of patients and it may be related to anesthetic agents and ECT or be associated with post-ECT headache. Dopamineblocking agents and a 5-HT3 receptor antagonist have been effective controlling ECT-associated nausea.

Conclusion ECT is the oldest biological treatment still used by today’s psychiatrist. Though other treatments have better side effect profiles, ECT retains an important niche in the treatment of affective illness.

References

1. Baldinger P, Lotan A, Frey R, et al: Neurotransmitters and electroconvulsive therapy. J ECT . 2014, 30: 116–121. 2. Bolwig TG: Neuroimaging and electroconvulsive therapy: a review. J ECT . 2014 Jun; 30(2): 138–142. 3. Bouckaert F, Sienaert P, Obbels J, et al: ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity. J ECT . 2014 Jun; 30(2): 143–151. 4. Detweiler MB, Mehra A, Rowell T, et al: Delirious mania and malignant catatonia: a report of 3 cases and review. Psychiatr Q . 2009; 80(1): 23–40. 5. Dolenc TJ, Barnes RD, Hayes DL, et al: Electroconvulsive therapy in patients with cardiac pacemakers and implantable cardioverter defibrillators. Pacing Clin Electrophysiol . 2004; 27(9): 1257–1263. 6. Dolenc TJ, Rasmussen KG: The safety of electroconvulsive therapy and lithium in combination: a case series and review of the literature. J ECT . 2005; 21(3): 165–170. 7. Fantz RM, Markowitz JS, Kellner CH: Sumatriptan for post-ECT headache. J ECT . 1998; 14(4): 272–274. 8. Fink M: Energy dosing in ECT: threshold stimulation or formula? Convuls Ther . 1997; 13(1): 4–6. 9. Gagné GG, Jr, Furman MJ, Carpenter LL, et al: Efficacy of continuation ECT and antidepressant drugs compared to long-term antidepressants alone in depressed patients. Am J Psychiatry . 2000; 157(12): 1960–1965. 10. Gálvez V, McGuirk L, Loo CK: The use of ketamine in ECT anaesthesia: A systematic review and critical commentary on efficacy, cognitive, safety and seizure outcomes. World J Biol Psychiatry . 2016 Nov; 28:1–21. 11. Geretsegger C, Nickel M, Judendorfer B, et al: Propofol and methohexital as anesthetic agents for electroconvulsive therapy: a randomized, doubleblind comparison of electroconvulsive therapy seizure quality, therapeutic efficacy, and cognitive performance. J ECT . 2007; 23(4): 239–243. 12. Guloksuz S, Rutten BP, Arts B, et al: The immune system and electroconvulsive therapy for depression. J ECT . 2014 Jun; 30(2): 132–7. 13. Haskett RF: Electroconvulsive therapy’s mechanism of action: neuroendocrine hypotheses. J ECT . 2014 Jun; 30(2): 107–110. 14. Hurtado AM, Fernandez-Robles C, Cusin C, et al: Electroconvulsive

15.

16. 17.

18.

19.

20. 21.

22. 23. 24. 25.

26.

therapy and neurotherapeutics. In: Stern TA, Freudenreich O, Smith FA, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 7th ed. Philadelphia: Elsevier: 2018. Kamel H, Cornes SB, Hegde M, et al: Electroconvulsive therapy for refractory status epilepticus: a case series. Neurocrit Care . 2010; 12(2): 204–210. Kelly KG, Zisselman M: Update on electroconvulsive therapy (ECT) in older adults. J Am Geriatr Soc . 2000; 48(5): 560–566. Kennedy R, Mittal D, O’Jile J: Electroconvulsive therapy in movement disorders: an update. J Neuropsychiatry Clin Neurosci . 2003; 15(4): 407– 421. doi: 10.1176/jnp.15.4.407. Kurnutala LN, Kamath S, Koyfman S, et al: Aspiration during electroconvulsive therapy under general anesthesia. J ECT . 2013 Dec; 29(4): e68. Lally J, Tully J, Robertson D, et al: Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: A systematic review and meta-analysis. Schizophr Res . 2016; 171(1–3): 215–224. MacPherson RD, Loo CK, Barrett N: Electroconvulsive therapy in patients with cardiac pacemakers. Anaesth Intensive Care . 2006; 34(4): 470–474. Merkl A, Heuser I, Bajbouj M: Antidepressant electroconvulsive therapy: mechanism of action, recent advances and limitations. Exp Neurol . 2009 Sep; 219(1): 20–26. Miller LJ: Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry . 1994; 45(5): 444–450. Mueller PS, Schak KM, Barnes RD, et al: Safety of electroconvulsive therapy in patients with asthma. Neth J Med . 2006; 64(11): 417–421. Mukherjee S, Sackeim HA, Lee C: Unilateral ECT in the treatment of manic episodes. Convuls Ther . 1988; 4(1): 74–80. National Institute of Mental Health (NIMH) Washington, DC: NIMH; 2008. [January 12, 2009]. The numbers count: Mental disorders in America. Available at http://www.nimh.nih.gov/health/publications/the-numberscount-mental-disorders-in-america.shtml#Intro. Ostergaard SD, Bolwig TG, Petrides G: No causal association between electroconvulsive therapy and death: a summary of a report from the

Danish Health and Medicines Authority covering 99,728 treatments. J ECT . 2014; 30(4): 263–264. 27. Pagnin D, de Queiroz V, Pini S, et al: Efficacy of ECT in depression: a meta-analytic review. J ECT . 2004; 20(1): 13–20. 28. Palma M, Ferreira B, Borja-Santos N, et al: Efficacy of electroconvulsive therapy in bipolar disorder with mixed features. Depress Res Treat . 2016. 29. Philbrick KL, Rummans TA: Malignant catatonia. J Neuropsychiatry Clin Neurosci . 1994; 6(1): 1–13. 30. Pompili M, Lester D, Dominici G, et al: Indications for electroconvulsive treatment in schizophrenia: a systematic review. Schizophr Res . 2013; 146(1-3): 1–9. doi: 10.1016/j.schres.2013.02.005. 31. Rasmussen KG, Perry CL, Sutor B, et al: ECT in patients with intracranial masses. J Neuropsychiatry Clin Neurosci . 2007; 19(2): 191–193. 32. Rasmussen KG, Petersen KN, Sticka JL, et al: Correlates of myalgia in electroconvulsive therapy. J ECT . 2008; 24(1): 84–87. 33. Raveendranathan D, Narayanaswamy JC, Reddi SV: Response rate of catatonia to electroconvulsive therapy and its clinical correlates. Eur Arch Psychiatry Clin Neurosci . 2012; 262(5): 425–430. 34. Romanowicz M, Sutor B, Sola C: Safety and efficacy of electroconvulsive therapy for depression following cerebrovascular accident. Acta Neuropsychiatr . 2012; 24(4): 226–229. 35. Sackeim HA, Devanand DP, Prudic J: Stimulus intensity, seizure threshold, and seizure duration: impact on the efficacy and safety of electroconvulsive therapy. Psychiatr Clin North Am . 1991; 14(4): 803–843. 36. Sackeim HA, Haskett RF, Mulsant BH, et al: Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA . 2001; 285(10): 1299–1307. 37. Sackeim HA, Prudic J, Devanand DP, et al: A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry . 2000; 57(5): 425–434. 38. Sackheim HA: Central issues regarding the mechanisms of action of electroconvulsive therapy: Directions for future research. Psychopharmacol Bull . 1994; 30 (3): 281–308.

39. Saito S: Anesthesia management for electroconvulsive therapy: hemodynamic and respiratory management. J Anesth . 2005; 19(2): 142– 149. 40. Sartorius A, Demirakca T, Bohringer A, et al: Electroconvulsive therapy increases temporal gray matter volume and cortical thickness. Eur Neuropsychopharmacol . 2016; 26(3): 506–517. doi: 10.1016/j.euroneuro.2015.12.036. 41. Schak KM, Mueller PS, Barnes RD, et al: The safety of ECT in patients with chronic obstructive pulmonary disease. Psychosomatics . 2008; 49(3): 208–211. 42. Shiwach RS, Reid WH, Carmody TJ: An analysis of reported deaths following electroconvulsive therapy in Texas, 1993–1998. Psychiatr Serv . 2001; 52(8): 1095–1097. 43. Sutor B, Rasmussen KG: Electroconvulsive therapy for agitation in Alzheimer disease: a case series. J ECT . 2008; 24(3): 239–241. doi: 10.1097/YCT.0b013e3181587416. 44. Tendolkar I, van Beek M, van Oostrom I, et al: Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study. Psychiatry Res . 2013; 214(3): 197– 203. doi: 10.1016/j.pscychresns.2013.09.004. 45. Thirthalli J, Harish T, Gangadhar BN: A prospective comparative study of interaction between lithium and modified electroconvulsive therapy. World J Biol Psychiatry . 2011; 12(2): 149–155. 46. Tiller JW, Ingram N: Seizure threshold determination for electroconvulsive therapy: stimulus dose titration versus age-based estimations. Aust N Z J Psychiatry . 2006; 40(2): 188–192. 47. Tor PC, Bautovich A, Wang MJ, et al: A systematic review and metaanalysis of brief versus ultrabrief right unilateral electroconvulsive therapy for depression. J Clin Psychiatry . 2015; 76(9): e1092–1098. 48. Vaidya PV1, Anderson EL, Bobb A, et al: A within-subject comparison of propofol and methohexital anesthesia for electroconvulsive therapy. J ECT . 2012 Mar; 28(1): 14–19. 49. Wasan AD, Artin K, Clark MR: A case-matching study of the analgesic properties of electroconvulsive therapy. Pain Med . 2004 Mar;

5(1): 50–58. 50. Weiner RD, Volow MR, Gianturco DT, et al: Seizures terminable and interminable with ECT. Am J Psychiatry . 1980; 137(11): 1416–1418. 51. Weiner RD: Stimulus dosing with ECT: to titrate or not to titrate—that is the question. Convuls Ther . 1997; 13(1): 7–9. 52. Wilkinson ST, Helgeson L, Ostroff RB: Electroconvulsive therapy and cerebral aneurysms. J ECT . 2014 Dec; 30(4): e47–49.

CHAPTER Neurotherapeutics 51 TRACY A. BARBOUR, MD AND JOAN A. CAMPRODON, MD, MPH, PHD

KEY POINTS Transcranial Magnetic Stimulation: Overview: Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulatory therapy that uses powerful, rapidly-changing magnetic fields to cause changes in neural excitability when applied over the surface of the skull without inducing a seizure. Theoretical Basis: TMS is based on Faraday’s principle of electromagnetic induction, and it can modulate cortical excitability and network connectivity therapeutically. Indication and Clinical Application: Repetitive TMS (rTMS) was FDAcleared in 2008 for treatment of treatment-resistant major depressive disorder without psychotic features. In 2013, the use of deep TMS H-coils was also approved for the same indication. A course of TMS treatment usually consists of 5 days of treatment per week for 6 weeks. Traditional therapeutic protocols last approximately 20 to 40 minutes. Vagal Nerve Stimulation Overview: Vagal nerve stimulation (VNS) is an invasive neuromodulatory treatment that involves electrical stimulation of the left vagus nerve. Theoretical Basis: The vagal nerve projects to many limbic and cortical areas. In depression, VNS is thought to normalize metabolic hyperactivity in regions of the brain that regulate mood as well as affect areas of the brain associated with norepinephrine and serotonin-mediated systems. Indication and Clinical Application: VNS was FDA-cleared in 2005 for adjunctive treatment of adults with chronic or recurrent major depressive disorder or bipolar depression who have failed to respond to at least four different adequate medication trials and/or ECT.

Deep Brain Stimulation Overview: Deep brain stimulation (DBS) in an invasive neuromodulatory technique that uses stereotactically-implanted electrodes in disease-relevant brain regions, connected to a permanently-implanted, battery-powered internal pulse generator, to change neural activity. Theoretical Basis: While the mechanism of DBS is not fully understood, it is believed to inhibit pathological brain activity in the target of stimulation, and to normalize pathologic activity and connectivity within diseased neural circuits. Indication and Clinical Application: DBS of the ventral capsule/ventral striatum was FDA-approved for the treatment of severe, therapy- and medication-resistant, obsessive-compulsive disorder (OCD) in 2009. Ablative Limbic Surgery Overview: An invasive treatment that involves the application of small, targeted lesions in key diseased brain regions via surgical intervention or radiation therapy. Theoretical Basis: By disrupting pathologic activity in fronto-limbic circuits psychosurgery normalizes activity in affected brain regions and circuits. Indications and Clinical Applications: Currently, ablative treatments are reserved for severe, incapacitating OCD and/or MDD that has failed to benefit from exhaustive use of conventional treatments.

Overview and Classification Neurotherapeutic treatments (often referred to as somatic therapies, neuromodulation, or brain stimulation) are a group of device-based treatments that modulate the maladaptive physiology of pathologic brain regions and circuits (Psychiatric Neurotherapeutics – Contemporary Surgical and | Joan Camprodon | Springer , n.d.). These therapies are based on recent advances in neuroscience that have emphasized the role of neural circuits in the healthy brain and when psychopathology has been detected. Somatic therapies can be divided into invasive, convulsive, and non-invasive methods. Invasive modalities involve surgical procedures, and include vagal nerve stimulation, deep brain stimulation, and ablative surgery. Convulsive techniques include electroconvulsive therapy (ECT) and magnetic seizure therapy (MST, still experimental). Non-invasive techniques include transcranial

magnetic stimulation and transcranial direct current stimulation (tDCS, also in experimental stages). Although many patients with psychiatric illness respond to pharmacologic and psychotherapeutic treatment, a significant number of patients do not obtain sufficient symptomatic relief from these options. For example, based on the STAR*D data, approximately 50% of patients with unipolar depression fail to respond to the initial antidepressant, and an estimated 35% fail to respond after two courses of adequate treatment (Rush et al, 2009). Furthermore, only 35% to 45% of patients achieve remission with antidepressant treatment. Thus, there is a significant need to develop and utilize novel, yet validated, therapies for individuals who have a poor response to medication and therapy. Here, we focus on invasive and non-invasive neuromodulatory techniques that are widely used and cleared by the United States Food and Drug Administration (FDA) for a number of indications. ECT is discussed in Chapter 50 .

Transcranial Magnetic Stimulation Definition and Basic Principles Transcranial magnetic stimulation (TMS) is a non-invasive and non-convulsive neuromodulatory therapy that uses powerful, rapidly changing magnetic fields to cause changes in neural excitability and connectivity when applied over the surface of the skull. Since its introduction in 1985 (Barker et al, 1985) the use of TMS as a treatment, diagnostic, and research tool in Psychiatry, Neurology, and Neuroscience has greatly expanded. This growth is largely related to its noninvasive nature, as well as our ability to selectively stimulate or inhibit neural excitability in a parameter-dependent manner. TMS is based on Faraday’s principle of electromagnetic induction, which (overly simplified) states that a rapidly-changing electrical current flowing through a circular circuit will generate a magnetic field, and this magnetic field, when it interacts with a conductive material (e.g., a pick-up coil), will turn into a secondary electrical current (Barker et al, 1985). A basic TMS system consists of an electrical capacitor and a metal coil (usually made of copper), encased in a protective plastic cover. As electricity passes from the capacitor through the metal coil, a magnetic field is generated with a primary vector perpendicular to the plane of the coil. If the coil is placed on the surface of the scalp, this magnetic field moves unimpeded toward the intracranial space through the scalp and skull until it reaches the electrically conductive cortical neurons, which act

as a pick-up coil and allow magnetic energy to be converted back into electrical energy. This electrical current causes a change in membrane polarization, inducing an action potential in cortical neurons, which is transmitted transsynaptically through a given functional brain circuit. The direct neuromodulatory effects of TMS are limited to superficial cortical neurons: the magnetic field diminishes in intensity as it travels away from its source (the TMS coil), and it can induce action potentials only in neurons that lie within approximately 3 centimeters of the coil (that is the distance from the surface of the skull to the underlying cortex in humans). However, the targeted superficial cortical neurons propagate action potentials to post-synaptic neurons, leading to widespread changes within brain regions that are functionally connected in a circuit (Camprodon and Pascual-Leone, 2016). Thus, TMS allows for indirect trans-synaptic modulation of deep cortical and sub-cortical structures when the appropriate cortical target is selected, and its effects are at the level of entire brain networks and not just brain regions.

Treatment Parameters A number of technical parameters are important from a neurobiological and clinical perspective: location, focality, depth, frequency, pulse intensity, and duration (number of pulses in a session and number of sessions in a course of treatment) (see Table 51-1). The first three are anatomical, whereas the last three are physiological. Location is key because it determines the cortical target that will be directly stimulated and provides a window of modulatory access to a disease-relevant circuit of interest. After a neural target is determined, important anatomical considerations include stimulation focality and depth. These parameters are primarily determined by the choice of an appropriate TMS coil, although the intensity of stimulation is also important. Different coil characteristics (e.g., size, angle) determine the depth of penetration and the focality of the electrical field. Generally, coils have a depth-focality tradeoff: the deeper the magnetic field penetration, the larger the area of stimulation becomes. Depth and focality are important factors to consider when modulating activity of a target region without affecting non-targeted regions. After the anatomical aspects are taken into account, parameters that affect neural excitability and connectivity are determined. Depending on the frequency of magnetic pulses, populations of neurons can either be activated (high-frequency stimulation: ≥ 5 Hz) or inhibited (low-frequency stimulation: 1 Hz). Stimulation intensity is generally individualized based on the cortical excitability of each patient, as

determined by measuring the resting motor threshold (MT). The MT is the lowest stimulation intensity of a TMS pulse to the primary motor cortex (M1) needed to cause muscle contraction in the contralateral hand (usually the first dorsal interoseus or abductor pollicis brevis muscle) 50% of the time. The number of pulses per session and number of sessions in a treatment course will determine the duration of TMS treatment. The standard TMS antidepressant protocol applies high-frequency (10 Hz) TMS over the left dorsolateral prefrontal cortex at 120% of the individual MT intensity, and uses 3,000 pulses per session. An acute treatment course of TMS usually consists of 5 weekly sessions (conducted daily Monday through Friday) for 6 weeks, and is generally followed by a taper of two weekly sessions during three weeks. Table 51-1: TMS Treatment Parameters Parameter Anatomical Variable

TMS Variable

Location

Which pathological brain region/circuit is the target?

The target must be within range of the magnetic field generated by the TMS coil.

Depth

Distance of the target from the scalp

The coil type and pulse intensity effect the depth of penetration.

Focality

Size of target region

The coil type and pulse intensity effect the size of cortical surface area effected.

Parameter Physiologic Variable

TMS Variable

Frequency

Low frequency pulses (1 Hz) inhibit target regions, whereas, high frequency pulses (5–20 Hz) stimulate the target regions

Is the goal to inhibit or stimulate the target region?

Pulse Intensity Baseline cortical excitability

Commonly defined as a percentage of the individual’s motor threshold. The goal is to use a pulse intensity large enough to cause the desired physiologic change without increasing risk of seizures or discomfort to the patient.

Duration

The number of pulses per session determine how long a session lasts. The number of sessions needed determines how many weeks an acute treatment will last.

The number of pulses needed per session, and number of sessions needed to see the desired changes in circuit behavior

Safety TMS is a safe and well tolerated procedure. No long-term neurological, cognitive, or cardiovascular side effects have been reported. However, international safety guidelines should be followed because there is the potential for side-effects (Rossi et al, 2009). Absolute contraindications are limited to

metallic implants in the head and neck (e.g. surgical brain stimulators or brain aneurysm clips); some practitioners also consider cardiac pacemakers to be a contraindication. Seizures have been reported during TMS treatments, although the risk is generally lower than that of commonly used antidepressant medications. Patients should be screened carefully for a personal history of seizures and for factors (such as certain medications, alcohol/substance use, or brain lesions) that increase the risk of a seizure. The presence of these risk factors is not an absolute contraindication for TMS, but it allows clinicians to provide an accurate assessment of risks and benefits and to plan for measures to minimize iatrogenic outcomes. During the treatment, patients remain awake and experience a tapping sensation on their head as well as hear a clicking noise (earplugs are commonly used during treatment). Other possible side effects include headache, facial muscle contraction or twitching, and rarely vasovagal syncope or hypomania in patients with a history of bipolar spectrum disorders.

Clinical Efficacy TMS has been shown to be effective as a primary or adjunctive treatment for depression. The pivotal randomized controlled trial (RCT) that led to the FDA clearance of therapeutic TMS (O’Reardon et al, 2007). demonstrated that TMS is an effective treatment for depression, even as monotherapy. Patients had a response rate of 23.9% to 24.5% (compared to 12.3%–15.1% for placebo) and remission rate of 14.2% to 17.4% (compared to 5.5%–8.9% for placebo) after 6 weeks of treatment. After the post-acute tapering period (6 additional sessions over 3 weeks) clinical outcomes continued to improve (27.7% response and 20.6% remission rate). However, this study did not recruit typical patients under typical conditions. Typical patients are more likely to have co-morbid psychiatric and medical problems, to have more severe and refractory mood disorders, and would not be likely to receive TMS monotherapy (but may be on multiple psychotropic medications). An open-label, naturalistic trial, aimed to assess TMS effectiveness in a typical clinical setting (including patients with treatmentrefractory depression and psychiatric and medical co-morbidities) enrolled 339 patients and used the same TMS protocol as that used in the pivotal RCT that led to FDA clearance. This study allowed patients to continue their current psychiatric treatment-as-usual (medication and therapy) while undergoing TMS. After acute treatment (6 weeks), the response rate was 41.5% to 58% and the remission rate was 26.5% to 37.1% (Carpenter et al, 2012). At one-year follow-

up, two-thirds of the responders/remitters maintained their designation, and less than 30% of the initial responders/remitters relapsed (Dunner et al, 2014).

Indications Repetitive TMS (rTMS) was FDA-cleared in 2008 for treatment of unipolar, treatment-resistant major depressive disorder (MDD) without psychotic features. In 2013, the use of deep TMS H-coils was also cleared for the same indication. In 2015, two new devices were cleared for the treatment of MDD. Smaller studies have determined the efficacy of TMS in other disorders (such as obsessive-compulsive disorder [OCD], schizophrenia, anxiety disorders) and stroke rehabilitation; however, there is no current clinical indication for these disorders; larger as well as controlled pivotal studies are needed.

Vagal Nerve Stimulation Definition and Basic Principles Vagal nerve stimulation (VNS) was initially cleared by the FDA for treatmentresistant epilepsy in 1997. Reports of improvement in mood symptoms among patients with vagal nerve stimulators, irrespective of whether seizures were controlled, led to pilot studies investigating it as an augmenting treatment for depression (Harden et al, 2000). Although the exact antidepressant mechanism of VNS has not been elucidated, it has been shown that this treatment reduces metabolic activity in the amygdala, hippocampus, and cingulate gyrus, all structures known to be involved in the regulation of mood. Other evidence points to the effects that VNS therapy has on regions associated with norepinephrine (Krahl et al, 1998). and serotoninmediated neural systems.

Treatment Parameters When administered, an electrode is surgically implanted at the left vagus nerve (Kosel and Schlaepfer, 2003) because the majority of its fibers are afferents to the brain from end-organs (the right vagus nerve shows the opposite pattern with most fibers being efferent). This electrode is connected by wires to an internal pulse generator (implanted subcutaneously in the sub-clavicular area) which sends intermittent electrical currents through the vagus nerve via the nucleus tractus solitarius to both cortical and limbic brain areas. VNS parameters include duty cycle, stimulation frequency, pulse width, and intensity. VNS is not applied continuously but intermittently, and a typical duty

cycle uses 30 seconds of stimulation every 5 minutes, though more aggressive cycles are used for non-responders. Typical frequency and pulse width are 20 Hz and 500 μS, respectively. Intensity generally ranges from 0 to 3 mA.

Safety Possible side effects include infection at the site of device implantation, a hoarse voice, cough, shortness of breath, and difficulty swallowing.

Clinical Efficacy It is important to note that VNS is an adjunctive treatment for chronic or recurrent depression, and it is not indicated as monotherapy. Studies have found that most patients do not show benefit within the first 10 weeks (Rush et al, 2005), but at 1 year. Patients with VNS have a 27% response rate on the Hamilton Rating Scale for Depression, compared to 12% in the treatment-asusual group. At 2 years, patients with VNS have a 42% response rate and a 22% remission rate. Of note, these studies used more conservative treatment parameters generally used for epilepsy, than typically used for MDD today (for example, the median intensity was 0.75 mA ranging from 0 to 1.5 mA, whereas intensities around or above 2 mA are commonly used safely). In retrospect, it is possible that these trials may have used sub-therapeutic stimulation.

Indication VNS is an invasive neuromodulation treatment that was FDA-cleared in 1997 for medication-resistant epilepsy, and in 2005 for adjunctive treatment of patients at least 18 years old with chronic or recurrent MDD or bipolar depression. Patients must have failed to respond to at least four different adequate medication trials and ECT.

Deep Brain Stimulation Definition and Basic Principles Deep brain stimulation (DBS) in an invasive neuromodulatory technique that uses stereotactically-implanted electrodes to change neural activity. These electrodes are connected to a permanently-implanted battery-powered internal pulse generator. DBS is FDA-cleared for the treatment of movement disorders (Parkinson’s disease, dystonia, and essential tremor) and OCD. Beyond OCD, there is a long history of clinical and translational research aimed at developing DBS for the treatment of psychiatric disorders (Larson, 2008): it has been

extensively studied for the treatment of MDD (Kaur et al, 2013) (though recent double-blind controlled trials were negative) and smaller studies are underway for other pathologies (Arulpragasam et al, 2013). DBS is an alternative to ablative therapy, as it offers focal, modifiable, and reversible neuromodulation of pathological brain regions. Although the mechanisms of DBS are not fully understood, it is believed to inhibit local pathological brain activity, leading to circuit-wide changes (Mayberg, 2009). In OCD, the therapeutic effect is thought to be related to disruption of pathological activity mediated by white-matter tracts between the thalamus and orbitofrontal cortex and between the caudate and the lenticular nucleus. This is supported by functional neuroimaging data that consistently shows hyperactive cortico-striatal-thalamo-cortical circuits in patients with OCD, and the ability of DBS to normalize activity within this network. Like all neurosurgical treatments for psychiatric conditions, DBS candidates are evaluated by a multidisciplinary team that includes neurosurgeons, psychiatrists, and neurologists and ensures that stringent inclusion criteria (related to severity and treatmentresistance) are met.

Treatment Parameters DBS involves surgical implantation of electrodes in disease-related brain regions. OCD typically requires electrode placement in the ventral capsule/ventral striatum. Other disorders require implantation in different nodes that are pathologically altered by the specific pathophysiology of each condition. For example, strategies to treat depression have implanted electrodes in the subgenual cingulate cortex, the ventral capsule/ventral striatum, or the nucleus accumbens (Kaur et al, 2013). Electrical signals are sent to the electrodes by an internal pulse generator located in the pectoral region, and connected by wires that travel through the sub-cutaneous tissue of the head and neck. Clinicians are able to change the parameters of the stimulation wirelessly to maximize symptom relief and minimize side effects. Patients are also able to control a limited number of parameters wirelessly (when a clinician allows) and to turn the system on or off.

Safety Possible side effects are divided into surgically-related, device-related, and stimulation-related effects. Surgical complications include bleeding and infection at the insertion site, headache, scalp tingling/numbness, and seizure. Device-

related side effects include feeling the extension leads (in the neck or ear area) and feeling the internal pulse generator in the chest (like a small disk under the skin). Stimulation-related effects include: hypomanic symptoms; anxiety; disinhibition; stomach ache; dizziness; nausea; throbbing; flushing; memory complaints; depressive symptoms; altered sexual functioning; and suicidal ideation.

Clinical Efficacy A recent meta-analysis of 31 studies involving 116 patients showed that 60% of people responded to treatment (more than 35% reduction in Yale-Brown Obsessive-Compulsive Scale [Y-BOCS]) with a global percentage of Y-BOCS reduction of 45.1%. In this meta-analysis, no significant differences in outcome were found between brain targets in the striatum (ventral capsule/ventral striatum, nucleus accumbens, anterior limb of the internal capsule, and ventral caudate nucleus) compared to the sub-thalamic nucleus (Arulpragasam et al, 2013). Responders were likely to have an older age of symptom onset and to have obsessions and compulsions of sexual and religious content. Clinical trials are currently assessing the safety and efficacy of DBS for the treatment of MDD and other neuropsychiatric conditions, including Tourette’s syndrome, addictions, eating disorders, and neuro-degenerative dementias.

Indication DBS of the ventral capsule/ventral striatum was FDA-approved for the treatment of severe therapy- and medication-resistant OCD in 2009. It also has indications for Parkinson’s disease, dystonia, and essential tremor.

Ablative Limbic System Surgery In the middle of the twentieth century, the use of the frontal and pre-frontal lobotomy was a crude treatment for a wide array of mental disorders. These procedures were associated with severe side effects, including frontal lobe dysfunction, apathy, and even death. However, today the application of small, targeted lesions can be life-saving in very severe, treatment-refractory cases of anxiety and mood disorders. Like DBS, ablative therapy targets specific brain regions with the goal of modulating brain function by disrupting pathologic activity between frontolimbic circuits (Greenberg et al, 2010). Unlike DBS, ablative therapy is permanent, thus, it is imperative to determine target location and lesion size

accurately. Targets are identified using magnetic resonance imaging (MRI), stereotactic instruments, and specialized software. Procedures in use are the anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and limbic leucotomy (Greenberg et al, 2010). Studies in depression and OCD show that approximately 35% to 70% of patients report at least partial benefit (Greenberg et al, 2010; Shields et al, 2008), and many have a reduction in suicidality. Side effects related to the surgery are often temporary and include headache and nausea, with more serious effects that include bleeding, infection, infarction, seizure, weight gain, and cognitive impairment. It is important to highlight that modern ablative procedures have a safety profile similar to DBS, without increased morbidity and mortality, and with a much simpler follow-up that does not require the sophisticated management of a DBS specialist.

Indication Currently, ablative treatments are reserved for severe, incapacitating OCD and MDD that have failed to benefit from exhaustively-applied conventional treatments. Indications also exist for movement disorders and refractory cases of chronic pain.

Suggested Readings 1. Arulpragasam AR, Chou T, Kaur N, et al: Future directions of deep brain stimulation: Current disorders, new technologies. Psychiatr Ann . 2013; 43: 366–373. doi: 10.3928/00485713-20130806-05. 2. Barker AT, Jalinous R, Freeston IL: Non-invasive magnetic stimulation of human motor cortex. Lancet Lond Engl . 1985; 1: 1106–1107. 3. Camprodon JA, Pascual-Leone A: Multi-modal applications of transcranial magnetic stimulation for circuit-based psychiatry. JAMA Psychiatry . 2016; doi: 10.1001/jamapsychiatry. 2015.3127. 4. Carpenter LL, Janicak PG, Aaronson ST, et al: Transcranial magnetic stimulation (TMS) for major depression: a multi-site, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety . 2012; 29: 587–596. doi: 10.1002/da.21969. 5. Dunner DL, Aaronson ST, Sackeim HA, et al: A multi-site, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-

year follow-up period. J Clin Psychiatry . 2014; 75: 1394–1401. doi: 10.4088/JCP.13m08977. 6. Greenberg BD, Rauch SL, Haber SN: Invasive circuitry-based neurotherapeutics: Stereotactic ablation and deep brain stimulation for OCD. Neuropsychopharmacology . 2010; 35, 317–336. doi: 10.1038/npp.2009.128. 7. Harden CL, Pulver MC, Ravdin LD, et al: A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav . 2000; 1: 93– 99. doi: 10.1006/ebeh.2000.0046. 8. Kaur N, Chou T, Corse AK, et al: Deep brain stimulation for treatmentresistant depression. Psychiatr Ann . 2013; 43: 358–365. doi: 10.3928/00485713-20130806-04. 9. Kosel M, Schlaepfer TE: Beyond the treatment of epilepsy: new applications of vagus nerve stimulation in psychiatry. CNS Spectr . 2003; 8: 515–521. 10. Krahl SE, Clark KB, Smith DC, Browning RA: Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia . 1998; 39: 709–714. 11. Larson PS: Deep brain stimulation for psychiatric disorders. Neurother J Am Soc Exp Neurother . 2008; 5: 50–58. doi: 10.1016/j.nurt.2007.11.006. 12. Mayberg HS: Targeted electrode-based modulation of neural circuits for depression. J Clin Invest . 2009; 119: 717–725. doi: 10.1172/JCI38454. 13. O’Reardon JP, Solvason HB, Janicak PG, et al: Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multi-site randomized controlled trial. Biol Psychiatry . 2007; 62: 1208–1216. doi: 10.1016/j.biopsych.2007.01.018. 14. Rossi S, Hallett M, Rossini PM, et al: Safety of TMS Consensus Group, 2009. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol Off J Int Fed Clin Neurophysiol . 2009; 120: 2008–2039. doi: 10.1016/j.clinph.2009.08.016. 15. Rush AJ, Marangell LB, Sackeim HA, et al: Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry . 2005; 58: 347–354. doi: 10.1016/j.biopsych.2005.05.025.

16. Rush AJ, Warden D, Wisniewski SR, et al: STAR*D: revising conventional wisdom. CNS Drugs . 2009; 23: 627–647. doi: 10.2165/00023210200923080-00001. 17. Sheth SA, Neal J, Tangherlini F, et al: Limbic system surgery for treatmentrefractory obsessive-compulsive disorder: a prospective long-term followup of 64 patients. J Neurosurg . 2013; 118: 491–497. doi: 10.3171/2012.11.JNS12389. 18. Shields DC, Asaad W, Eskandar EN, et al: Prospective assessment of stereotactic ablative surgery for intractable major depression. Biol Psychiatry, Neurostimulatory and Neuroablative Treatments for Depression . 2008; 64: 449–454. doi: 10.1016/j.biopsych.2008.04.009.

References 1. Alonso P, Cuadras D, Gabriëls L, et al: Deep brain stimulation for obsessive-compulsive disorder: A meta-analysis of treatment outcome and predictors of response. Edited by Véronique Sgambato-Faure. PLOS ONE . 2015; 10(7): e0133591. doi: 10.1371/journal.pone.0133591. 2. Arulpragasam AR, Chou T, Kaur N, et al: Future directions of deep brain stimulation: Current disorders, new technologies. Psychiatric Annals . 2013; 43(8): 366–373. doi: 10.3928/00485713-20130806-05. 3. Barker AT, Jalinous R, Freeston IL: Non-invasive magnetic stimulation of human motor cortex. Lancet . London: 1985; 1(8437): 1106–1107. 4. Ben-Menachem E, Hamberger A, Hedner T, et al: Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Research . 1995; 20(3): 221–227. 5. Bridges PK, Bartlett JR, Hale AS, et al: Psychosurgery: Stereotactic subcaudate tractomy. An indispensable treatment. Br J Psychiatry . 1994; 165(5): 599–611. doi: 10.1192/bjp.165.5.599. 6. Camprodon JA, Pascual-Leone A: Multi-modal applications of transcranial magnetic stimulation for circuit-based psychiatry. JAMA Psychiatry . 2016; March. doi: 10.1001/jamapsychiatry.2015.3127. 7. Carpenter LL, Janicak PG, Aaronson ST, et al: Transcranial magnetic stimulation (TMS) for major depression: A multi-site, naturalistic,

8.

9.

10.

11.

12.

13.

14.

15.

16.

observational study of acute treatment outcomes in clinical practice. Depression and Anxiety . 2012; 29(7): 587–596. doi: 10.1002/da.21969. Deng ZD, Lisanby SH, Peterchev AV: Electric field depth-focality tradeoff in transcranial magnetic stimulation: Simulation comparison of 50 coil designs. Brain Stimulation . 2013; 6(1): 1–13. doi: 10.1016/j.brs.2012.02.005. Dunner DL, Aaronson ST, Sackeim HA, et al: A multi-site, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: Durability of benefit over a 1year follow-up period. J Clin Psychiatry . 2014; 75(12): 1394–1401. doi: 10.4088/JCP.13m08977. Elger G, Hoppe C, Falkai P, et al: Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Research . 2000; 42(2–3): 203–210. Faria MA: Violence, mental illness, and the brain – A brief history of psychosurgery: Part 1 – From trephination to lobotomy. Surg Neurology Int . 2013; 4(1): 49. doi: 10.4103/2152-7806.110146. Fitzgerald PB, Daskalakis ZJ: A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. Brain Stimulation . 2012; 5(3): 287–296. doi: 10.1016/ j.brs.2011.03.006. George MS, A. Rush AJ, Marangell LB, et al: A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry . 2005; 58 (5): 364–373. doi: 10.1016/j.biopsych.2005.07.028. Greenberg BD, Price LH, Rauch SL, et al: Neurosurgery for intractable obsessive-compulsive disorder and depression: Critical issues. Neurosurg Clin North Am . 2003; 14(2): 199–212. Greenberg BD, Rauch SL, Haber SN: Invasive circuitry-based neurotherapeutics: Stereotactic ablation and deep brain stimulation for OCD. Neuropsychopharmacology . 2010; 35(1): 317–336. doi: 10.1038/npp.2009.128. Harden CL, Pulver MC, Ravdin LD, et al: A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy & Behavior: E&B . 2000; 1(2): 93–99. doi: 10.1006/ebeh.2000.0046.

17. Haynes W IA, Mallet L: High-frequency stimulation of deep brain structures in obsessive-compulsive disorder: The search for a valid circuit. Eur J Neurosci . 2010; 32(7): 1118–1127. doi: 10.1111/j.14609568.2010.07418.x. 18. Health, Center for Devices and Radiological. 2016. Recently-approved devices – VNS Therapy System – P970003s050. WebContent. Accessed March 27. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsan ApprovedDevices/ucm078532.htm . 19. Henry TR, Bakay RA, Votaw JR, et al: Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: I. Acute effects at high and low levels of stimulation. Epilepsia . 1998; 39(9): 983–990. 20. Kaur N, Chou T, Corse AK, et al: Deep brain stimulation for treatmentresistant depression. Psychiatric Annals . 2013; 43(8): 358–365. doi: 10.3928/00485713-20130806-04. 21. Kim M, Lee TK, Choi CR: Review of long-term results of stereotactic psychosurgery. Neurologia Medico-Chirurgica . 2002; 42(9): 365–371. doi: 10.2176/nmc.42.365. 22. Kopell BH, Greenberg B, Rezai AR: Deep brain stimulation for psychiatric disorders. J Clin Neurophysiology . 2004; 21(1): 51–67. doi: 10.1097/00004691-200401000-00007. 23. Kosel M, Schlaepfer TE: Beyond the treatment of epilepsy: New applications of vagus nerve stimulation in psychiatry. CNS Spectrums . 2003; 8(7): 515–521. 24. Krahl SE, Clark KB, Smith DC, et al: Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia . 1998; 39(7): 709–714. 25. Larson PS: Deep brain stimulation for psychiatric disorders. Neurotherapeutics: J Am Soc Exper NeuroTherapeutics . 2008; 5(1): 50–58. doi: 10.1016/j.nurt.2007.11.006. 26. Mayberg HS: Targeted electrode-based modulation of neural circuits for depression. J Clin Investigation . 2009; 119(4): 717–725. doi: 10.1172/JCI38454. 27. Mitchell-Heggs N, Kelly D, Richardson A: Stereotactic limbic leucotomy–a follow-up at 16 months. Br J Psychiatry 1976; 128(3): 226–240. doi:

10.1192/bjp.128.3.226. 28. Nahas Z, Marangell LB, Husain MM, et al: Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry . 2005; 66(9): 1097–1104. 29. O’Reardon JP, Solvason HB, Janicak PG, et al: Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multi-site randomized controlled trial. Biol Psychiatry . 2007; 62(11): 1208–1216. doi: 10.1016/j.biopsych.2007.01.018. 30. Psychiatric Neurotherapeutics – Contemporary Surgical and Joan Camprodon Springer. 2016. Accessed April 13. http://www.springer.com/us/book/9781934115503 . 31. Rossi S, Hallett M, Rossini PM, Pascual-Leone A, and Safety of TMS Consensus Group. 2009. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology . 120(12): 2008– 2039. doi: 10.1016/j.clinph.2009.08.016. 32. Rush AJ, Marangell LB, Sackeim HA, et al: Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial. Biol Psychiatry . 2005; 58(5): 347–354. doi: 10.1016/j.biopsych.2005.05.025. 33. Rush AJ, Warden D, Wisniewski SR, et al: STAR*D: Revising conventional wisdom. CNS Drugs . 2009; 23(8): 627–647. doi: 10.2165/00023210-200923080-00001. 34. Schlaepfer TE, Frick C, Zobel A, et al: Vagus nerve stimulation for depression: Efficacy and safety in a European study. Psychological Med . 2008; 38(5). doi: 10.1017/S0033291707001924. 35. Sheth SA, Neal J, Tangherlini F, et al: Limbic system surgery for treatmentrefractory obsessive-compulsive disorder: A prospective long-term followup of 64 patients. J Neurosurgery . 2013; 118(3): 491–497. doi: 10.3171/2012.11.JNS12389. 36. Shields DC, Asaad W, Eskandar EN, et al: Prospective assessment of stereotactic ablative surgery for intractable major depression. Biol Psychiatry, Neurostimulatory and Neuroablative Treatments for Depression . 2008; 64(6): 449–454. doi: 10.1016/j.biopsych.2008.04.009.

37. Williams NR: Role of functional imaging in the development and refinement of invasive neuromodulation for psychiatric disorders. World J Radiology . 2014; 6(10): 756. doi: 10.4329/wjr.v6.i10.756 .

CHAPTER 52 Lithium ANA IVKOVIC, MD AND THEODORE A. STERN, MD

KEY POINTS Overview Lithium salts are an inexpensive yet efficacious treatment for bipolar disorder. Lithium is United States Food and Drug Administration–approved for the treatment of acute mania and for the maintenance treatment of bipolar disorder. Pharmacology Lithium is a naturally-occurring salt whose activity lies in its ability to affect numerous biochemical reactions. Lithium inhibits glycogen synthetase kinase-3 (which is an important downstream target of monoaminergic neurotransmission); inhibits inositol monophosphatase (which lowers brain inositol levels and decreases the ability of neurons to generate second messengers); modulates synapsin II (a neuronal phosphoprotein); downregulates NMDA receptors; and increases levels of brain-derived neurotrophic factor (BDNF). These properties might explain lithium’s antidepressant and neuro-protective effects. The usual dose of lithium is between 900 and 1,200 mg/day; its serum therapeutic range is 0.6 to 1.2 mEq/L; however, in the elderly, lower levels (0.4 to 0.8 mEq/L) are often utilized to minimize the risk of toxicity. Side Effects and Toxicity Lithium’s adverse effects include sedation, cognitive dulling, polyuria, polydipsia, tremor, nausea, diarrhea, acne, psoriasis, weight gain, as well as the development of sick sinus syndrome and hypothyroidism. Lithium toxicity becomes more common and more serious as the serum levels of lithium rise above 1.2. mEq/l. Lithium used during the first trimester increases the risk of Ebstein’s anomaly (1 in 20,000 live births). Drug Interactions with Lithium

Co-administration of several agents (e.g., ACE inhibitors, thiazide diuretics, non-steroidal anti-inflammatory drugs) increase serum lithium levels, whereas others (e.g., xanthines {e.g., caffeine, theophylline], and osmotic diuretics [e.g., mannitol) decrease serum lithium levels.

Overview Lithium salts are an inexpensive yet efficacious treatment for bipolar disorder. Moreover, lithium is one of the first of an expanding list of FDA-approved medications for the treatment of mania (along with aripiprazole, asenapine, carbamazepine, chlorpromazine, divalproex, olanzapine, quetiapine, risperidone, and ziprasidone). However, despite the introduction of other agents, lithium remains the “gold standard” for the treatment of bipolar disorder. It is more effective in pure mania (i.e., with euphoria and grandiosity) than it is with mixed episodes, rapid-cycling disorders, or in bipolar patients with co-morbid substance abuse. In addition, evidence confirms lithium’s ability to decrease the risk of suicide. Unfortunately, lithium has a low therapeutic index and it can be lethal in overdose.

History In the 1940s, an Australian physician John Cade first reported on the antimanic properties of lithium. Double-blind studies in the 1960s followed and led to its United States Food and Drug Administration (FDA)–approval in 1970. For more than a decade after that, lithium was the only approved treatment for bipolar disorder. The anticonvulsants carbamazepine and valproic acid were subsequently (in the 1980s and 1990s, respectively) found to be efficacious for mania. Since the turn of the last century, the list of FDA-approved anti-manic psychotropics has expanded to include a bevy of antipsychotics (i.e., asenapine, aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, ziprasidone).

Indications Lithium is FDA-approved for the treatment of acute mania and for the maintenance treatment of bipolar disorder. Non-FDA-approved but evidencesupported uses of lithium include the treatment of bipolar depression and its use as a combination agent for the treatment of unipolar depression. It is also beneficial in conjunction with antipsychotics for schizoaffective disorder, bipolar

type. For women of child-bearing age with a history of bipolar disorder (the strongest risk factor for post-partum psychosis), lithium has demonstrated efficacy for the prevention of post-partum psychosis; it is often initiated on the first post-partum day (in non-breast-feeding mothers). If started sooner, increased monitoring of lithium levels is important given tremendous fluid shifts during childbirth, which increase the risk for lithium toxicity. Lithium is not indicated for the treatment of schizophrenia, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), or personality disorders. In more purely neurological conditions, lithium is a second-line treatment for the prevention of cluster headaches. Its neuro-protective properties have also led to its study in neuro-degenerative illnesses and mild cognitive impairment.

Pharmacology Lithium is a naturally-occurring salt whose therapeutic activity lies in its ability to affect numerous biochemical reactions. Its standard formulation, lithium carbonate, is available in both immediate- and sustained-release forms. Lithium citrate (immediate-release) is an additional formulation that is better tolerated by patients with significant gastrointestinal (GI) upset. Extended and sustainedrelease carbonate formulations (Eskalith and Lithobid) lead to lower serum peaks of lithium and appear to be associated with fewer cognitive side effects; however, these formulations are also thought to have more adverse effects on the kidney. To date, no gender or race-related differences in kinetics have been demonstrated with lithium. For sustained-release preparations, a twice-daily dosing schedule is commonly employed, although a single evening dose can be given instead, enabling increased adherence. The usual dosage of lithium is between 900 and 1,200 mg/d. It is often given in split dosing (two or three times daily), but its mean 18- to 36-hour half-life permits once-daily dosing. The serum therapeutic range for an average adult is 0.6 to 1.2 mEq/L. Lower levels (0.4–0.8 mEq/L) are sought in the elderly to minimize the risk of toxicity given decreases in glomerular filtration rate (GFR) that accompany aging. A standard level for acute and maintenance treatment is typically 0.8 mEq/L (0.4 mEq/L in the elderly). Its efficacy reliably correlates with serum concentrations. Lithium is rapidly and completely absorbed after oral administration, and it is excreted unchanged by the kidney. Other medications (e.g., ACE-inhibitors, thiazide diuretics, NSAIDs) can increase lithium levels, whereas still others (e.g., caffeine, aminophylline, mannitol) can promote an osmotic diuresis thereby lowering lithium levels. Low levels of dietary salt can

result in increased lithium re-absorption in the proximal tubules and lead to a rise in lithium levels (see Table 52-1). Table 52-1: Drug Interactions Associated with the Co-Administration of Lithium and Other Drugs Increased Lithium Levels Angiotensin converting enzyme inhibitors (ACE inhibitors) Angiotensin II receptor antagonists Antibiotics Metronidazole Spectinomycin Tetracycline Calcium channel blockers COX -2 inhibitors Diuretics Ethacrynic acid Spironolactone Thiazide diuretics Triamterene Non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen Indomethacin

Decreased Lithium Levels Carbonic anhydrase inhibitors Acetazolamide Osmotic diuretics Mannitol Sodium bicarbonate Sodium chloride load Xanthine diuretics Aminophylline Caffeine

Theophylline

Dosing and Titration The average lithium dosage range is 900 to 1,200 mg/day, administered in divided doses. Typically, lithium is titrated slowly as clinically indicated and as tolerated. The lowest dose of lithium associated with a therapeutic response should be used to minimize adverse effects and toxicity. Trough lithium levels (obtained after 5 days on a regular dosing schedule, and drawn 10–12 hours after the last dose) combined with clinical response should guide dosing. Alternatively, to more rapidly achieve a therapeutic serum level, a 600-mg loading dose of lithium can be given and a 24-hour lithium level obtained; this result is then compared to a nomogram that guides further daily dosing. When lithium maintenance therapy is discontinued, a gradual taper (over 3 months) is favored over a rapid discontinuation; this strategy minimizes the risk of relapse and the possibly of suicide.

Mechanisms of Action The precise molecular mechanisms by which lithium regulates behavior are still poorly understood. Lithium’s main mechanisms of action are thought to involve the effects of second messengers and neurotransmitter. Lithium inhibits glycogen synthase kinase-3 (GSK-3), which is an important downstream target of monoaminergic neurotransmission and is thought to regulate cellular apoptosis. Increased GSK-3 activity is associated with mania in mice, whereas inhibition of GSK-3 by lithium might reduce neuronal cell death that is caused by excessive excitatory neurotransmission associated with mania. Lithium also inhibits inositol monophosphatase (IMP), which lowers brain inositol levels and decreases the ability of neurons to generate second messengers. The net effect of this is a decrease in the neuronal hyperactivity that occurs with mania. Finally, lithium can modulate synapsin II (SYN2 ), a neuronal phosphoprotein and a possible candidate gene for the etiology of bipolar disorder and/or the response to lithium treatment. Neurotransmitters affected by lithium include glutamate, dopamine, and γ amino butyric acid (GABA). After 1 to 2 weeks on lithium, down-regulation of NMDA receptors occurs, and the uptake of glutamate (an excitatory neurotransmitter) is restored to normal. Lithium might decrease dopamine neurotransmission by attenuating G-protein function and by inhibiting

downstream second-messenger systems. Finally, lithium is thought to increase the concentration of GABA within the brain, thereby decreasing neural overexcitation. Lithium also has mildly pro-serotonergic and anti-oxidant effects and has been shown to increase levels of brain-derived neurotrophic factor (BDNF). These properties can explain its antidepressant and neuroprotective effects.

Side Effects and Toxicity Lithium has been associated with a broad range of adverse effects (e.g., sedation, cognitive dulling, polyuria, polydipsia, tremor, dry mouth, nausea, diarrhea, acne, psoriasis, a metallic taste to foods, weight gain) that can result in non-adherence with lithium treatment. More serious adverse effects include renal, endocrine, and cardiac dysfunction; lithium is also linked with teratogenicity (e.g., Ebstein’s anomaly). Weight gain is associated with lithium use (although it is lower than with atypical antipsychotics, such as olanzapine). Polydipsia and polyuria persist in about 25% of patients during maintenance treatment with lithium. When severe, this increased urination might indicate nephrogenic diabetes insipidus, a condition caused by lithium’s inhibition of the kidney’s sensitivity to antidiuretic hormone (ADH, or vasopressin). Lithium-associated skin problems include the worsening of cutaneous conditions characterized by neutrophilic infiltration (e.g., psoriasis and acne). Some of lithium’s side effects are treatable. For example, over-sedation and cognitive impairment can be improved by use of controlled-release formulations; dry mouth can be minimized by use of sugar-free candy; increased weight can be managed by carbohydrate restriction (since lithium has a mild insulin-like effect) and by exercise; nausea and diarrhea can respond to use of the citrate formulation; hand tremor can improve with the use of beta-blockers (e.g., propranolol), and polydipsia and polyuria can improve with the use of thiazide diuretics. However, because thiazide diuretics reliably increase serum lithium levels, lithium doses should be halved when thiazides and lithium are coadministered; lithium levels should be closely followed when this combination is employed. Because lithium has mild insulin-like effects, the insulin regimen of diabetic patients receiving lithium might need to be altered. Unfortunately, despite use of these measures, a sizable number of individuals are unable to tolerate lithium (due to persistent side effects), leading to non-adherence (Table 52-2). In addition, co-administration of lithium and neuromuscular blocking

agents (e.g., succinylcholine, pancuronium, decamethonium) can lead to prolongation of muscle paralysis. Table 52-2: Rank Order of Reasons for Non-Compliance with Lithium Side effects Indefinite intake/chronicity of illness Feeling less creative Feeling well; see no need to take lithium Feeling less productive Missing the highs Finding oneself less interesting to one’s spouse Disliking the idea of one’s moods being controlled by medication Finding it difficult to remember things Feeling depressed, thinking mood would improve off medication Note: Non-compliance was based on self-report by patients that they did not comply with lithium (from Jamison et al, 1979).

Serious side effects can affect the kidneys, the endocrine system, and the heart; teratogenic effects are also noteworthy. Lithium’s most common renal effects include a reduced urine concentrating ability (which is reversible when lithium is discontinued). A recent review and meta-analysis of the literature showed little evidence for lithium-induced renal failure and only a small decrease in GFR from its chronic use. Even with chronic lithium use, the risk of renal toxicity and end-stage renal disease (ESRD) is low (0.53% compared with 0.2% in the general population). Regardless, safe and effective use of lithium requires regular monitoring of renal function; the development of azotemia warrants careful consideration of its use and or switching to an alternative antimanic agent (Table 52-3). Table 52-3: Monitoring of Lithium Therapy Before initiating treatment: Renal function tests (creatinine, blood urea nitrogen [BUN]) Thyroid panel Serum calcium and parathyroid hormone (PTH) levels EKG (for patients > 50 years old)

Baseline weight During treatment: Renal and thyroid function tests every 6 months Lithium plasma levels every 3 months Serum calcium and PTH levels Weight (at regular intervals) Adapted from 2006 NICE guidelines; calcium, PTH recommendations based on Khandwala’s 2006 review.

Adverse endocrine effects include lithium-induced hypothyroidism and hyperparathyroidism. These effects can occur at any point in treatment and are typically reversible after stopping lithium. Data from randomized controlled trials (RCTs) indicate that approximately 4% of lithium-treated patients developed hypothyroidism. Lithium appears to have a direct antithyroid effect, and it inhibits the thyroid gland’s sensitivity to thyroid stimulating hormone (TSH). High TSH levels on laboratory testing indicate a need to either discontinue lithium or supplement its use with thyroid hormone replacement. With regard to parathyroid effects, studies consistently demonstrate an increase in parathyroid hormone (PTH) and serum calcium levels by 10%. The mechanism by which this occurs is unclear, but it might be due to direct action on the pituitary gland and a resultant PTH release. Hypercalcemia occurs in approximately 15% of lithium-treated patients. Thyroid and/or parathyroid abnormalities together occur in about 25% of patients receiving lithium. Adverse cardiac effects include a decrease in cardiac conduction efficiency at the sinoatrial node, which can result in a sick sinus syndrome. Other effects include: atrioventricular blockade; non-specific ST and T-wave changes; premature ventricular beats; and the unmasking of Brugada syndrome (due to lithium’s blockade of cardiac sodium channels) in susceptible individuals, which increases the risk for sudden cardiac death.

Teratogenicity Lithium use during the first trimester of pregnancy has been associated with the development of Ebstein’s anomaly (congenital downward displacement of the tricuspid valve into the right ventricle). All women of child-bearing age beginning treatment with lithium should be advised of this risk. Ebstein’s anomaly occurs in 1 in 20,000 live births in the general population; with newborns exposed to lithium, the incidence appears higher (i.e., as much as 400-

fold higher according to some studies). However, a systematic review and metaanalysis failed to show any increase in congenital malformations in lithiumexposed pregnancies. This suggests the association between Ebstein’s anomaly and lithium is lower than what earlier reports indicated. Moreover, the risk is probably much lower than the risks of neural tube defects associated with the use of anticonvulsant mood stabilizers (e.g., divalproex, carbamazepine) in pregnancy; thus, in the severely manic patient who requires treatment, lithium use might be necessary, ideally after the first trimester whe n drugs are considered safer for the fetus. As always, a careful risk–benefit analysis should be done before prescribing lithium treatment during pregnancy.

Toxicity Lithium toxicity often occurs in adults when the lithium level exceeds 1.2 mEq/L (Table 52-4); adverse effects include tremor, nausea, diarrhea, and ataxia. Moreover, nausea and diarrhea often contribute to dehydration that can further increase lithium levels and cause greater degrees of neuropsychiatric dysfunction. Levels from 1.5 to 2.0 mEq/L are associated with a higher risk of neurotoxicity and seizures (including non-convulsive status epilepticus). Above 2.0 mEq/L dialysis might be warranted to reduce neurotoxic effects. With a lithium level above 2.5 mEq/L, coma and death can occur, and dialysis is, in general, indicated. In the elderly, signs of toxicity can occur at “therapeutic” levels. When renal failure develops, lithium levels are apt to rise rapidly, greatly increasing the risk of death. Table 52-4: Toxicity Table and Levels for Non-Elderly Adults (Divide Levels in Half for the Elderly) Lithium Level (mEq/L) Side Effects Below 1.2

Generally non-toxic: sedation, nausea, diarrhea, cognitive effects, polyuria, polydipsia, weight gain, psoriasis, tremor

1.2–1.5

Borderline toxicity: Moderate nausea and diarrhea, more polyuria/polydipsia, increasing tremor, mild ataxia, more severe cognitive difficulties, fine hand tremor

1.5–2.0

Mild-to-moderate toxicity: Coarse hand tremor, dizziness, vomiting, severe diarrhea, ataxia, confusion

2.0–2.5

Moderate-to-severe toxicity: Delirium, abnormal EEG, abnormal renal function, cardiac arrhythmias, risk of coma

Above 2.5: dialysis

Severe toxicity: Acute renal failure, seizures, death

indicated

Severe lithium toxicity can result in persistent neurologic dysfunction including cerebellar demyelination. The so-called “Syndrome of Irreversible LithiumEffectuated Neurotoxicity” (SILENT) is thought to worsen with coadministration of haloperidol. Moreover, higher doses of neuroleptics have led to reports of neurotoxicity in patients with therapeutic lithium levels. Thus, the combination of lithium and neuroleptics should be used with caution given this association, albeit an uncommon one.

Clinical Effectiveness Acute Mania Lithium monotherapy is recommended by most clinical practice guidelines as a first-line agent for the treatment of acute mania. In practice, it is typically initiated in combination with an atypical antipsychotic (e.g., olanzapine) given that lithium’s antimanic action can take up to 6 to 10 days. Lithium is less effective than are anticonvulsants in mixed (depressive, dysphoric) mania.

Prophylaxis Lithium monotherapy is effective in the prophylaxis of manic and depressive episodes. It helps to prevent manic relapse better than it prevents depression.

Acute Bipolar Depression Generally, there is a paucity of RCTs for lithium use in bipolar depression. Lithium’s anti-manic effects are more impressive than its antidepressant effects, which require 6 to 8 weeks. Lithium is safer in the treatment of bipolar depression than are standard antidepressants because those agents have a serious risk of switching a person into a manic state. Lithium is also modestly effective as part of a combination strategy for treatment-resistant unipolar depression and has been shown to be superior to placebo in the maintenance phase of unipolar depression.

Rapid Cycling and Mixed States Lithium is probably not as effective as anticonvulsants in the treatment of rapid-cycling bipolar disorder (defined by 4 or more mood episodes per year) or with mixed bipolar states.

Co-Morbid Substance Abuse

Co-morbid substance abuse is a predictor of poor response to lithium therapy. This might be related to the increased incidence of rapid cycling or mixed features in patients with co-morbid bipolar disorder and substance use.

Reduction in Mortality from Suicide Randomized prospective studies have established that lithium exerts a preventive effect on suicide, whereas carbamazepine has failed to demonstrate that effect. Lithium reduces mortality in bipolar disorder by reducing the suicide risk. The mechanism by which lithium exerts its anti-suicide effect might be related to its serotoninergic activity leading to a reduction in impulsiveaggressive behavior, a known risk factor for suicide.

Clinical Factors Affecting Response Chronic use of antidepressants can interfere with lithium response in bipolar disorder. Psychotic features might predict loss of response to lithium. Undetected hypothyroidism can lead to rapid cycling and a poor response to lithium.

Suggested References 1. Adityanjee, Munshi K, Thampay A: The syndrome of irreversible lithiumeffectuated neurotoxicity. Clin Neuropharmacol . 2005; 28(1): 38–49. 2. Baldessarini RJ, Tondo L, Davis P, et al: Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord . 2006 Oct; 8(5 Pt 2): 625–639. 3. Bowden C, Brugger A, Swann A, et al: Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA . 1994; 271: 918–924. 4. Cohen LS, Friedman JM, Jefferson JW, et al: A re-evaluation of risk of in utero exposure to lithium. JAMA . 1994; 271(2): 146–150. 5. El-Mallakh RS: Lithium: Actions and Mechanisms. Washington, DC: American Psychiatric Press; 1996. 6. Geddes JR, Goodwin GM, Rendell J, et al: Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomized open-label trial. Lancet . 2010 Jan 30; 375(9712): 385–395. 7. Gelenberg AJ, Kane JM, Keller MB, et al: Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar depression. N

Engl J Med . 1989; 321(22): 1489–1493. 8. Gentille-Lorente DI, Lechuga-Duran I: Brugada type 1 pattern and lithium therapy. Actas Esp Psiquiatr . 2015 Nov-Dec;43(6):235–236. 9. Goodwin FK, Jamison KR: Manic Depressive Illness. New York: Oxford University Press; 1990. 10. Goodwin FK, Murphy DL, Dunner DL, et al: Lithium response in unipolar versus bipolar depression. Am J Psychiatry . 1972; 129(1): 44–47. 11. Harrow M, Goldberg JF, Grossman LS, et al: Outcome in manic disorders. Arch Gen Psychiatry . 1990; 47: 665–671. 12. Hetmar O, Brun C, Ladefoged J, et al: Long-term effects of lithium on the kidney: functional-morphological correlations. J Psychiat Res . 1989; 23(3/4): 285–297. 13. Ivkovic A, Stern TA: Lithium-induced neurotoxicity: Clinical presentations, pathophysiology, and treatment. Psychosomatics . 2014; 55 (3): 296–302. 14. Jamison K, Gerner R, Goodwin F: Patient and physician attitudes toward lithium: relationship to compliance. Arch Gen Psychiatry . 1979; 36: 866– 869. 15. Khandwala H, Van Uum S: Reversible hypercalcemia and hyperparathyroidism associated with lithium therapy: case report and review of the literature. Endocr Pract . 2006 Jan-Feb; 12(1): 54–58. 16. Malhi GS: The science and practice of lithium therapy. Aust N Z J Psychiatry . 2012; 46(3): 192–211. 17. Manji HK, Hsiao JK, Risby ED, et al: The mechanisms of action of lithium I: Effects on serotoninergic and noradrenergic systems in normal subjects. Arch Gen Psychiatry . 1991; 48: 505–512. 18. Manji HK, Potter WZ, Lenox RH: Signal transduction pathways: molecular targets for lithium’s actions. Arch Gen Psychiatry . 1995; 52: 531–543. 19. Maxmen JS: Psychotropic Drugs: Fast Facts. New York: Norton; 1991. 20. McKnight R, Adida M, Budge K, et al: Lithium toxicity profile: a systematic review and meta-analysis. Lancet . 2012; 379(9817): 721–728. 21. Rybakowski JK: Lithium in neuropsychiatry: a 2010 update. World J Biol Psychiatry . 2011; 12(5): 340–348. 22. Sachs GS, Lafer B, Truman CJ, et al: Lithium monotherapy: miracle, myth

and misunderstanding. Psychiatric Annals . 1994; 24: 299–306. 23. Schou M: Lithium treatment of manic-depressive illness. JAMA . 1988; 259(12): 1834–1836. 24. Stern TA, Lydiard RB: Lithium therapy revisited. Psychiatric Medicine . 1987; 4: 39–68. 25. Tredget J, Kirov A, Kirov G: Effects of chronic lithium treatment on renal function. J Affect Disord . 2010; 126(3): 436–440. 26. Yeung CK, Chan HH: Cutaneous adverse effects of lithium: epidemiology and management. Am J Clin Dermatol . 2004; 5(1): 3–8. 27. Young A: More good news about the magic ion: lithium may prevent dementia. Br J Psychiatry . 2011; 198(5): 336–337.

CHAPTER Anti-Epileptic Drugs and 53 Psychiatric Illness ALLISON S. BAKER, MD AND SCOTT R. BEACH, MD

KEY POINTS Overview Anti-epileptic drugs (AEDs) have been widely used by psychiatrists to treat disorders other than epilepsy for the past four decades, including bipolar disorder. Since the inception of their psychiatric use, AEDs have also been used to target specific symptoms of psychiatric illness (e.g., impulsivity) independent of their causality. Although AEDs are widely used in psychiatry for affective illness, substance use disorders, and personality disorders, only two AEDs have FDAindications: valproate for bipolar mania, and lamotrigine for bipolar maintenance. Valproate Valproate is indicated for acute mania; it is also used for the treatment of alcohol withdrawal, as well as the impulsivity associated with traumatic brain injury. It is believed to work by increasing levels of γ -amino butyric acid in the brain. Potential toxicities include aplastic anemia and liver failure; monitoring of blood counts, liver function tests, and valproate levels is therefore essential. Other side effects include an association with polycystic ovarian syndrome, pancreatitis, hyperammonemia, and teratogenic effects. Carbamazepine Carbamazepine and its analogue oxcarbazapine are used for bipolar disorder, and occasionally for alcohol withdrawal. Both are believed to exert their effect via inhibition of voltage-dependent sodium channels. Carbamazepine induces the metabolism of many drugs including itself, and therefore requires close blood-level monitoring.

Oxcarbazepine has fewer drug–drug interactions. Carbamazepine is rarely associated with agranulocytosis and liver failure. Other side effects of both AEDs include hyponatremia secondary to the syndrome of inappropriate anti-diurectic hormone secretion, and dizziness. Lamotrigine Lamotrigine is approved for maintenance use in bipolar disorder, and is particularly effective at preventing depressive episodes. It is also used to treat mood reactivity in borderline personality disorder. Lamotrigine is believed to work by inhibiting glutamate release and inhibiting voltage-gated sodium channels. It requires a slow titration due to the risk of Stevens-Johnson syndrome. Other side effects include dizziness and blurred vision.

Introduction Over the past four decades anti-epileptic drugs (AEDs) have increasingly been used to treat psychiatric illness (see Table 53-1). Initially, carbamazepine and valproate were used to treat bipolar disorder. More recently, with the approval of newer AEDs, the use of these drugs for the treatment of other disorders has expanded. This chapter focuses on both the properties and uses of a variety of AEDs. Because of the preponderance of controlled, blinded, trials using valproate, lamotrigine, and carbamazapine, these agents are the focus of our discussion; gabapentin, oxcarbazepine, and topiramate are also be covered because of their extensive clinical use. Other agents are covered in less detail. Of note, the only AEDs approved by the United States Food and Drug Administration (FDA) for use in psychiatric illnesses are valproate (for acute mania) and lamotrigine (for maintenance treatment in bipolar disorder). Table 53-1: Uses of Anticonvulsants in Psychiatry

Medication Carbamazepine (Tegretol, Tegretol XR)

FDA Indications in Psychiatry Other Usages in Psychiatry None

Bipolar mania, bipolar maintenance, TLE, pain syndromes, alcohol/sedative withdrawal, impulsivity

Valproate (Depakote, Depakote ER, Depakene)

Bipolar mania

Bipolar maintenance, TLE, pain syndromes, alcohol/sedative withdrawal, impulsivity (especially in traumatic brain injury), borderline personality disorder

Lamotrigine (Lamictal, Lamictal XR)

Bipolar maintenance

Bipolar depression, pain syndromes, borderline personality disorder

Gabapentin (Neurontin) None

Pain syndromes, generalized anxiety disorder, social phobia, panic disorder, alcohol dependence, borderline personality disorder

Oxcarbazepine (Trileptal)

None

Bipolar mania, bipolar maintenance, pain syndromes, impulsivity

Topiramate (Topamax)

None

Pain syndromes, borderline personality disorder, alcohol use disorder, stimulant (cocaine) use disorder

Pregabalin (Lyrica)

Fibromyalgia

Pain syndromes, generalized anxiety disorder

TLE = temporal lobe epilepsy

The ideal AED would have highly consistent oral bioavailability, low proteinbinding, a long half-life (to allow for once or twice a day dosing), linear kinetics, no active metabolites, renal elimination, no hepatic enzyme induction or inhibition, and no drug–drug interactions. The older AEDs have only a few of these properties, which makes their use difficult given the polypharmacy common in serious mental illness. Even though their efficacy in mental illness has not always been demonstrated in controlled trials, the newer AEDs are popular because of their ease of use.

Valproate Valproate (valproic acid [Depakene] and divalproex sodium [Depakote]) is an AED that is FDA-approved for use in acute mania, but not for maintenance treatment of bipolar disorder. Other indications include seizure disorders and migraine headaches.

Pharmacology Valproate is rapidly absorbed after oral ingestion; peak plasma levels are achieved 1 to 2 hours after taking valproate on an empty stomach and longer (3– 8 hours) with food in the stomach or when the divalproex formulation is employed. It is metabolized by the liver and has no active metabolites. Valproate is highly protein-bound, a property that can lead to interactions with other protein-bound medications (e.g., warfarin, digitalis, other AEDs). It has a short biological half-life (8 hours). When used as an AED, blood levels are typically 50 to 100 µg/ml, though they can be higher; blood levels for treatment of mania

are not well established, though a range of 80 to 100 µg/ml is generally recommended. Co-administration of enzyme-inducers like carbamazepine and phenytoin can lead to lower serum levels of valproate. Co-administration of valproate leads to higher serum levels and to increased toxicity of lamotrigine. Though valproate is often started at low doses (250 mg/d) and gradually increased, it can be started with a loading dose of 20 mg/kg/d for the acute treatment of mania. Several forms are available, including an intravenous form as well as a sprinkle preparation that is useful in older patients or in those who have difficulty swallowing pills. An extended-release formulation (Depakote ER) is also available and can be dosed once daily, typically at night. Total daily dosing for Depakote ER is typically greater than total daily dosing for the immediate-release form. For further details about the pharmacology of valproate, see Table 53-2. Table 53-2: Pharmacology of Anticonvulsants Presumed Mechanism Medication of Action

Typical Usual Route of Dosing Starting Therapeutic Excretion Frequency Dose Dose Range

Carbamazepine (Tegretol, Tegretol XR)

Inhibits voltage-dependent and presynaptic sodium channels

Liver

Two or three times daily (twice daily for Tegretol XR)

200 mg daily

400–800 mg daily

Valproate (Depakote, Depakote ER, Depakene)

Increases levels of GABA

Liver

Two or three times daily (once daily for Depakote ER)

500 mg daily

1,000–2,000 mg daily

Lamotrigine (Lamictal, Lamictal XR)

Inhibits glutamate release; inhibits voltage-gated sodium channels

Liver

Once or twice daily

25 mg daily 100–300 mg daily

Gabapentin (Neurontin)

Decreases glutamate

Kidney

Three times daily

300 mg daily

900–3,000 mg daily

Oxcarbazepine (Trileptal)

Inhibits voltage-dependent sodium channels

Liver

Twice daily

300 mg daily

600–1200 mg daily

Topiramate (Topamax)

Inhibits the rapid firing of sodium channels; enhances GABA effect at GABAA receptors, and antagonizes kainate at AMPA receptors

80% kidney; 20% liver

Twice daily

50 mg daily 200–400 mg daily

Pregabalin (Lyrica)

Decreases glutamate

Kidney

Three times daily

150 mg daily

GABA = γ -amino butyric acid; AMPA = 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid

150–300 mg daily

Toxicity The most worrisome effects of valproate are on the liver. Fifteen to 30% of patients will develop a mild and transient rise in transaminases that usually occurs only in the first three months; patients generally remain asymptomatic. Cases of fatal hepatotoxicity have been reported with the use of valproate in children under the age of 10 years, usually when valproate is used along with another AED for a neurological problem. Very rare major toxicities include hemorrhagic pancreatitis and aplastic anemia. Routine monitoring of liver function tests (LFTs) and the complete blood count (CBC) is recommended, especially during the initiation of therapy. Valproate can also lead to polycystic ovarian syndrome (PCOS) and to menstrual irregularities in as many as 10% of female users, especially for women who start the drug in their teenage years. Valproate can also lead to hyperammonemia in the absence of other laboratory abnormalities, which can result in mental status changes. For common side effects and teratogenic effects, see Table 53-3 . Of note, valproate is more likely than is carbamazepine to cause neural tube defects when administered during the first trimester of pregnancy.

Uses Valproate has been shown in double-blind, controlled studies to be effective in the treatment of acute mania at response rates similar to (but slightly less than) those seen with lithium. Older literature suggested that valproate might be more effective than lithium in the treatment of mixed bipolar states and rapid-cycling bipolar disorder, though more recent studies have found no difference. Some recent trials have suggested that valproate is less effective than lithium as monotherapy for maintenance of bipolar disorder, and little evidence exists for valproate’s efficacy for depressive episodes. Valproate is also useful in the treatment of some pain syndromes. In controlled studies, prophylaxis with valproate was effective in 65% of those with migraines. Valproate can also be effective in the treatment of trigeminal and post-herpetic neuralgias. Case reports and a small study have shown that valproate can also be used in the treatment of benzodiazepine withdrawal. In cases of alcohol withdrawal, valproate improved symptoms rapidly and decreased the need for benzodiazepines. Like carbamazepine, valproate is effective in preventing complex partial seizures and reducing the psychiatric symptoms associated with them. In addition, case reports indicate that valproate might reduce behavioral outbursts, especially in those with head injuries or other

organic brain syndromes; moreover, it is commonly used to manage agitation in the hospital setting, particularly in patients with dementia. Finally, valproate has also shown some promise in treating impulsivity in patients with borderline personality disorder.

Lamotrigine Lamotrigine (Lamictal) is approved for maintenance use in bipolar disorder and as adjunctive treatment for refractory partial seizures.

Pharmacology Lamotrigine is rapidly (1–3 hours) and completely (nearly 100%) absorbed after oral administration. It is moderately protein-bound (50%–60%) and is unaffected by use of other AEDs. Its biological half-life is 25 hours, though it is shorter (15 hours) when used with enzyme-inducing drugs. Valproate inhibits the metabolism of lamotrigine and can cause toxicity and side-effects when coadministered. Carbamazepine, phenobarbital, and phenytoin induce its metabolism and lead to lower levels when co-administered. Lamotrigine does not affect the metabolism of other medications. It is conjugated by the liver and can cause some autoinduction at higher doses. The titration needs to be slower when used with valproate and faster when used in conjunction with an enzymeinducer. For further details about the pharmacology of lamotrigine, see Table 532.

Toxicity The most serious side-effect of lamotrigine is rash that can lead to StevensJohnson syndrome, which typically occurs within the first two months of treatment. A slower titration, typically 25 to 50 mg/d every one to two weeks, reduces the risk of rash. The incidence of significant rash in patients with bipolar disorder is 0.8 per 1,000 for monotherapy, and 1.3 per 1,000 among patients also being treated with other agents. For common side effects and teratogenic effects, see Table 53-3. Table 53-3: Side Effects of Anticonvulsants Medication Common Side Effects Concerning Side Effects

Teratogenic Effects

Carbamazepine (Tegretol, Tegretol XR)

Neural tube defects; increase in minor birth defects, possible liver

Dizziness, ataxia, clumsiness, sedation, and dysarthria, nausea/vomiting, weight gain

Aplastic anemia, agranulocytosis, liver failure, Stevens-Johnson syndrome, SIADH, slowed intraventricular

conduction

failure

Valproate (Depakote, Depakote ER, Depakene)

Nausea/vomiting, heartburn, diarrhea, sedation, dizziness, ataxia, tremor, alopecia, weight gain

Aplastic anemia, thrombocytopenia, liver failure, pancreatitis, PCOS, hyperammonemia

Neural tube defects; cleft lip, heart defects; neonatal liver disease

Lamotrigine (Lamictal, Lamictal XR)

Headaches, blurred vision, ataxia, dizziness, nausea/vomiting, fatigue

Stevens-Johnson syndrome

Cleft lip/palate

Gabapentin (Neurontin)

Sedation, ataxia, dizziness, dry mouth, fatigue

None

Unknown

Oxcarbazepine (Trileptal)

Headache, sedation, dizziness, diplopia, benign rash, nausea/vomiting

SIADH

Unknown

Topiramate (Topamax)

Sedation, dizziness, ataxia, weight loss

Kidney stones, cognitive dysfunction

Unknown

Pregabalin (Lyrica)

Dizziness, sedation

None

Unknown

SIADH = syndrome of inappropriate antidiuretic hormone secretion

Uses Multiple randomized, controlled trials point to lamotrigine’s effectiveness in treating bipolar disorder. These effects were initially investigated because use of lamotrigine seemed to improve energy and alertness in epilepsy patients, and it might have led to improvement in some cases of depression. It is currently FDAapproved for the maintenance treatment of patients with bipolar disorder. Lamotrigine reduces bipolar depression relapse in patients. The evidence for its efficacy in the treatment of bipolar depression remains limited, though a metaanalysis suggests that patients with severe depression might be most likely to benefit from it’s use. It’s efficacy in treating manic episodes has not been demonstrated, though there is a small effect size for the prevention of manic episodes. In addition, lamotrigine has been studied for the treatment of various pain syndromes; it seems to be effective in treating neuralgia, central pain, and neuropathic pain syndromes. In some cases, lamotrigine was effective when carbamazepine and valproate had failed. Lamotrigine is also used commonly in patients with borderline personality disorder (to decrease anger and affective lability).

Carbamazepine

Carbamazepine (Tegretol) is an iminostilbene AED that is structurally similar to tricyclic antidepressants (TCAs). It has no indication for the treatment of bipolar disorder, though it has been widely used for this disorder for decades. It is also used to treat partial seizures, with and without complex symptomatology, as well as generalized, tonic-clonic seizures.

Pharmacology Carbamazepine is absorbed erratically and unpredictably; peak blood levels are achieved within 4 to 8 hours. Approximately 65% to 80% of the drug is proteinbound. It is metabolized by the liver, resulting in an active metabolite that generates levels up to 20% of the parent compound. The initial elimination halflife is 18 to 55 hours; this decreases to 5 to 20 hours after hepatic enzymes are induced. Carbamazepine induces its own metabolism, which results in the need to increase the dose after 2 to 3 weeks to maintain the same blood level. This enzyme-induction also leads to the lowered levels of many other drugs (e.g., certain antipsychotics, antidepressants, benzodiazepines, oral contraceptives, other AEDs, warfarin). Co-administration of phenytoin, phenobarbital, and primidone can cause decreased levels of carbamazepine, while concomitant use of some selective serotonin re-uptake inhibitors (SSRIs), cimetidine, erythromycin, and isoniazid lead to higher carbamazepine levels. Blood levels can be monitored to assure adequate dosing and to prevent toxicity; carbamazepine has a low therapeutic index. When used to treat patients with epilepsy, carbamazepine’s therapeutic level is 4 to 12 µg/ml; though the evidence regarding treatment of bipolar disorder is less clear, the accepted carbamazepine blood level is 8 to 12 µg/ml. For further details about the pharmacology of carbamazepine, see Table 53-2.

Toxicity The most common side effects of carbamzepine are lethargy, sedation, nausea, tremor, and ataxia. Carbamazepine can cause agranulocytosis and liver failure. However, these adverse effects are very rare and are thought to be prevented by routine monitoring. Aplastic anemia and agranulocytosis occur at a rate of less than 1 in per 20,000 people treated. Rarer still is non-dose-related idiosyncratic hepatitis that can be fatal; when it occurs, it develops during the first month of treatment. To prevent lethal outcomes, routine blood monitoring of the CBC and LFTs is recommended before starting treatment and approximately every two weeks for the first two months of treatment; thereafter, these lab values can be checked every three months. Most clinicians believe that carbamazepine should

be stopped if the white blood cell (WBC) count drops below 3,000/µl, if the neutrophil count falls below 1,500/µl, or if the LFTs increase by three-fold. A benign rash can develop with carbamazepine usage, and Stevens-Johnson syndrome is seen rarely. Hyponatremia, as a result of the syndrome of inappropriate anti-diuretic hormone (SIADH) secretion can also occur. Carbamazepine also slows intraventricular conduction, especially in overdose. For common side effects and teratogenic effects, see Table 53-3. Side effects are usually managed by slow titration and maintenance of the dose within the therapeutic range.

Uses Multiple studies, including two more recent large placebo-controlled trials, have shown that carbamazepine is effective for the treatment of acute mania. Meta-analyses have suggested that carbamazepine is similar to valproate in terms of efficacy and tolerability. The efficacy of carbamazepine for the prophylaxis of mood swings in bipolar disorder is less clear; however, numerous studies have shown maintenance rates similar to that of lithium. Furthermore, lithium and carbamazepine have often been used in combination for the treatment of refractory bipolar illness. The evidence for carbamazepine’s efficacy in depression (bipolar or unipolar) is less convincing because only a minority of patients (20%–50%) respond to monotherapy. Even with its efficacy established, carbamazepine has fallen out of favor because of its drug interactions (enzyme induction) and low tolerability. Carbamazepine might be the drug of choice for the treatment of psychiatric symptoms associated with complex partial seizures ( temporal lobe epilepsy [TLE]). It is better for treatment of the symptoms associated with ictal events than it is for the treatment of residual inter-ictal psychotic or mood symptoms. It remains unclear if the suppression of ictal events with carbamazepine reduces or prevents the development of the inter-ictal syndrome. Carbamazepine is also effective treatment for pain syndromes. It was originally used to treat paroxysmal pain syndromes, like trigeminal neuralgia (for which it is more effective than phenytoin); currently, it is used for the treatment of diabetic neuropathy, post-herpetic neuralgia, phantom-limb pain, and multiple sclerosis. In addition, carbamazepine has been used in the treatment of behavioral outbursts and violent behavior; these therapeutic effects seem to be most potent in cases associated with seizures or mania. In addition, multiple uncontrolled

reports have documented carbamazepine’s efficacy in the treatment of behavioral outbursts in individuals with head injuries, other organic syndromes, and intellectual disability. Carbamazepine has also been studied in the treatment of withdrawal symptoms, especially those associated with high-potency benzodiazepines. One study showed that carbamazepine was as effective as oxazepam for severe alcohol withdrawal and that it produced fewer symptoms of psychological distress. Carbamazepine can treat symptoms of protracted withdrawal.

Gabapentin Gabapentin (Neurontin) is a novel AED indicated for the adjunctive treatment of partial and generalized seizures.

Pharmacology Gabapentin’s unique properties have made it a very popular drug. It is well absorbed orally (approximately 60%). However, its absorption is non-linear because it is primarily absorbed by intestinal amino acid transporters that can be saturated at higher dosages. Gabapentin is excreted unchanged by the kidneys. It does not bind to plasma proteins. Gabapentin’s serum half-life is 6 to 7 hours, though its central nervous system (CNS) half-life appears to be longer. The serum level of gabapentin is increased in renal failure and it is effectively cleared by hemodialysis. Its use is associated with few drug–drug interactions. Cimetidine can decrease renal clearance and aluminum/magnesium antacids can decrease absorption. For further details about the pharmacology of gabapentin, see Table 53-2.

Toxicity Significant side effects are not prevalent with gabapentin. For common side effects and teratogenic effects, see Table 53-3. Reports of gabapentin being abused, particularly in prison populations, have emerged in the past two decades.

Uses Because of gabapentin’s low side effect profile and lack of drug–drug interactions, it has been used for a wide variety of psychiatric disorders. Despite its brief popularity as a treatment for bipolar disorder, there has never been any evidence to support its use for treating mania or depression, and it is not recommended for use in any phase of bipolar disorder.

Gabapentin has been used extensively in the treatment of anxiety disorders. It has the advantage of having a high-degree of safety. One controlled study of gabapentin in social phobia showed that after 14 weeks there was a moderate response in 39% in the gabapentin group, compared to 19% in the placebo group. A placebo-controlled study also demonstrated efficacy in the subpopulation of patients with panic disorder who have severe symptoms. Gabapentin is also used frequently as an adjunctive treatment in generalized anxiety disorder (GAD) and to treat anxiety and to reduce affective dysregulation in patients with borderline personality disorder. Gabapentin has become the first-line AED prescribed by many pain specialists. Placebo-controlled, blinded, trials have shown its efficacy in treating neuropathies (diabetic and mixed) as well as neuralgias.

Oxcarbazepine Oxcarbazepine (Trileptal) is the oxygenated congener of carbamazepine. Like carbamazepine, it is used to treat partial seizures (with and without complex symptomatology), and is used as an adjunctive treatment in children with epilepsy.

Pharmacology Oxcarbazepine is readily absorbed and quickly metabolized by the liver, converted to a 10-monohydroxy derivative, the primary active component. It is not highly protein-bound. The half-life of the active component is 8 to 10 hours. Oxcarbazepine lacks the auto-inducing effects of carbamazepine and therefore does not require repeated assays of serum concentration. It impacts the metabolism of other medications to a significantly lesser degree than does carbamazepine, but it can still have important effects on the metabolism of oral contraceptives, reducing their efficacy. For further details about the pharmacology of oxcarbazepine, see Table 53-2.

Toxicity Oxcarbazepine is not known to cause aplastic anemia. It also lacks the excessive sedation sometimes associated with carbamazepine. Oxcarbazepine can cause hyponatremia via SIADH, at rates (up to 2.5% of patients) greater than those associated with carbamazepine. For common side effects and teratogenic effects, see Table 53-3.

Uses

Some evidence from small studies has suggested that oxcarbazepine might be effective in treating acute mania. However, there remains no published placebocontrolled studies of oxcarbazapine in adults with bipolar disorder. Oxcarbazepine is routinely used to treat pain syndromes, including trigeminal neuralgia. At least one study has shown superiority of oxcarbazepine over placebo in the treatment of impulsive aggression.

Topiramate Topiramate is a drug approved for the adjunctive treatment of partial seizures in adults.

Pharmacology Topiramate is well absorbed orally and has a half-life of 20 hours. It has low protein-binding. In the presence of enzyme-inducing drugs, more topiramate is metabolized by the liver, and its half-life is decreased. Though it does not induce the metabolism of other drugs, it seems to decrease the effectiveness of oral contraceptives. For further details about the pharmacology of topiramate, see Table 53-2.

Toxicity Topiramate’s concerning side effects include nephrolithiasis and cognitive dysfunction. Cognitive difficulties (affecting speech and language) are insidious in onset and they affect up to one-fourth of patients. Notably, unlike most other AEDs, topiramate does not cause weight gain and is, in fact, associated with weight loss. For common side effects and teratogenic effects, see Table 53-3.

Uses Though it was initially felt to hold promise in the treatment of bipolar disorder, more recent evidence from four trials have suggested that it offers no benefit over placebo. It has been employed with some success in the treatment of symptoms (including mood lability and impulsivity) of borderline personality disorder. Studies have also shown that topiramate effectively decreases heavy drinking in alcohol-dependent patients and reduces alcohol craving. Use in this population is significantly limited, however, by adverse cognitive side effects. Topiramate has also been used to treat binge-eating, with some success shown in clinical trials.

Other New AEDs Pregabalin Pregabalin (Lyrica) is used as an adjunct therapy for partial seizures (with or without secondary generalization), and it is FDA-approved for use in fibromyalgia. It has a mechanism of action similar to that of gabapentin, and like gabapentin is rapidly absorbed, has low protein-binding, and is excreted by the kidney unchanged. For common side effects and teratogenic effects, see Table 53-3. Pregabalin is approved for GAD in Europe, but not in the United States. It remains under investigation for use in bipolar disorder.

Levetiracetam Levetiracetam (Keppra) has no approved uses in psychiatry, but is notable for being thought of as having a higher rate of adverse neuropsychiatric side effects than other agents, though some recent studies have suggested no difference from other antiepileptics. Side effects associated with its use include depression, mania, agitation, and (rarely) psychosis.

Suicidal Ideation and AEDs In 2008, the FDA issued a warning that all AEDs may increase suicidal thoughts or behaviors in patients taking them (for any reason). This was based on a pooled analysis of 199 placebo-controlled trials involving 11 different medications, which suggested that patients randomized to an AED had nearly twice the risk of suicidal thinking or behaviors compared to patients randomized to placebo. The frequency of suicidal thoughts or behaviors in these trials remained very low, and questions remain about the validity of the FDA’s conclusions.

Suggested References 1. Bowden CL: Anticonvulsants in bipolar disorders: current research and practice and future directions. Bipolar Disorders . 2009; 11(Supp l2): 20– 33. 2. Centorrino F, Albert MJ, Berry JM, et al: Oxcarbazepine: clinical experience with hospitalized psychiatric patients. Bipolar Disorders . 2003; 5: 370–374.

3. Hesdorffer DC, Kanner AM: The FDA alert on suicidality and antiepileptic drugs: fire or false alrarm? Epilepsia . 2009; 50(5): 978–986. 4. Ostacher MJ, Hsin H: The use of antiepileptic drugs in Psychiatry. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016; pp. 532–537. 5. Perlis RH, Ostacher MJ, Patel JK, et al: Predictors of recurrence in bipolar disorder: Primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry . 2006; 163; 217–224. 6. Stevens JR, Fava M, Rosenbaum JF, et al: Psychopharmacology in the Medical Setting. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed . Philadelphia, PA: Saunders/Elsevier, 2010; 441–466.

CHAPTER Stimulants, Atomoxetine, 54 Beta-Adrenergic Blocking Agents, and Alpha-Adrenergic Blocking Agents JEFFERSON B. PRINCE, MD AND NICHOLAS H. CAGGIANO, BS

KEY POINTS Overview A variety of stimulant preparations are currently FDA-approved for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults, as well as for narcolepsy. Mechanism of action: Stimulants increase intra-synaptic concentrations of dopamine and to a lesser degree norepinephrine. Stimulants are rapidly absorbed after oral administration and are preferentially taken up in the central nervous system. Alpha-adrenergic blockers: Alpha-2 adrenergic receptors are widely distributed in the brain, Clonidine has alpha-2 adrenergic agonist properties; it has a half-life from 8 to 12 hours. Guanfacine is a longer-acting, less sedating, and more selective agent; it is eliminated by renal excretion.

Stimulants Indications A variety of stimulant preparations are currently United States Food and Drug Administration (FDA)–approved for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults, as well as

for narcolepsy. However, stimulants can also have efficacy as adjunctive agents in the treatment of depression and apathy, and they can potentiate the effects of narcotic analgesics. The two classes of stimulants medications are methylphenidate (MPH) (i.e., Ritalin) and amphetamine (AMPH) (dextroamphetamine [Dexedrine], or a mixture of AMPH salts [Adderall]).

General Properties Actions: Stimulants have been shown to increase intra-synaptic concentrations of dopamine (DA) and to a lesser degree norepinephrine (NE). Both MPH and AMPH bind to the DA transporter protein, blocking the re-uptake of DA into the pre-synaptic neuron. Whereas MPH remains outside the cell, AMPH travels into the pre-synaptic neuron, causing several actions that result in more DA being released from pre-synaptic neurons into the inter-neuronal space. Stimulants (AMPH > MPH) also increase levels of NE and serotonin (5hydroxytryptamine; 5-HT) in the inter-neuronal space. Pharmacodynamics and pharmacokinetics: Stimulants are rapidly absorbed after oral administration and are preferentially taken up into the central nervous system (CNS). Food has little impact on the absorption of MPH but it can delay the absorption of AMPH. Stimulants bind poorly to plasma proteins and are rapidly metabolized by both hepatic and extra-cellular routes. MPH is primarily metabolized by plasma-based esterases, whereas 80% of AMPH is excreted in the urine unchanged and 20% is metabolized via several hepatic routes. Acidification of the urine can enhance excretion.

Methylphenidate Oral administration of immediate-release (IR) MPH results in a variable peak plasma concentration within 1 to 2 hours, and it has a half-life of 2 to 3 hours. Behavioral effects of MPH peak 1 to 2 hours after administration and tend to dissipate within 3 to 5 hours. Plasma levels of the sustained-release (SR) preparation of MPH peak in 1 to 4 hours, and have a half-life of 2 to 6 hours. Peak behavioral effects of this preparation occur 2 hours after ingestion and last up to 8 hours. Extended-delivery (ED) preparations of MPH are available with two different pharmacokinetic profiles. The first can be thought of as a “double camel hump” profile in which 50% of the MPH is delivered in a fashion similar to the IR preparation, and the remaining 50% is delivered approximately four hours after taking the medication (e.g., Ritalin-LA, Focalin-XR, Aptensio). There are

several other ED preparations that deliver MPH in an “ascending” pharmacokinetic profile. These MPH preparations (e.g., Concerta, Metadate-CD, Methylin-ER, Daytrana, Quillichew) deliver a smaller amount of MPH initially (22% of the dose for Concerta, 30% of the dose for Metadate-CD, and 30% for Quillichew) and their respective delivery system (the OROS system for Concerta and the Diffucaps systems of beads for Metadate, the trans-dermal system for Daytrana and ion exchange for Quillichew) spread the remainder of the MPH out over the course of the day, with levels peaking approximately 5 to 6 hours after dosing of Metadate-CD, 7 to 8 hours after dosing of Concerta, approximately 5 hours for Qullichew and 8 to 9 hours after dosing of Daytrana. Whereas generic MPH has a similar pharmacokinetic profile to Ritalin, it is more rapidly absorbed and peaks sooner. A variety of the ED preparations are now available as generics (see Tables 54-1, 54-2, 54-3, and 54-4). Tab le 54-1: FDA-Approved Treatments for ADHD

Medication

Usual Starting Dose

FDA Approved Daily Dose

Off-Label Max per Day*

Methylphenidate Preparations Immediate delivery MPH (Ritalin)

5 mg BID

60 mg

> 50 kg; 100 mg

Dex-MPH (Focalin)

2.5 mg BID

20 mg

50 mg

MPH (Methylin)

2.5 mg BID

Intermediate-delivery MPH SR (Ritalin SR)

10 mg QAM

60 mg

> 50 kg; 100 mg

MPH ER (Methylin ER)

10 mg QAM

60 mg

> 50 kg; 100 mg

MPH CD (MetadateCD)

10 mg QAM

60 mg

> 50 kg; 100 mg

MPH LA (Ritalin-LA) 20 mg QAM

60 mg

> 50 kg; 100 mg

MPH (Quilllichew)

20 mg QAM

60 mg

Dex-MPH-XR (Focalin XR)

5 mg QAM

30 mg

50 mg

MTS* (Daytrana)

10 mg QAM

30 mg

Not yet known

Extended-delivery

OROS-MPH (Concerta)

18 mg QAM

72 mg

MPH ER (Aptensio XR)

10 mg QAM

60 mg

MPH ER (Quillivant XR)

20 mg (4mL)

60 mg

108 mg

Amphetamine Preparations Immediate-delivery D-amphetamine (Dexedrine)

2.5-5 mg QD or BID

40 mg

>50kg; 60 mg

MAS (Adderall)

2.5-5 mg QD or BID

40 mg

>50kg; 60 mg

MAS XR (Adderal XR)

5-10 mg QD

30 mg

>50kg; 60 mg

LDX (Vyvanse)

20 mg QD

70 mg

Not yet known

Dexedrine Spansule

5-10 mg QD or BID

40 mg

>50kg; 60 mg

Amphetamine (Adzenys XR)

3.1 mg

18.8 mg

Atomoxetine (Strattera)

< 70 kg: 0.5 mg/kg/day for 4 days; then 1 mg/kg/day for 4 days; then 1.2 mg/kg/day

Lesser of 1.4 Lesser of 1.8 mg/kg/day or 100 mg mg/kg/day or 100 mg

Guanfacine XR (Intuniv)

1 mg

4 mg

Not yet known

Clonidine extendedrelease (Kapvay)

0.1 mg

0.4 mg

Not yet known

Extended-delivery

Table 54-2: Approved Ages of Medications for ADHD Medication Generic (Brand)

> 3 years > 6 years Adolescents Adults

Methylphenidate Preparations Immediate-release MPH (Ritalin)



Dex-MPH (Focalin)



Intermediate-delivery MPH SR (Ritalin-SR)



MPH ER (Methylin)



MPH CD (Metadate-CD)





MPH LA (Ritalin-LA) Extended-delivery Dex-MPH-XR (Focalin-XR)



MTS* (Daytrana)



OROS-MPH (Concerta)







Amphetamine Preparations Immediate-release D-amphetamine (Dexedrine)



MAS (Adderall)



Extended-delivery MAS XR (Adderall-XR)



LDX (Vyvanse)







Atomoxetine (Strattera)







Guanfacine XR (Intuniv)





Clonidine Extended-Release (Kapvay)





Dexedrine Spansule (Dexedrine)





MAS = mixed amphetamine salts; MTS = methylphenidate transdermal system; LDX = lisdexamphetamine.

Table 54-3: Medications Approved for ADHD: Methylphenidate (MPH) Preparations Available

Medication

Usual Starting Daily Dose

Therapeutic Range* (mg) (Ages 6–12; 13–18; Adult)

Usual Daily Dosing

Duration of Effect

MPH OROS (Concerta)

18 mg

18–54; 18–72; 18- or 36–72

Once

~12 hours

MTS (Daytrana)

10 mg

10–30; —; —

Once

~12 hours (worn for 9)

dex -MPH (Focalin XR)

5 mg

5–20; 5–20; 5–20

Once

10–12 hours

MPH (Metadate CD) 20 mg

10–60; —; —

Once

~8 hours

MPH (Ritalin LA)

10 mg

10–60; —; —

Once

~8 hours

MPH (Methylin ER)

5 or 10

5–60

Twice

~8 hours

d -MPH (Focalin)

2.5 mg

5–20† ; 5–20† ; —

Twice

~5 hours

MPH (Ritalin or Methylin)

5 mg twice

10–60; 10–60; 10–60

3 times

~4 hours

MPH (Quillivant or Quillichew)

20 mg once

10–60; 10–60; 10–60

Once

~4 hours

MPH (Aptensio XR)

10 mg once

10–60; 10–60; 10–60

Once

~4 hours

MTS = methylphenidate transdermal system

Table 54-4: Medications Approved for ADHD: Amphetamines Preparations Therapeutic Range* (mg) Starting (Ages 6–12; Usual Daily Daily Dose 13–18; Adult) Dosing

Duration of Effect

l -Lysinedextroamphetamine (Vyvanse)

20 mg once daily 20-70; —; 20-70

Once

~12 hours

MAS XR (Adderall XR)

5 to 10 mg

5–30; 5-20; 5–20

Once

~12 hours

Dextroamphetamine (Dexedrine Spansule)

5 mg once or twice

5–40; 5–40; 5–40

Once or twice

6-8 hours

Dextroamphetamine (Dexedrine)

2.5 to 5 mg once 5–40; 5–40; 5–40 or twice

2 or 3 times

4 hours

MAS (Adderall)

2.5 to 5 mg

5–40; 5–40; 5–40

2 or 3 times

4 hours

Amphetamine (Dyanavel XR)

2.5 mg/mL to 5 mg

2.5–20 mg

Once

4 hours

Amphetamine (Evekeo)

5 mg

2.5–20 mg

Once

4 hours

Amphetamine (Adzenys XR-ODT)

3.1 mg

18.8 mg

Once

4 hours

Medication

Concerta (OROS-MPH) uses an osmotic pump to deliver a 50:50 racemic mixture of d, l-threo-MPH. OROS MPH is available in 18, 27, 36, and 54 mg caplets. A single morning dose of the 18-mg caplet provides an initial 4-mg bolus of MPH, delivering the additional MPH in an ascending profile, with serum levels peaking approximately 7 to 8 hours after dosing. This 18-mg dose provides effective coverage for up to 12 hours, reduces tachyphalaxis (e.g., acute tolerance) in the afternoon and is equivalent to administering 5 mg of IR-MPH TID. Metadate CD (MPH MR) capsules contains two types of coated beads, IRMPH and ER-MPH (ER-MPH), in a 30:70 ratio. Therefore, the 20 mg MPH MR capsule consists of 6 mg of IR-MPH and 14 mg of ER-MPH. The IR-MPH

beads deliver 30% of d, l-threo-MPH initially, with initial peak serum concentration 1.5 hours after dosing. The ER-MPH beads deliver the remaining 70% of d, l-threo-MPH several hours later, achieving a second peak of similar magnitude 4.5 hours after dosing. MPH MR is available in capsules of 10, 20, 30, 40, 50, and 60 mg, which can be sprinkled on food and provides approximately 7 to 8 hours of coverage. Ritalin-LA (MPH-ERC) uses beaded technology to achieve a bi-modal release profile, which delivers 50% of its d, l-threo-MPH initially and another bolus approximately 3 to 4 hours later. MPH-ERC is available in capsules of 10, 20, 30, and 40 mg, essentially delivering an equivalent amount of MPH as 5-, 10-, 15-, or 20-mg IR-MPH dose in the morning and at noon, thus providing around 8 hours of coverage. The content of these capsules can be sprinkled on food, as well. Focalin-XR (d-threo-MPH-XR, d-MPH-XR) uses beaded technology to deliver d-threo-MPH a bi-modal release profile with 50% of its d-threo-MPH release immediately and another bolus approximately 4 to 5 hours later. As originally formulated, MPH was produced as an equal mixture of d, l-threoMPH and d, l-erythro-MPH. It was quickly recognized that the erythro form of MPH produced cardiovascular side effects, and thus MPH is now manufactured as an equal mixture of d, l-threo-MPH. Studies indicate that the primarily active form of MPH is the d-threo isomer. In terms of potency it is important to recognize that 10 mg of MPH is biologically equivalent to 5 mg of d-MPH. dMPH-XR is available in capsules of 5, 10, 15, 20, 30, and 40 mg, essentially delivering an equivalent amount of d-MPH as 2.5-, 5-, 10-, 15-, or 20-mg IR dMPH dose in the morning and at noon, usually providing coverage for 10 to 12 hours. The content of these capsules can be sprinkled on food, as well. Methylin ER is a tablet that delivers d, l-threo-MPH and is more slowly and extensively absorbed. A 10-mg ER tablet is bioequivalent to take IR-MPH in the morning and at noon, thus providing about 8 hours of coverage. Methylin ER is available as 10- and 20-mg tablets. Methylin IR is also available as an oral solution (5 mg/5 mL 10 mg/5 mL) or as a chewable tablet (2.5, 5, 10 mg), with each dose providing approximately 4 hours of coverage. Daytrana (MTS) use a trans-dermal system to deliver d, l-threo-MPH. MTS is applied to the skin once daily, takes approximately 90 to 120 minutes to begin to take effect, is intended to be worn for 9 hours and then removed. Peak MPH levels occur approximately 8 to 9 hours after dosing and when worn for 9 hours

provides approximately 12 hours of coverage. MTS is available in 10-, 15-, 20-, and 30-mg patches. Aptensio XR (methylphenidate extended release) uses a capsule to deliver d, l-threo-MPH. This system delivers MPH in two “peaks”, one approximately two hours after it is taken and another about eight hours later. Aptensio XR capsules are available in 10, 15, 20, 30, 40, 50, and 60 mg. It is important to note that Capsule/capsule of Aptensio XR content should not be crushed, chewed, or divided. QuillliChew ER releases d, l-threo-MPH via a chewable tablet which releases medication from sodium polystyrene sulfonate particles via ion exchange (30% IR, 70% ER) and provides approximately 8 hours of coverage. This MPH preparation is available in strengths of 20-, 30-, and 40-mg chewable ER tabs (20-mg and 30-mg tabs are scored). Quillivant XR delivers, l-threo-MPH via an extended-release oral suspension (25 mL/5mL). The recommended starting dose is 20 mg (4 mL) given orally once daily in the morning. Dosage can be increased weekly in increments of 10 mg (2 mL) to 20 mg (4 mL) per day. Daily dosage above 60 mg (12 mL) is not recommended. It’s important to remember to shake the bottle well before drawing the solution into the plunger (included with the medication).

Dexedrine (Dextroamphetamine) Dextroamphetamine achieves peak plasma levels 2 to 3 hours after oral administration, and it has a half-life of 4 to 6 hours. Behavioral effects of dextroamphetamine peak 1 to 2 hours after administration, and last 4 to 5 hours. Immediate release Dextroaphetamine is now available in several preparations; Dextrostat tablets (5-mg or 10-mg tablets), ProCentra oral solution (1 mg/mL) or as tablets of Zenzedi (available in 2.5-, 5-, 7.5-, 10-, 15-, 20-, and 30-mg tablets). For dextroamphetamine spansules, these values are all somewhat longer. Vyvanse (lisdexamfetamine ) is a capsule containing l-lysine co-valently bound to dextroamphetamine. In the gastrointestinal (GI) tract this co-valent bond is broken and dextroamphetamine is released. This formulation means that lisdexamfetamine is less likely to be misused (i.e., it cannot be snorted with effect because the dextroamphetamine is not released) or overdosed on (breaking the bond is a rate-limiting step and the GI transit will cause much of an overdose to be excreted unabsorbed), however it still can be shared. Lisdexamphetamine appears to be more gradually absorbed than MAS XR and it appears to be approximately half as potent (meaning that a patient who requires 30 mg of

MAS XR will likely need 60 mg of Vyvanse). Lisdexamphetamine is available in capsules of 20, 30, 40, 50, 60, and 70 mg and provides up to 12 hours of coverage from an AM dose.

Adderall (Mixed AMPH salts) Adderall is a racemic mixture of d- and l-amphetamine. The two isomers have different pharmacodynamic properties. Some patients with ADHD might have a preferential response to one isomer over another. Data in youth with ADHD suggest that when compared to IR Ritalin, peak behavioral effects of Adderall occur later and are more sustained. Adderall XR (MAS XR) is an ED preparation of MAS. MAS XR is a capsule containing two types of beads present in a 50:50 ratio, with IR beads designed to release MAS in a fashion similar to MAS tablets, and delayed-release beads designed to release MAS 4 to 6 hours after dosing. MAS XR is available as 5-, 10-, 15-, 20-, 25-, and 30-mg capsules.

Additional Recent Amphetamine Preparations Adzenys XR-ODT (amphetamine) was approved by the FDA in January of 2016 as the first orally-disintegrating tablet (ODT) of amphetamine. This orange-flavored tablet should be placed on tongue and allowed to disintegrate, with or without water but should not be chewed, crushed, or swallowed whole. Adzenys XR-ODT delivers amphetamine using two different kinds of “microparticles” with 50% of the particles dissolving immediately, whereas the other 50% dissolve slowly, releasing medication across the course of 12 hours. Adzenys XR-ODT is available in strengths of 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, and 18.8 mg (see Table 54-5). Table 54-5: Equivalent Doses of Adzenys XR-ODT and Adderall XR Adzenys XR-ODT(TM) Adderall XR 3.1 mg

5 mg

6.3 mg

10 mg

9.4 mg

15 mg

12.5 mg

20 mg

15.7 mg

25 mg

18.8 mg

30 mg

Dyanavel XR (amphetamine ER suspension) delivers amphetamine in a liquid solution that is released from sodium polystyrene sulfonate resin via ion exchange. It is available as 2.5-mg/mL oral suspension. It should be administered once daily in the morning without regard to meals. It is important to remember to shake the bottle well prior to dosing. Evekeo (amphetamine) delivers a 1:1 ratio of amphetamine:dextroamphetamine in 5- and 10-mg scored tablets. It provides coverage for approximately 9 hours.

Using Stimulants ADHD Either IR or ED preparations of stimulants can be used initially in the treatment of ADHD. Given the wide variance in appropriate dose the pharmacologic treatment of ADHD should be tailored for each patient. This usually results in patients using a combination of IR and ED preparations to provide the best balance between tolerability, efficacy, and effectiveness, although the efficacy of this practice has not been well demonstrated. Short-acting stimulants are typically initiated at low doses (2.5–5 mg/day for children and adolescents; 5–10 mg/day in days in adults), given in the morning with food. Every few days the dose can be increased (usually in increments of 2.5–5 mg/day in children and adolescents; 5–10 mg/day in adults), generally given in divided doses. Although none of the stimulants are approved based on weight and there is a wide range of effective doses, weight is often used as a clinical guide. Suggested daily dose ranges are 0.3 to 1.5 mg/kg/day for AMPH and 1.0 to 2.0 mg/kg/day for MPH preparations. There are importance differences in potency between stimulants. Five mg of AMPH is approximately equal to 10 mg of MPH.

Extended Delivery (ED) Preparations Since 2000, a number of ED formulations of MPH and AMPH have become available. Although these preparations deliver either MPH or AMPH, the manner in which they are dosed varies. It is important to understand the various pharmacokinetic preparations. At present, treatment for ADHD is usually initiated with any one of these ED preparations; there is no “holy grail” of treatment. Any one of the IR or ED stimulant preparations (or a non-stimulant) can be used initially. The process of identifying the best treatment often involves answering two clinical questions: “How well is the medication tolerated?” and “How well does it work?” Collaboration between the clinician and patient/family

as well as the answers to these questions guides treatment. At the beginning of the process it is usually wise to encourage taking the medication day-by-day. This practice permits patients and their significant others to observe them in a variety of contexts, which usually differ in demands and supports. After identifying the best treatment, the clinician and patient/family collaborate to identify in which context is it best to treat. For some patients this means, “while awake” (i.e., throughout the time), whereas for others treatment might only be necessary in circumscribed situations. Unfortunately, serum stimulant levels do not help in determining an effective dose. Recently it has been suggested that patients who require higher doses of stimulants might inefficiently absorb stimulants from the GI track and can use peak serum levels to document how much of a dose is being absorbed. Numerous short-term (less than 12 weeks) clinical trials show that approximately 70% of patients with ADHD respond to a stimulant; a positive dose–response relationship is present for both the behavioral and cognitive effects of stimulants (when used in children, adolescents, and adults with ADHD). Clinicians face a number of challenges when prescribing stimulants. Because stimulants can decrease appetite in this patient population, it is often useful to administer stimulants during or after meals. Food might even enhance their bioavailability. Stimulant-induced sleep disturbances are common and can diminish their efficacy. Such disturbances might require alteration of the timing or the amount of medication given, or require the administration of a sleep aid. Irritability or dysphoria can occur either 1 to 2 hours after administration of stimulants (that suggests an absorption peak phenomenon, which might respond to lower, more frequent doses).

Co-Morbidity Typically, ADHD is co-morbid with other disorders that can alter the stimulants’ effectiveness. For instance, a patient with ADHD and a co-morbid mood or anxiety disorder might respond differently to a stimulant depending on the clinical state of their co-occurring disorder. In addition, stimulants can exacerbate tics, obsessions, or compulsions, although they are frequently used in patients with these conditions.

Tolerance and Abuse Clinicians are often concerned about growth delays, tolerance, and abuse among stimulant-treated patients. Although short-term decreases in weight are

often seen in children treated with stimulants, follow-up studies into adulthood have not demonstrated a decrease in the ultimate height attained. Although tolerance to the effects of stimulants on ADHD symptoms has been debated, recent data from the National Institute of Mental Health (NIMH) Multi-modal Treatment of ADHD demonstrated the persistence of stimulant-medication effects. In usual clinical doses, tolerance to the effects of stimulants on ADHD symptoms does not appear to develop. Stimulants are schedule II medications that have the potential for abuse. Although the rates of substance abuse in patients with ADHD are increased, the use of stimulants does not appear to increase the risk of substance abuse; recent data suggests that successful stimulant treatment of children with ADHD might delay or decrease their risk of substance abuse in adolescence.

Narcolepsy and Depression in the Medically Ill In the treatment of narcolepsy , both MPH and dextroamphetamine are used in doses of 20 to 200 mg/day. Stimulants appear most effective in treating the daytime somnolence and sleep attacks associated with narcolepsy, and less beneficial for cataplexy. Stimulants also have a role in the treatment of depressed, apathetic states in the medically ill or elderly and can rapidly improve mood, interest, medical compliance, and even appetite. Stimulants can also be useful in reducing the narcotic requirement of terminally ill patients and diminishing the sedation associated with high doses of narcotics.

Side Effects Stimulants can cause clinically significant anorexia, nausea, difficulty falling asleep, rebound phenomena, anxiety, nightmares, dizziness, irritability, dysphoria, and weight loss. They also are associated with small increases in heart rate and blood pressure that tend not to be clinically significant. Occasionally, they can elicit a depressive reaction or psychosis. Stimulant use might exacerbate tics or Tourette’s syndrome. Concerns over stimulant-induced growth impairment remain but have not been borne out. Even though a physical withdrawal is not associated with stimulants, patients who have used high doses for a long time can experience fatigue, hypersomnia, hyperphagia, dysphoria, and depression upon their discontinuation. Given the abuse potential of these medications, it is important to inquire about concomitant use of drugs and alcohol.

Drug Interactions

The interactions of stimulants with other prescription and non-prescription medications are generally mild. Concomitant use of sympathomimetic agents (e.g., pseudoephedrine) can potentiate the effects of both medications. Concurrent use of antihistamines can diminish the effects of stimulants. Coadministration of monoamine oxidase inhibitors (MAOIs) with stimulants can result in a hypertensive crisis and be potentially life threatening. Although recent data on the co-administration of stimulants with tricyclic antidepressants (TCAs) suggests little interaction between these compounds, careful monitoring is warranted when prescribing stimulants with either TCAs or anticonvulsants.

Beta-Adrenergic Blockers Indications Beta-blockers (ß -blockers) have a variety of uses in psychiatry. They are frequently used in the treatment of performance anxiety, lithium-induced tremor, and neuroleptic-induced akathisia. They are also reported to be useful in the control of aggressive outbursts in patients with brain injury, autism, or intellectual disability. They have also been used in combination with other agents in the treatment of panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), ethanol withdrawal, and ADHD, as well as with severe aggression or impulsivity. Their non-psychiatric uses include the treatment of hypertension, arrhythmia, neurally-mediated hypotension, migraine prophylaxis, glaucoma, symptoms of thyrotoxicosis, and acute myocardial infarction. The ß -blockers most commonly used in psychiatry include propranolol, nadolol, metoprolol, and atenolol.

General Effects ß -blockers act as competitive antagonists of epinephrine (EPI) and norepinephrine (NE) at post-synaptic beta-adrenergic receptors. Peripherally, EPI and NE modulate control of blood pressure and are released as stress hormones by the adrenal medulla. ß 1 receptors are located on the heart; they stimulate it chronotropically and inotropically. ß 2 receptors are found in the lung and on blood vessels. ß 2 receptor stimulation produces bronchodilation and vasodilation. Centrally, the role of EPI is limited; however, the noradrenergic system is involved in the regulation of anxiety, mood, hormone release, sleep, pain, and vigilance. In the brain, ß 1 receptors are located on neurons throughout the noradrenergic system, whereas ß 2 receptors are primarily located on glial cells.

ß -blockers differ in their selectivity of ß 1 and ß 2 receptor blockade, lipophilicity, route of elimination, and half-life (see Tables 54-6 and 54-7). Propranolol and nadolol are non-selective ß -blockers, whereas metoprolol and atenolol are selective ß 1 receptor antagonists. These medications differ in their lipophilicity, which distinguishes their central and peripheral effects. Propranolol and metoprolol are highly lipophilic and thus easily cross the blood-brain barrier, whereas atenolol and nadolol have few central effects. Propranolol and metoprolol are metabolized by hepatic enzymes, whereas atenolol and nadolol are eliminated by the kidneys. Table 54-6: Beta-Adrenergic Blockers Brand Name

Generic Name

Daily Dose (mg/d)

Daily Dosing Schedule

Preparations Available

Inderal

propranolol

10–640

BID–TID

10, 20, 40, 60, 80, 90, 4 or 8 mg/ml

Inderal-LA

propranolol-LA

80–320

QD

60, 80, 120, 160

Lopressor

metoprolol

50–450

BID–TID

50, 100

Toprol XL

metoprolol-XL

50–400

QD

50, 100, 200

Tenormin

atenolol

25–100

QD

25-, 50-, 100-mg tablets

Corgard

nadolol

20–320

QD

20-, 40-, 80-, 120-, 160-mg tablets

Kerlone

betaxolol

5–20

QD

10- or 20-mg tablets

Table 54-7: Beta-Adrenergic Blockers Medication

Selectivity Lipophilicity Half-life (hrs) Route of Elimination

Inderal (propranolol)

ß 1, ß 2

high

3–6

Liver

Lopressor (metoprolol) ß 1

high

3–4

Liver

Tenormin (atenolol)

ß 1

low

6–9

Kidney

Corgard (nadolol)

ß 1, ß 2

low

14–24

Kidney

Kerlone (betaxolol)

ß 1

low

14–22

Kidney

Using ß -Blockers General Guidelines

ß -blockers should be started at low doses and then gradually titrated up. Patients should be educated about how to monitor blood pressure and pulse. Side effects (such as hypotension, dizziness, bradycardia, and bronchospasm) should be monitored. Doses should be held if the blood pressure is less than 90/60 mm Hg or the pulse is less than 55 beats/minute. In adults, propranolol should be started in dosages of 10 mg three times daily when using the regular-release preparation, or at 80 mg once daily for the longacting (LA) preparation. Propranolol can be titrated up (until the desired therapeutic effect is achieved) with a maximum dose of 640 mg/d of the regular preparation and 320 mg/d of the LA form. In children, the dosage range is generally 1 to 5 mg/kg/d. Metoprolol is usually begun at 50 mg twice daily, with a maximum dosage of 450 mg/d of the regular-release preparation; the ER form is begun at 50 mg once daily with a maximum of 400 mg/d. Nadolol is started at 20 mg once daily with a maximum of 320 mg/d. Atenolol is begun at 25 mg once daily with a maximum of 100 mg/d.

Use in Selected Conditions When selecting a ß -blocker, consideration needs to be given to the desired therapeutic effect as well as to the patient’s other conditions. For performance anxiety a single dose of 10 to 40 mg of propranolol given 30 minutes prior to the event is often useful. A test dose in an anxiety-provoking environment, but prior to the actual event, is usually indicated to assess tolerability. Because most symptoms of performance anxiety are peripheral, less lipophilic compounds (like nadolol or atenolol) might be equally useful. Lithium-induced tremor often responds to 20 to 160 mg of propranolol per day. Nadolol or atenolol can be as effective and lessen concern over worsening of depression by ß -blockers. For neuroleptic-induced akathisia, both propranolol (30–80 mg/d) and nadolol (40–80 mg/d) are reported useful. Due to its generic availability, low lipophilicity (doesn’t cross the blood–brain barrier), high ß -1 selectivity, low medication interactions, and long half-life (permitting once-daily dosing), clinicians should consider the use of bextaxolol (5–20 mg/d). For the hyper-aroused state associated with ethanol withdrawal, atenolol (50– 100 mg/d) has utility as an adjunct to benzodiazepines. ß -blockers are not adequate as a single medicine for detoxification. In the treatment of ADHD, propranolol (in dosages up to 640 mg/d) has been found to be useful in adults with severe temper outbursts. Several clinical reports

indicate that combining ß -blockers with stimulants can be useful in improving the tolerability of the stimulants. There are reports of using high doses of propranolol (50–1600 mg/d) to control aggressive outbursts in children and adults with organic brain dysfunction. Several open case series describe the utility of propranolol (dosages 2.5 mg/kg/d) in the treatment of children with PTSD. A recent systematic review and meta-analysis of randomized controlled trials investigated the efficacy of propranolol in the treatment of anxiety disorders. Although pooled analysis found no difference between propranolol and benzodiazepines in the treatment of panic with or without agoraphobia, the authors found no evidence to support the use of propranolol for reducing PTSD symptom severity through inhibition of memory re-consolidation. Despite a long history of seemingly utility, these authors conclude, based on the studies that meet criteria for inclusion, that at this time the evidence base does not support the use of propranolol in the treatment of anxiety disorders.

Side Effects ß -blockers can have a variety of clinically-significant side effects, including hypotension; bradycardia; dizziness; bronchoconstriction(less problematic with selective agents); nausea; diarrhea; constipation; impotence; fatigue; depression; insomnia; vivid dreams; worsening of hypoglycemia in patients with diabetes; and rebound hypertension (if abruptly discontinued). Less frequent reactions include Raynaud’s phenomenon, Peyronie’s disease, psychosis, and allergies. ß blockers can also suppress melatonin and might potentiate the effects of growth hormone. ß -blockers have little adverse effect on memory, and they might enhance performance. ß -blockers should not be given to patients with untreated pheochromocytoma, and these agents have been reported to aggravate psoriasis.

Drug Interactions Those ß -blockers metabolized hepatically (i.e., propranolol and metoprolol) are primarily metabolized by the P-450 CYP2D6 enzyme. Thus, medications that inhibit 2D6 activity (e.g., fluoxetine, sertraline, desipramine, clomipramine, haloperidol, fluphenazine, paroxetine, thioridazine) will increase the levels of these ß -blockers, necessitating a decrease in dosage. Similarly, medications that induce 2D6 activity (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) might increase the metabolism of these ß -blockers, which results in decreased effects. Reports of increased levels of theophylline, thyroxine, and imipramine after the addition of ß -blockers have been made. Propranolol is highly protein-

bound; this is an important factor when considering drug interactions. ß blockers must be used cautiously and with close monitoring if used with other anti-arrhythmic medications. If ß -blockers are used with amiodarone, an antiarrhythmic agent with negative chronotropic properties, these effects can be additive. Disopyramide is a Type I anti-arrhythmic drug with potent negative inotropic and chronotropic effects that has been associated with severe bradycardia, asystole, and heart failure when administered with ß -blockers. In the prefrontal cortex (PFC) many α 2A -receptors are found on the dendritic spines of these neurons. When NE binds to post-synaptic, α 2A -receptors, it results in the closing of potassium channels, strengthening synaptic transmission and thus facilitating the connectivity of the PFC to regulate attention, behavior, and/or emotion.

Atomoxetine Indications: Although originally studied as an antidepressant , atomoxetine (ATMX) is indicated to treat ADHD in children (6 years or older), adolescents, and adults. General Actions: ATMX, a highly selective NE re-uptake inhibitor, has recently been approved for the treatment of ADHD in children, adolescents, and adults. Unlike the stimulants, ATMX is not a class II medication; therefore, clinicians can provide samples as well as prescribe refills. ATMX acts by blocking the NE re-uptake pump on the pre-synaptic membrane, thus increasing the availability of intrasynaptic NE. ATMX is thought to primarily enhance NE neurotransmission in the PFC. In rats, ATMX has been shown to enhance the interneuronal concentration of both NE and DA. Using ATMX: In many patients ATMX is initiated at 0.5 mg/kg/day and after a few days it can be increased to a target dose of 1.2 mg/kg/day; however, some patients require a slower titration. Although ATMX was initially titrated up to 2 mg/kg/day in divided doses, the current dosing guidelines recommend a maximum dosage of 1.4 mg/kg/day in a single daily dose (usually after breakfast). Whereas the plasma half-life appears to be around 5 hours, the CNS effects appear to last longer than 24 hours. Therefore, many patients can be effectively covered by a single daily dose, although some patients can benefit from twice-daily dosing. Although benefits can be seen early in treatment, the full benefit of ATMX might take several weeks. Plasma levels

are generally not used to direct ATMX dosing. ATMX is a schedule IV medication; therefore, clinicians can provide refills. ATMX is rapidly absorbed after oral administration, reaching peak concentration 1 to 2 hours after dosing (see Table 54-8). Food does not appear to affect the absorption of ATMX. ATMX is metabolized primarily in the liver to 4hydroxyatomoxetine by the cytochrome (CYP) P450 2D6 enzyme. In extensive metabolizers, the steady-state plasma half-life of ATMX is 3.28 hours with Cmax of N -desmethylatomoxetine of 22.67 ± 98.4 ng/mL. The minor metabolite of ATMX is desmethylatomoxetine that is primarily formed by CYP 2C19. In patients with compromised CYP 2D6 function, other enzymes were observed to be capable of forming 4-hydroxyatomoxetine. Although patients identified as “poor metabolizers” (i.e., low 2D6 activity) appear to generally tolerate ATMX; these patients seem to have more side effects, and a reduction in dose might be necessary. For patients who are taking medications that are strong 2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine), it might be necessary to reduce the dose of TMX. Use of ATMX is contraindicated with MAOIs. ATMX has been coadministered with albuterol (600 mcg IV) in patients with asthma. Mild elevations in heart rate and blood pressure with ATMX alone have been observed. ATMX is primarily excreted in the urine. Table 54-8: FDA-Approved Non-Stimulants Medications for ADHD Medication

Starting Target Dose Dose

Duration of Usual Daily Dosing Effect

Norepinephrine Re-Uptake Inhibitor Atomoxetine (Strattera)

0.5 mg/kg/d 1.2 mg/kg/d Once

Up to 24 hours

1 mg/d

Alpha-2a Receptor Agonist Guanfacine XR (Intuniv)

Clonidine extended-release (Kapvay) 0.1 mg

1–4 mg/d

Once

About 12 hours

0.1–0.4

BID

About 12 hours

ATMX can be associated with reduced appetite, dyspepsia, fatigue, sexual side effects, and dizziness. Extensive laboratory testing in controlled clinical trials suggests that ATMX causes no organ toxicity. However, there are reports of significant hepatoptoxicity in two patients taking ATMX (out of millions of patients exposed), fortunately, both patients recovered upon discontinuation of ATMX. The manufacturer recently added a bolded warning to the labeling about

hepatotoxicity ( www.fda.gov/bbs/ topics/ANSWERS/2004/ANS01335.html ). The warning indicates that ATMX should be discontinued in patients with jaundice and that patients should contact their doctors if they develop pruritis, jaundice, dark urine, right-upper-quadrant tenderness, and/or unexplained “flu-like” symptoms. Hepatic impairment significantly reduces clearance of ATMX. At this time, laboratory monitoring outside of routine medical care is usually not necessary. The impact of ATMX on the cardiovascular system appears minimal and extensive electrocardiogram (EKG) monitoring indicates that ATMX has no apparent effect on QTc intervals, and EKG monitoring outside of routine medical care does not appear necessary.

Alpha-Adrenergic Blockers Indications Clonidine (Catapres) has been used in the treatment of hypertension in adults since the 1960s. In psychiatry, clonidine has been used for opioid withdrawal, nicotine withdrawal, Tourette’s syndrome, ADHD, mania, neuroleptic-induced akathisia, behavioral dyscontrol in autism, anxiety disorders, PTSD, and sleep disturbances. Kapvay, an ED formulation of clonidine is FDA-approved for the treatment of ADHD, either alone or in combination with stimulants. Guanfacine (Tenex) has been used for PTSD, ADHD, Tourette’s syndrome, and sleep disorders. Intuniv, an ED formulation of guanfacine is FDA-approved for the treatment of ADHD, either alone or in combination with stimulants. Prazosin (minipress) is FDA approve for the treatment of hypertension and is used for PTSD and its related sleep disturbances (see Table 54-9). Table 54-9: Alpha-Adrenergic Blockers Brand Name

Generic Name

Daily Dose (mg/d)

Daily Dosing Schedule

Preparations Available

Catapres-TTS

catapres-TTS

0.1–0.9

one patch per week

0.1-, 0.2-, 0.3-mg/d patches

Catapres

clonidine

0.05–2.4

QD-QID

0.1-, 0.2-, 0.3-mg tablets

Kapvay

clonidine

0.1–0.4

QD-BID

0.1-, 0.2-mg tablets

Tenex

guanfacine

0.5–3

QD-TID

1-, 2-mg tablets

Intuniv

guanfacine

1–4

QD

1-, 2-, 3-, 4-mg tablets

Minipress

prazosin

1–15

QHS-BID

1-, 2-, 5-mg capsules

General Effects ∝ -2-adreneric receptors are widely distributed in the brain. Pre-synaptic ∝ -2adreneric receptors are located on noradrenergic neurons in the locus coeruleus and the brainstem. These receptors function as inhibitory auto-receptors to suppress cell firing, inhibit release of NE, and down-regulate central noradrenergic neurotransmission. Post-synaptic ∝ -2-adreneric receptors modulate neuronal excitability and regulate release of neurotransmitters (e.g., DA. 5-HT) and hormones (e.g., growth hormone). Clonidine is an imidazoline derivative with ∝ -2-adreneric agonist properties. It is almost completely absorbed after oral administration and it achieves peak plasma concentrations in 1 to 3 hours. Clonidine’s plasma half-life ranges from 8 to 12 hours in children and from 12 to 16 hours in adults. Clonidine is highly lipophilic and it easily crosses the blood–brain barrier. Although some clonidine is metabolized by the liver, most is excreted unchanged by the kidney. Guanfacine is a longer-acting, less sedating, and more selective ∝ -2 adrenergic agonist that appears to mimic the actions of NE on the ∝ -2a adrenergic receptor, especially in the PFC. Guanfacine is eliminated by renal excretion; it has an excretion half-life of 17 hours in adults. Guanfacine is more selective than clonidine for the ∝ -2a adrenergic receptor. Guanfacine binds poorly to imidazoline receptors in the brainstem, which modulate the antihypertensive effects of clonidine, and it has one-tenth of the affinity of clonidine for presynaptic ∝ -2-adreneric receptors. This characteristic can prove advantageous because these receptors appear to be located primarily in the PFC. Thus, guanfacine might have a more selective beneficial effect on attention. Prazosin hydrochloride is a quinazoline derivative that is lipid soluble and acts as a α -1 adrenergic receptor blocker. In the vasculature, this effect causes a reduction in total peripheral resistance and directly relaxes vascular smooth muscle. In the CNS, this effect is thought to decrease sympathetic outflow. After oral administration prazosin has a Tmax of 0.5 to 3 hours, a bioavailability of 56% to 63%, is highly protein bound (92–97%), and its Cmax is not affected by food. Prazosin is extensively metabolized in liver via demethylation and conjugation, forming O-demethylated metabolites that are active. The half-life of prazosin is 2 to 3 hours, and is primarily excreted in the feces.

Using Clonidine, Guanfacine, and Prazosin When using these medications (see Table 54-9), it is critical to begin at a low dose and titrate it slowly because of sedation and adverse cardiovascular effects.

Clonidine is manufactured in 0.1-, 0.2-, and 0.3-mg tablets. Depending on the age and size of the patient, clonidine is generally begun at half of a 0.1-mg tablet once or twice a day. Titration should proceed slowly and carefully until the desired benefit is reached. The behavioral effects of clonidine seem to last between 3 to 6 hours, and thus multiple daily doses are typically required. There is also a trans-dermal therapeutic system (Catapres-TTS). The patch provides more sustained coverage and eliminates the need for repeated doses. It should be placed on a clean, dry, hairless patch of skin. The patch can be irritating to the skin, and dermatitis can limit its tolerability. Kapvay is the ED formulation and is usually started at a dose of 0.1 mg at night, and it can be titrated up in weekly fashion by 0.1 mg. Doses over 0.1 mg are given twice daily, approximately 12 hours apart. Guanfacine is generally less sedating than is clonidine and it is used in the treatment of ADHD, tic disorders, and to some degree, in sleep disorders. Two uncontrolled studies noted improvements in hyperactivity, inattention, and immaturity with no effect on mood or aggression. Guanfacine is one-tenth as potent as clonidine. It is generally begun with half of a 1-mg tablet daily and gradually titrated upward until the desired benefit is achieved. Intuniv, the oncedaily formulation of guanfacine, should be started at 1 mg daily, often given at bedtime, but it can be then switched to the morning. It is titrated in weekly fashion up to 4 mg daily. Clinically some patients benefit from twice-daily dosing. It is important not to confuse the dosages of clonidine and guanfacine. Prazosin, which is FDA-approved for treatment of hypertension, is initiated at 1 mg orally at bedtime. Clinical trials suggest efficacy of titrating up to doses of 1 to 4 mg at bedtime in children and adolescents and up to 15 mg/day (fourtimes-daily or twice-daily dosing) in adults. Prazosin improves nightmares and overall PTSD symptoms and can help with the sleep disturbances, total sleep time, and sleep quality.

Side Effects The ∝ -adrenergic agonists can have several clinically-significant side effects, including dry mouth or eyes, sedation, postural hypotension, fatigue, vivid dreams or nightmares, nausea, and depression. Cardiac side effects including dysrhythmia, bradycardia, non-conducted P-waves, supraventricular premature complexes, intraventricular conduction delays, and T-wave abnormalities have been described. Rare idiosyncratic side effects include hallucinations, rash, pruritus, alopecia, hyperglycemia, gynecomastia, and an increased sensitivity to

alcohol. If these medications are abruptly withdrawn, there is a risk (especially when used in doses greater than 0.6 mg/d) of a rebound hypertensive crisis. Symptoms usually begin 18 to 20 hours after the last dose. These medications should be tapered, not abruptly discontinued. Dermatitis can develop if the transdermal patch is used; this can be treated with hydrocortisone cream.

Drug Interactions Clonidine should not be administered concomitantly with ß -blockers, because severe adverse reactions have been reported. Although concerns were raised about the concomitant administration of clonidine and methylphenidate, the combination of both methphenidate and clonidine as well as methyphenidate and guanfacine are now FDA-approved. Prazosin administered with asenapine, tadalafil, vardenafil or sildenafil can result in additative hypotensive effects.

Suggested References 1. Arnsten AFT, Pliska SR: Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacology, Biochemistry and Behavior . 2011; 99: 211–216. 2. Labbate LA, Fava M, Rosenbaum JF, et al: Handbook of Psychiatric Drug Therapy . 6th ed . Philadelphia, PA: Lippincott Williams & Wilkins; 2010. 3. Prince JB: Pharmacotherapy of attention-deficit hyperactivity disorder in children and adolescents: update on new stimulant preparations, atomoxetine, and novel treatments. Child Adoles Psychiatric Clin North Am . 2006; 15(1): 13–50. 4. Singh B, Hughes AJ, Mehta G, et al: Efficacy of prazosin in post-traumatic stress disorder: A systematic review and meta-analysis. Prim Care Companion CNS Disord . 2016 Jul 28; 18(4). doi: 10.4088/PCC.16r01943. 5. Steenen SA, van Wijk AJ, van der Heijden GJ, et al: A. Propranolol for the treatment of anxiety disorders: Systematic review and meta-analysis. J Psychopharmacol . 2016 Feb; 30(2): 128–139. doi: 10.1177/0269881115612236. 6. Stevens JR, Wilens TE, Stern TA: Using stimulants for attentiondeficit/hyperactivity disorder: clinical approaches and challenges. Prim Care Companion CNS Disord . 2013; 15(2). pii: PCC.12f01472. doi:

10.4088/PCC.12f01472. Epub 2013 Mar 28. 7. Wilens TE, Morrison NR, Prince J: An update on the pharmacotherapy of attention-deficit/hyperactivity disorder in adults. Expert Rev Neurotherapeutics . 2011; 11(10): 1443–1465.

CHAPTER Drug–Drug Interactions in 55 Psychopharmacology JONATHAN E. ALPERT, MD, PHD

KEY POINTS Overview Drug–drug interactions involving psychotropic medications are ubiquitous. Fortunately, only a small number are life-threatening, such as those related to serotonin syndrome or hypertensive crises, though many involve clinicallysignificant changes in drug tolerability or efficacy. This chapter describes mechanisms and precepts relevant to understanding clinically-significant drug–drug interactions in psychiatry as well as a detailed description of important interactions in clinical practice. Classification Drug–drug interactions can be classified as pharmacodynamic, pharmacokinetic, mixed, or idiosyncratic. Pharmacodynamic interactions involve interference of drug action at biologically-relevant target sites rather than changes in drug levels or concentrations and can be antagonistic, additive, or synergistic. Competition between yohimbine and guanfacine at the α 2 adrenergic receptor is an example of a pharmacodynamic interaction. Pharmacokinetic interactions involve changes in drug serum levels and/or tissue concentrations related to interference with one of the four pharmacokinetic processes: absorption, distribution, metabolism, or excretion. Potentially increased lithium levels due to high-dose non-steroidal antiinflammatory agents or decreased quetiapine levels due to phenobarbital are examples of pharmacokinetic interactions. Mixed interactions involve both a pharmacodynamic and pharmacokinetic component, such as the increased levels of dextromethorphan and potential for serotoninergic toxicity when the cough suppressant is co-administered with paroxetine. Idiosyncratic drug–drug interactions refer to sporadic interactions, often

exemplified in case reports, whose mechanism has not yet been elucidated. Approach By knowing more about rare but catastrophic drug–drug interactions as well as more common, though rarely life-threatening, drug–drug interactions, clinicians are in a stronger position to anticipate and avert adverse drug–drug interactions when treating patients on complex regimens and are more likely to recognize and address clinically-significant drug–drug interactions expeditiously in the setting of perplexing and worrisome clinical presentations.

Introduction Drug–drug interactions refer to alterations in drug levels and/or drug effects attributed to the administration of two or more prescribed, illicit, or over-thecounter (OTC) agents in close temporal proximity. Although many drug–drug interactions involve drugs administered within minutes to hours of one another, some drugs interact days to weeks after their discontinuation by virtue of their long half-lives and/or long-term impact on the activity of metabolic enzymes. Therefore, recent as well as current drug use must be considered in the evaluation of potential drug–drug interactions. The most significant consequences of drug–drug interactions include serious adverse events, such as cardiac arrhythmias, seizures, gastrointestinal (GI) bleeding, falls, serotonin syndrome, or hypertensive crises. Among patients over the age of 55 years, serious adverse consequences of drug–drug interactions are believed to account for up to 5% of hospital admissions. Drug–drug interactions can also account for unexpectedly high or low serum drug levels, side effects that jeopardize tolerability and adherence, or reduced drug efficacy leading to non-response or to loss of a previous stable response to a drug whose levels or receptor activity have been altered by a second agent.

Relevance to Clinical Decisions Drug-drug interactions involving psychotropic medications are ubiquitous, particularly among patients with treatment-refractory psychiatric disorders and those with co-morbid psychiatric or medical illnesses who are likely to require multiple medications.

Fortunately, most drug–drug interactions between psychotropic and other medications do not contraindicate their combined use. Rather, awareness of such interactions should prompt particularly close attention to dosing, monitoring, and educating patients and should facilitate the timely assessment and treatment of patients who present with unexpected symptomatology or blood levels. The anticipated clinical significance of drug–drug interactions must be judged in comparison to the influence of other factors that can alter drug responses, including age, gender, hepatic or renal disease, smoking, alcohol use, nutritional status, dietary habits, compliance with recommended dosing, and genetic polymorphisms in the activity of metabolic enzymes. These factors often account for considerable inter-individual variability in the response to medication in the context of which the additional impact of some drug–drug interactions might be small. Consideration of potential drug–drug interactions is particularly crucial when: Medications with a low therapeutic index (i.e., for which the margin between a toxic dose and a therapeutic dose is small) are prescribed. These drugs include digoxin (Lanoxin), warfarin (Coumadin), theophylline (Slobid, Theodur), carbamazepine (Tegretol), and lithium (Eskalith, Lithobid, Lithonate). Medications with a narrow therapeutic margin (i.e., drugs that are thought to be relatively ineffective at doses below and above a specified therapeutic range) are prescribed. These drugs include tricyclic antidepressants (TCAs), such as nortriptyline (Pamelor), and immunosuppressants, such as cyclosporine. Drugs associated with rare but catastrophic drug–drug interactions, such as hypertensive crises (from monoamine oxidase inhibitors [MAOIs]) or torsades de pointes (from cisapride [Propulsid]), are used. Medications or other substances known to be potent inducers (e.g., carbamazepine), or inhibitors (e.g., ketoconazole, cimetidine) of metabolism are used. Enhanced surveillance for drug–drug interactions is also important when: Approaching the laudable challenge of streamlining a complex, polypharmaceutical, regimen in which existing drug–drug interactions can

account for a mix of both beneficial and adverse effects which can abate as medications are discontinued. A perplexing clinical picture (including unexplained mental status changes, clinical deterioration or refractoriness to standard treatment, or unexpectedly extreme or erratic drug plasma levels) evolves as medications are added. Clinical states (including liver and kidney disease, cachexia, gastrectomy, and congestive heart failure) are present in which drug absorption, serum protein-binding, and/or elimination may be markedly altered. Elderly or medically-unstable patients are placed at risk for adverse effects, such as hypotension or urinary retention, that pose particular hazards. A drug overdose has occurred, in which the quantity of drug ingested can lead to significant interactions not typically observed within the usual dose range. Although drug–drug interactions are often described pejoratively, it is important to remember that certain drug–drug interactions may be used to advantage in clinical settings such as: Reversal of central nervous system (CNS) depression following opiate (with naloxone [Narcan]) or benzodiazepine (with flumazenil [Romazicon]) overdose. Treatment of anticholinergic-induced side effects, e.g., urinary retention arising with bethanechol (Urecholine), extrapyramidal symptoms (EPS) associated with antipsychotic medications with benztropine (Cogentin), or nausea associated with serotonin re-uptake inhibitors (SRIs) with 5hydroxytryptamine (5-HT)-3 receptor antagonists, such as odansetron or mirtazapine. Enhancement of drug activity or elimination half-life, via augmentation of conventional antidepressant medications (with agents such as lithium or buspirone), or inhibition of metabolism of cytochrome P450 isoenzyme substrates (such as cyclosporine or clozapine) through addition of specific isoenzyme inhibitors (such as ketoconazole, fluvoxamine, or grapefruit juice) to reduce the need for high doses and/or to reduce the frequency of administration of the substrate.

Classification Drug–drug interactions can be described as idiosyncratic, pharmacodynamic, or pharmacokinetic based on the presumed mechanism of interaction. Mixed drug–drug interactions involve more than one of these mechanisms. Idiosyncratic interactions occur unpredictably in a small number of patients and are unexpected from the known pharmacokinetic and pharmacological properties of the drugs involved. Evidence for such interactions is typically inconclusive and based upon a small number of case reports concerning complex patients on complicated medical regimens. Examples include sporadically-reported cases of reversible or irreversible neurotoxicity associated with the combined use of lithium and verapamil (Calan, Isoptin), or the administration of either drug with carbamazepine (Tegretol). Pharmacodynamic interactions involve a known, direct pharmacological effect at biologically-active (receptor) sites and do not involve an alteration in drug plasma levels. These interactions can be additive, synergistic, or antagonistic. They can occur when two or more drugs interact with the same site or when these drugs interact with inter-related sites. Knowledge about pharmacodynamic interactions is often based upon prediction from basic and pre-clinical studies and subsequent confirmation in clinical case reports. Examples of pharmacodynamic drug–drug interactions include: CNS depression, when alcohol, benzodiazepines, and/or barbiturates are used concurrently. Cardiac conduction delays, when drugs with quinidine-like effects (including low-potency antipsychotics, such as chlorpromazine [Thorazine], TCAs, such as amitriptyline [Elavil], high-dose citalopram [Celexa], and/or Class I anti-arrhythmics, such as disopyramide [Norpace]) are co-administered. Bleeding risks, particularly risks of GI bleeding, when drugs that interfere with platelet function or other aspects of hemostasis or mucosal integrity, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or warfarin are combined with serotonergic agents, including SRIs. Anticholinergic toxicity (including ileus, urinary retention, hyperthermia, and delirium) when drugs sharing anti-muscarinic properties (including TCAs, low-potency antipsychotics, and diphenhydramine [Benadryl]), are

combined. Hypotension, when drugs associated with α 1 -adrenergic blockade (including atypical and heterocyclic antidepressants, such as trazodone or imipramine, low-potency antipsychotics, and atypical antipsychotics, such as clozapine [Clozaril] and olanzapine [Zyprexa]) are used together. The interference with a dopamine agonist or precursor, such as pramipexole (Mirapex) or levodopa, during treatment of restless legs syndrome, Parkinson’s disease, or hyperprolactinemia via concurrent administration of antipsychotic drugs, such as risperidone (Risperdal). Pharmacokinetic interactions involve a change in the plasma level and/or tissue distribution of drugs, rather than in their pharmacological activity. Pharmacokinetic interactions are mediated by effects on drug absorption, distribution, metabolism, or excretion. Drug–drug interactions affecting drug absorption might reduce or enhance the bioavailability of orally-administered drugs. Examples include the effect of drugs that do the following: Accelerate gastric emptying (metoclopramide [Reglan], cisapride [Propulsid]) or diminish intestinal motility (TCAs, morphine, cannabis) potentially promoting greater contact with, and absorption from, the mucosal surface of the small intestine. Bind to other drugs (cholestyramine [Questran], charcoal, kaolin-pectin, non-absorbable fats) forming complexes that pass un-absorbed through the intestinal lumen. Alter gastric pH (aluminum hydroxide, magnesium hydroxide, sodium bicarbonate) potentially altering the non-polar, un-ionized fraction of drug available for absorption. Inhibit metabolic enzymes present in the stomach or intestine (e.g., monoamine oxidase and P450 3A4) potentially retarding local degradation of certain drugs or other exogenous substances metabolized by those enzymes (e.g., tyramine) resulting in elevated concentrations of these substrates that reach the portal circulation.

Drug distribution from the systemic circulation to tissue depends upon a variety of factors including regional blood flow, lipophilicity, amount of drug that is bound to tissue and to plasma proteins, and the adipose to lean body mass ratio of the individual. Examples of drug–drug interactions that may influence distribution include: Competition for protein-binding sites by two or more drugs that can result in displacement of a previously bound drug (which, in the un-bound state, becomes available for pharmacological activity). Most psychotropic drugs are more than 80% protein-bound and many are more than 90% proteinbound (“highly protein-bound”) to albumin, α 1 -acid glycoproteins or lipoproteins. Exceptions include lithium, gabapentin (Neurontin), pregabalin (Lyrica), acamprosate (Campral), memantine (Namenda), levomilnacipran (Fetzima), and venlafaxine (Effexor), which are minimally protein-bound; and citalopram (Celexa), fluvoxamine (Luvox), molindone (Moban), quetiapine (Seroquel), lamotrigine (Lamictal), paliperidone (Invega), guanafacine (Tenex), and carbamazepine (Tegretol), which are moderately (60%–85%) protein-bound. Although potentially vital to the dosing and monitoring of drugs with a low therapeutic index (e.g., warfarin), the practical significance of protein-binding interactions for clinical management is otherwise often small given that the transient rise in plasma concentrations due to displacement of previously-bound drug is offset by rapid re-distribution of active drug to tissue where it is metabolized and excreted. Alterations in regional blood flow produced by one drug can impede or enhance delivery of other drugs to relevant receptors in tissue. Competition for, or other interference with, active transport to tissue (e.g., across the blood–brain barrier) can hinder access of some agents to relevant receptor sites. Most drugs undergo several types of metabolism (biotransformation), usually enzyme-mediated, resulting in metabolites that might or might not be pharmacologically active. Many clinically-important pharmacokinetic drug–drug interactions involving psychotropic drugs are based upon interference with this process. Phase I metabolic reactions (including oxidation, reduction, and hydrolysis) reactions, produce intermediate metabolites, which then undergo Phase II

metabolic reactions (including glucuronidation and acetylation) that result in highly polar, water-soluble metabolites suitable for renal excretion. Most psychotropic drugs undergo both Phase I and II reactions. Exceptions include the 3-hydroxy substituted benzodiazepines (lorazepam [Ativan], oxazepam [Serax], and temazepam [Restoril]) and clonazepam (Klonopin) that undergo only Phase II reactions (glucuronidation and acetylation, respectively). Lithium and gabapentin (Neurontin) are excreted by the kidneys without undergoing biotransformation in the liver. A growing understanding of metabolic enzymes, particularly the cytochrome P450 isoenzymes, has contributed to more rational prediction of drug–drug interactions. Other enzyme systems (includin g flavin-containing monooxygenases [FMOs], uridine diphosphate-glucuronysl-transferases [UGTs], sulfotransferases, and methyltransferases) are also critical for the metabolism of a variety of drugs. Many drugs utilize multiple enzyme pathways for metabolism, potentially moderating the impact of drug–drug interactions that affect a single enzyme. Some drugs are closely associated with metabolic induction or inhibition of other medications and are therefore frequently involved in drug–drug interactions (Tables 55-1, 55-2). Introduction of inducing agents results in increased synthesis of metabolic enzymes thereby producing a slow decline over days to weeks in the blood levels of the co-administered drugs metabolized by these enzymes. The discontinuation of inducing agents is associated with a gradual rise in the levels of the co-administered drugs. Introduction of agents that inhibit metabolic enzymes, however, results in a typically rapid (hours to days) elevation of blood levels of co-administered drugs whose metabolism they inhibit. The discontinuation of metabolic inhibitors is associated with a rapid fall in those blood levels. Table 55-1: Common Inducers of Hepatic Drug Metabolism Carbamazepine

Alcohol (chronic)

Phenobarbital

Cigarette smoking

Phenytoin (Dilantin)

Charbroiled meats

Primidone (Mysoline) Cruciferous vegetables (e.g., broccoli) Prednisone

Rifampin St. John’s wort

Table 55-2: Common Inhibitors of Drug Metabolism Anti-fungals (ketoconazole [Nizoral], miconazole [Monistat], itraconazole [Sporanox]) Macrolide antibiotics (erythromycin, clarithromycin [Biaxin]) Fluoroquinolones (ciprofloxacin, norfloxacin, enoxacin) Anti-malarials (chloroquine, primaquine) Isoniazid Protease inhibitors (ritonavir, saquinavir, indinavir, nelfinavir) SSRIs (except venlafaxine, citalopram, escitalopram) Bupropion (Wellbutrin, Zyban) TCAs Psychostimulants (methylphenidate) Phenothiazines Divalproex sodium [Depakote] Beta-blockers, lipophilic (propranolol, pindolol, timolol, labetalol) Calcium channel blockers (diltiazem [Cardizem], verapamil [Calan]) Cimetidine (Tagamet) Quinidine Disulfiram (Antabuse) Alcohol ingestion, acute Grapefruit juice

Drug–drug interactions based upon interference with renal excretion have little relevance to most psychotropic drugs because the majority of these agents present for excretion in the form of inactive metabolites with only a small fraction of the parent compound. The principal exception is lithium for which drug–drug interactions involving renal excretion can alter lithium levels substantially. Drug–drug interactions involving renal excretion are also sometimes utilized in the emergency management of drug overdose. Acidification of urine (with agents such as ammonium chloride) enhances excretion of weak bases (such as phencyclidine [PCP] or amphetamines) while alkalization (with agents such as acetazolamide) promotes excretion of weak acids (such as phenobarbital).

Interactions Involving Cytochrome P450 Isoenzymes

A sub-set of important pharmacokinetic drug–drug interactions involve the cytochrome P450 isoenzymes, a heterogeneous group of more than 30 oxidative metabolic enzymes located predominantly in the endoplasmic reticulum of hepatocytes as well as the GI tract and the brain. These enzymes are involved in the Phase I metabolism of a wide variety of drugs as well as in endogenous substances (such as prostaglandins, fatty acids, and steroids). The substrates, inhibitors and inducers of P450 isoenzymes 1A2 and 2D6 and the 3A3/4 and the 2C subfamily have been particularly well characterized (Table 55-3). Table 55-3: Selected Cytochrome P450 Isoenzyme Substrates, Inhibitors, Inducers 1A2

Substrates Acetaminophen, aminophylline, asenapine (Saphiris), caffeine, clozapine, haloperidol, olanzapine (Zyprexa), phenacetin, tertiary tricyclic antidepressants, theophylline, pro-carcinogens Inhibitors Cimetidine, fluoroquinolones (ciprofloxacin), fluvoxamine (Luvox), grapefruit juice Inducers

2C

Charbroiled meats, cigarette smoking, cruciferous vegetables, modafinil (Provigil), omeprazole (Prilosec)

Substrates Barbiturates, citalopram (Celexa), diazepam, losartan, mephenytoin, NSAIDs, propranolol, tertiary TCAs, THC, tolbutamide, warfarin Inhibitors Armodafinil (Nuvigil), cimetidine, fluoxetine, fluvoxamine, ketoconazole, modafinil (Provigil), omeprazole (Prilosec), sertraline Inducers

2D6

Carbamazepine, norethinidrone, rifampin, prednisone

Substrates Aripiprazole (Abilify), atomoxetine (Strattera), beta-blockers (lipophilic), brexpiprazole (Rexulti), codeine, debrisoquine, donepezil (Aricept), dextromethorphan, encainide, flecainide, haloperidol, hydroxycodone, iloperidone (Fanapt), phenothiazines, risperidone (Risperdal), SSRIs, tamoxifen, TCAs, tramadol (Ultram), trazodone, venlafaxine (Effexor), vortioxetine (Viibryd) Inhibitors Anti-malarials, bupropion, duloxetine, fluoxetine, methadone, moclobemide, paroxetine, phenothiazines, protease inhibitors (ritonavir), quinidine, sertraline, TCAs, yohimbine Inducers

Dexamethasone, rifampin

3A3/4 Substrates Alprazolam (Xanax), amiodarone, ariprazole (Abilify), brexpiprazole (Rexulti), buspirone (BusPar), calcium channel-blockers, carbamazepine, cariprazine (Vraylar), cisapride (Propulsid), clozapine, cyclosporine, diazepam, disopyramide (Norpace), estradiol, eszopiclone, HMG-CoA reductase inhibitors (lovastatin, simvastatin), lidocaine, loratadine, methadone, Midazolam (Versed), oral contraceptives, pimozide (Orap), progesterone, propafenone (Rhythmol), quetiapine (Seroquel), quinidine, Sildenafil (Viagra), suvorexant (Belsomra), testosterone,tertiary TCAs, triazolam (Halcion), vilazodone (Viibryd), vinblastine, warfarin, Zaleplon (Sonata), Zolpidem (Ambien) Inhibitors Anti-fungals (ketoconazole), calcium channel blockers (verapamil), cimetidine (Tagamet), fluvoxamine (Luvox), grapefruit juice, macrolide antibiotics (erythromycin), nefazodone (Serzone) Inducers

Armodafinil (Nuvigil), carbamazepine, glucocorticoids, modafinil (Provigil), oxcarbazepine (Trileptal), phenobarbital, phenytoin, rifampin, St. John’s wort

Many of the cytochrome enzymes, including 2D6, 2C9, 2C19, and 3A4, exhibit polymorphisms, genetically-based differences in enzyme structure (isoforms) that result in altered enzyme activity and a bimodal distribution of efficient or “extensive” metabolizers” and of “poor” metabolizers. There appear to be significant racial and ethnic differences in the population distributions of these polymorphisms. Thus, for example, between 7% and 10% of Caucasians are “poor” metabolizers of 2D6 substrates, as compared with 1% to 3% of AfricanAmericans and Asian-Americans. In contrast, 15% to 20% of AfricanAmericans and Asian-Americans are “poor” metabolizers of 2C19 substrates compared with 1% to 5% of Caucasians. “Extensive” metabolizers will be converted, in effect, to “poor” metabolizers in the presence of an inhibitor of the relevant isoenzyme. “Poor” metabolizers show higher baseline concentrations of a substrate, lower concentrations of metabolites, and little or no effect from isoenzyme inhibition or induction. Poor metabolizers can have adverse effects (e.g., prolonged QT interval on citalopram) at lower doses than other patients or can have less effect of drugs that require the enzyme activity for conversion to an active form (e.g., tamoxifen, codeine, tramadol).

Drug–Drug Interactions According to Psychotropic Drug Class Although drug–drug interactions can be broadly classified in terms of their presumed mechanism, in clinical situations, drug–drug interactions are most often discussed according to the particular classes of drugs for which they are relevant, as described in the sub-sections that follow.

Mood Stabilizers The principal mood stabilizers—lithium , valproate , and carbamazepine—are involved in a number of significant drug–drug interactions (Tables 55-4, 55-5, 55-6) particularly by virtue of their distinctive pharmacokinetic properties. Lithium is more than 95% eliminated unchanged by the kidney. It is reabsorbed in the proximal tubules and to a lesser extent in the loop of Henle; both valproate and carbamazepine are metabolized hepatically. Table 55-4: Drug–Drug Interactions Involving Lithium

Increased lithium levels

Thiazide diuretics ACE inhibitors (captopril, enalapril, lisinopril) Angiotensin II receptor antagonists (valsartan, losartan) High-dose NSAIDs (except sulindac, aspirin) Metronidazole, spectinomycin, tetracycline

Decreased lithium levels

Aminophylline, theophylline Urinary alkalinization (acetazolamide, sodium bicarbonate) Sodium chloride Osmotic diuretics (mannitol, urea)

Increased anti-thyroid effect

Anti-thyroid drugs (propylthiouracil, methimazole)

Neurotoxicity (rare)

Antipsychotics, calcium channel-blockers, carbamazepine, methyldopa

Prolonged neuromuscular blockade Neuromuscular blockers (succinylcholine, pancuronium, decamethonium) Serotonin syndrome (rare)

SSRIs, SNRIs, serotonergic TCAs, tramadol (Ultram), tryptophan

Table 55-5: Drug–Drug Interactions Involving Valproate Increased valproate levels

Aspirin (increased un-bound fraction), cimetidine, erythromycin, ibuprofen, phenothiazines

Decreased valproate levels

Carbamazepine, lamotrigine, oral contraceptives, phenobarbital, phenytoin, rifampin

Inhibited metabolism Lorazepam (Ativan), oxazepam (Serax), temazepam (Restoril), diazepam (Valium), of co-administered carbamazepine (10,11-epoxide) metabolite, lamotrigine (Lamictal), phenobarbital, tolbutamide, agents warfarin, zidovudine (AZT) Absence seizures (rare)

Clonazepam (Klonopin)

Table 55-6: Drug–Drug Interactions Involving Carbamazepine Increased carbamazepine levels

Valproate (active CBZ-E metabolite), P450 3A4 inhibitors: Anti-fungals, macrolide antibiotics, calcium channel-blockers, fluvoxamine (Luvox), grapefruit juice, isoniazid, nefazodone (Serzone), protease inhibitors.

Decreased carbamazepine levels

Carbamazepine (auto-induction), glucocorticoids, modafinil (Provigil), phenobarbital, phenytoin (Dilantin), primidone (Mysoline), St. John’s wort

Induced metabolism of co-administered agents

Anticonvulsants (ethosuximide [Zarontin], phenytoin, lamotrigine, valproate) Antidepressants Antipsychotics Benzodiazepines Cyclosporine Glucocorticoids Methadone Oral contraceptives Warfarin

Carbamazepine is a potent inducer of metabolism; to a lesser extent, valproate inhibits metabolism. Carbamazepine is associated with an active metabolite, carbamazepine-10,11epoxide, which has anticonvulsant as well as potentially adverse CNS sideeffects. Lithium is not protein-bound, carbamazepine is only moderately proteinbound, and valproate is moderately to highly protein-bound. The mood-stabilizing anticonvulsant, lamotrigine (Lamictal) is moderately protein-bound and is metabolized by the liver, where its clearance is subject to significant inhibition by valproate , which causes lamotrigine levels to rise up to several fold. Conversely, oral contraceptives can induce metabolism of lamotrigine and valproate causing those anticonvulsant levels to fall. Lamotrigine can itself cause modest metabolic induction of some agents, including valproate. In contrast, gabapentin (Neurontin) is excreted largely unchanged by the kidney, is not appreciably protein-bound, and neither inhibits nor induces the metabolism of other agents.

Antidepressants The selective serotonin re-uptake inhibitors (SSRIs ) have been implicated in a wide variety of pharmacokinetic interactions (mediated by the cytochrome P450 isoenzymes), as well as in the serotonin syndrome (which involves a pharmacodynamic interaction). Selected drug–drug interactions involving the SSRIs are presented in Table 55-7. Table 55-7: Drug–Drug Interactions Involving Selective Serotonin Re-Uptake Inhibitors Inhibited metabolism of coadministered agents

Anti-arrhythmics metabolized by P450 2D6 and 2C Antihistamines metabolized by P450 3A4 (astemizole, loratadine) Antipsychotics metabolized by P450 1A2 (clozapine, olanzapine, haloperidol, asenapine), 2D6 (risperidone, aripiprazole, brexpiprazole, iloperidone, phenothiazines) and 3A4 (quetiapine, aripiprazole, brexpiprazole, pimozide, cariprazine) Benzodiazepines metabolized by P450 2C (diazepam), 3A4 (triazalobenzodiazepines) Beta-blockers (lipophilic) metabolized by P450 2C, 2D6 Calcium channel-blockers metabolized by P450 3A4 Cisapride (Propulsid) metabolized by P450 3A4 Codeine metabolized by P450 2D6 into active (morphine) metabolite Methylxanthines (aminophylline, theophylline) metabolized by P450 1A2 Secondary amine TCAs metabolized by P450 2D6 Tertiary amine TCAs metabolized by P450 1A2, 2C, 2D6, 3A/4

Tamoxifen metabolized into its active form by 2D6 Warfarin (variable effects) Serotonin syndrome

Monoamine oxidase inhibitors (contraindicated), lithium , serotonergic agents

The SRIs, except for venlafaxine (Effexor), levomilnacipran (Fetzima), vortioxetine (Brintellix), citalopram (Celexa), and escitalopram (Lexapro), are generally moderate to potent inhibitors of one or more P450 isoenzymes. The P450 isoenzyme 1A2, responsible for metabolism of theophylline, clozapine, olanzapine, and asenapine, is inhibited by fluvoxamine (Luvox). The 2C isoenzyme sub-family, responsible for metabolism of warfarin, citalopram (Celexa) and diazepam, is inhibited by fluoxetine, sertraline, and fluvoxamine. The 2D6 isoenzyme, responsible for metabolism of TCAs, 1C-antiarrhythmics, beta blockers, and many antipsychotics (such as risperidone, aripiprazole, brexpiprazole, perphenazine, and thioridazine), as well as being necessary for the conversion of the pro-drugs codeine, tramadol, and tamoxifen into their active forms, is inhibited by fluoxetine, paroxetine, and to a lesser extent, sertraline. The serotonin norepineprhine re-uptake inhibitor (SNRI) duloxetine (Cymbalta) as well as the dopamine norepinephrine re-uptake inhibitor, bupropion (Wellbutrin, Zyban) are also potent inhibitors of P450 2D6. On the other hand, citalopram (Celexa) is a weak, and probably negligible, inhibitor of 2D6 under most circumstances, as are vilazodone (Viibryd) and desvenlafaxine (Pristiq). The 3A3/4 isoenzymes, responsible for metabolizing cisapride (Propulsid), carbamazepine, pimozide (Orap), cariprazine (Vraylar), methadone, calcium channel blockers, statins, sildenafil (Viagra) cyclosporine, zolpidem (Ambien), and alprazolam (Xanax) are inhibited by fluvoxamine (Luvox) as well as by the atypical antidepressant, nefazodone (Serzone). Other SSRIs, particularly fluoxetine and sertraline, appear to be less potent inhibitors of these isoenzymes. The serotonin syndrome is a rare but potentially-fatal pharmacodynamic complication associated with the combined use of highly serotonergic agents or the contraindicated overlapping use of MAOIs and SSRIs. Signs and symptoms of the serotonin syndrome include myoclonus, hyperreflexia, nausea, hyperthermia, autonomic instability, agitation, delirium, and coma. The TCAs are associated with a broad range of pharmacodynamic drug–drug interactions and are also subject to drug–drug interactions involving metabolic

induction or inhibition. Significant drug–drug interactions involving TCAs and SSRIs are presented in Table 55-8. Table 55-8: Drug–Drug Interactions Involving TCAs Increased TCA levels

Anti-fungals Beta-blockers (lipophilic) Bupropion Calcium channel-blockers Cimetidine Duloxetine Macrolide antibiotics Methylphenidate Phenothiazines Quinidine SSRIs

Decreased TCA levels

Carbamazepine Phenytoin Phenobarbital Primidone Rifampin

Prolonged cardiac conduction

Anti-arrhythmics (Type I) Antipsychotics (low potency) Calcium channel-blockers

Hypotension

Antihypertensives Antipsychotics (low-potency, atypicals) Trazodone MAOIs Vasodilators

Attenuated anti-hypertensive effects Clonidine, guanethidine Anticholinergic toxicity

Antipsychotics (low-potency) Benztropine (Cogentin) Diphenhydramine (Benadryl) Mirtazapine (Remeron)

The secondary amine TCAs, including nortriptyline and desipramine, are hydroxylated by P450 2D6. Generally, the more sedating tertiary amine TCAs, including amitriptyline and imipramine, are demethylated and hydroxylated by

P450 1A2, 2C, 2D6, and 3A4. In addition to serving as substrates for the P450 isoenzymes, the TCAs are also enzyme inhibitors, particularly of P450 2D6. The potential for pharmacodynamic drug–drug interactions is higher for the TCAs than for other antidepressants by virtue of their broad spectrum of activity on muscarinic, histaminic, and α 1-adrenergic receptors, and on monoamine reuptake mechanisms and cardiac conduction. Among the psychotropics, the MAOIs are most closely associated with potentially fatal drug–drug interactions.

Hypertensive (Hyper-Adrenergic) Crisis Abrupt elevation of blood pressure, severe headache, nausea, vomiting, diaphoresis, cardiac arrhythmias, intracranial hemorrhage, and myocardial infarction can occur when a variety of prescribed and OTC sympathomimetics, particularly indirect sympathomimetics, are used concurrently with MAOIs. Sympathomimetic drugs include: L-dopa; dopamine; cocaine; amphetamines; phenylpropanolamine; oxymetazoline (Afrin); phentermine; mephentermine; metaraminol; ephedrine; pseudoephedrine; phenylephrine (Neo-Synephrine); norepinephrine; isoproterenol; and epinephrine. Safe OTC allergy, cold, and cough medications include plain chlorpheniramine (Chlor-Trimeton), brompheniramine (Dimetane), and guaifenesin (Robitussin). The widely available combined preparations that include decongestants or dextromethorphan must be scrupulously avoided. Although dextromethorphan is not associated with hypertensive crises, its use with MAOIs has been linked to acute confusional states. Serotonin syndrome can occur when highly serotonergic agents, including the SSRIs and venlafaxine (Effexor), clomipramine (Anafranil), or tryptophan, are combined with MAOIs. A minimum wash-out interval of two weeks is necessary following discontinuation of MAOIs before the initiation of one of these drugs. Reciprocally, a minimum of two weeks must elapse after discontinuing most serotonergic drugs before starting an MAOI. In the case of fluoxetine, a minimum delay of five weeks is necessary because of its long half-life. Although not associated with a serotonin syndrome the combination of buspirone (Buspar) with MAOIs has been associated with episodes of blood pressure elevation. Agitation, convulsions, blood pressure instability, hyperpyrexia, respiratory depression, peripheral vascular collapse, coma, and death can occur when meperidine (Demerol) is administered concurrently with the MAOIs. Their combined use is absolutely contraindicated. Other narcotic analgesics (e.g.,

codeine, morphine) appear to be safer, although their analgesic and CNS depressant effects can be potentiated and dose adjustments might be necessary. Cases of adverse, though reversible, events including fever, delirium, convulsions, hypotension, and dyspnea have been reported when MAOIs and TCAs have been combined. The concurrent use of these two classes of antidepressants is generally contraindicated. However, very cautious addition of an MAOI to an established treatment with a TCA has been carried out successfully in the treatment of exceptionally treatment-resistant depressed patients. The effects of CNS depressants, insulin, sulfonylurea hypoglycemic drugs, antihypertensive, or vasodilator medications can be potentiated, with the exception of guanethidine (Esimil, Ismelin), whose antihypertensive effects might be blocked. There have been reported cases of hypertension and of bradycardia on beta-blockers and of hypertension and mental status changes with reserpine and methyldopa. The beta-agonistic effects (including tachycardia, palpitations, and anxiety) of methylxanthines and inhaled bronchodilators might be enhanced. Phenelzine (Nardil) can potentiate neuromuscular blockade on succinylcholine. The atypical antidepressants are not known to inhibit or induce P450 cytochrome isoenzymes, with the exception of nefazodone (Serzone), which is a moderately potent inhibitor of P450 3A4. Although relatively little is known about MAOI-atypical antidepressant drug interactions, concerns about serious toxicity contraindicate their co-administration. Mirtazapine (Remeron) is a potent antagonist of the α 2-adrenergic receptor; like yohimbine (Yocon), it also blocks the histamine, muscarinic, and α 1adrenergic receptors, properties shared with many TCAs and antipsychotic agents. Thus, pharmacodynamic interactions with these agents would be expected. Blockade of the 5-HT3 receptor by mirtazapine accounts for its ability to attenuate nausea from SRIs. Bupropion (Wellbutrin, Zyban) is metabolized by a distinct P450 isoenzyme, 2B6, as is nicotine and cyclophosphamide. The metabolism of bupropion can be inhibited by the muscular relaxant, orphenadrine (Norflex, Noradex) and can be induced by carbamazepine and phenobarbital. Like some of the SSRIs and SNRIs, bupropion is potent inhibitor of P450 2D6.

Antipsychotics Drug–drug interactions involving antipsychotics are presented in Table 55-9.

Table 55-9: Drug–Drug Interactions Involving Antipsychotic Medications Decreased antipsychotic levels

Beta-blockers (lipophilic) Carbamazepine Phenobarbital Phenytoin Rifampin

Interference with antipsychotic drug absorption Antacids (aluminum, magnesium) Prolonged cardiac conduction

Calcium channel-blockers TCAs

Hypotension

Anti-hypertensives MAOIs TCAs Trazodone Vasodilators

Anticholinergic toxicity

TCAs Benztropine Diphenhydramine Mirtazapine

Interference with dopaminergic effects

Bromocriptine L-Dopa Mirapex

Additive risk of myelosuppression (clozapine)

Carbamazepine AZT

The lower-potency agents, such as chlorpromazine, and the atypical antipsychotics, are generally more likely than are the high-potency agents, such as haloperidol, to participate in pharmacodynamic interactions with drugs (such as TCAs), that cause anticholinergic effects, sedation, hypotension, and prolonged cardiac conduction. Metabolism of atypical antipsychotics including clozapine, olanzapine (Zyprexa), asenapine (Saphiris), and haloperidol, involves multiple pathways, including P450 1A2. Their clearance may therefore be inhibited by fluvoxamine (Luvox) and fluoroquinolone antibiotics, such as ciprofloxacin (Cipro), and may be induced by omeprazole (Prilosec) and by cigarette smoking. Phenothiazines, such as perphenazine (Trilafon), are both substrates and inhibitors of P450 2D6. Risperidone (Risperdal), aripiprazole (Abilify), brexpiprazole (Rexulti) and iloperidone (Fanapt) are also 2D6 substrates.

Quetiapine (Seroquel), aripiprazole (Abilify), brexpiprazole (Rexulti), cariprazine (Vraylar), and pimozide (Orap), are P450 3A4 substrates whose concentration may be increased by isoenzyme inhibitors (such as erythromycin), and decreased by inducers (such as carbamazepine and rifampin).

Anxiolytics Pharmacodynamic Interactions The most common and potentially serious drug–drug interactions involving benzodiazepines are the additive CNS depressant effects that result when these agents are co-administered with barbiturates, ethanol, narcotics, antihistamines, TCAs, and zolpidem (Ambien). These effects commonly include sedation and psychomotor impairment. At high doses or in severely compromised patients, fatal respiratory depression can occur. Flumazenil (Romazicon) is a competitive inhibitor of the benzodiazepine receptor; therefore, it antagonizes benzodiazepine effects. The anticholinesterase, physostigmine, also blocks benzodiazepine binding in brain and can also reverse CNS depression caused by benzodiazepines.

Pharmacokinetic Interactions Even though infrequently life-threatening, alterations in blood levels of the benzodiazepines can account for the emergence of side-effects (such as unsteadiness or slurred speech), or for loss of antianxiety or hypnotic efficacy when a new drug is co-administered. Antacid suspensions (aluminum and magnesium hydroxide) can delay the rate, but less likely the extent, of absorption of orally-administered benzodiazepines, a property more important for single, as needed (prn) dosing rather than maintenance dosing of benzodiazepines. Inducers of Phase I metabolic processes (including carbamazepine, phenobarbital, and rifampin) can reduce the levels of most benzodiazepines, which are subject to oxidative metabolism, while leaving levels of lorazepam, oxazepam, and temazepam unchanged. Inhibitors of metabolism account for a variety of drug–drug interactions with benzodiazepines. Specific inhibitors of the cytochrome P450 3A3/4 sub-class (Table 55-3) including the macrolide antibiotics, antifungals, nefazodone (Serzone), fluvoxamine (Luvox), and grapefruit juice, can increase plasma levels of the

triazalobenzodiazepines (alprazolam [Xanax], triazolam [Halcion], and midazolam [Versed]) by interfering with hydroxylation. Specific inhibitors of the cytochrome P450 2C class (Table 55-2) (including omeprazole [Prilosec] as well as ketoconazole, and certain SSRIs, including fluoxetine, fluvoxamine [Luvox], and sertraline) can increase plasma levels of diazepam (Valium) by interfering with the N-demethylation. Inhibitors of glucuronide conjugation (Phase II metabolism), including valproate and probenecid, can increase plasma levels of the 3-hydroxy substituted benzodiazepines (lorazepam, oxazepam, and temazepam), which are not altered by inhibitors of Phase I metabolism.

Idiosyncratic Interactions Absence seizures have been described in some patients receiving both valproate and clonazepam (Klonopin), although this drug combination is widely and safely used in many patients with bipolar disorder or seizure disorders.

Miscellaneous Zolpidem (Ambien). Additive CNS-depressant effects are likely to occur when other sedating agents (including alcohol, barbiturates, and benzodiazepines) are co-administered with zolpidem, which interacts with the γ -amino butyric acid (GABA) A-benzodiazepine complex. The sedative/hypnotic effects of zolpidem are reversed by the benzodiazepine receptor antagonist, flumazenil (Romazicon). Like the triazalobenzodiazepines, zolpidem levels and levels of related agents including zaleplon (Sonata) and eszopiclone (Lunesta) are potentially affected by drug–drug interactions involving cytochrome P450 3A4, as are the levels of the novel sedative-hypnotic suvorexant (Belsomra), potentially enhancing side effects including daytime sedation, confusion, or unsteadiness. Donepezil (Aricept) is a substrate for 2D6 and 3A4; its clearance is therefore susceptible to inhibition by such agents as fluoxetine and ketoconazole. Donepezil (Aricept) is not known to be either an inhibitor or an inducer of the metabolism of other agents. Cholinergic toxicity is possible when either cholinesterase inhibitor is combined with other cholinomimetic agents, such as bethanechol (Urecholine). Methadone is a substrate for cytochrome P450 isoenzyme 3A4 and, to a lesser extent, 2D6. It is also a 2D6 inhibitor, which can potentially interfere with the clearance of other 2D6 substrates, such as desipramine. The association of methadone with QT prolongation as well as respiratory depression underscores

the importance of considering drug interactions when dosing methadone or adding medications to a stable methadone regimen. Disulfiram (Antabuse). In addition to inhibiting aldehyde dehydrogenase thereby resulting in the accumulation of acetaldehyde following ethanol ingestion, disulfiram inhibits other hepatic microsomal enzymes that interfere with the metabolism of a variety of drugs (including warfarin, phenytoin, benzodiazepines, antipsychotics, and antidepressants). The severity of the disulfiram-alcohol reaction is increased by a variety of agents (including MAOIs, vasodilators, alpha- or beta-adrenergic antagonists, and paraldehyde). Severe confusional states can occur when metronidazole has been administered within two weeks of disulfiram; therefore, its concurrent use is contraindicated.

Selected References 1. Alpert JE: Drug–Drug interactions in psychopharmacology. In: Stern TA, Fava M, Wilens T, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby Elsevier; 2016: pp. 552–566. 2. Buckley NA, Dawson AH, Isbister G: Serotonin syndrome. BMJ . 2014; 348: 33–35. 3. Ciraulo DA, Shader RI, Greenblatt DJ, et al, eds.: Drug Interactions in Psychiatry . 3rd ed. Baltimore, MD: Williams and Wilkins; 2006. 4. English BA, Dortch M, Ereshefsky L, et al: Clinically significant psychotropic drug–drug interactions in the primary care setting. Curr Psychiatry Rep . 2012; 14: 376–390. 5. Golan D, Armstrong EJ, Armstrong AW: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy . 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2016. 6. Madhusoodanan S, Velama U, Parmar J, et al: A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry . 2014; 26(2): 120–138. 7. Sandson NB, Armstrong SC, Cozza KL, et al: Drug-Drug Interaction Primer: A Compendium of Case Vignettes for the Practicing Clinician . Washington, DC: American Psychiatric Publishing, Inc.; 2007. 8. Smith FA, Wittman, CW, Stern TA: Medical complications of psychiatric

treatment. Crit Care Clin . 2008; 24: 635–656. 9. Stevens JR, Fava M, Rosenbaum JF, et al: Psychopharmacology in the medical setting. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Sanders Elsevier; 2010: pp. 441–466. 10. Wilkinson GF: Drug metabolism and variability among patients in drug response. N Engl J Med . 2005; 352: 2211–2221. 11. Wynn GH, Oesterheld JR, Cozza KL, et al: Clinical Manual of Drug Interaction Principles for Medical Practice . Arlington, VA: American Psychiatric Publishing, Inc.; 2008.

CHAPTER Cardiovascular and Other 56 Side Effects of Psychiatric Medications CHRISTOPHER M. CELANO, MD; SCOTT R. BEACH, MD; JEFF C. HUFFMAN, MD; AND THEODORE A. STERN, MD

KEY POINTS Overview Pharmacologic treatments for psychiatric illness often have undesirable effects on other organ systems. General Principles for the Management of Side Effects Adhering to several principles related to side effects can greatly enhance patient safety and adherence. These generally involve discussing potential side effects prior to the initiation of treatment, gradually titrating medications to the lowest effective doses, and having ongoing discussions with patients about the incidence of side effects and plans to manage them. Cardiovascular Side Effects Many psychiatric medications, especially antidepressant and antipsychotic medications, can affect the cardiovascular system. Low-potency typical antipsychotic medications and tricyclic antidepressants frequently cause orthostatic hypotension, whereas some newer medications can increase blood pressure. Many psychiatric medications can cause cardiac conduction abnormalities, including QTc interval prolongation, in patients with and without cardiovascular disease. Due to these and other potential side effects, certain medications (e.g., selective serotonin re-uptake inhibitors, atypical antipsychotic medications) frequently are preferred treatments for patients with pre-existing cardiovascular disease.

Central Nervous System Side Effects Psychiatric medications frequently cause side effects related to the central nervous system. Sleep changes, including both insomnia and sedation, can be seen with a variety of psychiatric medication types and classes. Antipsychotic medications can induce changes in muscle tone and movement, including acute dystonic reactions, akathisia, or tardive dyskinesia. Certain antipsychotic and antidepressant medications can reduce the seizure threshold, and several different types of psychiatric medications can lead to cognitive dulling or impairment. Other Side Effects Other side effects include anticholinergic, gastrointestinal, hematologic (e.g., thrombocytopenia, agranulocytosis), metabolic (e.g., weight gain), dermatologic (e.g., Stevens Johnson syndrome), endocrine (e.g., hyperprolactinemia), and sexual side effects. Alternative treatments or methods for managing side effects are available.

Introduction Psychiatric illness is regularly complicated by medical symptoms and disorders. The more severe the medical illness, the more frequent is the impact of medical illness on psychiatric disorders. In a fashion similar to primary psychiatric disorders, proper management of many combined medical and psychiatric disorders requires use of medications. Physicians have long feared the effects of psychiatric medications in medically ill patients; they continue to be wary of them in severely medically compromised patients. Historically, many psychiatric medications have been recognized for their potential adverse effects on the cardiovascular (CV) system and on other organ systems. Knowledge of side effects and their prevalence is a requirement for safe and effective treatment of all patients.

General Principles for the Management of Side Effects

Safe administration of psychiatric medications involves the anticipation and management of potential side effects. Abiding to several general principles can enhance patient safety and adherence. First, it is useful to anticipate potential or probable side effects and discuss them (and strategies to minimize them) with the patient prior to initiating treatment (Table 56-1, Table 56-2). Second, to minimize the incidence of common side effects, it is prudent to: use medications with the smallest chance of exacerbating current medical problems; use the lowest effective doses; and titrate the dosage gradually. If side effects are encountered, management with adjunctive agents rather than switching to another agent might prevent delaying therapeutic response. Finally, routine communication with the patient (during appointments) about anticipated and experienced side effects can help to optimize adherence to a medication regimen and to strengthen treatment alliance. Table 56-1: Side Effects Profiles of Psychiatric Medications Drug

Conduction Sedation Anticholinergic Hypotension Hypertension Tachycardia Slowing

Antidepressants (cyclics) Amitriptyline (Elavil)

+++

+++

+++

−

+++

Yes

Amoxapine (Asendin)

+

+

+++

−

+

Yes

Clomipramine (Anafranil)

+++

+++

+++

−

+++

Yes

Desipramine (Norpramin)

+

+

+++

++

+

Yes

Doxepin (Sinequan) +++

+++

+++

−

+++

Yes

Imipramine (Tofranil)

++

++

+++

−

++

Yes

Maprotiline (Ludiomil)

++

+

++

−

+

Yes

Nortriptyline (Pamelor)

+

+

+

−

+++

Yes

Protriptyline (Vivactil)

+

+++

++

−

+++

Yes

Trimipramine (Surmontil)

+++

++

++

−

++

Yes

Antidepressants (SSRIs) Citalopram (Celexa) +

−

−

−

−

−

Fluoxetine (Prozac) +

−

−

−

−

−

Fluvoxamine (Luvox)

+

−

−

−

−

−

Paroxetine (Paxil)

+

−

−

−

++

−

Escitalopram (Lexapro)

+

−

−

−

−

−

Sertraline (Zoloft)

+

−

−

−

−

−

Antidepressants (MAOIs) Phenelzine (Nardil) +

+

+++

+

−

−

Tranylcypromine (Parnate)

+

++

+

−

−

+

Antidepressants (other) Bupropion (Wellbutrin)

+

−

−

−

−

−

Desvenlafaxine (Pristiq)

+

−

−

+

−

−

Duloxetine (Cymbalta)

+

−

−

−

−

−

Levomilnacipran (Fetzima)

−

−

+

+

++

−

Mirtazapine (Remeron)

++

+

+

−

−

−

Nefazodone (Serzone)

++

−

+

−

−

−

Trazodone (Desyrel)

+++

−

++

−

−

Yes

Venlafaxine (Effexor)

+

−

−

++

+

−

Vilazodone (Viibryd)

+

−

−

−

−

−

Vortioxetine (Brintellix)

−

−

−

−

−

−

+++

−

+++

Yes

Antipsychotics (low potency; typical) Chlorpromazine (Thorazine)

+++

++

Mesoridazine (Serentil)

++

++

++

−

++

Yes

Thioridazine (Mellaril)

+++

+++

+++

−

+++

Yes

Antipsychotics (moderate potency; typical) Loxapine (Loxitane)

++

++

++

−

++

Yes

Perphenazine (Trilafon)

+

+

+

−

+

Yes

Antipsychotics (high potency; typical) Droperidol (Inapsine)

+

−

+

−

−

Yes, with IV form

Haloperidol (Haldol)

+

−

+

−

−

Yes, with IV form

Pimozide (Orap)

+

+

+

−

+

Yes

Thiothixene (Navane)

+

+

+

−

+

Yes

+

−

+

−

+

−

Asenapine (Saphris) +

−

−

+

+

Yes

Clozapine (Clozaril) +++

+++

+++

−

+++

Yes

Iloperidone (Fanapt)

+

−

+

−

++

Yes

Lurasidone (Latuda) +

−

−

−

+

−

Olanzapine (Zyprexa)

+

++

+

−

++

Yes

Paliperidone (Invega)

+

−

+

−

++

Yes

Quetiapine (Seroquel)

++

−

++

−

+

Yes

Risperidone (Risperdal)

+

−

++

−

+

Yes

Ziprasidone (Geodon)

+

−

+

−

+

Yes

−

++

−

−

Yes

Antipsychotics (atypical) Aripiprazole (Abilify)

Mood stabilizers Carbamazepine (Tegretol)

++

Lamotrigine (Lamictal)

+

−

−

−

−

−

Lithium (Eskalith)

++

−

−

−

−

Yes

Oxcarbazepine (Trileptal)

++

+

+

-

-

Yes

Topiramate (Topamax)

+

−

−

−

−

−

Valproic acid (Depakote)

++

−

−

−

−

−

Dextroamphetamine − (Dexedrine)

−

−

+++

++

−

Methylphenidate (Ritalin)

−

−

++

++

−

Psychostimulants

−

+ = weak; ++ = moderate; +++ = strong.

Table 56-2: Unique Side Effects of Psychiatric Medications Medication

Side Effect

Thioridazine (Mellaril) Retinal pigmentosis Clozapine (Clozaril)

Myocarditis, eosinophilia, toxic megacolon, sialorrhea

Quetiapine (Seroquel) Cataracts Lithium

Sick sinus syndrome, Ebstein’s anomaly (risk to fetus in pregnancy)

Trazodone

Priapism

Effects on the Cardiovascular System Hemodynamic Effects Orthostatic Hypotension Orthostatic hypotension (OH )—a common side effect of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and certain antipsychotic medications—is correlated with alpha blockade and with alphanoradrenergic receptor affinity. OH is of greatest concern for the elderly, for those on antihypertensive medications, and for patients with CV disease. Many antidepressants, especially TCAs and MAOIs, cause OH. Regarding TCAs, imipramine, desipramine, and amitriptyline are equally likely to produce OH. Doxepin is also apt to cause OH, whereas nortriptyline is the least likely of the

TCAs to induce OH. For TCAs, the incidence of OH in patients with a normal electrocardiogram (EKG) is 7%, with a bundle branch block (BBB) it is 32%, and with heart failure it is 50%. Patients whose blood pressure (BP) falls upon standing prior to the initiation of a TCA appear to be at the greatest risk for worsening OH in response to the addition of a TCA. OH occurs before the therapeutic effect of TCAs. Over time, the objective fall in BP will persist, but subjective complaints will diminish. MAOI-induced OH is common, but not predicted by a pre-drug orthostatic fall in BP. Mild OH occurs in 47% of patients, and severe OH occurs in 5% to 10% of MAOI-treated patients. The maximum effect appears after 3 to 4 weeks, and OH can subside after 6 weeks. Among other antidepressants, trazodone and levomilnacipran are associated with a moderate risk of OH; nefazodone and mirtazapine are associated with a low incidence of OH; and fluoxetine, sertraline, paroxetine, citalopram, escitalopram, bupropion, fluvoxamine, vilazodone, vortioxetine, and venlafaxine are not associated with OH. However, data indicates that selective serotonin re-uptake inhibitor (SSRI)–treated patients remain at elevated risk for falls unrelated to OH. Low-potency antipsychotic medications can cause significant OH, especially in patients who are dehydrated or who are taking other BP-lowering agents. Highpotency agents are much less likely to lower BP. In general, OH is worst following the initiation of a new medication and improves over time. Therefore, it is recommended that the starting dose be low and that it be titrated slowly. Of the atypical antipsychotic medications, clozapine is most frequently associated with OH. Quetiapine, iloperidone, and risperidone also have been linked to OH to a lesser extent, whereas ziprasidone, aripiprazole, lurasidone, and olanzapine are infrequently associated with OH.

Hypertension Essential hypertension can arise with the use of some medications. Venlafaxine produces a dose-related elevation of supine diastolic BP in 7% of patients taking doses of 200 to 300 mg/day. It occurs in up to 13% in those with daily doses greater than 300 mg/day. Duloxetine, despite a similar mechanism of action, is less commonly associated with elevations in BP. Psychostimulants can aggravate hypertension, and levomilnacipran can cause mild increases in systolic and diastolic blood pressure in a small subset of patients. Hypertensive crisis, a potentially fatal interaction, is characterized by an elevation of BP, severe headache, nausea, vomiting, and diaphoresis. It occurs

when patients on MAOIs ingest large amounts of tyramine-containing foods. Hypertensive crisis requires immediate medical attention to reduce BP with the α 1-adrenergic antagonist phentolamine. Another potentially fatal interaction, serotonin syndrome, produces hypertension, tachycardia, hyperpyrexia, delirium, agitation, myoclonus, and hyperreflexia (this is reviewed in Chapter 31 ).

Cardiac Conducting System Effects Heart rate can be affected by antipsychotic and anticholinergic medications. Tachycardia , arising from anticholinergic vagolytic effects, can pose additional risk to the cardiac patient. Although low-potency antipsychotics and TCAs produce a statistically significant increase in heart rate, several atypical antipsychotics increase the heart rate, as well. Clozapine causes sustained tachycardia of 10 to 15 beats/min in 25% of all patients, and olanzapine can cause a small amount of tachycardia. Tachycardia also has occurred in patients using psychostimulants. Though SSRIs typically cause a predictable 7 to 9 beats/minute reduction in heart rate, bradycardia rarely occurs and is usually seen in the elderly or in those following a significant overdose. Major depression is associated with a higher prevalence of ventricular arrhythmias , including ventricular tachycardia and reduced heart rate variability, and psychiatric medications often additionally interfere with cardiac conduction. All TCAs appear to prolong both atrial and ventricular depolarization by sodium and potassium channel inhibition. The main effect of TCAs is the prolongation of the conduction in the His-ventricular portion of the His bundle, as occurs with the group IA anti-arrhythmic drugs. Even though nortriptyline is the least cardiotoxic TCA, all TCAs should be avoided in patients with ventricular arrhythmias. Both typical and atypical antipsychotic medications also can cause conduction abnormalities that lead to prolongation of the QT interval. In contrast to the TCAs, antipsychotic medications generally prolong the QTc through inhibition of delayed rectifier potassium channels. Among the typical antipsychotic medications, lower potency medications appear to cause greater QTc prolongation, making higher potency antipsychotic medications preferable in patients with conduction disturbances. Carbamazepine can produce conduction abnormalities at toxic doses. In patients with pre-existing abnormalities, even therapeutic levels of carbamazepine can result in conduction abnormalities. QT prolongation is thought to be a surrogate marker for torsades de pointes (TdP), a lethal ventricular arrhythmia, and sudden death. Patients are believed to

be at higher risk if their QTc is greater than 450 ms. Risk factors for QT prolongation include age, number and severity of medical conditions, female gender, electrolyte abnormalities (hypokalemia, hypocalcemia, and hypomagnesemia), and concomitant use of alcohol or cocaine. All TCAs cause prolongation of the QT interval, but generally pose a significant risk of ventricular arrhythmia only in patients with pre-existing cardiac disease. As a class, TCAs prolong the QT interval by 13 ms compared to placebo. Though SSRIs were previously thought to prolong the QT interval minimally, all have now been associated in case reports with prolongation of the QT interval, and, as a class, they prolong the QT interval by 6 ms as compared to placebo. Citalopram appears to be associated with more QT prolongation that other SSRIs, and the United States Food and Drug Administration (FDA) has recommended a maximum dose of 40 mg/day in healthy patients and 20 mg/day in older patients or those with liver disease. Antipsychotics can also prolong the QT interval, and thioridazine carries the greatest risk. Generally, lower-potency agents are associated with a greater risk of QTc prolongation than higher-potency agents. Among atypical antipsychotics, ziprasidone has caused the greatest mean QTc prolongation, followed by iloperidone, risperidone, and olanzapine; each of these causes equal to or greater mean QTc prolongation than orally-administered haloperidol. Quetiapine has also been implicated in QT prolongation and TdP, and has a specific FDA recommendation to limit its use in patients with other risk factors. Lurasidone, paliperidone, and aripiprazole have not been associated with significant QT prolongation compared to placebo. Clozapine is also not typically associated with significant QT prolongation. Intravenous (IV) haloperidol, often used in emergency situations, carries a risk of QTc prolongation and TdP (especially at higher doses). With lengthening of the QT interval, potassium and magnesium levels need to be checked and repleted prior to treatment. Less-severe atrial arrhythmias can occur with psychiatric medications. Lithium can cause sinus node dysfunction and first-degree atrioventricular block. The elderly are especially prone to the inhibitory effects of lithium on impulse generation within the atrium. Valproic acid in overdose has been associated with heart block. Amoxapine has been the subject of case reports of atrial flutter and fibrillation. Clozapine has been associated with a number of adverse CV effects. In addition to causing OH and tachycardia, clozapine has been associated with the development of myocarditis in otherwise healthy patients. Therefore, the diagnosis of myocarditis should be considered in patients with unexplained

fatigue, dyspnea, fever, chest pain, or other symptoms of heart failure while taking clozapine. Clozapine has also been associated with cardiomyopathy, pericarditis, and pericardial effusion. Fortunately, many psychiatric medications have minimal to no effect on the cardiac conduction system. These include MAOIs, bupropion, benzodiazepines, buspirone, and naltrexone.

Medication Concerns in Patients with Cardiovascular Disease Major depressive disorder (MDD) and other psychiatric illnesses are common in patients with CV disease and can be associated with an increased incidence of coronary artery disease (CAD), recurrent cardiac events, and mortality. Unfortunately, many psychiatric medications must be used with caution in patients with CAD. TCAs and low-potency antipsychotics increase the risk of angina or myocardial infarction because of tachycardia induced by anticholinergic vagolytic effects. In contrast, SSRIs are safe in patients with CAD and can be effective at treating depression in this population. Sertraline is the antidepressant most studied in this population and considered by many safest, given its limited medication interactions. Disulfiram (Antabuse) is contraindicated in patients with significant CAD. Psychostimulants should also be used with caution in this population because of their effects on heart rate and BP. All psychiatric medications should be used with caution for 4 to 6 weeks after myocardial infarction. TCAs do not appear to exacerbate heart failure, even in patients with left ventricular dysfunction. SSRIs, including sertraline and escitalopram, have demonstrated good safety in controlled trials in this population; however, randomized controlled trials have not found them to be more effective than placebo in this population. Low-potency antipsychotics and clozapine should be avoided in patients with heart failure.

Central Nervous System Effects Some of the more common central nervous system (CNS) side effects associated with psychiatric medications are tremor, anxiety, and restlessness. A high-frequency tremor can occur as a side effect of TCAs, SSRIs, MAOIs, bupropion, lithium, valproic acid, carbamazepine, lamotrigine, and antipsychotics; this can be exacerbated by caffeine or by anxiety and can be improved through the use of low-dose beta blockers (e.g., propranolol 10 mg

TID) or low-dose benzodiazepines. Increased anxiety and jitteriness might be seen during the initiation of TCAs, SSRIs, venlafaxine, desvenlafaxine, bupropion, aripiprazole, asenapine, lurasidone, risperidone, and ziprasidone. These symptoms often remit within a few weeks and can be minimized by starting at low doses, titrating cautiously, or using augmenting agents (such as benzodiazepines). Parkinsonism , acute dystonia, and akathisia are common movement disorders caused by the use of antipsychotics, especially high-potency typical antipsychotics. They also are known as extrapyramidal symptoms (EPS). When parkinsonism occurs, the dose of medication should be reduced, an anticholinergic medication can be added, or a less potent dopamine-blocking agent can be chosen. Acute dystonia can develop hours to days after the initiation of a antipsychotic medication and constitutes a psychiatric emergency; treatment involves the use of anticholinergic (e.g., benztropine or diphenhydramine) medications. Akathisia is characterized by the subjective feelings of restlessness or the appearance of restlessness. Besides dose reduction or a change of medication, use of beta-adrenergic blocking drugs or benzodiazepines is often helpful. EPS are somewhat less common with asenapine, iloperidone, and ziprasidone, and are quite rare with olanzapine, quetiapine, and clozapine. Aripiprazole, a dopamine partial agonist, has relatively low rates of dystonic reaction but frequently can cause akathisia. Some patients on SSRIs experience an akathisia-like motor restlessness that can respond to low-dose propranolol or benzodiazepines. Medication-induced tardive dyskinesia (TD) is a late-appearing disorder of involuntary movements. The most common movements involve the face, fingers, and toes. TD is most common with conventional antipsychotics; the risk of developing TD on these agents appears to be 4% to 5% per year for at least the first 4 years. Atypical antipsychotics appear to have lower rates of TD, though the amount of risk reduction is not entirely clear. Of the atypical antipsychotic medications, risperidone appears to have the highest risk for TD; olanzapine, quetiapine, and ziprasidone have been linked to TD in case reports, whereas clozapine has not been associated with TD. At this time, the risk for TD of newer atypical antipsychotic medications (aripiprazole, paliperidone, lurasidone, asenapine) is unknown; however, given the receptor binding profiles of these medications, the risk of TD with these medications is likely to be similar to other atypical antipsychotics. Other risk factors for TD include a greater duration of treatment with antipsychotics, female gender, increasing age, and the presence of

mood or cognitive disorders. In patients who develop TD, treatment might involve switching to a second-generation antipsychotic medication with a lower affinity for dopamine receptors, if the patient is able to tolerate this medication change. Several medications, including benzodiazepines (e.g., clonazepam), tetrabenazine, and botulinum toxin, also might be helpful as adjunctive treatments for persistent and disabling TD, though the evidence for these interventions is mixed. Neuroleptic malignant syndrome (NMS) is a life-threatening complication of antipsychotic medications discussed further in Chapter 31 . The symptoms include muscular rigidity with increased creatine phosphokinase (CPK), agitation, delirium, and autonomic dysfunction. Both too little and too much sleep can be associated with psychiatric medications. Fatigue and sedation can be manifestations of psychiatric symptoms or medication side effects. TCAs, MAOIs, trazodone, nefazodone, mirtazapine, lithium, valproic acid, topiramate, and antipsychotics are each likely to produce sedation. Among atypical antipsychotics, clozapine, quetiapine, ziprasidone, and olanzapine are associated with the most sedation. The side effect of sedation can be used to induce sleep in some patients. Insomnia can occur with SSRIs, bupropion, venlafaxine, desvenlafaxine, psychostimulants, aripiprazole, asenapine, lurasidone, and MAOIs. Reducing caffeine, eliminating day-time naps, moving medication dosing to earlier in the day, and practicing sleep hygiene (e.g., restricting activities in the bedroom to sleep or sexual relations) can be effective. Hypomania or mania related to antidepressant use occurs in 1% to 5% of patients without a history of bipolar disorder. Patients with bipolar disorder who are not on a mood stabilizer are at much higher risk. Switching of mood states can occur with any antidepressant, though a recent meta-analysis suggested that TCAs were most likely to induce manic symptoms. Seizure threshold can be reduced in patients taking bupropion and clozapine. Doses of bupropion greater than 150 mg (and daily doses of greater than 450 mg) should be avoided to reduce the risk of seizures. Clozapine-associated seizures occur in approximately 5% of individuals in the first year of treatment. The relationship between clozapine and seizures appears to be dose-dependent, with a higher risk associated with higher doses and serum levels. Generally, doses above 600 mg per day or serum levels above 1,000 ng/ml are associated with a higher risk of seizures; therefore, consideration should be given to adding

valproic acid or another anticonvulsant for seizure prophylaxis if it is expected that the clozapine dose will be at least 600 mg per day. Finally, cognitive slowing has been described with a variety of psychiatric medications. It can be difficult to distinguish the effects of fatigue, sedation, loss of hypomanic symptoms, and other effects of treatment from “true” cognitive dysfunction, but a number of agents have been associated with cognitive slowing. Among the mood-stabilizing agents, topiramate has been most strongly associated with cognitive impairment. Lithium, valproic acid, and carbamazepine have been associated with poor concentration, attention, and memory. Lamotrigine appears to have few negative cognitive effects. The anticholinergic effects of TCAs can adversely affect cognitive function, whereas SSRIs, bupropion, venlafaxine, and other antidepressants do not appear to impair cognition. Finally, conventional antipsychotics (especially low-potency agents with anticholinergic effects) have been associated with cognitive impairment, whereas the atypical agents can be associated with mild improvements as seen on neuropsychological batteries, though this relationship is still being debated.

Anticholinergic Effects Anticholinergic activity varies greatly among psychiatric medications. It is greatest for the tertiary amine TCAs (amitriptyline, imipramine, doxepin) and low-potency typical antipsychotics, and minimal for the newer antidepressants (SSRIs, venlafaxine, bupropion, mirtazapine, nefazodone). Of the atypical antipsychotics, clozapine has the most anticholinergic activity, with olanzapine being the runner-up. Typical anticholinergic side effects include xerostomia (dry mouth), flushing, hyperthermia, blurry vision, urinary retention, and confusion. The severity of these side effects is greater in cases of overdose, but they can be present even at typical doses of these medications. Tolerance often develops to many of the anticholinergic side effects over time. Xerostomia can result in bad breath, stomatitis, and dental caries. Often sugarless gum or hard candy can stimulate salivation. Dry eyes can be treated with artificial tears. Blurred vision usually lessens with time, but when persistent can be managed by addition of pilocarpine 1% drops or bethanechol. Patients with narrow-angle glaucoma can experience dangerous elevations of intraocular pressure when anticholinergic medications are used. Urinary hesitancy and retention can occur in patients on anticholinergic medications. This can be complicated by urinary tract infections and even renal

damage. Elderly patients and those with prostatic hypertrophy or other outflow problems are at higher risk. Severe urinary retention mandates the discontinuation of the medication. CNS anticholinergic toxicity can present with confusion, memory loss, delirium, and psychosis. Usually this is accompanied by other signs of anticholinergic excess (increased temperature, dry skin, xerostomia, flushing, and urinary retention). Elderly patients, children, and brain-injured patients are at increased risk. Management includes reducing or discontinuing the dose and infusing physostigmine (1–2 mg IV push over 2 minutes). This requires close careful monitoring of vital signs, hemodynamics, the EKG, and the mental status.

Gastrointestinal Adverse Effects Gastrointestinal (GI) side effects are very common in patients taking certain psychiatric medications, such as SSRIs. They typically occur during initiation or titration of the medication dose and usually resolve over the course of days to weeks. Nausea and dyspepsia are common side effects and can be relieved by the use of divided dosing or dosing with meals. Adjuvant treatment includes over-thecounter antacids, bismuth salicylate, and H2 blockers. Diarrhea is more commonly seen with the use of newer serotonergic antidepressants, such as the SSRIs, most of which lack significant anticholinergic activity. Management strategies include the use of anti-diarrheal agents or probiotic formulations. Diarrhea and other GI side effects associated with lithium might respond to a change in the preparation (e.g. from lithium carbonate to Eskalith CR, or vice versa); similarly, nausea, vomiting, and diarrhea with valproic acid might resolve with a switch to divalproex sodium (Depakote). Constipation is common with TCAs but can be seen with all antidepressants. In the elderly, severe constipation and paralytic ileus can be a serious health risk. Hydration and adequate over-the-counter bulk laxatives (Metamucil) or stool softeners can be useful. Bethanechol relieves the constipation caused by anticholinergic antidepressants. Constipation can also be seen with other anticholinergic agents, such as olanzapine, and low-potency typical antipsychotics. Cases of toxic megacolon as a complication of severe constipation have been described with the use of clozapine.

Valproic acid causes dose-dependent rises in liver enzymes and rarely causes fatal hepatotoxicity. Independent of these effects, it can also result in hyperammonemia, causing cognitive dysfunction. Valproic acid has also been associated with pancreatitis. Carbamazepine might cause an idiosyncratic doserelated hepatitis. Antipsychotics have been associated with cholestatic jaundice, which presents with nausea, malaise, fever, pruritus, abdominal pain, and jaundice within the first 2 months of starting an antipsychotic treatment. The antidepressant nefazodone has also been associated with elevated rates of hepatotoxicity; this usually occurs within the first six months of treatment. For this reason, nefazodone has largely fallen out of favor. Duloxetine has also been associated with drug-induced liver injury, including cholestatic jaundice and hepatitis in patients with chronic liver disease or cirrhosis. Its use, therefore, is contraindicated in patients with chronic alcohol use or chronic liver disease. Disulfiram and naltrexone have also been associated with dose-related elevation of liver enzymes and rare hepatotoxicity, though these effects usually occur at doses higher than those typically used.

Hematological Effects Agranulocytosis, one of the most serious hematologic side effects is potentially life-threatening and is seen most commonly with clozapine and rarely with phenothiazines. A white blood cell (WBC) count drop of 50% or a count of less than 3,000 should lead to immediate discontinuation of the offending agent. If the WBC count drops to less than 2,000 or the absolute neutrophil count drops to less than 1,000, the causative agent should be discontinued permanently. Other medications that affect the hematopoietic system include carbamazepine, valproic acid, mirtazapine, and lithium. Carbamazepine is associated with benign as well as severe hematological toxicities with depression of red blood cells, WBCs, or platelets. Evaluation of a complete blood count (CBC), closer evaluation of patients with baseline abnormalities, and regular monitoring is required. Importantly, oxcarbazepine, a related compound, has not been associated with blood dyscrasias. Valproic acid can cause thrombocytopenia or platelet dysfunction; only rarely is it associated with bleeding problems. Patients on valproic acid should have their platelet count and bleeding time checked before any surgery. Mirtazapine has been rarely associated with agranulocytosis and neutropenia. Such hematological effects appear to resolve with discontinuation of the agent. Lithium can produce a benign, relative leukocytosis without impairing leukocyte function. The WBC count rarely exceeds 15,000 as

a result of lithium treatment alone. Finally, clozapine has rarely been associated with eosinophilia. Although usually benign in nature, it has been associated with end organ damage in rare instances. Therefore, the manufacturer recommends interrupting treatment if the eosinophil count rises above 4,000/mm3 .

Renal Effects Renal side effects are most commonly seen with lithium use. Although lithium commonly causes defects in urine-concentrating ability, it rarely causes renal failure in patients whose lithium levels are maintained in the therapeutic range. The amount of renal damage is higher in those patients who receive lithium in divided doses rather than once-daily dosing. The most common renal problem due to lithium is polyuria. This can be partly due to lithium’s effect on the renal action of antidiuretic hormone, leading to an inability to concentrate urine. Polyuria can occur in up to 70% of patients with long-term lithium treatment; 10% of lithium-treated patients are diagnosed with nephrogenic diabetes insipidus (DI). The treatment includes maintaining the lowest effective lithium level, administering the drug at a single bed-time dose, and using diuretics. The diuretics, amiloride and hydrochlorothiazide, markedly reduce urine volume caused by DI. Lithium also causes an occasional acute rise in serum creatinine, which abates with lithium discontinuation. Lithium-induced nephrotic syndrome has also been reported in the literature. Intravenous lorazepam also can have renal side effects. Although lorazepam itself is not toxic to the kidneys, the carrier molecule (propylene glycol) in the intravenous formulation can lead to renal damage, especially in higher doses. This can become relevant in patients requiring repeated doses of intravenous lorazepam (e.g., patients with severe alcohol withdrawal or catatonia). With few exceptions, psychiatric medications are primarily metabolized hepatically. However, several psychiatric medications rely significantly upon renal clearance to be eliminated from the body. Aside from lithium, medications dependent on renal clearance include gabapentin, pregabalin, paliperidone, memantine, venlafaxine, desvenlafaxine, topiramate, and acamprosate. Therefore, patients who develop acute renal failure can develop symptoms of toxicity due to rising serum levels of these medications. If a patient is taking one of these medications, the dose should be reduced or discontinued entirely in the setting of acute renal failure.

Weight Gain Weight gain is a common cause of medication non-compliance and, among

antidepressants, is most strongly associated with tertiary amine TCAs (e.g., amitriptyline, imipramine, doxepin), MAOIs (phenelzine), and mirtazapine. Weight gain can be related to the antihistaminic or serotonergic effects of the agents. The SSRIs, venlafaxine, duloxetine, nefazodone, and, especially, bupropion are less likely to cause weight gain. Among mood-stabilizing agents, both lithium and valproic acid have been associated with long-term weight gain; carbamazepine is less commonly associated with weight gain. Lamotrigine appears to be weight-neutral, and topiramate is associated with weight loss. Weight gain is a serious problem with all typical antipsychotics. Of the typical antipsychotics, low-potency agents have been shown to increase appetite in a dose-related curve and have been associated with significant weight gain; highpotency agents are associated with less weight gain. The atypical antipsychotics have also been linked to significant weight gain. Of the atypical agents, clozapine appears to have the greatest propensity to cause increased weight. More than 75% of patients on clozapine gain weight, with an average increase of 9 to 25 lbs. Olanzapine is also strongly associated with weight gain, with an average weight gain of approximately 8 lbs. in the first 10 weeks of treatment, and more than half of patients gain more than 7% of their body weight (at least 12 lbs for the average subject) with maintenance treatment. Early weight gain with clozapine and olanzapine appears to be a predictor of total weight gain. Iloperidone, quetiapine, and risperidone are also associated with significant weight gain, though less than with clozapine and olanzapine. Though ziprasidone, lurasidone, asenapine, and aripiprazole are marketed as being “weight-neutral,” weight gain can still occur, particularly in antipsychotic-naïve patients. If weight gain occurs, dietary modification and increased exercise can be effective counter-measures. There is some evidence that metformin might be helpful for reducing weight gain or increasing weight loss in patients taking antipsychotic medications. Topiramate also has been used with some success in the treatment of psychiatric medication-associated weight gain. There is little experience with the combination of weight loss agents and antidepressants.

Dermatological Effects Up to 10% of patients experience cutaneous reactions to psychiatric medications. The usual reaction is an erythematous maculopapular rash that tends to occur early in treatment and that is usually self-limited. The decision to continue a medication depends upon the agent used, the level of discomfort,

evidence of systemic involvement, and the patient’s history. Rashes that are associated with the mood-stabilizing agents most often require discontinuation of the offending agent. Systemic involvement (e.g., fever, leukocytosis, elevated liver function) usually indicates a generalized immune response, and discontinuation of the offending medication is necessary. Severe reactions, including generalized urticaria, erythema multi-forme, and toxic epidermal necrolysis, can occur. Lamotrigine has been associated with the development of serious dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Furthermore, approximately 10% of patients taking lamotrigine can have a maculopapular rash or erythema. Such dermatological reactions usually occur in the first 8 weeks of treatment or with fluctuations in blood levels; they are approximately three times more common in children than in adults. The risk of rash can be minimized with slow upward titration of the dose. Carbamazepine and oxcarbazepine have also been associated with the development of dangerous dermatological reactions (such as Stevens-Johnson syndrome), though less commonly than with lamotrigine. Cutaneous erythematous plaques with atypical and lymphoid infiltrates and pseudolymphomas have been reported in some patients on SSRIs and benzodiazepines. The development of severe atypical dermatologic reactions requires discontinuation of the offending agent and dermatologic consultation. Photosensitivity and skin pigmentation changes might also be seen in patients taking antipsychotic medications, especially chlorpromazine. Development and exacerbation of acne has occurred in patients taking lithium.

Endocrinological Side Effects Antipsychotics have been associated with the development of type 2 diabetes (T2D), with patients taking antipsychotic medications at a 2- to 3-fold increased risk of T2D compared to individuals not taking antipsychotics. Many of the atypical antipsychotics have been associated with the development of new-onset T2D, with clozapine and olanzapine being the most commonly implicated agents. Quetiapine, risperidone, iloperidone, paliperidone, and typical antipsychotics have also been associated with the development of T2D. The manifestations of this antipsychotic-associated T2D have ranged from borderline abnormalities of glucose regulation to full-blown diabetic ketoacidosis. The mechanisms for the development of T2D in association with antipsychotics remains unclear but can include weight gain, reduced insulin secretion, and

increased insulin resistance. Treatment usually involves standard dietary and pharmacologic interventions and, where possible, a switch from the offending agent. Hyperprolactinemia can result from the use of dopamine-blocking agents. Typical antipsychotics, paliperidone, and risperidone in particular, have been associated with the development of prolonged elevation of prolactin levels. The mechanism of this effect is related to the action of dopamine in the tuberoinfundibular tract. Dopamine typically inhibits the release of prolactin in this tract; however, when dopamine-blocking agents are administered, prolactin release into the bloodstream is increased. Clinical consequences of hyperprolactinemia can include galactorrhea, amenorrhea, gynecomastia, and impotence. Lurasidone, olanzapine, and ziprasidone have an intermediate effect on prolactin levels, whereas other atypical antipsychotics, including iloperidone, asenapine, clozapine, and olanzapine, have been associated with hyperprolactinemia, though to a lesser extent. Aripiprazole and quetiapine are not associated with prolactin elevations, and aripiprazole has been shown in some studies to reduce prolactin levels. As such, aripiprazole is the treatment of choice for patients with prolactin-secreting tumors requiring antipsychotic medication.

Sexual Side Effects Sexual dysfunction occurs in roughly one-third of patients treated with antidepressants. Erectile dysfunction can result from the anticholinergic or antialpha-adrenergic effects of medications. Delayed orgasm and anorgasmia may be serotonergically-mediated. Sexual side effects have been noted with SSRIs, TCAs, MAOIs, venlafaxine, vortioxetine, and duloxetine. Nefazodone, mirtazapine, vilazodone, and bupropion are not associated with decreased sexual desire or function. Sexual dysfunction can occur in up to 60% of all patients on antipsychotic medications. Sexual dysfunction is under-reported unless it is specifically asked about and can lead to medication non-compliance if not addressed by the physician. Decreased libido can also be a symptom of depression or medication use. If it persists after improvement of mood symptoms, a medication effect should be suspected. Priapism can occur with antidepressants or antipsychotics. It is most frequently reported with trazodone use (1 in 1,000 men). All men who receive trazodone

should be warned that priapism is a medical emergency that requires evaluation by a urologist. Treatment of sexual side effects involves use of adjunctive agents or the discontinuation of the offending medication. A dose reduction or drug holiday in anticipation of sexual activity is sometimes successful. A variety of adjunctive agents have been used in the treatment of antidepressant-induced sexual dysfunction. These include agents with dopamine or noradrenergic agonism (e.g., bupropion, psychostimulants, amantadine), serotonergic agents (e.g., cyproheptadine, buspirone), and agents acting on nitric oxide (e.g., sildenafil, tadalafil). Yohimbine, an α 2-adrenergic antagonist, can improve erectile and orgasmic dysfunction. Yohimbine is contraindicated in patients taking MAOIs. Cholinergic agonists (e.g., bethanechol, 10–80 mg/day) can enhance libido and improve erectile function and ejaculatory problems.

Conclusions Knowledge of the risk of side effects is a requirement for the safe and effective treatment of all patients. Clinicians should anticipate the side effects likely to develop and select medications that have the smallest chance of exacerbating medical problems. The lowest effective dose should be used and gradually titrated to an effective dose. Maintaining open communication with patients can help to increase adherence and ensure the safe treatment of psychiatric illness.

Suggested Readings 1. Beach SR, Celano CM, Noseworthy PA, et al: QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics . Jan-Feb 2013; 54(1):1–13. 2. Caroff SN, Mann SC, Campbell EC, et al: Atypical antipsychotics and movement disorders. J Clin Psychiatry . 2002; 63 (suppl 4): 12–19. 3. Holt RI, Mitchell AJ: Diabetes mellitus and severe mental illness: mechanisms and clinical implications. Nat Rev Endocrinol . Feb 2015; 11(2): 79–89. 4. Huffman JC, Beach SR, Stern TA: Side effects of psychotropic medications. In Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby Elsevier; 2016: pp. 567–580.

5. Labbate LA, Fava M, Rosenbaum JF, Arana GW: Handbook of Psychiatric Drug Therapy . 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. 6. Leucht S, Cipriani A, Spineli L, et al: Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments metaanalysis. Lancet . Sep 14 2013; 382(9896): 951–962. 7. Leung JY, Barr AM, Procyshyn RM, et al: Cardiovascular side-effects of antipsychotic drugs: the role of the autonomic nervous system. Pharmacol Ther . Aug 2012; 135(2): 113–122. 8. Perlis RH, Fava M, Nierenberg AA, et al: Strategies for treatment of SSRIassociated sexual dysfunction: a survey of an academic psychopharmacology practice. Harv Rev Psychiatry . 2002; 10: 109–114. 9. Stevens JR, Fava M, Rosenbaum JF, et al: Psychopharmacology in the Medical Setting. In Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: pp. 441–466.

CHAPTER Natural Medications in 57 Psychiatry DAVID MISCHOULON, MD, PHD AND ANDREW A. NIERENBERG, MD

KEY POINTS Overview The term “natural medication,” refers to medications derived from natural products, but generally not approved by the United States Food and Drug Administration for their purported indication. These medications include plants and herbs, hormones and vitamins, fatty acids, amino acid derivatives, homeopathic preparations, as well as other products. Theoretical Basis The popularity of natural remedies is fueled by several factors. These include: dissatisfaction with the medical profession and managed care; the growth of information about these products through the Internet and other media; the ready availability of natural medications without a prescription; the heightened sense of independence associated with self-prescribing; recommendations from non-physician practitioners; and, ease of treatment, often at a lower cost. Their safety and efficacy, however, is relatively poorly characterized compared to registered medications. Classification of Methodology Sub-types Natural remedies are available for many psychiatric conditions, as outlined in the following. Indications Antidepressants of the natural category include St John’s wort (hypericum perforatum L. ), S-adenosyl methionine, folic acid, and vitamin B12 , Omega-3 fatty acids (EPA and DHA in particular), dehydroepiandrosterone, and inositol.

Putative natural anxiolytic-hypnotics include Valerian (Valeriana Officinalis ), Kava (Piper Methysticum ), and melatonin. N -acetyl cysteine can be effective for bipolar disorder and for obsessivecompulsive disorder. Black Cohosh and Chaste Tree berry can be used to treat menopausal and PMS symptoms, respectively. Ginkgo biloba can be used for memory and cognitive enhancement in cases of early dementia. Homeopathy can be used for a wide range of psychiatric condition, but like most of the other remedies discussed here, is generally lacking in rigorous systematic data on efficacy. Clinical Applications The best candidates for natural therapies can include: mildly symptomatic patients with a strong interest in natural remedies; those who have failed multiple trials of conventional remedies; and those who are highly intolerant of side effects. Important Historical Proponents Historically, natural remedies and other forms of complementary and alternative medicine have been largely neglected in medical training, although this is changing. Psychiatric practitioners need to understand the actions and hazards of natural medicines to properly advise patients who may be considering, or are already using, these therapies.

Introduction The term “natural medication,” as used here, refers to medications derived from natural products, but generally not approved by the United States Food and Drug Administration (FDA) for their purported indication. These medications include plants and herbs, hormones and vitamins, fatty acids, amino acid derivatives, homeopathic preparations, as well as other products (Table 57-1). Table 57-1: Natural Medications and Their Indications and Usage Active

Putative

Possible Mechanisms Suggested Adverse

Medication

Components Indications of Action

Doses

Events

Black cohosh (Cimicifuga racemosa)

Triterpenoids, isoflavones, aglycones

Menopausal symptoms

Suppression of luteinizing hormone

40 mg/day

Gastrointestinal upset, dizziness, headache, weight gain

Chaste tree berry (Vitex agnus castus)

Unknown

Pre-menstrual symptoms

Prolactin inhibition, interaction with dopaminergic receptors

200–400 mg/day

None

Dehydroepiandrosterone Adrenal gland (DHEA) steroid hormone

Depression and GABA antagonism, 5–100 mg/day dementia NMDA in b.i.d.-t.i.d. potentiation, dosing increase in brain serotonin and dopamine activity

Acne, irritability, insomnia, headaches, menstrual irregularities, increased ocular pressure, palpitations

Folic acid

Vitamin

Depression

Neurotransmitter synthesis

400 μg/day; 7.5–15 mg/day of 5MTHF (Deplin)

None

Ginkgo biloba

Flavonoids, terpene lactones

Dementia

Nerve cell stimulation and protection, membrane/receptor stabilization, free radical scavenging, PAF inhibition

120–240 mg/day in b.i.d.-t.i.d. dose

Mild gastrointestinal upset, headache, irritability, dizziness; bleeding

Homeopathy

Various herbs and Various minerals disorders

Unknown

Varies with preparation

Mild transient worsening of target symptoms

Inositol

Second messenger Depression, precursor panic, OCD, pediatric bipolar disorder

Second messenger 12–18 g/day synthesis, sensitization of serotonin receptors

Mild

Kava (Piper methysticum)

Kavapyrones

Anxiety

Central muscle relaxant, anticonvulsant, GABA receptor binding

60–120 mg/day

Gastrointestinal upset, allergic skin reactions, headaches, dizziness, ataxia, hair loss, visual problems, respiratory problems, dermopathy, severe liver toxicity

Melatonin

Pineal gland hormone

Insomnia

Circadian rhythm regulation in suprachiasmatic nucleus

0.25–0.3 mg/day (as high as 5 mg/day in

Sedation, confusion, inhibition of fertility, decreased sex drive, hypothermia, retinal

nucleus

mg/day in

hypothermia, retinal

some cases)

damage

N -acetyl cysteine (NAC)

Cysteine supplier

Bipolar disorder, obsessivecompulsive disorder

Reduction of free radicals via glutathione synthesis

2 grams/day

Mild gastrointestinal upset

Omega-3 Fatty acids

Essential fatty acids (primarily EPA and DHA)

Depression, bipolar disorder, psychotic disorders (?)

Inhibition of membrane signal transduction; antiinflammatory effects

1,000–2,000 mg/day

Gastrointestinal upset

S-Adenosyl Methionine (SAMe)

Methyl donor

Depression

Methyl donor involved in neurotransmitter synthesis

400–3,200 mg/day; some may need higher doses

Insomnia, loss of appetite, constipation, nausea, dry mouth, sweating, dizziness, nervousness; increased anxiety, mania or hypomania in bipolar patients

Depression

Cytokine production, decreased serotonin receptor density, decreased neurotransmitter re-uptake, MAOI activity

900–1,800 mg/day in b.i.d.-t.i.d. dosing

Dry mouth, dizziness, constipation, phototoxicity, serotonin syndrome when combined with SSRIs, adverse interactions with other drugs

Insomnia

officinalis)

Valepotriates, sesquiterpenes

Decrease GABA breakdown

450–600 mg/day

Blurry vision, dystonias, hepatotoxicity, mutagenicity?

Vitamin B12

Vitamin

Depression

Neurotransmitter synthesis

6 μg/day

None

Hypericin, (Hypericum perforatum hyperforin, polycyclic L.) phenols, pseudohypericin

St. John’s wort

Valerian (Valeriana

The Popularity of Natural Remedies Natural medications have been used for thousands of years worldwide, and are increasingly popular in the United States. Widely featured on television, newspapers, books, and Internet sites, these agents are now used by the majority of the world’s population. Surveys have shown that more visits were made to alternative practitioners nationwide than to primary care physicians, and more than 70% of the population worldwide uses non-traditional treatments. Historically, natural remedies and other forms of complementary and alternative medicine (CAM) have been largely neglected in medical training, although this

is changing. Psychiatric practitioners need to understand the actions and hazards of natural medicines so as to properly advise patients who might be considering, or are already using, these therapies.

Factors That Contribute to Widespread Use of Natural Medicines The popularity of natural remedies is fueled by a number of factors. These include: dissatisfaction with the medical profession and managed care; the growth of information about these products through the Internet and other media; the ready availability of natural medications without a prescription; the heightened sense of independence associated with self-prescribing; recommendations from non-physician practitioners; and, ease of treatment, often at a lower cost.

Problems Associated with the Use of Natural Medications Efficacy Issues The benefits of natural remedies are not clear. Manufacturers, suppliers, and the government have traditionally avoided sponsoring clinical research on natural remedies. There are fewer systematic studies that address the efficacy of these agents as compared to placebo and registered antidepressants, and many clinical trials are limited by small samples and by methodological problems.

Safety Issues Many people mistakenly believe that because these products are “natural” they are automatically safe. Although there are relatively few reports of serious adverse effects from these medications, there have been cases of toxicity (often when more than the recommended dosage has been ingested). Likewise, there is limited data regarding the safety and efficacy of combining natural remedies with conventional medications. Natural medications (except homeopathic remedies) are not tightly regulated by the FDA, and there is limited guidance about optimal doses, contraindications, interactions, and potential toxicities. Finally, different preparations can vary in their potency, quality, purity, and hence their efficacy.

Cost Issues

Some over-the-counter (OTC) treatments can be expensive and might even cost more than conventional medications. Because insurance companies generally do not cover these treatments, patients often must pay out-of-pocket for them. Therefore, these treatments might prove to be more costly in the long run, and less cost-effective if they do not work.

What Can Natural Medications Treat? There are different kinds of natural remedies available for almost any medical problem, but relatively few of them target psychiatric problems; these are mainly limited to mood, anxiety and sleep disorders, as well as dementia, and possibly psychotic disorders.

Natural Antidepressants St. John’s Wort (Extract of Hypericum Peforatum L. ) Efficacy There are about 40 published placebo-controlled trials that overall suggest that hypericum is effective for mild-to-moderate depression, and more effective than placebo. In various studies, hypericum was as effective as low-dose tricyclic antidepressants (TCAs). More recently, larger-scale clinical trials have compared hypericum against the selective serotonin re-uptake inhibitors (SSRIs), fluoxetine and sertraline, with mixed results. Some of these studies included individuals with more severe depression, and this might have influenced the results. Many systematic reviews and meta-analyses have emerged in recent years, which generally support hypericum’s antidepressant efficacy, though they caution that the results have been overall inconsistent. Studies have not shown benefit in attention deficit disorder, anxiety, and o bsessive-compulsive disorder (OCD).

Presumed Active Components Plant-based medication extracts usually consist of many chemicals. Hypericum contains polycyclic phenols, hypericin, pseudohypericin, and hyperforin, among others. Hypericin, hyperforin, and adhyperforin are generally believed to be the main active components, and many preparations of hypericum are standardized by the percentage of these components.

Proposed Mechanisms of Action

Because of the various potentially active ingredients, it is not surprising that hypericum is thought to work by different mechanisms. These include: the inhibition of cytokines (resulting in changes in interleukins IL-6 and IL-1β , and cortisol); decreased serotonin (5-HT) receptor density; decreased re-uptake of neurotransmitters; and, monoamine oxidase inhibition (although no special diet is needed, hypericum should not be combined with SSRIs, because of the possibility of development of serotonin syndrome). St. John’s wort (SJW) is metabolized by the liver.

Suggested Dose The recommended dose of hypericum is 900 to 1,800 mg/day, usually administered on a three-times-daily basis; however, different preparations can vary in the amount of their active product.

Adverse Effects Although hypericum is generally well tolerated, common side effects include dry mouth, dizziness, and constipation. There is a risk of phototoxicity, although it appears to be uncommon in humans. Little is known about its safety in overdose. There have been bipolar patients who switched to mania with its use. Many cases of adverse drug–drug interactions with hypericum have emerged. Hyperforin induces CYP-3A4 expression, and might reduce the therapeutic activity of a number of medications, including warfarin, cyclosporin, oral contraceptives, theophylline, fenprocoumon, digoxin, indinavir, camptosar, and zolpidem. Transplant rejection has also resulted from SJW-cyclosporin interactions. Transplant recipients and HIV-positive individuals receiving protease inhibitors should therefore not use hypericum.

Summary SJW appears better than placebo and equivalent to low-dose TCAs and probably to SSRIs for the treatment of depression. It can be most effective for milder forms of depression. It appears to be safe, but care must be taken because of drug–drug interactions.

S-Adenosyl Methionine Efficacy S-Adenosyl Methionine (SAMe ) has demonstrated a mood-elevating effect in depressed patients. There are more than 50 published clinical trials suggesting that parenteral ( intravenous [IV] or intramuscular [IM]) and oral SAMe

preparations are superior to placebo and as effective as TCAs. The first published placebo-controlled trial comparing SAMe with an SSRI (escitalopram) showed benefit in all treatment arms, but the high placebo response rate produced no significant differences between treatment arms. SAMe can be combined safely and effectively with TCAs, SSRIs, and serotoninnorepinephrine re-uptake inhibitors (SNRIs). SAMe can have a relatively faster onset-of-action than conventional agents. Other indications for SAMe can include: treatment of cognitive deficits in dementia; relief of distress during the purpuerium; reduction of psychological distress during opioid detoxification; antidepressant benefit for the alcoholic; use in medically ill depressed patients for whom conventional antidepressants might be contraindicated; and effectiveness in arthritis or other disease of the joints. Recent evidence suggests that SAMe might be more effective for depression in men than in women and might also ameliorate sexual dysfunction in men.

Proposed Mechanism of Action SAMe is a major methyl donor in the brain. It donates methyl groups to hormones, neurotransmitters, nucleic acids, proteins, and phospholipids. SAMe might exert its antidepressant effect by donating methyl groups in the reactions that result in the synthesis of acetylcholine, serotonin, acetylcholine, and (indirectly) dopamine, deficiencies of which have been associated with mood disorders. SAMe synthesis depends on the vitamins folate and B12 . Deficiencies in folate and B12 are also associated with development of depression and/or refractoriness to treatment, and SAMe might represent a final common pathway to depression secondary to vitamin deficiencies.

Suggested Doses Recommended doses of SAMe, based on clinical studies, range from 400 to 3,200 mg/day. Clinical experience suggests that some patients might need even higher doses. SAMe is relatively expensive compared to other natural remedies, and the cost can be prohibitive to many patients, particularly those requiring higher doses.

Adverse Effects SAMe is relatively free of adverse effects, and has no apparent hepatotoxicity. Side effects include mild insomnia, lack of appetite, constipation, nausea, dry mouth, sweating, dizziness, and nervousness. Recent studies suggest that gastrointestinal side effects are the most common. There are some reports of

increased anxiety, mania, or hypomania in patients with bipolar depression. So far, there are no reports of adverse drug–drug interactions with SAMe.

Summary SAMe appears to be safe and effective for depression, both as monotherapy and as augmentation, but larger studies are needed to establish this with certainty. In particular, more comparisons with newer antidepressants are called for.

Folic Acid Folic acid is required for synthesis of SAMe, which is needed for synthesis of several key neurotransmitters involved in mood regulation. Between 10% to 30% of depressed patients can have low serum folate, and patients with low folate respond less well to antidepressants. Studies have shown that folate supplementation in hypo-folatemic patients as well as in normo-folatemic patients might help to alleviate depression. One folate form, 5methyltetrahydrofolate (5-MTHF), is able to cross the blood–brain barrier and can therefore be more active in the brain. It is available by prescription under the name Deplin. A recent controlled trial of Deplin augmentation in SSRI nonresponders found benefit from addition of Deplin at 15 mg/day compared to placebo. Deplin is FDA-approved for treatment or prevention of vitamin deficiencies and is available by prescription only. There are preparations, such as Cerefolin and Cerefolin NAC, that contain additional nutrients (vitamins B2 , B6 , B12 , and N -acetyl cysteine) and are thought to potentially have benefits in dementia, but further study is needed to address this question.

Vitamin B12 Vitamin B12 is converted to methylcobalamin, which is also involved in the synthesis of central nervous system (CNS) neurotransmitters. B12 deficiency can result in an earlier onset of depression; however, it is not clear whether B12 supplementation in itself can have antidepressant properties.

Summary Physicians should check levels of B12 and folate in treatment-resistant patients, particularly if they have concurrent medical illness or other risk factors, such as alcoholism and poor oral intake. Correction of folate and B12 deficiency might improve depressive symptoms and response to antidepressant therapy. The

recommended dose of folate is 400 μg daily, although prescription-strength 5MTHF is typically dosed at 7.5 to 15 mg/day. The recommended dose of B12 is 6 μg daily. Both agents are well tolerated and lack significant side effects. Although there have been concerns about excessive doses producing health problems, none of these have been substantiated in rigorous investigations.

Dehydroepiandrosterone Dehydroepiandrosterone (DHEA ) is an adrenal steroid that is converted to testosterone and estrogen. Some studies have suggested beneficial effects in depression as well as in Alzheimer’s disease, though these studies were limited by small sample sizes and by non-significant results.

Summary Suggested doses of DHEA are 5 to 50 mg/day, but OTC strength and purity are not regulated. Side effects can include acne, irritability, insomnia, headaches, menstrual irregularities, increased ocular pressure, and palpitations. It is not clear how safe DHEA might be in women. There is still limited evidence for DHEA as an effective nootropic, and additional research is needed.

Omega-3 Fatty Acids Classification Omega-3 fatty acids are polyunsaturated lipids derived primarily from fish oil. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are thought to have psychotropic effects. Alpha linolenic acid (ALA) is another omega-3 fatty acid found in flax seed oil, but it is not thought to be psychotropically active.

Efficacy The omega-3 fatty acids might have a protective role against mood disorders, based on lower rates of depression in countries where large amounts of fish are consumed. There are more than 30 published double-blind, placebo controlled, trials of EPA, DHA, and combinations of the two that suggest efficacy in major depression, both as monotherapy and as an adjunctive therapy. Omega-3 fatty acids might also have a role in the treatment of bipolar disorder. However, there are fewer studies for this indication, and results suggest that the majority of the benefit is for the depressive rather than for the manic phase of the illness. Omega-3s are also promising in the treatment of depression during pregnancy and the post-partum period, but the evidence is still preliminary. There has been

a suggestion of beneficial effects of omega-3 fatty acids in psychotic disorders and personality disorders, but the data for this is much more limited.

Proposed Mechanisms of Action Omega-3 fatty acids may function similarly to mood stabilizers. They seem to inhibit G-protein signal transduction via reduced hydrolysis of phosphatidylinositol and other membrane phospholipids, which are precursors to second messengers. They also have anti-inflammatory effects that might in turn produce benefits in mood. Recent evidence, in fact, supports greater antidepressant efficacy of EPA in patients with elevated inflammatory biomarkers at baseline as well as obesity (which is associated with increased inflammation). Likewise, the omega-3s might have a preventive antidepressant effect in individuals who are taking interferon therapy for hepatitis.

Suggested Doses Commercially available preparations of omega-3 can have up to 1,000 mg (1g) of omega-3, with varying ratios of EPA:DHA. Preparations of EPA or DHA alone are also available. Clinical trial evidence suggests that psychotropicallyactive doses of omega-3 might be in the range of 1 to 2 g/day.

Adverse Effects Omega-3s are well tolerated. Mild dose-related gastrointestinal distress appears to be the main side effect. There have been cases of cycling to mania in bipolar patients who take omega-3s. There have been concerns about bleeding with doses greater than 3 grams per day, and, historically, the omega-3s have not been recommended in people with bleeding disorders or in those who are taking anticoagulants, but recent evidence suggests greater safety than previously thought.

Summary Overall, the omega-3s appear safe and promising, especially in unipolar depression. However, larger studies are needed.

Inositol Inositol is a polyol precursor in brain second-messenger systems. It has been shown to be decreased in the cerebrospinal fluid of patients with depression. Administration of inositol might reverse desensitization of serotonin receptors.

Efficacy

Inositol has been studied in a variety of conditions, including depression, panic disorder, and OCD, with encouraging results, although these are primarily small pilot studies of short duration. Investigations into their efficacy for bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD), Alzheimer’s disease, autism, and electroconvulsive therapy (ECT)–induced cognitive impairment have not suggested as strong a benefit. Recent work supports efficacy in pediatric bipolar disorder when combined with omega-3 fatty acids. Inositol has no apparent toxicity and it has a benign side effect profile.

Summary Overall, inositol is a promising treatment with multiple potential indications, but trials so far are small. Larger patient samples are required to achieve a better understanding of this drug’s effectiveness.

N -Acetyl-Cysteine Efficacy In a double-blind study of bipolar patients (N = 75) who had a mood episode in the past 6 months and who were stable for at least one month, N -acetyl-cysteine (NAC ) (2 grams per day) or placebo was added to ongoing medications. Measures of depression, quality of life, and functioning were all better with NAC compared to placebo by week 24; no differences were found in manic or hypomanic symptoms, but these symptoms were minimal at baseline and during the study. Improvements that occurred during the trial stopped after discontinuation of NAC. NAC has also been found to be useful for OCD symptoms.

Mechanism of Action NAC, by supplying cysteine, increases synthesis of the free radical scavenger glutathione, which, in turn, reduces oxidative stress. Glutathione, a tri-peptide composed of glutamate, cysteine, and glycine, is the most abundant thiol antioxidant in the brain. Oral NAC prevents glutathione depletion in the brain by increasing cysteine and synthesis of glutathione systemically. Furthermore, NAC has been found to be neuroprotective and can prevent oxidative damage in complex 1 in the mitochondrial electron transport chain.

Suggested Doses Doses studied range between 1,000 to 1,800 mg twice a day.

Adverse Effects Mild gastrointestinal upset has been reported with NAC.

Summary NAC appears to be a promising addition for the long-term treatment of bipolar disorder and OCD.

Natural Anxiolytics Valerian (Valeriana Officinalis ) Valerian is an herbal sedative and mild hypnotic. It is not considered optimal for the acute treatment of insomnia, but it promotes natural sleep after several weeks of use. Valerian is very popular among Hispanics.

Efficacy There are about 40 controlled, clinical trials of valerian. It decreases sleep latency and improves sleep quality; apparently there is no dependence or daytime drowsiness. When compared with flunitrazepam, it was found to have the same efficacy but fewer side effects. It also appears well tolerated and effective in children and in the elderly. A recent study showed benefit in menopausal women. However, a recent meta-analysis suggested a lack of objective evidence of efficacy.

Components and Proposed Mechanism of Action Valerian’s activity is attributed primarily to valepotriates and sesquiterpenes. These chemicals may function similarly to benzodiazepines; they might decrease γ -aminobutyric acid (GABA) breakdown, and cause changes in sleep architecture as measured by the electroencephalogram (EEG).

Suggested Doses Valerian is generally dosed at 450 to 600 mg, about 2 hours before bedtime. It is advisable to not expect immediate benefits as occur with use of benzodiazepines.

Adverse Effects Side effects from valerian are rare and can include blurry vision, dystonias, and hepatotoxicity. Mexican or Indian valerian should not be used, because some components may present a mutagenic risk.

Summary Overall, data for valerian is promising, but there needs to be larger doubleblind trials and trials that compare valerian to more conventional anxiolytics/hypnotics. Limitations to double-blinding include valerian’s distinctive and powerful smell (from isovaleric acid). Recently, new placebos that contain some of valerian’s inactive ingredients have served to provide a similar smell compared to the active medication. This should lead to better quality studies.

Kava (Piper Methysticum ) Kava is a plant-based drug that originated in the Polynesian Islands, where it is used in tribal rituals. It is believed to have a calming effect without altering consciousness. About 12 controlled double-blind studies suggest it might be helpful for mild anxiety states, including agoraphobia, specific phobia, generalized anxiety disorder (GAD), and adjustment disorder.

Components and Proposed Mechanism of Action Kava’s effect is thought to be due to kavapyrones that function as central muscle relaxants and as anticonvulsants. They are thought to bind to GABA receptors, and might also inhibit norepinephrine uptake. The net effect is to reduce excitability of the limbic system, perhaps as well as benzodiazepines, but without inducing dependence or predisposing to withdrawal.

Suggested Doses Kava is generally dosed at 60 to 120 mg/day. Bioavailability and half-life can vary, depending on the preparation.

Adverse Effects Side effects tend to be mild and can include gastrointestinal (GI) upset, allergic skin reactions, headaches, and dizziness. Toxic reactions (e.g., ataxia, hair loss, visual and respiratory problems, and kava dermopathy [a transient yellowing of the skin]) can occur with high doses or prolonged use. These toxic effects are reversible if use is discontinued. In the past decade, there have been about 80 cases of severe hepatotoxicity related to kava, including some cases that have required liver transplantation. A direct relationship between kava and liver disease is not uniformly clear, however, and some individuals may have been taking excessive doses and/or using kava for longer-than-recommended periods. Some have suggested that the

toxicity was secondary to fungal contamination in some preparations resulting from long periods between harvest and preparation. Several countries have removed kava from the market, and the FDA continues to investigate its safety. Physicians should proceed with caution regarding prescriptions of kava. Kava should not be administered for more than 3 months, and in cases of longer use, liver function tests should be monitored regularly; the drug should be immediately discontinued if elevations are observed. Individuals with a history of liver disease, alcohol use, or those who are taking concurrent medications with potential liver toxicity should avoid kava.

Summary Kava appears to be more effective than placebo for mild anxiety states, but additional comparisons to other anxiolytics are needed. Concerns about safety have significantly curtailed the use of kava and research on its efficacy.

Melatonin Melatonin is a hormone (derived from serotonin) that is made in the pineal gland. It is involved in organization of circadian rhythms. Melatonin first gained popularity among travelers who used it to reset their biological clock when traveling across time zones. Melatonin is believed to be an effective hypnotic that works within one hour of administration, regardless of the time of day it is taken. It might be more effective for people with insomnia due to circadian disturbances. It has been shown to be safe and effective in children and in the elderly.

Proposed Mechanisms of Action Melatonin might work at the level of the suprachiasmatic nucleus. Its effect is to reset the circadian pacemaker and attenuate the alerting process as well as to have a direct soporific effect.

Suggested Doses Studies have shown that 0.25 to 0.30 mg/day can decrease sleep latency, but many preparations can have as much as 5 mg of melatonin. It is probably safest to begin with lower doses and to increase them gradually. There are prolongedrelease forms of melatonin that may provide more sustained sleep during the course of the night.

Adverse Effects

Melatonin is well tolerated and has few side effects. These can include: daytime sleepiness or confusion with high doses; inhibition of fertility; decreased sex drive; hypothermia; and retinal damage. It should not be taken by pregnant women or by people with immunocompromised status (e.g., HIVpositive individuals, those who take steroids or other immunosuppressant drugs).

Summary Melatonin appears promising, and it is generally accepted as safe and effective; however, more clinical trials are needed. It might also have potential use in children with sleep disorders.

Medications for Pre-Menstrual Syndrome (PMS)/Menopausal Symptoms Black Cohosh (Cimicifuga Racemosa ) Black Cohosh is an herbaceous plant used for alleviation of physical and psychological menopausal symptoms. A few placebo-controlled studies have shown that doses of 40 mg/day are efficacious, as measured by changes in various psychometric scales.

Proposed Mechanisms of Action Black Cohosh contains many potentially active ingredients, including triterpenoids, isoflavones, and aglycones. It might work in part via suppression of luteinizing hormone in the pituitary gland.

Suggested Doses The recommended dose is 40 mg/day. Black Cohosh potency can vary with different preparations.

Adverse Effects Side effects from Black Cohosh tend to be very mild and can include GI upset, headache, dizziness, and weight gain. No specific toxicity has been associated with its use. Nonetheless, the duration of use is not recommended beyond 3 months. It should not be taken by pregnant women or by people with cardiovascular illness, including hypertension.

Summary Black Cohosh appears promising but it requires further study.

Chaste Tree Berry Chaste tree berry consists of the dried fruit of the chaste tree (Vitex agnus castus ). Historically, it was used by medieval monks to keep their vows of chastity via decreasing their sex drive. Today, it is typically used for PMS alleviation. The clinically active ingredient is not well characterized. There are a few small clinical trials that suggest efficacy for PMS.

Proposed Mechanisms of Action Chaste tree berry might work via prolactin inhibition. D2 receptors might be involved.

Suggested Doses and Adverse Effects Chaste tree berry is usually dosed at 200 to 400 mg/day. No serious adverse effects have been reported.

Summary More systematic trials are needed before recommendations can be made for the use of Chaste tree berry.

Cognition-Enhancing Remedies Ginkgo Biloba The seed from Ginkgo Biloba tree has been used in Chinese medicine for more than 2,000 years, primarily for treatment of cognitive deficits and affective symptoms in organic brain diseases, such as Alzheimer’s disease. Target symptoms include impairment in memory and abstract thinking as well as affective symptoms. Ginkgo might also improve learning capacity. It might also have a potential role in treatment of antidepressant-induced sexual dysfunction.

Efficacy More than 30 double-blind trials suggest that symptoms of dementia improve with Ginkgo. However, many early studies did not examine activities of daily living (ADLs) and a reduced need for care as outcome measures. More recent studies have examined these components, and suggest both subjective and objective improvement. A few studies have compared Ginkgo against registered nootropic agents. Cholinesterase inhibitors seem to have a slight advantage in efficacy, but Ginkgo is usually better tolerated. There is also evidence that the combination of Ginkgo and cholinesterase inhibitors might be more effective than either agent individually.

Components and Proposed Mechanisms of Action Active components of Ginkgo include flavonoids and terpene lactones. Ginkgo is thought to work by stimulation of still-functional nerve cells as well as protection of them from pathologic effects (e.g., hypoxia, ischemia, seizures, peripheral damage). Other functions can include membrane and receptor stabilization, and free radical scavenging.

Suggested Doses Ginkgo is usually dosed at 120 to 240 mg/day (administered on a BID-TID basis). A minimal 8-week course is recommended because Ginkgo tends not to have acute effects. Patients should be re-evaluated regularly during its use, and full assessment of its effect might require up to one year of use.

Adverse Effects Side effects from Ginkgo are mild and can include mild GI upset, headache, irritability, and dizziness. Ginkgo also inhibits platelet activating factor (by Ginkgolide B); therefore, it should be avoided in individuals with bleeding disorders, and it should be discontinued prior to surgery.

Summary Overall, Ginkgo appears effective with very low toxicity, and without interactions with other drugs. It might also have a potential role in the amelioration of antidepressant-induced sexual dysfunction, but its full range of effectiveness remains to be clarified.

Homeopathy Homeopathy was developed more than 200 years ago in Germany by Samuel Hahnemann. Homeopathic remedies are derived from plants and minerals. They are regulated by the FDA for safety, and sold over-the-counter.

Efficacy Most research on homeopathy has focused on physical, rather than mental, health. Homeopathy has been used in cases of social phobia, panic, MDD, attention deficit disorder (ADD), and chronic fatigue. The data suggests that homeopathy can be useful, but most studies have not been rigorously designed. Homeopathic remedies are administered orally and allowed to dissolve on, or under, the tongue. Improvement tends to be gradual, on the order of weeks to months. Transient aggravation of symptoms may occur early in treatment.

Proposed Mechanisms of Action The potency of homeopathic medications is believed to be proportional to their degree of dilution; therefore, preparation involves dilution to minute quantities. The “Principle of Similars,” involving a notion that symptoms represent the body’s attempt to heal itself, requires that the medication must paradoxically cause the symptoms it intends to alleviate. The homeopath obtains a careful history, with the goal of finding the one medication or combination of medications which will help the body heal its symptoms. Personality, diet, sleep pattern, reaction to temperature and weather are also considered. The mechanism of homeopathy is controversial and not well understood. It has drawn on various disciplines to explain it, none entirely convincingly. These include quantum theory, water clathrate formation, and thalamic neuron theory, among others.

Adverse Effects Side effects from homeopathy are usually benign, except for the initial worsening of symptoms that can often result in discontinuation of treatment. Homeopathy has no known drug interactions or overdose risk.

Summary Homeopathy has yielded promising results in some cases, but further studies are needed. For long-term use of these remedies, it is best to seek assistance from a certified homeopathic practitioner, in view of the frequent need for combination treatments.

Recommendations for Practitioners Practitioners should routinely inquire about patients’ use of natural medications given that many patients will not volunteer information about their use of these remedies. Patients should be monitored carefully while they are on multiple medications, because of increasing evidence of interactions with some natural products. Patients should be informed that these alternative medications are relatively untested and that it is unclear whether natural medications are appropriate or even preferable to conventional psychotropics. The best candidates for natural therapies might include: mildly symptomatic patients with a strong interest in natural remedies; those who have failed multiple trials of conventional remedies; and those who are highly intolerant of side effects.

Conclusions Natural medications are the subject of a growing field in psychopharmacology; in time, they might prove a valuable addition to the pharmacological armamentarium. Research data for many treatments are promising. But to recommend them as effective and safe, we need more systematic, controlled studies on adequate patient samples. The National Institutes of Health and National Institute of Mental Health have supported larger-scale studies of complementary therapies since the 1990s, and it is hoped that continued research will eventually produce more useful guidelines and recommendations for clinicians.

Suggested References 1. Alpert JE, Mischoulon D, Nierenberg AA, et al: Nutrition and depression: focus on folate. Nutrition . 2000; 16: 544 –546. 2. Alpert JE, Papakostas G, Mischoulon D, et al: S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or non-response to selective serotonin re-uptake inhibitors or venlafaxine. J Clin Psychopharmacol . 2004 Dec; 24(6): 661–664. 3. Alpert JE, Papakostas GI, Mischoulon D: One-carbon metabolism and the treatment of depression: roles of s-adenosyl-l-methionine and folate. In: Mischoulon D, Rosenbaum J, editors. Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 68–83. 4. Amri H, Abu-Asab M, Le Bars P, et al: Ginkgo Biloba extract (EGb 761) in cognitive disorders. In: Mischoulon D, Rosenbaum J, eds. Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 163–190. 5. Appleton KM, Rogers PJ, Ness AR: Updated systematic review and metaanalysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr . 2010 Mar; 91(3): 757–770. 6. Bell IR, Pappas PA: Homeopathy and Its Applications in Psychiatry. In: Mischoulon D, Rosenbaum J, eds.: Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 303–320.

7. Belmaker RH, Levine J: Inositol in the treatment of psychiatric disorders. In: Mischoulon D, Rosenbaum J, eds.: Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 105–115. 8. Benjamin J, Agam G, Levine J, et al: Inositol treatment in psychiatry. Psychopharmacol Bull . 1995; 31: 167–175. 9. Borrelli F, Ernst E: Alternative and complementary therapies for the menopause. Maturitas . 2010 Aug; 66(4): 333–343. 10. Caraci F, Crupi R, Drago F, et al: Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin re-uptake inhibitors and hypericum extract. Curr Drug Metab . 2011 Jul; 12(6): 570– 577. 11. Carpenter DJ: St. John’s wort and S-adenosyl methionine as “natural” alternatives to conventional antidepressants in the era of the suicidality boxed warning: what is the evidence for clinically relevant benefit? Altern Med Rev . 2011 Mar; 16(1): 17–39. 12. Deepmala, Slattery J, Kumar N, et al: Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev . 2015 Aug; 55: 294–321. 13. Dording CM, Mischoulon D, Shyu I, Alpert JE, Papakostas GI. SAMe and sexual functioning. Eur Psychiatry . 2012 Aug; 27(6): 451–454. 14. Eisenberg DM, Kessler RC, Foster C, et al: Unconventional medicine in the United States: prevalence, costs, and patterns of use. N Engl J Med . 1993; 328: 246–252. 15. Fava M, Mischoulon D: Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry . 2009; 70(Suppl 5): 12– 17. 16. Freeman MP, Fava M, Lake J, et al: Complementary and alternative medicine in major depressive disorder: the American Psychiatric Association Task Force report. J Clin Psychiatry . 2010 Jun; 71(6): 669– 681. 17. Freeman MP, Hibbeln JR, Wisner KL, et al: Omega-3 fatty acids: Evidence basis for treatment and future research in psychiatry. J Clin Psychiatry . 2006; 67(12): 1954–1967.

18. Fusar-Poli P, Berger G: Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. J Clin Psychopharmacol . 2012 Apr; 32(2): 179–185. 19. Janssen IM, Sturtz S, Skipka G, et al: Ginkgo biloba in Alzheimer’s disease: a systematic review. Wien Med Wochenschr . 2010 Dec; 160(2122): 539–546. 20. Linde K, Berner MM, Kriston L: St John’s wort for major depression. Cochrane Database Syst Rev . 2008; (4): CD000448. 21. Matsumoto J: Molecular mechanism of biological responses to homeopathic medicines. Med Hypotheses . 1995; 45: 292–296. 22. Mischoulon D, Fava M, Stahl S: Folate supplementation. [Response to letter] J Clin Psychiatry . 2009; 70: 767–769. 23. Mischoulon D, Fava M: Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr . 2002; 76(5 Suppl): 1158S-1161S. 24. Mischoulon D, Nierenberg AA, Schettler PJ, et al: A double blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression. J Clin Psychiatry . 2015 Jan; 76(1): 54–61. 25. Mischoulon D, Price LH, Carpenter LL, et al: A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-l-methionine (SAMe) vs. escitalopram in major depressive disorder. J Clin Psychiatry . 2014 Apr; 75(4): 370–376. 26. Mischoulon D, Raab MF: The role of folate in depression and dementia. J Clin Psychiatry . 2007; 68 Suppl 10: 28–33. 27. Mischoulon D: Herbal remedies for anxiety and insomnia: kava and valerian. In: Mischoulon D, Rosenbaum J, eds.: Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 119–139. 28. Mischoulon D: Nutraceuticals in psychiatry, Part 1: social, technical, economic, and political perspectives. Contemporary Psychiatry . 2004; 2 (11): 1–6. 29. Nierenberg AA, Lund HG, Mischoulon D: St. John’s wort: a critical evaluation of the evidence for antidepressant effects. In: Mischoulon D,

30.

31.

32.

33. 34.

35.

36.

37.

38.

39.

Rosenbaum J, eds.: Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 27–38. Papakostas GI, Alpert JE, Fava M: S-adenosyl methionine in depression: a comprehensive review of the literature. Curr Psychiatr Rep . 2003; (5): 460–466. Papakostas GI, Mischoulon D, Shyu I, et al: S-adenosyl methionine (SAMe) augmentation of serotonin re-uptake inhibitors (SRIs) for SRInon-responders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry . 2010 Aug; 167(8): 942–948. Papakostas GI, Shelton RC, Zajecka JM, et al: L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry . 2012 Dec 1; 169(12): 1267– 1274. Parker G, Gibson NA, Brotchie H, et al: Omega-3 fatty acids and mood disorders. Am J Psychiatry . 2006; 163(6): 969–978. Pittler MH, Ernst E: Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol . 2000; 20: 84–89. Rapaport MH, Nierenberg AA, Schettler PJ, et al: Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry . 2016 Jan; 21(1): 71–79. Sarris J, Kavanagh DJ: Kava and St. John’s wort: current evidence for use in mood and anxiety disorders. J Altern Complement Med . 2009 Aug; 15(8): 827–836. Sarris J, LaPorte E, Schweitzer I: Kava: a comprehensive review of efficacy, safety, and psychopharmacology. Aust N Z J Psychiatry . 2011 Jan; 45(1): 27–35. Sarris J, Mischoulon D, Schweitzer I: Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials. Bipolar Disord . 2011 Aug-Sep; 13(5-6): 454–465. Sarris J, Mischoulon D, Schweitzer I: Omega-3 for bipolar disorder: metaanalyses of use in mania and bipolar depression. J Clin Psychiatry . 2012

Jan; 73(1): 81–86. Epub. 2011 Aug 9. 40. Sarris J, Price LH, Carpenter LL, et al: Is S-adenosyl methionine (SAMe) for depression only effective in males? A re-analysis of data from a randomized clinical trial. Pharmacopsychiatry . 2015 Jul; 48(4-5): 141– 144. 41. Schulz V, Hänsel R, Blumenthal M, et al: Rational Phytotherapy: A Reference Guide for Physicians and Pharmacists . 5th ed. Berlin: Springer; 2004: pp. 43–124. 42. Stoll AL: Omega-3 fatty acids in mood disorders: a review of neurobiologic and clinical actions. In: Mischoulon D, Rosenbaum J, eds.: Natural Medications in Psychiatric Disorders , 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 39–67. 43. Sublette ME, Ellis SP, Geant AL, et al: Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry . 2011 Dec; 72(12): 1577–1584. 44. Taavoni S, Ekbatani N, Kashaniyan M, et al: Effect of valerian on sleep quality in post-menopausal women: a randomized placebo-controlled clinical trial. Menopause . 2011 Sep; 18(9): 951–955. 45. Teschke R, Sarris J, Schweitzer I: Kava hepatotoxicity in traditional and modern use: The presumed Pacific kava paradox hypothesis revisited. Br J Clin Pharmacol . 2012 Feb; 73(2): 170–174. 46. van Die MD, Burger HG, Teede HJ, et al: Vitex agnus-castus (ChasteTree/Berry) in the treatment of menopause-related complaints. J Altern Complement Med . 2009 Aug; 15(8): 853–862. 47. Wachira JK, Larson MK2, Harris WS: n-3 Fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. Br J Nutr . 2014 May;111(9): 1652–1662. 48. Webster DE, Dentali SJ, Farnsworth NR, et al: Chaste tree fruit and premenstrual syndrome. In: Mischoulon D, Rosenbaum J, eds.: Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 216–227. 49. Wolkowitz OM, Reus VI, Maninger N, et al: Dehydroepiandrosterone in the treatment of neuropsychiatric conditions. In: Mischoulon D, Rosenbaum J, eds. Natural Medications for Psychiatric Disorders: Considering the Alternatives , 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins;

2008: pp.84–104. 50. Wozniak J, Faraone SV, Chan J, et al: A randomized clinical trial of high eicosapentaenoic acid omega-3 fatty acids and inositol as monotherapy and in combination in the treatment of pediatric bipolar spectrum disorders: a pilot study. J Clin Psychiatry . 2015 Nov; 76(11): 1548–1555. 51. Yancheva S, Ihl R, Nikolova G, et al: GINDON Study Group Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer’s disease with neuropsychiatric features: a randomised, doubleblind, exploratory trial. Aging Ment Health . 2009 Mar; 13(2): 183–190. 52. Zanarini MC, Frankenburg FR: Omega-3 fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry . 2003; 160: 167–169. 53. Zhdanova V, Friedman L: Melatonin for treatment of sleep and mood disorders. In: Mischoulon D, Rosenbaum J, eds. Natural Medications for Psychiatric Disorders: Considering the Alternatives . 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: pp. 140–1 60.

CHAPTER Suicide 58 REBECCA WEINTRAUB BRENDEL, MD, JD; KATHERINE A. KOH, MD, MSC; ROY PERLIS MD, MSC; AND THEODORE A. STERN, MD

KEY POINTS Overview Suicide is the 10th leading cause of death in the United States. Suicide rates have risen steadily between 1999 and 2014. 90% of patients who commit suicide are thought to have a psychiatric diagnosis. Epidemiology and Risk Factors A clinician’s ability to predict suicide based upon risk factors alone is poor. The best predictors of suicidal behavior are prior attempts and current suicidal ideation. In the United States, use of firearms is the most common means of completed suicide, suffocation is second, and poisoning is third. Women attempt suicide at a significantly higher rate than men, but men are more likely to complete suicide. Suicide rates increase in older age groups, and the lethality of attempts is greatest in the elderly. In the United States suicide rates are highest among Caucasian and Native American populations. Other risk factors for suicide include divorce, loss of a spouse, living alone, unemployment, financial difficulty, medical illness, experience in the military, a family history of suicide, and a family history of psychiatric illness. Mood disorders are found in 50% of suicides, anxiety disorders and posttraumatic stress disorder in 15% to 20%; substance use disorders in 25%; psychosis in 10%; and personality disorders in 5% to 10%.

Neurobiology of Suicide Suicide is a behavior that results from both neurobiological and psychological factors. There appears to be a relationship between low levels of CSF 5-HIAA and suicide risk. Management of the Suicidal Patient Evaluation of a suicidal patient should include not only a psychiatric assessment, but a medical assessment looking for delirium, acute intoxication, and withdrawal. A safe environment within a healthcare environment is essential for both patients and providers. Evaluation A careful clinical examination includes performing a thorough psychiatric exam, eliciting a patient’s thoughts and feelings about suicide, formulating a diagnosis, and assessing suicide risk. The intensity, frequency, and duration of suicidal thoughts must be assessed, as well as details of the suicide plan, degree of planning and preparation, precipitants, and potential protective factors. Disposition and Treatment A general hospital admission, a locked psychiatric unit, or a partial program should be considered depending on the patient’s medical and psychiatric acuity. A variety of psychotherapeutic modalities are effective in addressing underlying psychiatric illness and suicidal behaviors. Outpatient supports must be enhanced upon discharge, as the risk of suicide significantly increases after discharge from a psychiatric facility. Clinicians should develop a plan with the patient for management of suicidal ideation after discharge.

Overview As the 10th leading cause of death in the United States, suicide represents a significant public health problem. Each year, more than 40,000 people commit

suicide; this accounts for 1.6% of the total number of deaths every year in the United States. For each person who completes suicide, approximately 10 to 40 attempts are made. Recent trends suggest that after a period of decline in suicide rates in the United States from 1986 to 1999, suicide rates have increased steadily between 1999 and 2014, with greater annual percent increases after 2006. Up to 50% of those who commit suicide visit a primary-care provider in the month prior to committing suicide, although only 60% of them communicate overt thoughts about suicide during the visit. Thus, regular screening for suicidal ideation and assessing risk factors provide an opportunity to intervene before an attempt occurs. Such screening is essential in psychiatric populations because up to 90% of patients who commit suicide have at least one major psychiatric diagnosis.

Epidemiology and Risk Factors Overall , a clinician’s ability to predict suicide based upon risk factors alone is poor. One 5-year study of risk factors found a false positive rate of 30% (i.e., suicide was predicted but did not occur) and a false negative rate of 44% (i.e., suicide was not predicted but occurred). Despite these difficulties, a careful assessment of risk factors is crucial in estimating risk, planning interventions, and providing a clinically relevant context for evaluating a patient’s thoughts and feelings. The best predictors of suicidal behavior are prior suicide attempts and current suicidal ideation. Half of all suicides occur in patients who have made at least one attempt. In fact, in the year following an attempt, the risk for suicide can be 100 times greater than that of the general population. In the United States, use of firearms is the most common means of completed suicide, suffocation (including hanging) is second, and poisoning (often using prescribed medications) is third. Drug overdose is the most common method of failed suicide attempts. Population-based studies demonstrate that suicide rates vary widely among different demographic groups. Gender, age, ethnicity, marital status, and employment are all significant epidemiological risk factors. Women attempt suicide at rates three times that of men, although men are four times more likely to succeed. Suicide rates increase with age; people older than 65 years are 1.5 times more likely to commit suicide than are younger individuals, whereas white men over age 85 years have an even higher rate of suicide. Furthermore, the lethality of attempts is greatest in the elderly: 1 in 4 attempts in the elderly

versus 1 in 8 to 25 attempts in the general population result in a completed suicide. Adolescents (between the ages of 15 and 24 years) also represent a highrisk group; suicide is the second leading cause of death in this population. Moreover, for every completed attempt among adolescents, there are 100 to 200 unsuccessful attempts. In the United States, suicide rates are highest among Caucasian and Native American populations. Individuals who are divorced, widowed, live alone, unemployed, or in financial difficulty have higher suicide rates. For example, suicide rates are four times greater in those who are divorced compared to those who are married. On the other hand, the presence of children under the age of 18 years in the home decreases the suicide risk, as does the robustness of a patient’s social supports. Since 2003, there has been a steady increase in suicides among active duty soldiers. Between 2003 and 2008, there was an 80% increase in military suicides. The wars in Afghanistan and Iraq have been associated with the highest suicide rates in the United States military personnel since tracking began in 1980. Nearly 70% of soldiers who commit suicide have been in active combat, and nearly 50% are between the ages of 18 and 24 years. Desensitization to violence secondary to combat exposure, increased stress, and changing demographics of the wartime military recruit have all been conjectured as contributing factors, but research remains preliminary. Ninety percent of patients who commit suicide have mental illness. This population therefore must be carefully screened. Mood disorders (major depression and bipolar disorder) are found in approximately 50% of those who complete suicides. The presence of severe anhedonia, anxiety, panic attacks, global insomnia, impaired concentration, and alcohol abuse can significantly increase suicide risk in the first year, whereas severe hopelessness, ongoing suicidal ideation, and multiple suicide attempts increase the risk of suicide after the first year. Hopelessness itself, independent of mood symptoms, is a powerful risk factor for suicide. Anxiety disorders and post-traumatic stress disorder (PTSD) might play a role in 15% to 20% of suicides. The risk remains significant even after controlling for co-morbid depression and substance abuse. Substance use disorders, particularly alcohol and multiple substance use disorders, are a factor in at least 25% of suicides. Suicide risk is greatest later in the illness, peaking approximately 9 years after the start of the addiction. The presence of major depression, medical complications, and the recent loss of a close relationship all significantly elevate suicide risk in this population.

Although many patients will retract their suicidal statements when sober, a complete evaluation for safety will still be necessary as many of these patients remain at high risk. Furthermore, alcohol and drugs increase impulsivity and impair judgment. Nearly 20% of people who commit suicide are intoxicated at the time of death. Psychosis contributes to approximately 10% of suicides. In contrast to patterns seen in the general population, the patient with schizophrenia who commits suicide is most likely to be a newly diagnosed young male with high pre-morbid functioning and good insight into his illness. Akathisia and abrupt discontinuation of neuroleptics increase suicide risk as does the onset of depression after an acute psychotic episode. Command hallucinations to harm oneself also increase risk, and patients with psychosis should always be screened for these. Personality disorders, particularly borderline or antisocial personality disorder, contribute to 5% to 10% of suicides. Impulsive and often life-threatening manipulative acts are particularly common in this group; therefore, it is important to keep in mind that such attempts can turn fatal and should not be ignored. Medical disorders, particularly severe or chronic disorders, are associated with an increased risk for suicide. Medical disorders are identified in up to 40% of patients who attempt suicide. Associations have been demonstrated with many illnesses including chronic renal failure, acquired immunodeficiency syndrome (AIDS/HIV infection), lupus, epilepsy, cancer, multiple sclerosis, Huntington’s disease, and chronic pain. Several aspects of family history influence suicidality, likely through both dynamic and genetic mechanisms. A family history of suicide itself increases suicide risk two-fold as does a history of any family psychiatric illness. A chaotic early family environment (including abuse and parental separation) also confers increased risk.

Neurobiology of Suicide Suicide is a behavior that results from both neurobiological and psychological factors. Twin and adoption studies suggest that up to 50% of suicide risk is genetically mediated. Early investigations found that patients who committed suicide, particularly using violent means, had lower levels of serotonin metabolites (5-HIAA) in cerebrospinal fluid (CSF) than did control patients. Subsequent studies have continued to find decreased levels of CSF 5-HIAA in

patients who commit suicide, regardless of their psychiatric diagnosis. Low levels of CSF 5-HIAA correlate with higher lethality attempts and predict suicide. Abnormalities in noradrenergic neurotransmission and in the hypothalamic-pituitary-adrenal axis have also been described, although there are fewer studies and the data is mixed. Overall, ongoing attempts to identify specific genes that confer risk for suicide remain preliminary.

Management of the Suicidal Patient A suicidal patient might need to be medically evaluated and stabilized. The examiner should retain a high level of suspicion for un-reported or underreported self-harm, including drug ingestions. Gross alterations in attention, awareness, and arousal, consistent with delirium and acute intoxication, require prompt evaluation and intervention. Given the high co-morbidity of suicidality and substance abuse, patients should be monitored for physiological signs of intoxication and withdrawal. The examiner will need to create a safe environment. Although the least restrictive means necessary should be employed to ensure safety, a physician should err on the side of caution when treating a suicidal patient. Personal belongings might need to be secured. It is important to remember that many items found in an emergency room or doctor’s office can be used for further selfharm. Cutting, ingestions, falls, and hangings are commonly attempted in hospital settings, sometimes with lethal results. Potential means for self-harm should be removed from the reach of a patient at risk. Although frequently employed, there is no evidence that “contracts for safety” decrease a patient’s suicide risk; therefore, they should not be relied upon. Frequent checks or, if the patient is more acute, one-to-one supervision, allow for patient freedom while still ensuring safety. Physical restraints might be required if a patient resists continued attempts at containment and is at high risk for harm to self or others. If physical restraints are used, antipsychotics and/or sedating medications should be given concurrently to ensure patient comfort and safety. However, physical restraints do not substitute for supervision, particularly in an intoxicated patient, and the patient should be re-assessed regularly.

Evaluation Suicidal patients present in a variety of ways. Suicide risk should always be assessed in those who voice suicidal ideation or whose actions suggest suicidal

intent, including some patients who engage in risky activities. It is important to remember that asking about suicide will not increase a patient’s suicide risk; to the contrary, it can be protective. Many patients are ambivalent about their suicidal thoughts, and they are relieved to talk about them. A careful clinical examination includes performing a thorough psychiatric exam, eliciting a patient’s thoughts and feelings about suicide, formulating a diagnosis, and assessing suicide risk. Each of these four components should be carefully documented. An assessment of suicide risk includes identification of acute, short- and long-term risk for suicide, and determination of ways in which each can be diminished. The stress-diathesis model is commonly applied to understand suicide risk. This model considers acute precipitants (the stress) in the context of underlying vulnerabilities for suicide (the diathesis). A calm, non-judgmental and empathic approach allows a physician to establish rapport. It is important to remember that suicidal patients often elicit strong feelings (e.g., anger, anxiety) in clinicians. An awareness of these feelings can help to minimize their interference with the evaluation. Begin with general questions, such as, “Do you ever feel that life is not worth living?” and, as you build rapport, you can proceed to more direct questions such as “Have you ever thought about killing yourself?” You might need to ask these questions multiple times before a patient feels comfortable discussing his or her suicidal thoughts. If a patient endorses suicidal thoughts, it is important to ask about the intensity, frequency and duration of them, the details of his or her suicide plan, the degree of planning and preparation, the precipitants for suicidality, and potential protective factors. These questions allow clinicians to assess the potential lethality by formulating a risk/rescue ratio, in which the highest risk is associated with more lethal means and a smaller chance of rescue. For example, a patient who plans to drive to a remote location and shoot himself in the head would have a high risk/rescue ratio, whereas a patient who takes an extra aspirin in his therapist’s office has a low ratio. At the same time, the patient’s beliefs about risk and rescue need to be considered, because a patient who thinks that the extra aspirin would kill him would be at higher risk than an objective consideration of the risk/rescue ratio suggests. Access to firearms should be explicitly asked about given that use of firearms is the most common method for suicide in both men and women, accounting for nearly 60% of suicides in the United States. Adolescents with a gun in the house have a suicide rate 4 to 10 times greater than other adolescents.

Hopelessness is a more powerful predictor of risk than is depression itself; thus, the patient should be asked about future plans and beliefs about their future. Patients should also be asked about precipitants for their suicidality, as this knowledge can suggest possible interventions and help guide treatment. Collateral from family, friends, and other providers can be invaluable in these assessments; many patients who complete suicide had communicated their intent within 6 months of an attempt.

Disposition and Treatment After a patient has been evaluated, there are a number of treatment venues available. A general hospital admission, often with suicide precautions, might be necessary for a patient who needs further medical treatment. A medically stable patient who is acutely at risk requires hospitalization in a locked psychiatric unit. If the patient refuses this, he or she might need involuntary commitment. It is important to keep in mind that suicide risk does not necessarily subside following admission; 5% of suicides occur among psychiatrically ill inpatients. If a patient’s situation is less acute, he or she can be managed in a partial hospital or day-treatment program during the day and return home at night. Psychosocial interventions can be extremely useful for maintaining the safety of a suicidal patient. There is evidence that a variety of psychotherapeutic modalities are effective in addressing underlying psychiatric illness and suicidal behaviors, and these include psychodynamic psychotherapy, dialecticalbehavioral therapy (DBT) and cognitive-behavioral therapy (CBT). There are also a number of pharmacological and other somatic interventions, most of which target underlying psychiatric illness rather than suicidality itself. Antidepressants are commonly used, given the frequent association between depression and suicide, sometimes in combination with anxiolytics. The choice of medication should be guided, in part, by consideration of their lethality with overdose. Thus, selective serotonin re-uptake inhibitors (SSRIs) are usually considered to be first-line agents for the depressed patient. However, there are very few medications that directly decrease suicide risk; the two exceptions are clozapine (in psychosis) and lithium (in mood disorders), both of which can decrease long-term risk for suicide. It is unclear if this is a result of a direct antisuicide effect of these medications or their efficacy in treating the underlying psychiatric disorder. Finally, electroconvulsive therapy (ECT) is sometimes used in acutely suicidal patients because the onset of antidepressant effects is much more rapid than with pharmacotherapies.

Patients and families will often ask about reports of a possible increase in suicide risk with SSRIs. In the early 1990s, there were reports of a possible increase in suicidal behavior in children and adults with the use of SSRIs, resulting in an FDA “black box” warning in 2004 for an increase in the suicide risk in pediatric patients who use SSRIs. However, multiple subsequent studies have had variable results without any clear evidence for increased risk. Physicians should weigh this data against the benefit of using a medication that is relatively safe following an overdose when determining the appropriate treatment for a suicidal patient. When a patient is ready for discharge, clinicians should attempt to ensure that potential means of suicide are inaccessible (e.g., firearms removed from the home, medications in a lockbox, old medications discarded). The precipitants for suicide should be addressed as much as possible. The underlying psychiatric illness, including substance abuse, should be treated. A large number of patients at risk for suicide do not receive outpatient mental health treatment in a timely manner following discharge from emergency departments and inpatient psychiatric settings. The risk of suicide is three times as likely the first week after discharge from a psychiatric facility and remains high within the first year and first four years after discharge. Outpatient supports must therefore be enhanced, with plans for close follow-up with outpatient treaters. The clinician should develop a plan with the patient for management of future suicidal ideation after discharge.

Suggested Readings 1. Allen MH, Abar BW, McCormick M, et al: Screening for suicidal ideation and attempts among emergency department medical patients: instrument and results from the Psychiatric Emergency Research Collaboration. Suicide and Life-Threatening Behavior . 2013; 43: 313 –323. 2. Balderessarini RJ, Hennen J: Genetics of suicide: An overview. Harv Rev Psychiatry . 2004; 12: 1–13. 3. Brendel RW, Wei MH, Edersheim JG: An approach to the patient in crisis: Assessments of the risk for suicide and violence. Med Clin North Am . 2010; 94(6): 1089–1102. 4. Brent DA, Perper JA, Goldstein CE, et al: Risk factors for adolescent suicide. Arch Gen Psychiatry . 1988; 45: 87–89.

5. Currier D, Mann JJ: Stress, genes and the biology of suicidal behavior. Psychiatr Clin North Am . 2008; 31(2): 247–269. 6. Curtin SC, Warner M, Hedegaard H: Increase in Suicide in the United States, 1999–2014 NCHS Data Brief No. 241. Hyattsville, MD: National Center for Health Statistics; 2016. 7. Ernst C, Mechawar N, Turecki G: Suicide neurobiology. Prog Neurobiol . 2009; 89(4): 315–333. 8. Gaynes BN, West SL, Ford CA, et al: Screening for suicide risk in adults: A summary of the evidence for the U.S. Preventative Services Task Force. Ann Intern Med . 2004; 140: 822–835. 9. Hirschfeld RMA, Russell JM: Assessment and treatment of suicidal patients. N Engl J Med . 1997; 337: 910–915. 10. Hyman J, Ireland R, Frost L, et al: Suicide incidence and risk factors in active duty US military population. Am J Public Health . 2012; 102(Suppl 1): 138–146. 11. Kochanek KD, Murphy SL, Xu J, et al: Deaths: final data for 2014. Natl Vital Stat Rep . 2014; 65(4): 5. 12. Maltsberger JT: The Psycohdynamic Understanding of Suicide. In: Jacobs DG, ed.: The Harvard Medical School Guide to Suicide Assessment and Intervention . San Francisco: Jossey-Bass; 1999. 13. Mann JJ: A current perspective of suicide and attempted suicide. Ann Int Med . 2002; 136: 302–311. 14. Maris RW: Suicide. Lancet . 2000; 360: 319–326. 15. Marshal MP, Dietz LJ, Friedman MS, et al: Su icidality and depression disparities between sexual minority and heterosexual youth: A metaanalytic review. J Adolesc Health . 2011; 49(2): 115–123. 16. Pietrzak RH, Goldstein MB, Malley JC, et al: Risk and protective factors associated with suicidal ideation in veterans of Operations Enduring Freedom and Iraqi Freedom. J Affect Disord . 2010; 123: 102. 17. Richardson R, Lowenstein S, Weissberg M: Coping with the Suicidal Elderly: A Physician’s Guide. Geriatrics . 1989: 43–51. 18. Siegfried N, Bartlett M: Navigating suicide assessment: A roadmap for providers. A presentation at the joint commission’s 2014 Annual Behavioral Health Care Conference, Oct. 15–16, 2014.

19. Suicide Prevention Resource Center: Continuity of care for suicide prevention: The role of emergency departments. Waltham, MA: Education Development Center, Inc.; 2013.

CHAPTER Psychiatry and the Law I 59 Informed Consent, Competency, Treatment Refusal, and Civil Commitment RONALD SCHOUTEN, MD, JD

KEY POINTS Overview Informed consent and civil commitment are concepts that are essential to the treatment of patients who suffer from mental illness. Just as in the rest of medicine, patients with mental illness are presumed to be competent and to have a right to make their own treatment decisions. This includes informed consent, a process in which the treating clinician describes the proposed treatment and its risks and benefits, and the patient has an opportunity to ask questions and to make the final decision. Civil commitment is a legal process that allows the state to deprive a person of certain liberty interests (e.g., the right to move freely in the community) if they pose a danger to themselves or others by reason of mental illness. Theoretical Basis Informed consent represents an ethical obligation to respect the autonomy interests of individual patients, enforced by case law and statutes. Civil commitment proceedings are governed by the need to protect Constitutional rights. Clinical Applications Informed consent applies in all clinical interactions. There are exceptions to it, however, such as emergencies, waiver, incompetence, and therapeutic privilege. Civil commitment is a formal process that allows a person to be confined to a mental health facility for evaluation and treatment if they refuse voluntary

admission and are deemed to represent a danger to themselves or others. Important Historical Proponents The ethical basis of informed consent arises from libertarian philosophers, like John Stuart Mill, who emphasized the importance and benefits of allowing individuals to make their own life choices. The law of informed consent is based on the ancient tort of trespass or battery: the touching of another person without consent or justification could be the basis of a suit for monetary damages. Informed consent in medicine is a concept that was developed in the United States in the mid-20th century.

Overview Psychiatrists , more so than any other medical specialty, interact with the legal system on a regular basis. Issues related to informed consent, competency to consent to treatment, treatment refusal, and civil commitments are important aspects of daily clinical practice. These four topics are reviewed in this chapter. They are just four of the topics belonging to the sub-specialty of forensic psychiatry, which focuses on the application of clinical principles and practice to the legal system. Criminal competencies and criminal responsibility, which are other core areas of forensic psychiatry, are covered in Chapter 60 . The core of the Anglo-American legal system is case law, also known as common law or judge-made law, to reflect the fact that the legal principles are developed through decisions in cases that address similar legal issues. A substantial portion of civil law is case-based, whereas most of the criminal law is based on statutes enacted by legislatures. The four topics addressed in this chapter belong to the realm of the civil law. A major component of civil law is personal injury or tort law. A tort is a civil wrong that gives rise to a right to sue for damages; that is, A injures B, either intentionally or negligently, which gives B the right to sue A for compensation for the damages that occurred.

Informed Consent Relevance

One of the earliest principles of tort law prohibited the touching of another person unless consent had been obtained or there was some justification. In the absence of consent or justification, the unpermitted touching constitutes the civil wrong or tort of battery, and gives the victim the right to sue for damages. Consent to being touched can be express (the patient explicitly consenting to treatment) or implied (e.g., a patient standing in a clearly marked line to get an inoculation). Justification occurs when there is an emergency, i.e., failure to act would likely have an imminent, serious negative effect on the patient’s condition. Initially, simple consent was sufficient: the person being touched need only give a general consent to the touching, without any further explanation. The notion of informed consent , i.e., consent given after a sharing of knowledge and a chance to consider alternative options, existed only as an ethical concept until it was adopted by one of the American courts beginning in the 1960s, and it began to be converted to a legal duty on the part of physicians. From a clinical and ethical standpoint, informed consent arises from the physician’s obligation to respect the autonomy of the patient. Case law, and in many jurisdictions statutes, require that clinicians obtain informed consent before providing treatment, unless one of the exceptions to informed consent applies. Lack of informed consent is a basis for alleging medical malpractice.

Defining Informed Consent Informed consent is a process through which the physician gets the permission of the patient or a substitute decision-maker to provide treatment to the patient. The decision-maker must be competent (i.e., have the capacity to make the decision), must be given enough information to make an informed decision, and must make the decision voluntarily . The legal requirements of informed consent are likewise information, competency, and voluntariness. Each of these are described in more detail in the sub-sections that follow.

Information The amount and type of information that must be given to the patient in order to meet the requirements of informed consent varies among jurisdictions. Three basic standards—the professional standard, the materiality standard, and the combined standard—are used in this area. Professional standard: The clinician is expected to provide information to the same extent that a reasonable professional would do so under similar

circumstances. Materiality standard: The clinician must provide the degree of information that the average patient would require to make a decision under the same circumstances. This is also referred to as a patient-oriented standard. In some jurisdictions (e.g., Massachusetts), the concept is extended to require provision of the information that would be material to the particular patient’s decision. Combined standard: This standard requires that the clinician provide the information that the reasonable medical practitioner would provide, but also examines whether it was “sufficient to insure informed consent.” Providing the following information to patients will fulfill the information requirements in most jurisdictions: the nature of the condition to be treated and the treatment proposed; the nature and probability of the risks associated with the treatment (minor risks or side effects which occur frequently [e.g., dry mouth], and significant risks that occur infrequently [e.g., hepatic failure secondary to sodium valproate]) should be reviewed with the patient; the inability to predict the results of the treatment; the irreversibility of the procedure, if applicable; and, the alternative treatments available, including no treatment. This process should include a discussion of the risks and benefits associated with these options.

Competency For a patient to give adequate informed consent, he or she must have the physical and mental capacity to make informed treatment decisions. How much capacity is required depends upon the nature of the condition and the risks of the proposed treatment. Less capacity is required for low-risk treatments with a high likelihood of a good result (e.g., intravenous fluids for re-hydration). A higher level of capacity is required when the treatment is of higher risk or is more invasive, and the results are less likely to be favorable (e.g., aortic valve replacement in an 84-year-old patient with dementia). Technically, competency is a legal, rather than clinical, concept. In the eyes of the law, all adults are presumed to be competent to make their own treatment decisions, and only a court of law can declare someone legally incompetent. A legal declaration of incompetence strips a person of certain rights and privileges normally accorded to adults; for example, making treatment decisions, making contracts, voting, or executing a will. A clinician who opines that a patient is “incompetent” to make treatment decisions has no authority to declare the

person incompetent in a legal sense, however, that opinion will be considered if a court is asked to consider the matter of competency. There is a trend in the law for courts to use the term capacity, rather than competency, in an effort to be more specific in identifying what abilities the person in question possesses or lacks. Although they do not alter a patient’s legal status, clinical assessments of capacity (still generally referred to as competency evaluations) are the first step toward a legal declaration of incompetence and they often predict the likely outcome of any legal proceedings. In the face of doubts about a patient’s mental status, treatment will generally proceed if there is a clinical determination that a patient has adequate decision-making capacity. On the other hand, a conclusion that the patient lacks the capacity to give informed consent generally requires that an alternative decision-maker be found. Ideally, this decision-maker will have been previously appointed by the patient through a valid advance directive. Short of going to court for a formal declaration of incompetence and judicial appointment of a guardian, decisions are often made on behalf of the incompetent patient by family members or others who can utilize a substituted judgment analysis to reach a treatment decision that the patient would have made if competent. All adults are presumed to be competent under the law. That is, they are assumed to have the capacity to engage in the full range of activities commensurate with independent adult life. A declaration of incompetence (incapacity) can be global or task specific. Global incapacity refers to the inability to undertake and to carry out all the normal responsibilities and rights of an adult. A declaration of global incompetence by a court strips an individual of his or her rights as a legal person. As a result, courts prefer to declare people incompetent with regard to specific capacities, preserving as much of their autonomy as possible. The following are examples of specific capacities (e.g., testamentary capacity, testimonial capacity): Testamentary capacity: The capacity to execute a will. Specific legal standards for testamentary capacity apply in all jurisdictions and can vary. The usual standards require that the person executing the will: know the nature of the document being executed; know the contents of the estate; and know the persons who would normally inherit from him or her (the natural objects of his or her bounty). Testimonial capacity: The capacity to serve as a witness in court.

Assessing Capacity to Make Treatment Decisions The process of assessing a patient’s capacity to make treatment decisions focuses on his or her ability to understand and to process relevant information. A standard approach to assessing decision-making capacity was described by Appelbaum and Grisso in 1988. When evaluating the capacity to make treatment decisions, they suggested asking the following questions: Does the patient express a preference? Is the patient able to attain a factual understanding of the information provided? Is the patient able to appreciate the seriousness of the condition and the consequences of accepting or rejecting treatment? Can the patient manipulate the information provided in a rational fashion and come to a decision that follows logically from that information considered in the context of the individual’s personal beliefs, experience, and circumstances? It is the process of reaching a decision, not the decision itself that must be rational. Competent people have a right to make decisions for themselves that can seem irrational to the rest of the world. Disagreement with the treating clinician’s recommendations is not a basis, in and of itself, for saying that a patient is irrational.

Consequences of a Finding of Incapacity After a patient has been assessed as lacking capacity to make treatment decisions, there are several possible options, depending upon the nature of the condition and the law in that jurisdiction.

Guardianship of the Person A traditional model under these circumstances is for the court to appoint a guardian of the person . The person declared incompetent is the ward , and the guardian is any person appointed by the court to make decisions on behalf of the ward. The term “incapacitated person” is beginning to replace “ward” in many legal jurisdictions, although “ward” is still used commonly. Depending upon the jurisdiction, the guardian can make decisions based upon the perceived best interests of the ward or by means of a substituted judgment

analysis (what the individual would have decided if he or she were competent to make the decision). In cases involving extraordinary or invasive treatment, the substituted judgment analysis must be carried out by a judge rather than by the guardian.

Guardianship of the Estate (Conservatorship) This involves the appointment of an agent to act on behalf of the incompetent person specifically to deal with financial matters. A person can be deemed competent to make their own treatment decisions, but still be unable to manage their financial affairs.

Voluntary As one of the three elements of informed consent, this simply means free of coercion by those proposing the treatment. Persuasion by family members does not void informed consent so long as the circumstances do not put the physician on notice that the treatment is being imposed against the patient’s will or indicate that the patient is incompetent.

Exceptions to the Requirement of Informed Consent There are a number of situations in which the obligation to obtain fully informed consent is suspended. These can include emergency situations, waivers to informed consent, and therapeutic privilege. Emergency situations: An emergency is defined as a situation in which failure to act would result in a serious and imminent deterioration in the patient’s condition. The emergency exception allows for initiation of treatment and stabilization, not for ongoing treatment without obtaining proper consent. For cases in which a patient has previously informed his or her physician about treatment preferences in the event of an emergency, the physician is generally held to have an obligation to comply with those instructions. Waivers: A patient can make an informed decision to defer to someone else’s judgment regarding treatment decisions, including the treating clinician’s judgment. A waiver might be implied; for example, presenting oneself to the emergency room after being injured. Or, it might be explicit; for example, “Please don’t tell me anymore; you just do what’s best.” Patients must have the capacity to waive informed consent, which means that they must at least be aware of the nature of the condition, the level of risk involved in the treatment,

that they or someone else they choose has a right to make a decision, and that they are waiving that right. Therapeutic privilege: This exception applies in those relatively rare circumstances where the process of providing information and obtaining consent would result in a serious risk of deterioration in the patient’s condition. In those situations, the informed consent process can be deferred until the patient’s condition had improved sufficiently. The possibility that providing the information might lead to treatment refusal is not sufficient to invoke therapeutic privilege.

Treatment Refusal All competent people have a right to make their own medical treatment decisions, and all adults are presumed to be competent. This applies even when the individual is suffering from serious mental illness or is civilly committed. The presumption of competency persists until a court has declared a person to be incompetent, as described earlier. When a patient is believed to be incapacitated and unable to make treatment decisions, an alternative decision-maker should be sought rather than relying on the presumption of competence and allowing the patient to continue making treatment decisions. Individuals who are incompetent still have a right to individual autonomy, which can be honored by following their preferences for treatment expressed when they were competent or to the extent they can be determined in the absence of prior expression. The law concerning treatment refusal varies among the states. States generally draw a distinction between routine and ordinary medical care, (e.g., antibiotics, minor surgery), and extraordinary or invasive care (e.g., cancer chemotherapy, coronary artery bypass grafting) when determining what can be done when a patient refuses treatment. Benzodiazepines and antidepressants are generally considered to be routine, ordinary, and non-invasive. Antipsychotic medication, electroconvulsive therapy, and psychosurgery are considered to constitute extraordinary, dangerous, and invasive treatments in many states. States differ in terms of what legal steps must be taken before a patient’s refusal of treatment can be over-ridden. The basic rule in all states is that competent individuals have a right to make their own treatment decisions, including refusal of treatment that others believe is in the patient’s best interest. Exceptions to this rule exist in matters involving criminal law and the correctional system.

When a patient who appears to lack the capacity to make treatment decisions refuses routine and ordinary care, physicians can generally rely upon family members or significant others who know the patient to make a decision. When the care to be provided is extraordinary, invasive, or dangerous, many states require that a formal guardian be appointed to make the treatment decisions. As described above, guardianship is established after a hearing at which family members, treaters, and sometimes the patient, will testify. Not all states allow the guardian, once appointed, to make all decisions on behalf of the patient. In some states, only a judge can authorize extraordinary, invasive, or dangerous treatment, and only after a full adversarial hearing on the issue (Rogers v. Commissioner [Mass., 1983]). However, others (including federal courts) believe that professional judgment and administrative review satisfy the due process requirements without going to court (Rennie v. Klein [3rd Circuit, 1981]); U.S. v. Charters [4th Circuit, 1988]). Refusal of treatment by those awaiting trial or those already convicted of a crime has been the subject of considerable judicial attention. Antipsychotic medications can be administered over the refusal of convicted prisoners, competent or incompetent, if an independent review panel agrees that the prisoner suffers from a serious mental illness, is dangerous to himself or others, or is gravely disabled, and the medication proposed is in the prisoner’s best interests (Washington v. Harper [U.S., 1990]). Forced administration of antipsychotic medication for the purpose of rendering the inmate competent to be executed raises significant ethical issues for psychiatrists, as well as important questions of Constitutional law. Some states consider this permissible, while others hold that doing so violates constitutional principles (such as the right to privacy) and constitutes cruel, excessive, and unusual punishment (Louisiana v. Perry [La., 1992]). Forced administration of antipsychotic medication in order to render a defendant competent to stand trial violated the rights of the defendant under the Sixth and Fourteenth Amendments to the United States Constitution absent a showing by the state that the treatment was both medically necessary and appropriate, and furthers a compelling governmental interest (Riggins v. Nevada [U.S., 1992]; Sell v. United States [U.S., 2003]).

Civil Commitment The process of hospitalizing a person against his or her will is referred to as involuntary civil commitment . Civil commitment statutes are similar in the

various jurisdictions, as all states provide for commitment when a person poses a danger to him- or herself or others. Confinement of an individual against his or her will is considered to be a deprivation of fundamental rights guaranteed under the Constitution of the United States and state constitutions. Some states also require that the person being committed lack the capacity to make decisions regarding his or her own treatment. Civil commitment is considered to be an act of the government because it occurs under the authority of state or federal law. The United States Supreme Court has held that commitment to a mental hospital entails a curtailment of liberty interests and requires due process protection (Vitek v. Jones , 445 U.S. 480 [U.S., 1980]). Before the government can deprive someone of their fundamental rights, proper procedural protections (e.g., a court or administrative hearing before a neutral fact-finder) must be granted. Such procedures collectively constitute due process, which is guaranteed by the Constitution. Lawsuits for deprivation of civil rights, false imprisonment, and negligence can arise from improper civil commitment. A person can be involuntarily committed only if he or she is a danger to self or others, either by virtue of threats or attempts to cause harm, or being unable to provide for oneself in the community. The fact that a patient might demonstrate a clear-cut clinical need for treatment, in the absence of dangerousness, is not sufficient. The United States Supreme Court has held that a state cannot constitutionally confine a non-dangerous individual who is capable of surviving outside the hospital setting on his own or with the help of friends (O’Connor v. Donaldson [U.S., 1974]). The minimal standard of proof in all civil commitment cases is “clear and convincing” evidence: more than this is required in ordinary civil cases and less than the criminal standard of beyond a reasonable doubt (Addington v. Texas [U.S., 1979]). Individual states might provide additional protections, by requiring proof beyond a reasonable doubt for civil commitment. However, the details of the commitment process vary among the states. States also differ in how mental illness is defined. Some states, for example, do not consider substance abuse and disorders like Alzheimer’s disease as mental illnesses for the purpose of civil commitment. Where a patient is offered an opportunity to sign himself into a state hospital voluntarily and does so while lacking the capacity to make an informed decision, he has been deprived of his Constitutional right to due process of law, and the state and its agents can be held liable for a violation of the patient’s federal civil rights (Zinermon v. Burch [U.S. 1990]).

Although the details differ, all states use the criteria of danger to self or others as the basis for involuntary commitment. The danger must be the result of mental illness, rather than ordinary anger or antisocial behavior. For example, a hired killer would not be an appropriate candidate for involuntary commitment to a psychiatric hospital should his murderous intentions become known, absent evidence that a mental illness contributed to his dangerousness. However, an individual convicted of a violent crime can be committed to a hospital if it is determined that he poses a danger to himself or others. Danger to self means attempts at serious self-harm or suicide, or credible threats to cause such self-harm. Danger to others generally refers to threats or attempts to cause physical harm to others, or actual harm already inflicted. In addition, it might include situations in which others are placed in reasonable fear that they will be harmed by the patient. Individuals can also be involuntarily committed if they pose a substantial risk of harm because they are unable to provide for their own well-being in the community. In some states, this criterion is referred to as the gravely disabled criterion. Generally, mere difficulty caring for oneself is not enough to meet this criterion. The risk of harm—for example, believing that one is invincible and therefore can walk into traffic—must be substantial and imminent. A likelihood of harm in the distant future is not sufficient. Civil commitment under this criterion, as well as the others, is permissible only if no less restrictive alternative is available in the community (Lake v. Cameron [D.C. Cir., 1966]). Alternatives to civil commitment can include increased outpatient visits, voluntary hospitalization, day hospital programs, custodial care by relatives, or shelters. Civil commitment of criminal defendants and convicted individuals has been the subject of important court decisions. The due process clause requires that the reason for confinement and the nature of the confinement be reasonably related to the purpose of confinement. For example, in Jackson v. Indiana (U.S., 1972), Jackson was deaf, with limited ability to sign, and had limited intellectual ability. He had been found incompetent to stand trial on charges of shoplifting and was committed to the state hospital until he was restored to competency, which everyone agreed was unattainable under the circumstances. The Supreme Court held that if the state wanted to continue to confine Jackson to a mental institution, he must meet standard criteria for civil commitment. Individuals found not guilty by reason of mental illness (insanity acquittees) can be confined to psychiatric hospitals as long as they are mentally ill and

dangerous, but no longer. As the Supreme Court held in Jones v. United States (U.S., 1983) “...the Constitution permits the Government, on the basis of the insanity judgment, to confine (a defendant) to a mental institution until such time as he has regained his sanity or is no longer a danger to himself or society. This holding accords with the widely and reasonably held view that insanity acquitees should not be treated differently from other candidates for civil commitment. ” (Jones v. United States , 463 U.S. 354 [1983]) The Supreme Court has held that a state statute violated the Due Process Clause of the United States Constitution where it allowed a criminal defendant found not guilty by reason of insanity to be returned to the hospital, even if a hospital review committee found him no longer mentally ill, if he was determined at a court hearing to be dangerous (Foucha v. Louisiana [U.S., 1992]). The hospital psychiatrist testified that Foucha had recovered from the drug-induced psychosis that was the basis for his insanity defense, but also testified that Foucha had been in altercations at the hospital, had an antisocial personality disorder that was not a mental disease and was untreatable, and the psychiatrist would not “feel comfortable in certifying that he would not be a danger to himself or to other people.” The Court held that continued confinement in a mental institution is improper without a determination in civil commitment proceedings of current mental illness and dangerousness. The state’s legitimate interest in imprisoning convicted criminals for retribution and deterrence does not exist in the case of an insanity acquitee, who has not been found guilty and cannot be punished. The Supreme Court has also held that a state can legitimately detain people who are unable to control their behavior and thereby pose a danger to public safety, provided the confinement takes place pursuant to proper procedures and evidentiary standards. For example, it held that Kansas’ Sexually Dangerous Predator Act is not unconstitutional where it establishes procedures for the civil commitment of persons who, due to a “mental abnormality” or “personality disorder” are likely to engage in “predatory acts of sexual violence” (Hendricks v. Kansas [U.S., 1997]). Involuntary civil confinement, which follows conclusion of criminal sentence if the individual is found to be a sexuallydangerous person, did not constitute additional punishment for criminal behavior as it does not have the primary goals of retribution or deterrence. Procedures provided by the state, including the right to immediate release when the detainee proves he is no longer sexually dangerous, are adequate.

Suggested Readings

1. Appelbaum PS, Grisso T: Assessing patients’ capacities to consent to treatment. N Engl J Med . 1988; 319:1635 –1638. 2. Appelbaum PS, Lidz CW, Meisel A: Informed Consent: Legal Theory and Clinical Practice . New York, Oxford University Press; 1987. 3. Appelbaum PS: Assessment of patients’ competence to consent to treatment. N Engl J Med . 2007; 357:1834 –1840. 4. Grisso T, Appelbaum PS: Assessing Competence to Consent to Treatment . New York, Oxford University Press; 1998. 5. Grisso T: Evaluating Competencies . 2nd ed. New York: Kluwer Academic/Plenum; 2003. 6. Gutheil TG, Appelbaum PS: Clinical Handbook of Psychiatry and the Law . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000. 7. National Conference of Commisioners on Uniform State Laws: Uniform Adult Guardianship and Protective Proceedings Act. Chicago, IL: Uniform Law Commission; 2007. Available at http://www.uniformlaws.org/shared/docs/adult_guardianship/UAGPPJA_2011_Final%20 . Accessed March 26, 2016. 8. Winick BJ: The Right to Refuse Mental Health Treatment . Washington, D.C., American Psychological Association; 1997.

CHAPTER Psychiatry and the Law II 60 Criminal Issues and the Role of Psychiatrists in the Legal System RONALD SCHOUTEN, MD, JD

KEY POINTS Overview Most treating clinicians encounter the criminal justice system only in those infrequent instances when a patient finds himself or herself charged with a criminal violation. A defendant’s mental state plays a key role relative to the core concepts of the criminal justice system: competence to stand trial and criminal responsibility. Theoretical Basis A defendant must be competent to stand trial before he or she can be tried and either acquitted or convicted. To be considered competent to stand trial, the defendant must have sufficient present ability to consult with a lawyer with a reasonable degree of rational understanding, and a rational as well as a factual understanding of the charges presented. Society provides that people who commit crimes can be relieved of criminal responsibility if they suffered from a mental disease or defect and are determined to meet the criteria for the insanity defense in the jurisdiction where they are being tried. There are two basic types of insanity defense criteria. One requires that the defendant suffer from a mental disease or defect that prevents him or her from appreciating the wrongfulness of the conduct at the time of the crime. This is often referred to as the right–wrong test. The second type also uses the right–wrong test, but adds an alternative criterion: the defendant lacked substantial capacity to conform his or her behavior to the requirements of the law. This latter aspect, standing alone, is referred to as the irresistible impulse test.

Clinical Applications Treating psychiatrists should not offer opinions about their patients’ competency to stand trial or criminal responsibility. Those evaluations and opinions should be left to independent, objective forensic experts. However, the treating psychiatrist should cooperate with the forensic evaluator if the patient-defendant waives confidentiality. Important Historical Proponents The concept of an insanity defense has been known to multiple cultures for centuries. Competency to stand trial is a more recent development and had its origins in English common law.

Overview Psychiatrists play an important role in the courts as evaluators, consultants, and expert witnesses in both civil and criminal litigation. This chapter focuses on criminal competencies, criminal responsibility, the psychotherapist–patient privilege, and the role of the psychiatrist in court.

Competency in the Criminal System The question of a defendant’s competency arises regarding several different steps in the criminal justice process. The most common is competency to stand trial. The basic standard for competency to stand trial is whether the defendant “has sufficient present ability to consult with his lawyer with a reasonable degree of rational understanding, and whether he has a rational as well as a factual understanding of the proceedings against him” (Dusky v. U.S. [U.S., 1960]). This standard applies in all states, the District of Columbia, and federal courts. States can use their own criteria, so long as they provide as much, or more, protection of the defendant’s rights as the federal standard. Because it is so important that the defendant be competent to stand trial, the standard of proof for incompetence is “preponderance of the evidence,” i.e., the judge must be convinced that it is more likely than not that the defendant is incompetent. (Cooper v. Oklahoma [U.S., 1996]). Nevertheless, in practice the threshold for competency is generally low; that is, the defendant will usually be

found competent to stand trial if he or she meets the most minimal capacity requirements. The emphasis on a defendant being competent to stand trial is the result of several important principles (Drope v. Missouri [U.S., 1975]). These include: the fact-finding portion of the proceedings can be accurate only if the defendant can work with his or her attorney with an understanding of the proceedings; only a competent defendant can exercise the Constitutional rights to a fair trial and to confront his or her accuser in a meaningful way; the integrity and dignity of the legal process are preserved and the purposes of retribution and individual deterrence are served only if the convicted defendant is competent to stand trial.

The Competency Evaluation The focus of the competency evaluation is the defendant’s mental state at the time of the proceedings, not at the time of the alleged criminal act. A defendant’s competency can fluctuate over the course of the proceedings, and the question of a defendant’s competency to stand trial can be raised at any point in those proceedings and by any of the key participants: defense counsel, the prosecution, or the judge. When there is evidence of a lack of competency, the judge has an obligation to raise the question if the defense and prosecution fail to do so (Pate v. Robinson [U.S., 1966]). After it is determined that an evaluation is necessary, the judge can order that it take place. The evaluation can be done on an outpatient basis, but it is more commonly conducted on an inpatient unit with special capabilities to conduct forensic evaluations. The defendant’s consent is not necessary for a competency evaluation; the court can order it over the defendant’s objection (U.S. v. Hugenin [1st Cir., 1991]). Under the Sixth Amendment, the defendant has a right to consult with his or her attorney before the competency evaluation, but in federal courts, the defendant has no right to have counsel present at the evaluation itself. States can provide this right, if they choose (Buchanan v. Kentucky [U.S., 1987]) The decision as to whether the defendant is competent to stand trial is made by the trial judge. If the defendant is found to be incompetent to stand trial, he or she is committed to a state or federal hospital to be treated and restored to competency. Restoration to competency can occur on an outpatient basis, but this is less common. If the defendant cannot be restored to competency, he or she cannot be convicted and must be released from the hospital. However, the defendant can be held in the facility if he or she meets the usual criteria for civil commitment (Jackson v. Indiana [U.S., 1972]).

Forced administration of antipsychotic medication in order to render a defendant competent to stand trial violated the rights of the defendant under the Sixth and Fourteenth Amendments to the U.S. Constitution absent a showing by the state that the treatment was both medically necessary and appropriate and furthers a compelling governmental interest (Riggins v. Nevada [U.S., 1992]; Sell v. United States [U.S., 2003]).

Competency to Waive the Right to Counsel/Represent Oneself Defendants have a Constitutional right to have legal representation, and in felony cases are entitled to have legal representation provided by the government if they cannot afford it. Defendants also have the right to represent themselves and to waive the right to counsel; however, they must be deemed competent to do so. The Supreme Court has held that the standard for competency to waive this right is no higher than that for competency to stand trial, and essentially requires that the waiver must be knowing and voluntary. (Godinez v. Moran [509 U.S. 389, 1993]). In Indiana v. Edwards [554 U.S. 164 , 2008] the Supreme Court held that the right to self-representation is not absolute, that a defendant might be competent to stand trial but not to serve as his own attorney, and that the state can require such a defendant to proceed to trial with counsel.

Competency to Be Sentenced/Executed The Supreme Court has held that execution of a prisoner who is incompetent constitutes cruel and unusual punishment in violation of the Eighth Amendment to the Constitution (Ford v. Wainwright [U.S.,1986]). The standard for competency to be sentenced or executed is virtually identical to that for competency to stand trial: Whether the convicted individual understands the nature of the proceedings and an ability to participate in the process. The rationale for requiring that the convicted individual be competent for the sentencing and punishment phases is similar to the rationale for requiring that the defendant be competent to stand trial: to preserve the integrity of the sentencing and punishment process; to ensure that the convicted individual will have the ability to contest the decision through all stages of appeal prior to imposition of punishment; and to ensure that the deterrent function of punishment is served by only punishing those who have the requisite mental capacity to be sentenced or punished. The American Psychiatric Association’s position on ethical issues in death penalty cases is set forth in a 1990 Ethic’s Committee Opinion that stated: “It is unethical for a psychiatrist to participate in executions. It is not unethical for a

psychiatrist to conduct a competency evaluation in which the prisoner is told of the interview’s purpose and the limitations on confidentiality.” In addition to ethical quandaries, capital punishment raises a number of questions of constitutional law that have special relevance for psychiatrist who might be asked to evaluate competency to be executed. In Estelle v. Smith (U.S., 1982), the Court held that Smith’s Fifth Amendment rights to be free from selfincrimination and Sixth Amendment right to assistance of counsel were denied when the state’s psychiatrist, who had examined him solely for the purpose of assessing competency to stand trial, was allowed to testify as to Smith’s dangerousness at the penalty phase and Smith was not informed of the purpose of the evaluation or right to the presence of counsel. In Barefoot v. Estelle (U.S., 1983), the Court held that although the state could not compel a defendant to undergo a psychiatric evaluation, there is no Constitutional barrier to allowing psychiatric experts to testify to the defendant’s future dangerousness at the penalty phase based on hypothetical questions. The American Psychiatric Association filed an amicus curiae (friend of the court) brief in the case, pointing out the unreliability of dangerousness predictions. The Court rejected the arguments in that brief, holding that such assessments are not so inherently unreliable that they should be excluded totally and that the lack of reliability can be addressed as a credibility issue on cross examination. The Supreme Court has held that imposition of the death penalty on a mildly or moderately cognitively-impaired individual is not unconstitutional per se . However, a Texas statute that did not allow the jury to consider mitigating factors, such as a history of intellectual disability and child abuse but did allow consideration of aggravating factors, was unconstitutional (Penry v. Lynaugh [U.S., 1989]). Forced administration of antipsychotic medication for the purpose of rendering the inmate competent to be executed raises important questions of Constitutional law. Some states consider this permissible, whereas others hold that doing so violates constitutional principles, such as the right to privacy, and constitutes cruel, excessive, and unusual punishment (Louisiana v. Perry [La., 1992]). The Eighth Amendment prohibition against execution of incompetent mentally ill prisoners as cruel and unusual punishment was extended to other categories of defendants convicted on capital charges. These include those with moderate intellectual disability (Atkins v. Virginia [U.S., 2002]) and those who committed their offenses when they were less than 18 years of age (Roper v. Simmons [U.S., 2005]).

Criminal Responsibility For an act to be criminal, there must be both a guilty act (the actus reus ) and guilty intent (mens rea ). Mens rea , in the narrow sense, is the mental state required as an element of a specific crime—for example, larceny: knowingly taking possession of property that is not yours, for your own use, and with the intent of depriving the true owner of its use. In the general sense, mens rea refers to blameworthiness or legal liability. The defense of lack of criminal responsibility/not guilty by reason of insanity is based on the concept that some individuals who commit criminal acts should not be held morally blameworthy because they cannot be considered moral agents due to their mental state (Moore, 1984). Voluntary intoxication is not a basis for an insanity defense, although it can provide a basis for a diminished capacity defense. Mental illness caused by substance abuse, exacerbation of an existing mental illness due to intoxication, and pathologic intoxication can all provide a basis for an insanity defense.

Evolution of the Insanity Defense Standards Legal standards for the insanity defense have evolved over the years, but have continued to utilize the same core elements. One of the best-known standards is the M’Naghten test (England, 1843): “To establish a defense on the ground of insanity, it must be clearly proved that, at the time of the committing of the act the party accused was laboring under such a defect of reason, from disease of the mind, as not to know the nature and quality of the act he was doing, or, if he did know it, that he did not know he was doing what was wrong.” The M’Naghten test is a cognitive test, focusing only on whether the defendant knew what he was doing or that what he was doing was wrong. On the theory that individuals with mental illness or intellectual disability might be able to appreciate that a certain behavior is wrong, but not be able to control themselves, the English courts established the Irresistible Impulse/Loss of Control Test in Rex v. Davis (England, 1881). It was adopted and appended to the M’Naghten test in the United States in the case of Alabama v. Parson (Alabama, 1887). Under this rule, a defendant with a mental disease or defect would be held not responsible for criminal acts, even if he or she could tell right from wrong, if such disease or defect deprived him or her of power to choose right from wrong and the alleged crime was so connected with the mental disease as to have been the product of it solely. As such, this is a volitional, rather than a cognitive, test.

The combination of the M’Naghten rule and the Irresistible Impulse/Loss of Control Test provided the basis for the Model Penal Code/American Law Institute (ALI) standard that is still used in a number of states: “A person is not responsible for criminal conduct if at the time of such conduct as a result of mental disease or defect he lacks substantial capacity either to appreciate the criminality (wrongfulness) of his conduct or to conform his conduct to the requirements of the law.” For the purposes of that standard, the terms “mental disease or mental defect” do not include an abnormality manifested only by repeated criminal or otherwise antisocial behavior. This standard requires the presence of a mental disease or defect, but excludes personality or other disorders that have antisocial behaviors as their primary symptoms; for example, pedophilia, pyromania, and antisocial personality disorder itself. The disorder must cause an impairment in functioning that has a clear and direct causal connection or relationship with the alleged criminal act. John Hinckley’s assassination attempt on President Reagan, and his subsequent insanity acquittal, gave rise to calls for modification and narrowing of the federal insanity defense standard. With the guidance of the American Psychiatric Association, Congress adopted the following standard for federal criminal cases: “It is an affirmative defense to a prosecution under any Federal statute that, at the time of the commission of the acts constituting the offense, the defendant, because of a severe mental disease or defect, was unable to appreciate the nature and quality or the wrongfulness of his acts.” Unlike the ALI/Model Penal Code standard, the new federal standard requires an inability to appreciate the nature and quality or wrongfulness, not merely a lack of substantial capacity. The underlying mental disease or defect must be severe, and the lack of knowledge or appreciation complete—lacking substantial capacity so not sufficient. When a defendant is found not guilty by reason of insanity, he or she is generally remanded to a correctional facility, often a forensic hospital, where the person’s level of dangerousness and need for security are assessed. In rare cases the acquitted defendant might be released directly to the community, but it is far more common for the person to be committed to the hospital for at least some period, especially if the crime was one of violence. Key cases related to the civil commitment of insanity acquitees are discussed in the previous chapter. Guilty but mentally ill (GBMI) is a criminal defense that was developed as an alternative to the insanity defense, but it can be offered by a state as an additional option for the trier of fact (judge or jury). An individual found GBMI

is not legally insane and is held responsible for the act, but is acknowledged to have been mentally ill at the time of the act. It is available in a limited number of states. Diminished capacity is a defense that can be raised when an individual suffers from a mental illness or cognitive deficit that does not meet the requirements of the insanity defense, but nevertheless provides a basis for not holding the person fully responsible for the behavior. The result is usually to reduce the level of the conviction, e.g., reduction of the finding of guilt from first-degree murder to second-degree murder.

Demographics of the Insanity Defense Contrary to public perception, the insanity defense is not widely used, generally successful, or a “rich man’s defense.” It is raised in 0.1% of felony trials, and there are 2 insanity pleas per 1,000 felony arrests. The success rate for the insanity defense varies by state. Overall, juries hand down only 5% of insanity acquittals, 40% to 50% are decided by judges and the rest are the result of plea bargains. Insanity acquittees tend to be young (20–30 years old), white, with on average an eighth grade education, and to be employed as unskilled laborers.

The Role of Psychiatrists in the Legal System The first encounter psychiatrists have with the legal system commonly occurs when a patient becomes involved in litigation and the psychiatrist receives a subpoena for medical records or is asked to testify at a deposition or trial. Whether the psychiatrist submits the records or testifies is governed by the legal concept of psychotherapist–patient privilege. The psychotherapist–patient privilege is a corollary of confidentiality. Psychiatrists have an ongoing duty of confidentiality; that is, to protect the privacy of information revealed by patients during treatment. Testimonial privilege is the right to have matters revealed to a physician or therapist held in confidence and not revealed against the patient’s will in an administrative or judicial proceeding, except under certain circumstances. Whereas confidentiality is an ongoing obligation on the part of the physician, the privilege belongs to, and can only be raised or waived by, the patient: if the patient does not raise the privilege, the physician may be compelled to testify. Testimonial privilege in its modern form can be claimed regarding communications with psychotherapists, physicians, clergy members, spouses, and attorneys. Privileges were not an original part of English common law,

which held that the “King is entitled to everyman’s evidence.” However, it was eventually decided that society gained more from protecting the special relationships covered by the privileges and that it was more important than the information that would be excluded by application of the privilege. The psychotherapist–patient privilege exists in all 50 states, the District of Columbia, and all federal courts (Jaffee v. Redmond [U.S., 1996]). Just as there are exceptions to confidentiality, there are exceptions to the testimonial privilege. These exceptions include the following: express waiver by the patient (the patient expressly waives his or her right to exercise the privilege by putting his or her mental status at issue in the course of litigation; for example, claiming emotional damages in a personal injury suit); mandated reporting (as in cases of child abuse); and statutory exceptions (such as when the patient is involved in billing disputes or malpractice litigation against the physician).

The Psychiatrist as Forensic Evaluator/Expert Witness Broadly defined, a forensic evaluation is any psychiatric evaluation concerning issues that relate to litigation or administrative proceedings, or may do so. No clinical care is provided in a forensic evaluation, and it does not create a doctorpatient relationship in the traditional sense. Whereas a treating clinician has a fiduciary obligation to act only in the best interests of the patient, the forensic evaluator’s obligation is to the party requesting the evaluation. The client in a forensic evaluation may be the attorney, court, or agency that has retained the psychiatrist. In spite of that, forensic evaluators have an obligation to be objective, honest, and to take appropriate actions if the patient is found to pose a threat of harm to self or others. Confidentiality is absent in a forensic evaluation because, by definition, it is being conducted on behalf of a third party who has requested it. Thus, the forensic evaluator has an ethical obligation and, in some states, a legal obligation to obtain informed consent from the evaluee before conducting the examination. This includes warning the evaluee about the limitations on confidentiality.

The Psychiatrist as Expert Witness An expert witness is a witness who has knowledge related to the subject matter of the litigation beyond that of the average juror or judge, and who can offer information that will be useful to the judge or jury in reaching a decision in the matter. Anyone with such additional knowledge can technically be accepted as an expert, although the credibility of the expert can be attacked. For example, a

medical student might be accepted as an expert in medicine based on his or her studies, but the credibility of that expert would be attacked based on the lack of experience. Psychiatric experts can use any information they would normally use in the course of an evaluation as a basis for testimony, including hearsay (information that they did not obtain first-hand, but rather obtained through the reports of a third party). However, some states require that if the expert is to use hearsay evidence from another person, the source of that information must be available for cross examination. The job of the expert witness is to provide scientifically and clinically-accurate testimony, in an ethically-responsible manner, and to provide answers to the legal questions raised in the proceeding, to the extent possible. Upon being designated as an expert witness, a psychiatrist can provide the court with an expert opinion on an issue before the court; for example, whether the care of a patient was below the standard of care (malpractice), or whether the defendant has a mental illness that rendered him or her unable to conform his behavior to the requirements of the law (criminal responsibility). The fact witness (see the section that follows) is not allowed to offer such opinions.

The Psychiatrist as Fact Witness A fact witness is an individual who has information related to the matter being decided. There are no special requirements to be a fact witness, other than firsthand knowledge relevant to the case. Anyone, including a child, can be a fact witness. A fact witness cannot offer an expert opinion or use hearsay. A treating psychiatrist can be called to testify about the mental condition of a patient in a wide variety of settings; for example, personal injury litigation, workmen’s compensation claims, administrative hearings, and even criminal cases. The rules of the psychotherapist–patient privilege apply, if the patient raises it, however, the psychiatrist must testify if the patient does not raise the privilege. Even if the privilege is raised, the Court might decide that it does not apply and order the psychiatrist to testify. Refusal to testify can lead to a finding of contempt of court, justifying a fine or jail time. Where a patient is involved in litigation, but does not put his mental status in issue by claiming emotional distress damages, the records of the treating psychiatrist generally cannot be obtained. However, if the patient claims emotional damages, the records and testimony of the treating physician can be obtained by the other side.

Suggested Readings 1. Almanzor MC: The effect of intoxication as a “mitigating factor” for murder and manslaughter. 31 New Eng L Rev . 1079; 1997. 2. American Medical Association Council on Ethical and Judicial Affairs: Code of Medical Ethics . Annotation 2.06. Chicago: 1997. 3. Drogin EY, Dattilio FM, Sadoff RL, et al, eds.: Handbook of Forensic Assessment: Psychological and Psychiatric Perspectives . Hoboken, NJ: John Wiley & Sons; 2011. 4. Levine AM: Denying the settled insanity defense: another necessary step in dealing with drug and alcohol abuse. 78 B.U.L. Rev. 75; 1998. 5. Moore MS: Law and Psychiatry: Rethinking the Relationship . Cambridge, UK: Cambridge University Press; 1984. 6. Perlin ML: “The borderline which separated you from me”: the insanity defense, the authoritarian spirit, the fear of faking, and the culture of punishment. 82 Iowa L . Rev. 1375; 1997. 7. Reider L: Toward a new test for the insanity defense: incorporating the discoveries of neuroscience into moral and legal theories. 46 UCLA L . Rev. 289; 1998. 8. Schouten R: The psychotherapist-patient privilege. Harv Rev Psychiatry . 1998; 6: 44 –48. 9. Strasburger LH, Gutheil TG, Brodsky A: On wearing two hats: Role conflict in serving as both psychotherapist and expert witness. Am J Psychiatry . 1997; 154: 448–456. 10. Thomason SC: Criminal procedure-crazy as I need to be: The United States Supreme Court’s latest addition to the incompetency doctrine. 20 U . Ark. Little Rock L.J. 349; 1998.

CHAPTER Patient Adherence 61 LARA TRAEGER, PHD; JOHN B. HERMAN, MD; AND THEODORE A. STERN, MD

KEY POINTS Overview Adherence refers to the extent to which patients’ health behaviors align with recommendations that they have agreed upon with their clinicians. Optimal adherence increases the likelihood that patients will experience treatment response or remission, thereby reducing the burden of illness for patients, families, and health-care systems. Evidence strongly supports the notion that non-adherence is common across all branches of clinical medicine, with rates of non-adherence ranging between 25% and 75%. Contributors to Poor Adherence Challenges to adherence are multi-level, including patient factors (e.g., cognitive impairment), clinician factors (e.g., approach to patient care), structural issues (e.g., healthcare fragmentation), and social concerns (e.g., stigma of illness). Patients are less likely to adhere if they deny or have low insight into their condition, have a low readiness to change their health behaviors, or believe that the recommended treatment will be unnecessary or ineffective. Contributors to Enhanced Adherence Treatment decisions should account for patients’ perspectives about their health, acceptable treatment options, and adherence challenges that are nonmodifiable (e.g., health insurance parameters) versus modifiable (e.g., patient motivation). Patient medical, financial, and quality-of-life concerns about the treatment plan should be addressed up front.

Patients can also benefit from setting up daily reminders for medication-taking or other health behaviors, such as a daily alarm on their mobile phone, written reminders in key areas of the home, or targeted support from family or friends.

Overview Adherence refers to the extent to which patients’ health behaviors align with recommendations that they have agreed upon with their clinicians. For chronic health conditions, adherence typically is a moving target that requires ongoing coordination among the patient, the clinician and the relevant healthcare systems. Patients might need to tolerate treatment titrations and stay engaged in care over time in order to achieve or to maintain a clinically-significant outcome. Optimal adherence increases the likelihood that patients will experience treatment response or remission, thereby reducing the burden of illness for patients, families, and health-care systems. For patients, however, adherence commonly involves a complex series of tasks. Patients might face challenges in attending follow-up medical care, communicating with their physician, accessing and safely storing presc ribed medications, following prescribed regimens, and managing treatment side effects and complications. Evidence strongly supports the notion that non-adherence is common across all branches of clinical medicine, with rates of non-adherence ranging between 25% and 75%. These rates do not show consistent disparities by demographic or clinical factors, such as income, education, or diagnosis. Examples of nonadherence include missed follow-up visits or prescription refills, patterns of medication over- or under-dosing, or early treatment discontinuation. These problems can lead to increased morbidity and to excess healthcare utilization.

What Contributes to Poor Medical Adherence? Challenges to adherence are multi-level, including patient factors (e.g., cognitive impairment), clinician factors (e.g., approach to patient care), structural issues (e.g., healthcare fragmentation), and social concerns (e.g., stigma of illness). For instance, lack of trust or confidence in the patientphysician relationship is a key predictor of patient non-adherence. Additionally, insufficient resources for copayments, transportation, or child care might make it difficult for patients to attend follow-up visits. Patients also might fill some

medication prescriptions at the expense of others if they have difficulties balancing costs across co-morbid conditions. A patient’s perceptions of his or her disorder and its treatment can affect adherence. Patients are more likely to adhere if they perceive a high need for treatment but are faced with a low risk of side effects or complications. In turn, patients are less likely to adhere if they deny or have low insight into their condition, have a low readiness to change their health behaviors, or believe that the recommended treatment will be unnecessary or ineffective. Additional factors that affect adherence include a need to assert control over the physicianpatient relationship or to retain symptoms for secondary gain. Some chronic illnesses elevate the risk for symptoms of depression and anxiety that in turn can affect adherence. For instance, hopelessness can reduce motivation for treatment, whereas decreased energy or poor concentration can interfere with self-care and medication-taking. Substance misuse also increases a patient’s risk for poor adherence.

What Can You Do to Facilitate or Enhance Medical Adherence? Adherence is common, yet physicians and patients commonly underestimate the factors that impair it. Efforts to facilitate adherence reflect a dynamic equilibrium between science and the patient-physician relationship. Strategies to facilitate adherence should be integrated into all phases of patient care.

Treatment Planning During initial treatment selection, physicians should assess their patient’s history of healthcare beliefs and behaviors and current mental health status. Treatment decisions should account for patients’ perspectives about their health, acceptable treatment options, and adherence challenges that are non-modifiable (e.g., health insurance parameters) versus modifiable (e.g., patient motivation). Collaborative decisions can facilitate a sense of patient empowerment that is commonly threatened by the presence of the illness itself. With respect to motivation, the physician can present pros and cons of treatment options, highlighting ways in which the selected option can support aspects of quality of life that are important to the patient. The physician also can help manage expectations by reviewing potential treatment side effects and emphasizing that some treatments require time or adjustments prior to conferring detectable benefits.

To facilitate adherence, medications can be considered based on their profile of side effects or dosing frequencies, with avoidance of complicated dosing schedules when possible. Patient medical, financial, and quality-of-life concerns about the treatment plan should be addressed up front. Regimen instructions should be discussed, reviewed, and provided in writing, using clear, straightforward language and any relevant pictures or diagrams. Patients can also benefit from setting up daily reminders for medication taking or other health behaviors, such as a daily alarm on their mobile phone, written reminders in key areas of the home, or targeted support from family or friends.

Adherence Monitoring Adherence should be discussed regularly throughout the course of care. Although there is no “gold standard” measure of adherence, patients can be encouraged to keep daily diaries of health behaviors and relevant side effects, or use pill boxes or smart pill devices to track medication-taking. Information related to adherence also can be collected via a prescription refill history, assays, or informal caregiver feedback. Since adherence can change over time, regular follow-up visits should address ongoing or new adherence challenges. The physician might inquire about adherence in a non-judgmental way, including open-ended questions about what treatments or health behaviors the patient is using and how the patient is using them.

Adherence Interventions More intensive interventions can be used to increase patient knowledge, motivation, and/or skills for adherence. For instance, patients can benefit from increasing their understanding of the treatment regimen and its rationale, with information provided in varied formats. Patients also might benefit from support to build intrinsic motivation for ongoing treatment. Finally, education might be integrated with practical skills for problem-solving adherence challenges. Given the complexities of adherence, the physician might help the patient to devise and test plans for addressing challenges to each adherence task, such as the impact of housing instability on safe medication storage or the impact of irregular sleep patterns on daily dosing schedule. The physician also can work with the patient to write out a daily schedule that balances usual activities, such as brushing teeth and eating meals with the prescribed health behaviors. If family members are affecting optimal adherence, the physician and patient can discuss concerns with them in order to engage them in the treatment plan. Or, if

a patient faces non-modifiable challenges, such as limited health resources, the physician might refer their patient to resource specialists or available services.

Suggested Readings 1. Bosworth HB: Improving patient treatment adherence: a clinician’s guide . New York: Springer; 2010. 2. Christensen AJ: Patient adherence to medical treatment regimens: bridging the gap between behavioral science and biomedicine . New Haven, CT: Yale University Press; 2004. 3. Gonzalez JS, Peyrot M, McCarl LA, et al: Depression and diabetes treatment non-adherence: a meta-analysis. Diabetes Care . 2008; 31(12): 2398 –2403. 4. Miller WR, Rollnick S: Motivational interviewing: helping people change . New York: Guilford Press, 2013. 5. World Health Organization. Adherence to long-term therapies: evidence for action [Internet]. WHO. Available from: http://www.who.int/chp/knowledge/publications/adherence_report/en/ . 6. Zuckoff A: “Why won’t my patients do what’s good for them?” Motivational interviewing and treatment adherence. Surg Obes Relat Dis . 2012; 8(5): 514–521.

CHAPTER An Overview of the 62 Psychotherapies STEVEN C. SCHLOZMAN, MD

KEY POINTS Psychotherapies encompass a heterogeneous class of treatment options for a number of psychiatric symptoms and conditions. Although psychoanalytically-oriented/psychodynamic therapy remains the most common psychotherapeutic intervention, increasingly therapeutic interventions are eclectic and involve a combination of the nine forms of therapy summarized in this chapter. Psychotherapy involves interventions that primarily focus on listening to and talking to patients. There are multiple forms of psychotherapy summarized in this chapter. – Psychoanalytic/psychodynamic psychotherapy was first described in detail by Sigmund Freud and is based on theories of unconscious conflicts. It involves principles of transference, countertransference, resistance, and free association. – Behavioral therapy/cognitive-behavioral therapy is the form of therapy most studied and validated; it is based on the theory that behaviors can be changed by changing patterns of actions or patterns of cognition. – Interpersonal psychotherapy is based on the “here and now”; it is used for grief, role transitions, role disputes, and interpersonal deficits. – Dialectical behavior therapy is used most often for treatment of borderline personality disorder; it focuses on harm reduction. – Supportive psychotherapy helps patients deal with a specific crisis; it is brief and directive. – Multi-systemic therapy is most often used for disruptive teens; it brings multiple services together and therapy to the child. – Integrative psychotherapy tailors the approach to the patient; it utilizes all forms of therapy. – Brief therapies are time-limited but still psychodynamic; they are often deliberately anxiety-provoking to provoke change.

– Group therapies involve more than one patient with one therapist; it can follow multiple theories.

Overview Psychotherapies are most often categorized by their fundamental theoretical elements. These classifications include treatments (e.g., psychoanalytic psychotherapy, behavioral and cognitive-behavioral therapy [CBT], interpersonal therapy [IPT], and dialectical behavioral therapy [DBT]). Other classifications reflect their duration of treatment (e.g., brief or short-term psychotherapy) or the patients in attendance (e.g., group, couples, families). This chapter describes the nine common forms of psychotherapy: Psychoanalytic or psychodynamic psychotherapy Behavior therapy Cognitive and CBT IPT DBT Psychoeducational psychotherapy Supportive psychotherapy Multi-systemic treatment Integrative psychotherapy. Discussion includes which patients are referred for which therapy, and, when possible, to what extent each form of therapy has been studied in terms of efficacy and cost effectiveness.

Psychoanalytical Psychotherapy (Expressive or Psychodynamic Psychotherapy) Psychoanalytic-based psychotherapy , often called psychodynamic psychotherapy is likely the most commonly practiced type of psychotherapy in the United States. Nevertheless, this statistic is somewhat suspect due to varied definitions of what constitutes psychodynamic therapy. Psychodynamic therapy is based on the Freudian tradition of uncovering unconscious aspects of a patient’s mental life. To this end, term “psychodynamic” derives from the

driving conceptualization that the psyche is in motion—that it is literally dynamic and changing, despite our lack of conscious awareness. Unconscious conflicts, repressed feelings, family issues from early in a patient’s life, and difficulty with current relationships, are all themes commonly addressed in this kind of therapy. Typically, the therapist takes a non-directive posture, paying close attention to transference, countertransference, resistance, free association, and dreams as a means of understanding and delineating unconscious conflicts. Many of these terms deserve further consideration to better understand the fundamentals of psychodynamic therapy. Transference is the unconscious re-direction of feelings and desires retained from the past that are re-directed toward the therapist. Countertransference , on the other hand, is the unconscious association of feelings or desires from the past that the therapist develops for the patient. Resistance is the term used to describe those forces within the patient, conscious and unconscious, that oppose the purpose of the patient’s evaluation and the goals of treatment. These unconscious processes are accessed through a series of important techniques. Free association is the undirected expression of conscious thoughts and feelings as one of the most important means of gaining access to the patient’s unconscious. Other techniques involve the evaluation of dreams and the examination of humor and slips of the tongue. Slips of the tongue are instances when patients accidentally mis-speak and in so doing display an unconscious conflict. A patient might say, “I told my boss I’d call her at home,” rather than, “at the office,” thus uncovering attraction to the employer that would be considered an inappropriate or forbidden feeling. Although some argue that all forms of psychiatric suffering are appropriate for treatment with psychodynamic therapy, severe and chronic personality disorders as well as persistent problems in coping with difficult life events are among the most commonly approached issues treated by this modality. Anorexia nervosa also can be managed with long-term psychoanalytic-oriented psychotherapy. The length of therapy typically varies from a few months to a few years. Although increasing amounts of research have supported the efficacy of this form of treatment, it is important to remember that the nature of psychodynamic psychotherapy makes controlled studies difficult to conduct. In fact, some have suggested that new methods that track the level of empathic connectedness between patient and doctor stand to provide better and more robust evidence for the efficacy of these treatments. Still, lack of research does not necessarily correlate with lack of efficacy. Based on existing data, however, cognitive and

behavioral therapies (see below) might be more efficient in terms of symptom reduction and length of therapy, and have more rigorous research evidence of effectiveness. Finally, although mood and anxiety disorders can respond to psychoanalyticoriented psychotherapy, combinations of medication and cognitive or behavioral therapy might be more effective and efficient and cost less. Although insurance programs are often less likely to pay for this type of treatment, many patients pursue and pay out-of-pocket for psychoanalytic-oriented psychotherapy because they find it emotionally and intellectually compelling. There are four principal sub-types of psychoanalytic or psychodynamic psychotherapy associated with the specific individuals. Classic psychotherapy is usually attributed to the work of Sigmund Freud. Anna Freud built on these theories and founded the field of ego psychology. Melanie Klein and Donald Winnicott used these ideas to develop object-relations psychotherapy. Melanie Klein then went on to develop important concepts (such as the depressive, paranoid, and schizoid positions). Donald Winnicott, through his treatment primarily of children, became associated with several concepts (such as the transitional object and the good-enough mother). Heinz Kohut took a different approach and focused on the experience of the self as seen through the therapist’s interpretations. He called this approach selfpsychology. Kohut is therefore commonly associated with the concept of mirroring in psychotherapy.

Behavior Therapy Behavior therapy is based on reducing symptoms by learning relaxation techniques, changing factors that reinforce symptoms, and giving the patient graduated exposure to distressing stimuli. Joseph Wolpe published the first book on behavior therapy, and Isaac Mark demonstrated the effectiveness of behavior therapy on simple phobias. Behavior therapists usually are directive and encourage homework and experimentation. Homework might involve exposure to a feared situation (e.g., speaking out during a committee meeting). The purpose of this suggestion is to reduce the reinforcing expectation that catastrophe would occur if one speaks out. Mental imaging allows the patient to learn how to relax while imagining the feared situation. Behavior therapy equips the patient with concrete strategies that can be used after the termination of therapy.

Behavior therapy is generally brief, requiring 6 to 20 sessions. Research evidence has repeatedly demonstrated efficacy for behavior therapy for a variety of anxiety disorders, depression, and some psychosomatic symptoms (e.g., pain). Importantly, behavior therapy is manual-driven; each session has a documented direction and goal. Perhaps because manual-driven therapies more easily lend themselves to systematic study and research, there is a good deal of evidence in support of these modalities.

Cognitive Therapy and CBT Cognitive therapy is based on the assumption that negative thoughts promote depression or anxiety. Ideally, these negative thoughts are documented by the patient during depressing or anxious experiences that occur between visits, and, during therapy sessions, patients are encouraged to challenge these negative ideas. Aaron Beck first described cognitive therapy and demonstrated its effectiveness with case-controlled research. Research evidence has demonstrated that cognitive therapy is an effective treatment for depression. Cognitive therapy is also indicated for anxiety states and problems related to substance abuse. There are less robust findings that still suggest efficacy for post-traumatic stress disorder (PTSD), psychotic disorders, and substance abuse. CBT is the term used to describe the combination of cognitive and behavioral therapies. CBT is effective for anxiety disorders, such as obsessive-compulsive disorder (OCD) and depression and may be more effective for trauma and psychosis than cognitive therapy alone. CBT generally requires 10 to 20 sessions but its length can vary a great deal.

IPT IPT addresses relationships in the “here and now” that can contribute to depression. Four common interpersonal issues are reviewed to discover the best focus of therapy: grief, role transition, role dispute, and interpersonal deficits . Gerald Klerman is credited with the early description and research on IPT, and he developed this method primarily for the treatment of depression. The usual duration is 12 sessions. Since its inception, IPT has been useful as well for marriage therapy and post- and peri-partum depression. As with CBT, there is good research evidence that this manual-driven psychotherapy is effective.

DBT

DBT is an individual and group program for borderline personality disorder. The main goals of DBT are the reduction of self-injurious behavior and of hospitalizations. This is a manual-driven therapy with a psychoeducational focus on mindfulness, interpersonal effectiveness, emotion regulation, and distress tolerance. Marsha Linehan originally described DBT and has demonstrated its effectiveness with patients with borderline personality disorder in a controlled research protocol. Specifically, self-injurious behavior and the number of hospitalizations have been dramatically reduced among patients treated with DBT. DBT is typically longer than other manual-driven therapies, with a duration of at least 1 year.

Psychoeducational Therapy This form of therapy is used to support and educate patients and families about ways to manage and understand emotional or physical problems. Psychoeducational therapy has been used with patients (who suffer from schizophrenia) and with their families to teach low-expressed emotion strategies. Research has demonstrated the effectiveness of low expressed emotions in maintaining health for patients with psychotic disorders. Psychoeducational therapy is usually a long-term therapy used for chronic psychiatric problems.

Supportive Psychotherapy Supportive psychotherapy is usually brief, with an active focus on helping the patient deal with a specific life crisis. The therapist offers advice, sympathy, and support while reinforcing the patient’s strengths and sense of agency. Supportive psychotherapy is anecdotally extremely helpful, but formal research to demonstrate its effectiveness is lacking. Supportive psychotherapy appears especially effective for acute grief reactions.

Multi-Systemic Treatment Multi-systemic treatment involves multiple and active interventions for young people who are involved in violent acts. This form of therapy has attracted increasing attention during the past 15 years. Unlike traditional models, in which social service organizations and clinicians meet with young people in separate settings, multi-systemic treatment involves direct intervention in the settings in which the child has encountered the most problems. Interventions encourage a more structured parenting style, communication, and affection within the family, as well as positive peer relations, and lines of communication between parents and teachers by using programs such as after-school activities to promote

academic growth. Studies suggest that multi-systemic treatment reduces violent behavior, decreases the costs of caring for potentially violent youth, and improves academic performance.

Integrative Psychotherapy Integrative psychotherapy represents a combination of some or all of the therapies described above and offers a multi-modal approach to the patient’s problem. Integrative psychotherapy is widely practiced but has not been as formally researched to demonstrate its effectiveness when compared to other modalities. Virtually any psychiatric problem can be treated with a combination of integrated psychotherapies and appropriate pharmacotherapy. Arnold Lazarus and Paul Wachtel were early writers on integrative or multi-modal psychotherapy. Integrative psychotherapy varies in length from brief to long term.

Brief Psychodynamic Psychotherapies A number of theorists have developed a variety of brief psychodynamic psychotherapies. Peter Sifneos described a short-term anxiety-provoking psychotherapy that focuses on unconscious Oedipal issues. David Malan developed a form of time-limited psychotherapy that focuses on triangles of conflict (wish, threat, defense) and on triangles of insight (therapist, current, and past relationships). Habib Davanloo created a form of intensive short-term dynamic psychotherapy that focuses on breaking through defenses to unlock the unconscious. Lester Luborsky built on these ideas with what he called supportive expressive psychotherapy focusing on the core conflicts of relationships. Finally, James Mann created time-limited psychotherapy that focuses on time and loss and Hans Strupp developed time-limited dynamic psychotherapy that focuses on cyclical maladaptive patterns.

Group Therapies Group therapy has been used for a variety of Axis I conditions, including mood disorders, anxiety disorders, substance abuse and dependence, and schizophrenia. Groups have also been useful in the long-term management of personality disorders and in grief work. Some groups comprise patients with different diagnoses, some with the same diagnoses. Groups have been useful for support and education for patients with medical conditions (such as breast cancer and acquired immunodeficiency syndrome [AIDS]). David Spiegel conducted

ground-breaking research that focused on the efficacy of group therapy for women with breast cancer. Some groups are open-ended, with new patients beginning and other patients terminating over time. Other groups are time limited, with all patients beginning at the same time and the group terminating at a predetermined date. Group therapists might address the group as a whole or might focus on individual patients in the group. Finally, groups can embrace any of the aforementioned theoretical orientations.

Future Directions As greater acceptance of psychotherapy of all kinds gains momentum in concert with impressive advancements in biologically based modes of inquiry, new theories regarding the measurement of treatment efficacy continue to emerge. For example, some researchers have studied the extent to which therapist and patient are physiologically in synch throughout a session. By tracking metrics (such as heart rate, skin conductance, and other markers of autonomic arousal), researchers have correlated mirrored physiological responses between patient and therapist with treatment success. This model has been applied as well to other doctor-patient interactions outside of classic psychotherapeutic encounters. Closely related to these studies is the finding that qualities, such as trust and empathy, are perhaps the best markers for therapeutic success regardless of the modality of treatment. Add to this the observation that most therapists use aspects of all kinds of psychotherapy, often with the same patient, and it becomes clear that the most fundamental doctrines of psychotherapy are still the most important. Clinicians should be respectful and empathic toward the patient and employ the knowledge that he or she has as a psychotherapist. Ultimately, these practices will ensure the best possible outcomes.

Suggested Readings 1. Ablon JS, Marci C: Psychotherapy process: the missing link: comment on Westen, Novotny, and Thompson-Brenner. Psychol Bull . 2004 Jul; 130(4): 664 –568; author reply 677–683. 2. Abernethy RS: The integration of therapies. In: Rutan S, ed.: Current Trends in Psychotherapy . New York: Guilford Press, 1992. 3. Alonso A, Swiller HI: Group Therapy in Clinical Practice . Washington,

4. 5. 6. 7. 8.

9. 10.

11.

12. 13. 14.

15.

16.

17.

DC: American Psychiatric Press; 1993. Basch MP: Understanding Psychotherapy: The Science behind the Art . New York: Basic Books; 1988. Beck AT: Cognitive Therapy and the Emotional Disorders . New York: Meridian; 1976. Borduin C: Multi-systemic treatment of criminality and violence in adolescents. J Am Acad Child and Adoles Psychiatry. 1999; 39: 242–249. Gabbard GO, Gunderson JG, Fonagy P: The place of psychoanalytic treatments within psychiatry. Arch Gen Psychiatry . 2002; 59(6): 505–510. Hellerstein D, Pinsker H, Rosenthal R, et al: Supportive therapy as the treatment model of choice. J Psychotherapy Practice Res . 1994; 3: 300– 306. Klerman G, Weissman M, Rounsaville B, et al: Interpersonal Psychotherapy of Depression . New York: Basic Books, 1984. Leichsenring F, Leibing E: Psychodynamic psychotherapy: A systematic review of techniques, indications and empirical evidence. Psychology & Psychotherapy: Theory, Research & Practice . June 2007; 80(2): 217–228. Levy RA, Ablon JS, eds.: Handbook of Evidence-Based Psychodynamic Psychotherapy: Bridging the Gap between Science and Practice . New York: Humana Press; 2009. Linehan MM: Cognitive-Behavioral Treatment of Borderline Personality Disorder . New York: Guilford Press; 1993. Mann J: Time-limited Psychotherapy . Cambridge, MA: Harvard University Press, 1992. Marci C, Riess H: The clinical relevance of psychophysiology: Support for the psychobiology of empathy and psychodynamic process. Am J Psychother . 2005; 59(3): 213–226. Midgley N, Kennedy E. Psychodynamic psychotherapy for children and adolescents: a critical review of the evidence base. J Child Psychotherapy . December 2011; 37(3): 232–260. Roffman JL, Marci CD, Glick DM, et al: Neuroimaging and the functional neuroanatomy of psychotherapy. Psychol Med . 2005 Oct; 35(10): 1385– 1398. Rutan JS: Psychotherapy for the 1990s . New York: Guilford Press; 1992.

18. Sperling MB, Sack A: Psychodynamics and managed care: The art of the impossible? Am J Psychotherapy . 2002; 56(3): 362–377. 19. van Hees ML, Rotter T, Ellermann T, et al: The effectiveness of individual interpersonal psychotherapy as a treatment for major depressive disorder in adult outpatients: a systematic review. BMC Psychiatry . 2013 Jan 11; 13:22. 20. Wachtel PL: Psychoanalysis and Behavior Therapy: Toward an Integration . New York: Basic Books; 1977.

CHAPTER Brief Psychotherapy 63 JOHANNA C. MALONE, PHD; MARK A. BLAIS, PSYD; AND JA MES E. GROVES, MD

KEY POINTS Overview Interest in planned brief psychotherapy has grown enormously in the past few decades. A Brief History of Brief Psychotherapy Freud’s early treatments were often brief and symptom-focused; the psychoanalyst was active and desperate patients selected themselves for the fledgling venture. The Modern Brief Psychotherapies Here we focus on four schools of brief psychotherapy: psychodynamic, cognitive-behavioral, interpersonal, and eclectic. All four of these orientations share the essential features of brief therapy: brevity, patient selection, treatment focus, and high levels of therapist activity. – Psychodynamic short-term therapies (Sifneos; Malan; Davanloo) feature psychoanalytic interpretation of defenses and unconscious conflicts as their main “curative” agent. – Cognitive-behavioral brief therapies (Beck and Greenberg; Dewan, Steenbarger, & Greenberg) aim to bring the patient’s “automatic” (preconscious) thoughts into awareness, and demonstrate how these thoughts impact behavior and feelings. – Brief interpersonal therapy , developed by Klerman, is a highly formalized (manualized) treatment that focuses not on mental content but on the process of the patient’s interaction with others. In this approach, interpersonal communication is taken at face value rather than exploring the subtle meanings and complex nuances of relationships, as is done in more dynamic approaches.

– “Eclectic” brief therapies are characterized by combinations and integrations of multiple theories and techniques. Although some people approach psychotherapy as a long-term—even timeless —enterprise, most of the existing data indicate that psychotherapy as it is practiced in the real world is time limited. It is effective for reducing symptoms across a range of disorders. Brief psychotherapists should consider that from the start there must be a willing suspension of disbelief and cynicism about brief therapy and should cultivate an openness to what might be accomplished. Patient selection is the art of finding the right patient with the right problem for brief psychotherapy; it begins with the initial evaluation. A two-session evaluation format is recommended for determining if a patient is appropriate for brief therapy. The brief therapy patient should not be actively psychotic, abusing substances, or at significant risk for self-harm. What is needed is the establishment of a focus that both the therapist and the patient can agree upon and which fits the therapist’s treatment approach. Conducting a brief (12–16 session) psychotherapy requires that the therapist be very active.

Overview Interest in planned brief psychotherapy has grown enormously in the past few decades. Unfortunately, this interest has been fueled more by changing patterns of health care reimbursement than by an appreciation of the clinical value of brief psychotherapy. This chapter provides an overview of an eclectic approach to planned brief psychotherapy. Planned brief psychotherapy differs from the ubiquitous brief treatments that end prematurely or abruptly before a mutually determined ending. By presenting the important features of brief therapy in a general manner (rather than as a specific school of brief therapy), the essential features of this form of psychotherapy can more easily be assimilated into one’s ongoing psychotherapy practice. Still, to understand even an eclectic version of short-term therapy, we must have an historical context within which to place it.

A Brief History of Brief Psychotherapy Toward the end of the nineteenth century, when Breuer and Freud were developing psychoanalysis, hysterical symptoms (e.g., conversion, anxiety)

defined the focus of the work. Freud’s own early treatments were often brief and symptom-focused; the psychoanalyst was active, and desperate patients selected themselves for the fledgling venture (see e.g., Sterba, 1951, for an account). In time, free-association, exploration of the transference, and dream analysis became increasingly central to the therapeutic technique, while the duration of treatment greatly increased, and therapist activity decreased. Some creative therapists controversially experimented with traditional analytic approaches by manipulation of the interval and the spacing of sessions (Alexander, 1971) and endorsement of an active stance of the therapist (Ferenczi and Rank; see Tosone, 1997). These techniques were major contributions in the development of modern short-term therapy. Decreased frequency, irregular spacing, therapeutic holidays, and therapist-dictated scheduling (rather than patient- or symptom-dictated scheduling) all enhanced the reality-orientation of therapy. The next historical development for planned brief psychotherapy occurred following World War II with a glut of patients needing treatment for “shell shock” and “battle fatigue.” New concepts and theories emerged from treating so many patients so rapidly. Grinker and Spiegel’s treatment of soldiers and Lindemann’s work with survivors of the Cocoanut Grove fire highlight this period in the development of brief treatment. Finally, in the early 1960s, Sifneos and Malan each independently developed the first theoretically-coherent short-term psychotherapies. Over time, planned brief treatments have been met with opposition and bias due to concerns that they reduced the depth of experience, ambiguity, and relational components of the treatment (see Barasch, 1999, for a review). However, contemporary, directions of sophisticated brief psychotherapy models aim to retain an understanding of the individual as a complex transactional being who is beginning a specific piece of work rather than reducing the person to a set of symptoms or trying to complete a life-span work in a short amount of time. As Winnicott (1959) said, “We all hope our patients will finish with us and forget us, and that they will find living itself to be the therapy that makes sense.”

The Modern Brief Psychotherapies Although this chapter focuses on an eclectic approach to brief therapy, it is important to have some sense of the current brief psychotherapy schools. Here we focus on four schools of brief psychotherapy: psychodynamic, cognitivebehavioral, interpersonal, and eclectic. All four of these orientations share the

essential features of brief therapy: brevity, patient selection, treatment focus, and high levels of therapist activity. Psychodynamic short-term therapies (see Sifneos, 1992; Malan, 1976; Davanloo, 1992) feature psychoanalytic interpretation of defenses and unconscious conflicts as their main “curative” agent. Sifneos’ anxietyprovoking therapy is one example of a brief psychodynamic psychotherapy. This treatment runs for 12 to 20 sessions and focuses narrowly on issues such as the failure to grieve, fear of success, or triangular, futile love relationships. Unlike longer-term dynamic treatments, the therapist serves as a more didactic figure who holds to the focus, and challenges the patient to relinquish both dependency and intellectualization, while confronting anxiety-producing conflicts. One might think of this method as a classic oedipal-level defense analysis (i.e., identifying and modifying conscious and unconscious patterns of coping that might be more or less adaptive) with all the lull periods removed. One limiting feature of the Sifneos approach is that it is only indicated for 2% to 10% of the population (e.g., highly motivated, psychologically minded individuals who are able to tolerate the unremitting anxiety that occurs over the course of treatment). Cognitive-behavioral brief therapies (see Beck and Greenberg, 1979; Dewan, Steenbarger, & Greenberg, 2004) aim to bring the patient’s “automatic” (preconscious) thoughts into awareness, and demonstrate how these thoughts affect behavior and feelings. Compared to brief psychodynamic approaches, this style of therapy is thought to be more broadly applicable in terms of both patients and problems. The basic thrust of cognitive therapy, according to Beck, is to get the automatic thoughts more completely into consciousness, to challenge them consciously, and to practice new behaviors that change the picture of the world and the self in it. The patient is actively helped to challenge these automatic thoughts. Currently, highly-structured short-term cognitive-behavioral therapies (CBTs) are utilized to narrowly target a specific disorder or symptom either as an adjunctive treatment or standalone intervention (Barlow, 2007). Brief interpersonal therapy was developed by Klerman (1984) and is a highly-formalized (manualized) treatment. Interpersonal psychotherapy (IPT) focuses not on mental content but on the process of the patient’s interaction with others. In this approach, interpersonal communication is

taken at face value rather than exploring the subtle meanings and complex nuances of relationships, as is done in more dynamic approaches. IPT was developed primarily to treat patients with depressive episodes related to either grief or loss, interpersonal disputes, or interpersonal skill deficits. Other versions of brief relationship-focused approaches aim to identify patterns in relational narratives drawing at times upon psychoanalytic theories (Luborsky, 1984; Levenson, Butler, Powers, Breitman, 2002) For example, more recently Lemma, Target, and Fonagy (2013), developed a short-term Dynamic Interpersonal Therapy (DIT) for depression that blends interpersonal and psychodynamic principles and consists of three phases. The goal of the first phase (sessions 1–4) is to identify a primary unconscious “ interpersonal affective focus” (IPAF) or pattern that contributes to the maintenance of the depressive experience. In the second phase (sessions 5–12), therapists help patients work through their IPAF by focusing on how it is affecting relationships both in the patient’s life and directly with the therapist. In the final phase (sessions 13–16), the therapist helps the patient reflect on the emotional experience of the therapy and the meanings associated with termination. “Eclectic” brief therapies are characterized by combinations and integrations of multiple theories and techniques. Budman and Gurman (1988) present one very popular version of eclectic brief therapy, which focuses on three dimensions of mental life: the interpersonal, the developmental, and the existential. The model of Budman and Gurman pursues a systematic approach, beginning with the individual’s reason for seeking therapy. Major changes in the patient’s social support are reviewed. A major feature here is the belief that maximal benefit from therapy occurs early, and the optimal time for change is early in treatment. Non-perfectionism is a unique emphasis of the approach as patients are encouraged to regularly re-engage in treatment as they face normative developmental crises.

Why Brief Therapy? Whereas some people approach psychotherapy as a long-term—even timeless —enterprise, most of the existing data indicate that psychotherapy as it is practiced in the real world is time limited. For example, using national outpatient psychotherapy utilization data obtained in 1987 (before the nation-wide impact

of managed care), Olfson and Pincus (1994) found that 70% of psychotherapy users received 10 or fewer sessions. In fact, only 15% of their sample received 21 or more sessions. More recently, Olfson and Marcus (2010) found that between 1998 and 2007 rates of psychotherapy utilization remained constant (approximately 3%), but the average number of sessions dropped almost 20% (from 9.7 to 7.9 sessions). This data is highly consistent with earlier studies showing a median number of eight sessions for outpatient psychotherapy. Clearly, in the real world, most patients have a time-limited or brief psychotherapy experience. There can be a regularly recurring mismatch between the number of sessions therapists want their patients to have and the number of sessions patients intend to have. Passively assuming that patients who have expressed time constraints, limited resources or availability, or desire to complete a focused piece work will ultimately “come around” to a longer-term, open-ended model ultimately leads to frustration for both patient and therapist. It conveys to the patient that their needs will not be taken seriously or heard. In addition, there is evidence across theoretical perspectives that brief psychotherapy can effectively reduce symptoms of a wide range of disorders, including but not limited to both anxiety (Arch et al, 2012; Leichsering et, al, 2009; Lemma, Target, & Fonagy, 2013) and depressive symptomatology (Driessen et al, 2010, Nieuwsma et al, 2012). The material presented in this chapter will help providers deliver psychotherapy in a planned and thoughtful manner, which is better matched to psychotherapy’s natural course.

The Mindset of the Therapist in Brief Therapy A therapist hoping to successfully learn and practice brief treatment needs to adopt a certain self-reflective mindset. Using a literary analogy, Barasch (1999) compares brief psychotherapy to a short story, highlighing how it is different from the start from other literary forms such as a novel (because it is not simply a chapter), an unfinished manuscript, or an abridged book, instead it is a “rich literary form in its own right.” (p. 49). Therefore, brief psychotherapists should consider that from the beginning there must be a willing suspension of disbelief and cynicism about brief therapy and should cultivate an openness to what might be accomplished. An example of this would be a willingness to consider a quick positive response as something other than a temporary “flight into health.” Next, brief psychotherapy must be conceptualized as a time-limited enterprise, as something that will end at a known planned date. This appears deceptively

simple, but in practice it is a difficult cognitive change to make. To illustrate, briefly consider how one might approach a new patient, if from the beginning it were known that the therapy would last 14 sessions (or 3–4 months). Finally, the therapist must expect and accept that a patient will return to therapy periodically across their life span (sometimes called intermittent brief therapy across the life cycle). This relates to the notion of cure and what is an acceptable outcome for treatment. This is often the easiest of the three components to accept.

The Essential Features of Brief Therapy Patient Evaluation and Selection Initial Evaluation Patient selection is the art of finding the right patient with the right problem for brief psychotherapy; it begins with the initial evaluation. A two-session evaluation format is recommended for determining if a patient is appropriate for brief therapy. This format allows the clinician to conduct a complete psychiatric evaluation and assess the appropriateness of the patient for brief psychotherapy without feeling too much time pressure. To guide you in the selection of patients we present several inclusion and exclusion criteria (see Table 63-1). These criteria are fairly general, covering most forms of brief therapy, and restrictive; many patients will be screened out. However, for the new or novice brief therapist the use of these criteria will provide nearly ideal brief therapy patients. Table 63-1: Patient Selection Criteria for Brief Therapy Exclusion Criteria

Inclusion Criteria

Active psychosis

Moderate emotional distress

Substance abuse

A desire for relief

A significant risk of self-harm

A specific or circumscribed problem

Desire for long-term exploratory work History of positive relationships Function in one area of life Ability to commit to treatment

Exclusion Criteria What follows is a short list of exclusion criteria. The brief therapy patient should not be actively psychotic, abusing substances, or at significant risk for self-harm. The actively psychotic patient will not be able to make adequate use

of the reality-oriented/logical aspects of the brief treatment. Substance-abusing patients should be directed to substance abuse treatment prior to undertaking any form of psychotherapy. Patients at significant risk for self-harm are not appropriate for brief therapy due to possible complications associated with the ending their treatment at a planned time. These factors should be considered categorical in nature; the presence of any one of them should rule-out a patient for brief psychotherapy. This is especially true for a therapist just beginning to learn brief treatment.

Inclusion Criteria These criteria can be thought of as dimensions, with each patient being rated on how much of each dimension they have. The potential candidate for brief therapy should: be in moderate emotional distress (as this provides the motivation for treatment); want relief from his or her emotional pain (i.e., they should not have been sent to therapy reluctantly by a boss or spouse); be able to articulate a fairly specific cause of their pain or a circumscribed life problem (or be willing to accept your specific formulation of their difficulty); have a history of at least one positive (mutual) interpersonal relationship; still be functioning in at least one area of life; and have the ability to commit to a treatment contract. As stated earlier, patients should be rated for their standing on all of these dimensions. The more of these qualities (amount and number) that a patient has, the better the candidate is for brief therapy. The evaluation period is also a time to begin noting the patient’s strengths, areas of resilience, specific abilities, and typical ways of making positive change. These existing qualities should be noted and then drawn upon across all stages of treatment, to facilitate positive change (Anchin, 2003).

Developing a Treatment Focus Developing a treatment focus is probably the most misunderstood aspect of brief therapy. Many writers talk about “the focus” in a circular and mysterious manner, as if the entire success of the treatment rests on finding the one correct focus (Hall et al, 1990). This can be confusing and intimidating to those just learning brief therapy. Rather, what is needed is the establishment of a focus that both the therapist and the patient can agree upon and that fits the therapist’s treatment approach. This can be called a functional focus. The main technique for finding a functional focus is the “Why now?” technique developed by Budman and Gurman (1988). This technique is applied by repeatedly asking the patient, “Why did you come for treatment now?” “Why today rather than last

week, tomorrow, etc.…?” (This simple technique should be tried a few times to see how effective and powerful it can be). The goal is to find out what the triggering event for therapy was, because this might provide an ideal treatment focus. Budman and Gurman (1988) also describe four common treatment foci that are regularly utilized within planned brief treatments. Losses , past, present, or pending. These can be interpersonal (e.g., the loss of a loved one), intrapersonal (e.g., the loss of a psychological ability, the social loss of a support network), or functional (as in the loss of specific abilities or capacities). Developmental desynchronies (being out of step with expected developmental stages). This might be seen in people who are having difficulty initiating certain aspects of an adult lifestyle that they desire (e.g., maintaining employment, establishing adult relationships, becoming more self-sufficient). Interpersonal conflicts , usually repeated interpersonal disappointments, either with loved ones, bosses, or colleagues. Many patients present for psychotherapy simply with the desire for symptom reduction. Importantly, neuropsychiatric dysfunction (e.g., executive dysfunction) generally requires longer-term strategies. It is helpful to memorize these four common foci and think about them while conducting an initial evaluation assessment of their relevance to the patient. The most important thing to remember is that you are not finding the focus, only a focus for the therapy.

Completing the Initial Evaluation By the completion of the second evaluation session, you need to decide whether the patient is appropriate for brief treatment, select an agreed-upon focus, and have a clearly stated treatment contract (including the number of sessions, how missed appointments will be handled, and how post-termination contact will be handled). The two-session evaluation format also allows you to see how the patient responds to you and to the therapy. In fact, it can be very enlightening to give the patient some kind of homework to complete between the two sessions. An initial positive response, and feeling a little better in the second session, bodes well (whereas a strong negative reaction conveys a worse prognosis). A more ambivalent response (such as forgetting the task) can signal problems with motivation and should be explored. Importantly, within the initial evaluation

sessions, the therapist should already be consciously establishing the therapeutic alliance (Anchin, 2003).

Being an Active Therapist Conducting a brief (12–16 session) psychotherapy requires that the therapist be very active (see Table 63-2). According to one study, patients showed faster symptom reduction in short-term treatment when therapists were active, engaging, and extroverted (Heinonen, Lindfors, Laaksonen, Kenkt, 2012). This study also found that therapists with higher confidence and enjoyment in their work were more likely to have patients with better outcomes. This is timedemanding and work-intensive. The therapist performing such therapy must keep the treatment focused and the process of treatment moving forward. Several techniques have been designed to structure and direct the therapy. These include beginning each session with a summary of the important points raised during the last session and restating the focus. Assignment and review of homework (outof-session assignments designed to transfer gains from therapy to the patient’s life) are tasks that characterize the activity of the therapist. Interventions that focus on the “working alliance” or therapeutic alliance are important (see Safran and Muran, 1998), as are timely interventions, which limit silences and deviations from the focus. Table 63-2: Types of Therapist Activity Establishing clear treatment goals and realistic expectations. Structuring sessions Using homework Developing and addressing issues in the working alliance Limiting silences Clarifying vague responses Addressing positive and negative transference quickly Drawing (actively and explicitly) upon patient’s strengths, abilities, and areas of resilience Using empathic and supportive statements Encouraging a non-perfectionistic stance Limiting psychological regression Reviewing and acknowledging the effects of the phases of treatment on a patient’s engagement.

The goal of eclectic brief therapy is to restore or improve pre-morbid adaptation and function. Efforts are made by the therapist to limit and check psychological regressions. Asking, “What did you think about that?” rather than about feelings and affect (e.g., “How did that make you feel?”) can help with the exploration of potentially regressive material. Limited within-session regression is acceptable and often necessary in brief therapy; however, prolonged regressions accompanied by decreased function are to be avoided. Clarification is important in brief therapy. Requests for clarification should be made whenever a patient produces vague or incomplete material. This would include asking for examples or for specifics and empathically pointing out contradictions and inconsistencies. Similarly, it is also expected that the therapist be clear and be able to express ideas directly in ways that the patient can use. Transference occurs in all treatments, including brief psychotherapy, and can develop even in the opening session (Gill & Muslin, 1976). Even though many aspects of brief therapy are designed to discourage the development and utilization of transference, a more contemporary approach indicates that the therapist must be attuned and be ready to attend to transference and countertransference dynamics within brief psychotherapies. Two forms of transference are particularly important to recognize quickly: negative and overly-positive transferences. Negative transference can be suspected when the patient responds repeatedly with either angry or devaluing statements, or when he or she experiences the therapy as humiliating. An overly positive transference is signaled by repeated and excessively positive comments (e.g., “Oh, you know me better than anyone ever has”). In brief psychotherapy, these forms of transference should be dealt with quickly from the perspective of reality and the present. The therapist should review the patient’s feelings and reasoning and relate these to the actual interaction. For example, if the therapist was inadvertently offensive, this should be admitted to, while pointing out that the therapist’s motive was to be helpful. Attending to the intrapsychic effects and the reality of time in brief psychotherapy is a final activity of the therapist. Mann (1982; 1991), who developed a dynamic existential method, found that time itself could be used as the primary tool in brief treatments. The therapist should recognize that limited time places pressure, increases anxiety, and motivates the patient to work toward certain goals. The therapist should closely attend to the effects that the phases of treatment place on the patient and if necessary respond in ways that acknowledge the reality of the experience.

Phases of Planned Brief Therapy Several traditional phases of psychotherapy as they apply to brief treatment need review.

Initial Phase This phase (from evaluation to session 2 or 3) principally includes evaluation and selection of the patient, selection of the focus, and establishment of a working alliance. This phase is usually accompanied by some mild reduction in symptoms and a low-grade positive transference, particularly as a working relationship develops. The goal is to set the frame and the structure of the therapy, while also giving the patient hope.

Middle Phase In the middle phase (sessions 4 to 8 or 9), the work becomes more difficult. The patient usually becomes concerned about the time limit, feeling that the length of treatment will not be sufficient. Issues of separation and aloneness come to the fore and compete with the focus for attention. It is important for the therapist to reassure the patient (with words and a calm, understanding demeanor) that although difficult, the treatment approach has much to offer, and direct their joint attention back to the agreed-upon focus. The patient often feels worse during this phase and the therapist’s faith in the treatment process is often tested.

Termination Phase In this phase (sessions 8 to 12 or 16), the therapy usually settles down. The patient accepts the fact that treatment will end as planned and his or her symptoms typically decrease. In addition to the treatment focus, post-therapy plans and the situational loss of the therapy relationship are explored. At or around the actual termination of treatment it is not unusual for the patient to present some new and often interesting material for discussion. Even though the therapist might be tempted to explore this new material and thereby extend the treatment, doing so is usually (but not always) a mistake. Interest in the new material should be shown, but, unless clinically indicated, the treatment should end as planned in order to give the full experience and value that a planned brief treatment can provide (e.g., a clear beginning, middle, and end).

Post-Treatment Contact

Within the eclectic brief therapy framework, it is acceptable for patients to return to therapy at multiple points during their life. When a therapy is completed, a patient should wait about 6 months before considering further therapy. This allows patients to practice their newly-learned psychological insights and skills in the real world and take some time to assess their new level of adaptation and function. In other words, the impact of treatment is utilized both during and after the treatment. In considering post-treatment contact, the therapist should strive to help and be available to patients at times of environmental or psychological stress across the life-span. Patients who participate in brief psychotherapy have the benefit of personally knowing a therapist they can return to.

Suggested Readings 1. Abbass A, Town J, Driessen E: Intensive short-term dynamic psychotherapy: A systematic review and meta-analysis of outcome research. Harv Rev Psychiatry . 2012; 20: 97–108. 2. Anchin JC: Integratively oriented brief psychotherapy: Historical perspective and contemporary approaches. J Psychotherapy Integration . 2003; 13(3–4): 219. 3. Arch JJ, Eifert GH, Davies C, et al: Randomized clinical trial of cognitive behavioral therapy (CBT) versus acceptance and commitment therapy (ACT) for mixed anxiety disorders. J Consult Clin Psychol . 2012; 80(5): 750. 4. Barasch AS: Psychotherapy as a short story: Selection and focus in brief dynamic psychotherapy. J Am Acad Psychoanal . 1999; 27: 47–59. 5. Barlow D: Clinical Handbook of Psychological Disorders: A Step-By-Step Treatment Manual . 4th ed. New York: Guilford Press; 2007. 6. Beck S, Greenberg R: Brief cognitive therapies. Psychiatr Clin North Am . 1979; 2: 11–22. 7. Blais M: Planned brief therapy. In: Jacobson J, Jacobson A, eds.: Psychiatric Secrets . 2nd ed. Philadelphia: Hanley & Belfus; 2000. 8. Book H: How to Practice Brief Psychodynamic Psychotherapy: The Core Conflictual Relationship Theme Method . Washington D.C.: American Psychological Association, 1998.

9. Budman S, Gurman A: Theory and Practice of Brief Therapy . New York: Guilford Press; 1988. 10. Burk J, White H, Havens L: Which short-term therapy? Arch Gen Psychiatry . 1979; 36: 177–186. 11. Crits-Christoph P: The efficacy of brief dynamic psychotherapy: A metaanalysis. Am J Psychiatry . 1992; 1149: 151–158. 12. Davanloo H: Intensive short-term dynamic psychotherapy with highlyresistant depressed patients: Part I. Restructuring ego’s regressive defenses. Int J Short-Term Psychotherapy . 1987; 2: 99–132. 13. Davanloo H: Short-Term Dynamic Psychotherapy . New York: Jason Aronson, 1992. 14. Dewan MJ, Steenbarger BN, Greenberg RP: The Art and Science of Brief Psychotherapies: A Practitioner’s Guide . Washington DC, American Psychiatric Publishing; 2004. 15. Driessen E, Cuijpers P, de Maat SC, et al: The efficacy of short-term psychodynamic psychotherapy for depression: a meta-analysis. Clin Psychology Rev . 2010; 30(1): 25–36. 16. Gill MM, Muslin HL: Early interpretation of transference. J Am Psychoanal Assoc . 1976; 24: 779–794. 17. Groves J: Essential Papers on Short-Term Dynamic Therapy . New York: New York Universities Press; 1996. 18. Groves J: The short-term dynamic psychotherapies: an overview. In: Rutan S, ed.: Psychotherapy for the 90s . New York: Guilford Press; 1992. 19. Hall M, Arnold W, Crosby R: Back to basics: the importance of focus selection. Psychotherapy . 1990; 27: 578–584. 20. Heinonen E, Lindfors O, Laaksonen MA, et al: Therapists’ professional and personal characteristics as predictors of outcome in short-and long-term psychotherapy. J Affect Disord . 2012; 138(3): 301–312. 21. Klerman G, Weissman M, Rounsaville B, et al: Interpersonal Psychotherapy of Depression . New York: Basic Books; 1984. 22. Leibovich M: Short-term psychotherapy for the borderline personality disorder. Psychother Psychosom . 1981; 35: 257–264. 23. Leichsenring F, Salzer S, Jaeger U, et al: Short-term psychodynamic

24.

25.

26. 27. 28. 29. 30.

31. 32.

33. 34. 35.

36.

psychotherapy and cognitive-behavioral therapy in generalized anxiety disorder: a randomized, controlled trial. Am J Psychiatry . 2009; 166(8): 875–881. Lemma A, Target M, Fonagy P: Dynamic Interpersonal Therapy (DIT): Developing a new psychodynamic intervention for the treatment of depression. Psychoanalytic Inquiry . 2013; 33(6): 552–566. Levenson H, Butler SF, Powers TA, et al: Concise Guide to Brief Dynamic and Interpersonal Therapy . 2nd ed. Washington DC, American Psychiatric Publishing; 2002. Luborsky L: Principles of Psychoanalytic Psychotherapy: A Manual for Supportive-Expressive Treatment . New York, Basic Books; 1984. Malan D, Osimo F: Psychodynamics, Training and Outcome in Brief Psychotherapy . London: Butterworth-Heinemann; 1992. Malan D: The Frontier of Brief Psychotherapy . New York: Plenum Medical Book Company; 1976. Mann J, Goldman K: A Case-Book in Time Limited Psychotherapy . New York McGraw-Hill; 1982. Mann J: Time-Limited Psychotherapy. In: Crits-Christoph P, Barber JP, eds.: Handbook of Short-Term Dynamic Psychotherapy . New York: Basic Books, 1991, pp. 17–44. Messer SB: What makes brief psychodynamic therapy time efficient. Clin Psychology: Science and Practice . 2001; 8: 5–22. Nieuwsma JA, Trivedi RB, McDuffie J, et al: Brief psychotherapy for depression: a systematic review and meta-analysis. Int J Psychiatry in Med . 2012; 43(2): 129–151. Olfson M, Marcus SC: National trends in outpatient psychotherapy. Am J Psychiatry . 2010; 167: 1456–1463. Olfson M, Pincus HA: Outpatient psychotherapy in the United States: II. Patterns of utilization. Am J Psychiatry . 1994; 151: 1289–1294. Safran JD, Muran JC, eds.: The Therapeutic Alliance in Short Term Psychotherapy . Washington DC: American Psychological Association Publications; 1998. Selva P, Malan D: Intensive Short Term Dynamic Psychotherapy: Theory and Technique Synopsis . London: Karnac; 2004.

37. Sifneos P: Short-Term Anxiety Provoking Psychotherapy: A Treatment Manual . USA: Basic Books; 1992. 38. Sterba R: A Case of Brief Psychotherapy by Sigmund Freud. Psychoanal Rev . 1951; 38: 75–80. 39. Tosone C. Sándor Ferenczi: Forerunner of modern short-term psychotherapy. Psychoanal Soc Work . 1997; 4:23–41. 40. Winnicott DW: The use of an object. Int J Psycho-Anal . 1969; 50: 711– 716. 41. Winston A, Laikin M, Pollack J, et al: Short-term psychotherapy of personality disorders, Am J Psychiatry . 1994; 151: 190–194.

CHAPTER 64 Couples Therapy ANNE K. FISHEL, PHD

KEY POINTS Organizing Principles In couples therapy, there are three patients in the room: each member of the couple and the relationship. Two common psychodynamic explanations of mate choice are projective identification and repetition compulsion. There is a connection between the family of origin and the couple’s current relationship. The presenting problem should be contextualized within a normative, developmental perspective. Normative transitions are made more stressful when they resonate with difficulties in previous generation, occur “off cycle,” and coincide with other life stressors. Divorce is regarded as an unscheduled, but normative, transition. Marriage differentially affects men and women. Couples therapists should focus on how couples fight rather than on the content of their fight. Couples therapists should focus on communication that includes verbal and non-verbal expression. Couples Evaluation Evaluations should include an opportunity to discuss their relationship together and individually: scheduling a session with the couple, then having two individual meetings, and providing feedback with couple is helpful. Therapists should refrain from holding a secret with one partner about the other. Therapists should balance eliciting a working definition of the problem and expanding that definition. The therapist should come up with a relational or dyadic definition of the presenting problem. The therapist should ask about sex, family of origin, a better version of

relationship, and exceptions to the problem. The therapist should offer feedback at the end of the evaluation on positive qualities of the couple, the affective temperature of the relationship, stressors and developmental perspectives, a dyadic description of the problem, and recommendations for therapy. Treatment Interventions Psychodynamic: Focus on interpreting unconscious processes, like projective identification and transference, to clear up distortions from the family of origin. Cognitive-behavioral: Focus on communication strategies to improve listening and conflict management. Experiential: Use role-play and enactment to bring more affect into the hereand-now. Strategic: Employ paradoxical interventions to mirror the couple’s dual agenda for change and keeping the status quo. Narrative: Use shifts in language to create less constricting ways to talk about problems.

Introduction Couples therapy is a clinical sub-specialty that focuses on the pattern of interactions between two people while considering the individual history and contribution of each member. Clinical work with couples is typically part of a child’s evaluation, an ongoing child and adolescent psychotherapy, a divorce mediation, crisis work, or a child custody evaluation. Couples therapy is also an important component in the treatment of sexual dysfunction, alcoholism and substance abuse, the disclosure of infidelity, depression and anxiety disorders, infertility, and serious medical illness. Couples therapy is also useful in resolving polarized relational issues, such as the decision to marry or to divorce, the choice to have an abortion, or the decision to move to a distant city for one partner’s career. The term “couples therapy” rather than “marital therapy” is deliberately used throughout this chapter to include therapy with same-sex couples and unmarried heterosexual couples.

Organizing Principles for Couples Therapists

The couple’s therapist often locates the origins of the current dilemma in the nature of the initial attraction or mate choice. Two common explanations of mate choice are “opposites attract” (elaborated by the psychodynamic construct of “projective identification”) and “repetition compulsion.” With projective identification, an individual unconsciously looks for something in the other that is difficult for the self and then acts to elicit the very behavior in the other that has been disavowed. For example, a shy, self-effacing man might be attracted to a self-confident, ambitious woman; however, over time he complains that she is too self-absorbed. She might initially find his steadiness and calm attractive, only to later criticize him for his cold remove. What is initially problematic for the self eventually becomes contentious between the couple. Repetition compulsion or re-enactment is the notion that one falls in love with someone who resembles a loving caretaker from childhood, or who resembles an abusive caretaker with whom one wants a second chance to master the abuse. Murray Bowen, a psychodynamic therapist, observed that individuals at a similar level of psychological functioning tend to marry. Couples therapists are also very interested in the contribution that each member of the couple makes to the relationship from his or her family of origin. Regardless of theoretical orientation, most couples’ therapists posit a connection between past family experiences and current marital functioning. Beginning with the choice of a mate, each member of the couple brings an unconscious template of lover and then proceeds to distort the other to conform with the self’s needs. The process of couples therapy is, in large part, one of distinguishing between those distortions based on past familial relationships and the reality of one’s actual partner. The couple’s therapist is mindful of the developmental context, in which the relationship takes place. Because individuals’ psychological growth may take place at different rates, relationships must be able to tolerate divergent growth trajectories, as, for example, when one partner is ready for children, or for retirement, before the other. Life-cycle theorists have posited several predictable stages of development for married couples with children. Life events and a particular set of psychological tasks that require change prompt these stages. It is assumed that it is in the transition from one stage to another that couples and families are most at risk for divorce and for the appearance of individual symptomatology. Normative transitions are rendered more stressful when they resonate with similar difficulties in a previous generation; when they occur at a time of life that is

unexpected by the family or by the culture; and when they coincide with other life stressors. The stages, with the principal concomitant emotional task required, are outlined by McGoldrick et al (2016). The first stage is heralded by young adults leaving home; the major task during this phase is accepting emotional and financial responsibility for the self. The second stage is characterized by families joining through marriage; the focus at this juncture is on committing to and forming a new marital system, separate from each member’s family of origin. The third task is characterized by families making the transition to parenthood; at this stage, the couple must make room for new members in the marital system. The fourth life stage involves families raising adolescents and needing to increase the flexibility of family boundaries to include adolescents’ independence. In the fifth stage, children are launched and move on. During this stage, the couple will focus on marital and career issues, as parenting roles diminish. For families later in life, after retirement and beyond, acceptance is needed (of the shifting of generational roles to care for the older generation and of facing aging and loss in the middle generation). As the larger social context changes, the parameters of these stages shift, as well, to allow for changes in contemporary couples relationships. At present, couples can expect an average of 20 years from the time their youngest child marries until retirement, as compared with only 2 years for this launching stage at the turn of the last century. The lengthening of this stage is due to longer life expectancy and to women ending their childbearing at a relatively young age (with fewer children). Couple’s therapists now regard divorce as an unscheduled, often normative life transition that affects large numbers of families. Divorce rates have doubled between 1965 and 1980, and have leveled off since then. Certain factors are associated with a higher rate of divorce (e.g., couples who are 20 years of age or younger, those with less income and education). There are many gender and racial differences, as well. Women initiate nearly two-thirds of divorces and divorce rates are twice as high for the African-American population compared to Whites or Hispanics (McGoldrick et al, 2016). Couples therapists have documented the gender effects of marriage and divorce on men and women’s health and well-being (Williams, 2003; McGoldrick and Hardy, 2008). Several studies have noted that married men experience better health and greater marital satisfaction than do their female counterparts. Also, married men achieve greater occupational success than do single men, whereas

the opposite is true for married women. Even in dual-career marriages, women continue to do the lion’s share of household and childcare tasks, particularly the daily and routine tasks (e.g., cooking, doing laundry). Increasingly, couples therapists help divorcing couples make this transition as well as possible by emphasizing the ways that a divorce is a process that takes place over several years, ways to minimize the negative effects on the children, and focusing on coparenting of children (Ahrons, 2007; Kelly, 2007). Recent research has explored the similarities and differences among married same-sex couples, married heterosexual couples, and cohabiting couples, both straight and gay. Even though many of the dynamics and challenges are the same for any committed couples, some differences have been noted. For example, as compared to married straight couples, gay and lesbian couples tend to assign household labor more equitably and to resolve conflict more constructively and to receive more support from friends than from family (Gottman 2003; Kurdek, 2005; Green and Mitchell, 2015). Another important area for couple’s therapists is the assessment and management of conflict. Although all couples must learn to manage differences of opinion, it is often how couples fight with each other that becomes the focus of clinical attention. Gottman (2000, 2015) has found that the presence of defensiveness, criticism, stonewalling, and contempt during marital conflict is predictive of divorce. Conversely, couples who can repair their misunderstandings, use humor, and still make positive comments to one another during a fight, will fare better. Couples therapists are interested in the strengths evident in relationships and they have grappled with defining healthy marital functioning. In The Good Marriage , Wallerstein and Blakeslee (1995) interviewed 50 happily married couples and concluded that these couples had dealt successfully with nine tasks: They detached emotionally from each member’s family of origin. They built intimacy while maintaining a sense of autonomy. They relaxed the boundaries of the couple’s relationship to allow children in (while maintaining the emotional richness of marriage). They confronted the inevitable developmental changes of aging, loss, and illness (and came out of crisis with renewed strength). They safely expressed difference, anger, and conflict (without violence or capitulation).

They established a pleasurable sexual relationship (that changed in response to the stressors of aging, work, and family life). They shared laughter and humor. They provided emotional nurturance and encouragement, They allowed the marriage to be renewed by the elements of fantasy and attraction that first drew the partners to one another. A final focus of emphasis for couple’s therapists is communication. Early models of couple’s therapy stressed the importance of developing communication skills, sometimes at the expense of other relational dimensions (like gender, sex, and family of origin issues). The emphasis on communication stresses the importance of each partner being able to speak openly and frankly while the other listens with undefensive empathy. In part, this emphasis belies a bias about intimacy: that closeness can be achieved only through the full and open disclosure of each partner’s innermost feelings. More recent interpretations of the role of communication include a wider range of issues; not only talking and listening, but also refraining from making hurtful comments and focusing on non-verbal action (including acts of affection and sexuality, the giving and receiving of generous acts, and the sharing of mutually-enjoyed activities), even if they do not include self-disclosing conversation (Weingarten, 1990).

Conducting an Evaluation A couple’s evaluation should contain an opportunity for the couple to discuss their relationship together and to explore their individual histories separately. The evaluation offers a balance between clinical understanding and empathy on the one hand, and prodding the couple into thinking about their relationship in new, more flexible ways, on the other. Throughout the evaluation, the clinician looks for opportunities to re-establish hope, to point out resources and strengths of the couple, and to provide a forum for each partner’s position to be heard without judgment. The clinician will also look for opportunities to transform individual explanations of a problem into systemic, interactive descriptions. A successful evaluation will determine the motivation of each partner to participate in ongoing treatment and tease out when couples therapy is contraindicated, and when individual, group, or no therapy should be recommended instead.

The First Session (with Both Members of the Couple)

The therapist’s first job is to provide a context of safety and comfort. The clinician should set a time frame and then ask each member to introduce him- or herself separate from the problems that bring them in, and offer certain rules of discourse. For example, the “I pass” rule can be introduced. If anyone is asked a question that feels too intrusive, he or she is encouraged to “pass.” Also in the opening moves of the evaluation, the therapist should set the expectation that whatever is said in the individual meetings will be shared in the wrap-up meeting. This guideline prevents the therapist from getting in the untenable position of sharing a secret with one member of the couple about the other. Additionally, the therapist should summarize any previous contact he or she has already had with one member of the couple to demonstrate the therapist’s commitment to openness and equity. After this brief introduction, the therapist will ask about each couple member’s definition of the problem. It is essential that the clinician convey that both partners’ perspectives will be respected and contained, and that the therapist will not play the role of a judge, arbitrating two adversaries. Each individual should have an opportunity to tell his or her version without interruptions and qualifications by the other. As an opening question, the clinician might ask: “Often with couples, each member has a different view of the problem and different hopes for change. I’d like to hear from each of you regarding how you see your difficulties.” As the therapist listens to the couple’s description of their problems it is important to determine whether both parties are engaged in the evaluation process or whether one member has been dragged, coerced, or threatened by the other. The clinician might ask: “I’d like to hear how you made the decision to give me a call and whose idea it was.” The therapist will also want to know about the larger context in which the couple lives in order to understand other resources and other stressors. The therapist might ask: “Who else has been concerned and given advice or offered help?” And, “Have there been any other changes in the family in the last year?” (e.g., illnesses, job loss, deaths, moves, infertility, births). Often, a request for couple’s therapy will coincide with an accumulation of other stressors. When the therapist has a firm grasp on the couple’s current reasons for pursuing a couple’s therapist, the therapist can move to expanding the couple’s view of the problem. An evaluation should offer the couple ample opportunity to share their working definitions of the problem as well as a chance to have their ideas challenged and stretched in order to create new strategies for change.

Several questions help shift the couple’s current view to a more flexible, often interactional, definition that paves the way for each member of the couple to alter the pattern between them. The therapist tries to help the couple shift from a view that locates pathology within one partner, and move instead to a dyadic view. Here are some examples: “If you were to be in couples therapy for 6 months and at that point you declared that the therapy had been a wild success, what would I notice that would let me know that your relationship had changed in important ways? What, for example, would you be talking about or doing with each other or noticing about the other that is not happening now?” (De Shayzer, 1994). With these questions, the couple is asked to envision a solution and a way of knowing when the therapy would be over. Because most couples will experience sexual difficulties at some point in their relationship, it is worth asking every couple during an evaluation, even if it is not part of the stated problem: “You haven’t mentioned your sexual relationship. Perhaps that’s because it is going well, or because it’s unfamiliar to bring it up with a relative stranger. If we were to work together, would there be anything you would like to change about your sexual relationship?” Another question that stretches a couple’s presentation is about how the couple first met. Often one can detect the seeds of the current dilemma in the story of the couple’s initial attraction: “What first attracted you to one another?” Furthermore, most couples, no matter how upset or angry, will brighten and soften toward one another in answering this question. When there is not a palpable shift toward more positive affect, the therapist might be concerned that there is an absence of affection and friendship to draw on. Another surprising question is to ask each member of the couple: “What is it like being married to you?” (Karpel, 1994). When each member’s version of the self matches the partner’s view, the therapy is far more straightforward. When these versions do not match, the therapist will need to attend to the fact that there is no agreement on the relational problem. The therapist should also wonder and inquire about where the couple is developmentally. Attending to normative responses to life cycle changes will alert the therapist to inquire about commonly occurring reactions to these events. For example, if a couple has small children, the therapist will want to ask how their sexual relationship has changed, and do they have fights about the equity of childcare and housework. Another fruitful area of inquiry is each partner’s family of origin: “What can you tell me about the family you grew up in that will help me understand your

current dilemma?” This question probes for the themes and issues that each individual brings to the relationship and sets the groundwork for later exploration of projective identification. As it is important to learn about the couple’s strengths and problem-solving abilities, even when they are feeling discouraged about their relationship, the therapist might ask: “Tell me about an instance when the problem did not occur.” “What did you notice that each of you was doing differently?” These questions, derived from narrative therapy (White and Epston, 1990; Freedman and Combs, 2015), ask the couple to stand apart from their problem and notice the positive examples of their interactions. In addition, such an inquiry guides them to reflect on his or her contribution to the pattern between them. A special challenge for a couple’s therapist is the assessment of whether infidelity has occurred or might be an ongoing secret (Gordon et al, 2015). However, it is unlikely that if the therapist asks about a secret affair in the presence of the couple, that the truth will be told. If infidelity is asked about in an individual meeting the truth is more likely to be revealed, but then the therapist will be stuck holding a secret that will facilitate collusion with one member and likely enrage the other if the secret comes out. A couple’s therapist should avoid hearing information from an individual’s therapist about a secret affair because this information will then need to be withheld for reasons of confidentiality. An alternative to asking directly about infidelity is to test the waters by inquiring: “Has fidelity been a challenge for either of you to maintain?” “Are you concerned about the other’s fidelity?” “What has been your understanding about what constitutes infidelity?” When there is an ongoing affair or when one member is suspicious of the other’s fidelity, these questions will often elicit non-verbal cues of anxiety or anger.

The Two Individual Sessions (Meeting with One Member at Each Session) These sessions offer an opportunity to get to know the individuals better and to give the couple a chance to bring up whatever they want without having to share the time with their partner. In addition, it is useful to ask about each individual’s current level of commitment to the relationship; whether there is a history of, and current use of, drugs and alcohol; previous and current experiences with therapy and psychiatric hospitalizations; whether there is a history of depression, suicidality, anxiety, or other mental illness; whether there is a history of sexual abuse; current medical problems; whether there is a fear of your partner (e.g.,

“Do you feel sexually coerced by your partner? Do you feel free to make decisions? Do you have access to financial resources? Has your partner ever been violent toward you, your children, or inanimate objects?”).

The Fourth Session (Wrap-Up and Feedback with Both Members of the Couple) When one partner has been dragged to couples therapy, the evaluation can represent the end of the line and the feedback can give the couple ideas to work on even if they forgo further couple’s therapy. In this feedback, it is important to include five components. First, the therapist should comment on positive aspects of the relationship. This will convey an appreciation of the couple’s positive qualities, diminish defensiveness, promote hopefulness, and place the focus on the relationship. The therapist might note, for example, how intently the couple listened to each other, or how courageous it was for them to come to therapy, or how well they use humor. Second, the therapist should comment on the affective temperature of the relationship. It is crucial that the therapist accurately interpret the couple’s level of distress. Is this a couple on the verge of a break-up, in need of a tune-up in a few areas, or in conflict about the extent of the overhaul needed? Third, the therapist should identify the stressors and place the problem in a developmental perspective. Fourth, the therapist should offer a relational description of the problem that includes both of their perspectives as well as points to areas of change. Finally, the therapist should offer recommendations for treatment. Couples therapy will be indicated if one or more of the following conditions are met: When the therapist and the couple can agree on an interactional definition of the problem. When there is irreconcilable disagreement (as with a stalemate about whether to marry, to divorce, or to have children). With particular complaints (such as sexual difficulties, chronic fighting, adjustment to serious medical illness in one partner, or the aftermath of the disclosure of an affair). When the couple is having difficulty negotiating a life transition (as when a couple fears the dissolution of their marriage as they anticipate their oldest

child’s leave-taking, or when a couple with a newborn feels overwhelmed by the intensity of their fights with each other). Individual therapy might also be indicated under other circumstances: if one partner is motivated for therapy and the other is not; if an individual symptom requires specialized treatment (as when one member is clinically depressed, has an uncontrolled temper, or is experiencing post-traumatic stress disorder); if one member is maintaining a secret affair (and is conflicted about whether to end it and work on the marriage). Sometimes, couples therapy is contraindicated: When only one member can identify a desire to change or make a commitment to working on the relationship. When there is ongoing violence and the violent partner is unwilling or unable to negotiate a convincing no-violence contract. When there is history of lethality (such as substance abuse, restraining orders, weapons, threats to kill oneself or the other, obsession with the partner, or violence that has led to injury) (Bograd and Mederos, 1999). When there have been repeated failed attempts at couples therapy and a chronic relational problem (with a high degree of mistrust and a lack of any positive feelings between them). (Note: It is important to note that a recommendation against couples therapy is not the same as a recommendation that a couple separate or divorce).

Treatment Interventions Each of the interventions listed in this section belongs to a distinct theoretical orientation but these interventions represent only a sampling of those available. Couples therapists might want to offer a coherent treatment with interventions that derive from a discrete theoretical orientation, rather than using an array of techniques in a trial and error fashion. However, many couple’s therapists gravitate towards a more integrative model of practice (Fraenkel, 2009). Psychodynamically-informed interventions focus on making interpretations of unconscious processes that distort the ability of each member of the couple to perceive the other for who she or he really is. The distortions derive largely from unresolved family-of-origin issues. Therapeutic work focuses on the

interpretation of projective identification and of transference (with interpretations made between the members of the couple as well as between the couple and the therapist). Communication skills training (cognitive-behavioral model) focuses on active listening in which each partner practices, both inside of and outside of the session, how to listen with empathy and curiosity about the other. They take turns being the speaker and the listener, with the latter demonstrating understanding by paraphrasing what was said and asking for confirmation from the speaker. Another intervention involves developing a marital quid pro quo: Each individual makes a list of behaviors that are pleasing to him or her. Then, the therapist negotiates an increase in pleasing behaviors that is contingent on the other demonstrating comparable behavior. For example, one spouse might agree to make dinner in return for the other being physically affectionate. Another behaviorally informed intervention involves teaching the couple to fight constructively by following certain rules (e.g., sticking to one issue at a time, eliminating name-calling or sarcasm, asking for a specific change, asking for and giving feedback). Role-playing and other action-oriented techniques (experiential model) include the use of psychodramatic techniques that bring affect and a new experience into the therapy session. Each member of the couple may enact a present interaction that is repeatedly unsatisfactory or a situation from his or her family of origin that connects to a current marital dilemma. Each member of the couple can then enroll the other in a re-written enactment that corrects a past injustice. Or, if the husband directs his wife to role-play him, he can show her the way he would like to be responded to. Another related technique is rolereversal where the switching of customary roles can enhance empathy, increase the behavioral and affective repertoire of each member of the couple, and loosen polarized positions. Focusing on affect is at the core of the empirically-validated approach of emotionally-focused therapy (EFT), developed by Susan Johnson (2004, 2008). The couples’ current attachment to each other is explored by deepening their emotional responses. The therapist focuses on how their attachment injuries continue to be re-enacted to create negative repetitive interactions. Emotion in the present is highlighted with an emphasis on naming and experiencing unspoken feelings so that empathy can be enhanced. Paradoxical interventions (strategic model) are based on the premise that couples request and shun change simultaneously. To deal with this common dual

agenda, strategic therapists offer paradoxical interventions that mirror the couple’s conflicting requests to get out of their mess but without having to change. For example, with an intervention, known as the “therapeutic double bind,” the therapist might tell the symptomatic member not to change because the symptom is accomplishing an important function for the marriage. If the individual resists the intervention, then change occurs. If he complies, change still occurs, because the symptom will be viewed differently, as being under voluntary control. Narrative approaches (narrative model) include externalizing the problem where the therapist and couple collaborate on a name for the problem and attribute negative intentions to it. For example, a couple with chronic fighting might be asked to, “Describe the ways that you let your habit of bickering with one another ruin the rest of your relationship.” Another narrative technique involves exploring the unique outcome: There are times when the couple has resisted the problem’s pull or when the couple’s life was not dominated by the problem. The couple is asked to speculate about what made it possible at those times to resist the usual pattern. Another narrative device is for the therapist to use small shifts in language to construct a different view of the problem that is less constraining and more amenable to solutions.

Conclusion Regardless of their theoretical approach, couples’ therapists face several challenges unique to working with a dyad: the relationship between the couple is always more important than the one with the therapist, so transference is diluted; privacy, confidentiality, and secrets must be handled in a sensitive way so that the therapist does not end up in a collusion with one member of the couple; the therapist and the couple need to come to an agreement about what the focus of the work will be so that every session isn’t a negotiation between the couple about what to work on; most couples therapists will end up managing much more conflict in their offices than will individual therapists; and, finally, couples therapist will need to make room for three patients simultaneously—each member of the couple, and the couple’s relationship.

Suggested Readings 1. Ahrons C: Family ties after divorce: Long-term implications for children.

Family Process . 2007; 46: 53–65. 2. Bograd M, Mederos F: Battering and couples therapy: Universal screening and selection of treatment modality. J Marital and Family Therapy . 1999; 25(3): 291–312. 3. De Shayzer S: Words were Originally Magic . New York: Norton; 1994. 4. Fraenkel P: The therapeutic palette: A guide to choice points in integrative therapy. Clin Social Work J . 2009; 37 (3): 234–247. 5. Freedman J, Combs G: Narrative couple therapy. In: Gurman AS, Lebow JL, Snyder D, eds.: Clinical Handbook of Couple Therapy . 5th ed. New York: Guilford Press; 2002: pp. 308–334. 6. Gordon KC, Khaddouma A, Baucom D, Snyder D: Couples therapy and the treatment of affairs. In: Gurman AS, Lebow JL, Snyder D, eds.: Clinical Handbook of Couple Therapy . 5th ed. New York: Guilford Press; 2015. 7. Gottman JM, Levenson RW, Swanson K, et al: Observing gay, lesbian, and heterosexual couples’ relationships: mathematical modeling of conflict interaction. J Homosexuality . 2003; 45(1): 65–91. 8. Gottman JM, Levenson RW: The timing of divorce: predicting when a couple will divorce over a 14-year period. J Marriage and Family . 2000; 62(3): 737–745. 9. Gottman JM, Silver N: The Seven Principles for Making Marriage Work . Easton, PA: 2015. 10. Gottman JM: Why Marriages Succeed or Fail . New York: Simon and Schuster; 1994. 11. Green RJ, Mitchell V: Gay, lesbian, and bisexual issues in couples therapy. In: Gurman AS, Lebow JL, Snyder DS, eds.: Clinical Handbook of Couple Therapy . 5th ed. New York: Guilford Press; 2015. 12. Hetherington ME, Kelly J: For Better or for Worse: Divorce Reconsidered . New York: W.W. Norton; 2002. 13. Johnson SM: Emotionally focused couple therapy In: Gurman AS, Lebow JL, Snyder DS eds.: Clinical Handbook of Couple Therapy . 5th ed. New York: Guilford Press; 2015. 14. Johnson SM: The Practice of Emotionally Focused Couple Therapy: Creating Connection. 2nd ed. New York: Rutledge; 2004. 15. Karpel M: Evaluating Couples: A Handbook for Practitioners . New York:

Norton; 1994. 16. Kelly J: Children’s living arrangements following separation and divorce: Insights from empirical and clinical research. Family Process . 2007; 46: 35–52. 17. Kurdek LA: What do we know about gay and lesbian couples. Psychological Science . 2005:14(5) 251–254. 18. LoPiccolo L, LoPiccolo L, eds.: Handbook of Sex Therapy . New York: Plenum, 1978. 19. McGoldrick M, Garcia-Preto N, Carter B: The Expanded Family Life Cycle: Individual, Family and Social Perspectives . 5th ed. New York: Pearson; 2016. 20. McGoldrick M, Hardy L: Re-visioning Family Therapy: Race, Culture, and Gender in Clinical Practice . New York: Allyn and Bacon, 2008. 21. Wallerstein J, Blakeslee S: The Good Marriage: How and Why Love Lasts . Boston, MA: Houghton Mifflin; 1995. 22. Wallerstein JS, Lewis J, Blakeslee S: The Unexpected Legacy of Divorce: A 25-Year Landmark Study . New York: Hyperion; 2000. 23. Weingarten K: The discourses of intimacy: Adding a social constructionist and feminist view. Family Process . 1991; 30: 285–305. 24. White M, Epston D: Narrative Means to Therapeutic Ends . New York: Norton; 1990. 25. Williams L: Has the futu re of marriage arrived? A contemporary examination of gender, marriage, and psychological well-being. J Health and Social Behavior . 2003; 44(4): 470–487.

CHAPTER 65 Family Therapy ANNE K. FISHEL, PHD AND DAVID H. RUBIN, MD

KEY POINTS Overview Symptoms can have origins, meanings, purposes, relevance, and solutions within a family system. The field of family therapy can be divided into several distinct schools that have origins in both science and in the individuals that pioneered their theories and techniques. Schools of Family Therapy Psychodynamic: The goal is to increase self-awareness, making the unconscious, conscious. Experiential: The goal is the amplification of the expression of feeling which is valued over the acquisition of insight. Structural: The goal is to help a family adhere more closely to a “blueprint” of what a “normal” family should look like, allowing for a modest degree of cultural, ethnic, and economic variations. Strategic: The goal is to interrupt maladaptive behavioral sequences within a presupposed homeostatic family that guards the status quo even at the expense of a symptomatic family member. Systemic: The goal is to unlock the family’s power to change itself, which it will do by changing its beliefs or altering its understanding of the meaning of behaviors. Narrative: The goal is to use the transformative power of language to create change. Behavioral: The goal is to employ functional behavioral analysis to promote new adaptive behaviors while extinguishing their problematic predecessors. Psychoeducational: The goal is to remediate family deficits in acquirable skills and knowledge.

Introduction Symptoms can have origins, meanings, purposes, relevance, and solutions within a family system. All family therapies address symptoms in this context across a variety of diagnoses and levels of acuity. The field of family therapy can be divided into several distinct schools that have origins in both science and in the individuals that pioneered their theories and techniques. All of these schools share a number of additional guiding principles: the family is considered a resource as well as the important context in which individual symptoms develop, clinical attention must be focused on pattern recognition and family organization, and new communication is central to effective treatment. In the service of these guiding principles, schools distinguish themselves, in part, by how they characterize: the locus of power for change; the expected rate of progress; the prioritizing of affect, insight and/or behavior; the relative importance of the past, present, and future; and empiricism. The following will review the theoretical underpinnings, hallmark techniques of practice, and major historical proponents of the dominant schools of family therapy.

Psychodynamic Family Therapy The Theory: Derived from principles of object relations and Freudian theory, the goal for psychodynamic family therapy is to increase self-awareness, making the unconscious, conscious. Family problems are regarded as unresolved issues with the previous generation. Interpersonal functioning is distorted by attachments to past figures and by the generational transmission of secrets. The family therapist helps to free the family from excessive attachment to the previous generation by assisting family members to disclose secrets and concomitant feelings (e.g., of anger and grief). Insight creates change in each individual, in a serial fashion, as others look on. The Practice: Several tools characterize this treatment, including interpretation of transferential objects in the room, interpretation of projective identification, and genograms. Transferential interpretations are made among family members rather than between the patient and the therapist. For example, the therapist, observing disparaging comments made by a wife of her husband, might wonder if she was treated dismissively in her own family. Projective identification, the process “by which members split off disavowed or cherished aspects of themselves and project them onto others within the family group” (Zinner and Shapiro, 1972)

allows parents to reenact with their children the conflicts they had in their families of origin. These reenactments preserve these old relationships and help individuals achieve intrapsychic peace at the expense of interpersonal conflicts in the present. A man, for example, who is uncomfortable expressing emotion, might marry a very expressive woman. Over time, his internal difficulties with tolerating affect might be expressed as conflict with his wife for being, “too emotional.” Genograms, are typically employed to map at least three generations, revealing patterns (of similarity and difference) across generations and between the two sides of the family. Areas of focus would include parent–child and sibling roles, psychological symptoms, triadic patterns, developmental milestones, recurring stressors, and excommunication of family members (McGoldrick, Gerson, Prety, 2008). The genogram allows a search for any resonance between a current developmental issue and one in a previous generation. Intersection between past and present anxieties heightens the meaning and valence of a current problem (McGoldrick, Gerson, Prety, 2008). For example, a pregnant woman might be expected to be particularly anxious about her child’s birth if, in her family growing up, a younger sibling had died and in her husband’s family, his mother had experienced multiple miscarriages. The reverberations of these earlier experiences with tragic outcomes around the transition to parenthood might make it difficult for the couple to fantasize and plan for their baby’s birth. The Proponents: In an effort to bring the past into the present, James Framo (1976) invited parents and adult siblings to come to an adult child’s session. This “family of origin” work is usually brief and intensive, and is typically composed of two lengthy sessions on two consecutive days. The meetings might focus on unresolved issues from childhood or on the disclosure of secrets. The overall goal is to allow the adult child to become less reactive to his or her parents. Ivan Boszormenyi-Nagy (1973) introduced the “family ledger,” a multigenerational accounting system of obligations incurred and debts re-paid over time. Symptoms are understood in terms of an individual’s making sacrifices in his or her own life to repay an injustice from a previous generation. Murray Bowen (1978) stressed both the importance of the individual’s differentiation of self, as well as the individual’s ability to maintain a connection to the family. In order to promote increased independence, Bowen coached patients to return to their family of origin and to resist the pull of triangulated

relationships, by demanding that interactions with family members remain dyadic.

Experiential Family Therapy The Theory: The experiential therapist is primarily concerned with the here and now. Change occurs through growth experiences that arise in the session. These experiences are designed to disrupt familiar interactions among family members. The therapist tries to make something surprising and unexpected happen, amplifying the expression of feeling which is valued over the acquisition of insight. This model is atheoretical and is best understood in light of its practice. The Practice: The therapist is interested in small interactions that take place during the session. The therapist amplifies any communication that conveys warmth and closeness while interrupting antagonistic communication. Psychodramatic, or action-oriented techniques, create a new experience in the therapy session. A therapist might “sculpt” the family, physically posing them to demonstrate the way that the family is currently organized. After temporarily heightening feelings of frustration and alienation, the therapist might then relieve those tensions with a new sculpture that displays unity. These sculptures increase affect, create some focus away from the identified patient, and can organize or “position” the family in a more supportive way. The Proponents: Virginia Satir, an early luminary in family therapy (a field that was largely founded by men), believed that good communication depends on a feeling of self-confidence and value in each family member. She focused on the positive in a family and used non-verbal communication to improve family connections. She observed that most families underutilized all of their senses to communicate with one another, and believed that if families learned to see, to hear, and to touch more, they would have more resources available to solve problems. She is also credited with the invention of family sculpting. Carl Whitaker practiced “therapy of the absurd,” positing that most experience occurs outside of awareness: this method accesses the unconscious by the therapist’s use of humor, boredom, free association, and metaphors. He believed that symbolic, non-verbal growth experiences followed the disruption of rigid patterns of thought and behavior. Whitaker maintained that “the whole process of therapy is breaking the mask” (Haley and Hoffman, 1967, p. 320) by elevating anxiety in family members.

Structural Family Therapy The Theory: The structural family therapist downplays the importance of affect or insight in favor of focusing on the structural properties of the family. Structure is defined by: the rules of the family (e.g., “Can anger be expressed by the children, or only by the parents? Are girls as well as boys encouraged to compete and have ambitions?”); the boundaries within the family (e.g., “Do the children have a relationship as siblings or mainly as sons and daughters?”; “Do the parents close their bedroom door to allow for privacy?”); the boundaries between the family and the outside world (e.g., “Does the family try to keep people from visiting, or are there many outsiders who are offering advice?”); and the generational hierarchy (e.g., “Are the parents or the children in charge?”). Change occurs when the structure shifts and when symptoms are no longer necessary. This therapist works from a “blueprint” of what a “normal” family should look like, allowing for a modest degree of cultural, ethnic, and economic variations. In general, this blueprint calls for well defined parental, marital, and sibling subsystems; clear generational boundaries (with the parents firmly in charge); and flexible relationships with outsiders. Common, expected deviations from this blueprint might include: enmeshment (with little privacy and blurred boundaries between the generations so that children may be parentified); excessive overprotectiveness (so that any attempts by the children at autonomy are thwarted); rigidity in the face of change (so that stressors quickly overwhelm the family’s resources); and relative intolerance of individual differences (so that the family’s threshold is low for individuals who voice an unpopular position). The Practice: This therapist joins the family by supporting the existing rules of the family and by making individual relationships with each member. These relationships can be used to restructure the system, for example, by empowering the parents. The therapist, assessing the formal properties of the family, would earmark the alliance between the parents, the definition (or lack) of marital, parental, and sibling subsystems, and the appropriateness of boundaries within the family, and between the family and outsiders. As assessment turns into treatment, the therapist challenges deviations from the blueprint by imposing new rules. In the case of enmeshment, for example, each member will be required to speak only for herself or himself. The therapist might challenge an unclear generational hierarchy by insisting parents sit together, and that for parts of the session the children must leave the office.

The Proponents: Salvador Minuchin is regarded as the founding father of structural family therapy. He worked extensively while head of the Philadelphia Child Guidance Clinic with inner-city families and with families who faced delinquency and multiple somatic symptoms—populations that had not previously been treated with family therapy. He delineated how to assess the existing structure of a family and pioneered techniques (such as the imposition of rules of communication, manipulation of space, and use of enactments) to modify structure.

Strategic Family Therapy The Theory: Change occurs when maladaptive behavioral sequences are interrupted. Strategic family therapists view families as fundamentally homeostatic, protectors of the status quo even at the expense of a symptomatic family member. The therapist anticipates a power struggle with the family and develops strategies to destabilize the family’s power structure. The use of paradox is a hallmark to this approach, effectively meeting the family at the ambivalent place they present. The therapist presupposes a family stance: “help us get rid of the symptom, but don’t make us change.” The Practice: The therapist inquires about the behavioral sequences that occur around the presenting problem, suspecting that solutions that the family has devised have themselves become problems. For example, a parent might keep home from school a child who complains of a stomach ache, only to find that the comfort of having a parent’s undivided attention results in the child wanting to stay home the next day. This therapist, then, introduces change by use of a paradoxical strategy to disrupt the current behavioral sequence. A classic example of this strategy is to “prescribe the symptom.” For example, mandating that an anorexic-identified patient resist her parents’ efforts to get her to eat in order to prevent her premature compliance to parental authority. This creates a therapeutic double-bind, often mirroring the paradoxical communication in the family. The Proponents: Jay Haley, Paul Wazlawick, John Weakland, and Gregory Bateson, were the earliest proponents of strategic family therapy. They promoted the primary role of power in the therapeutic relationship, illuminating the fundamental paradoxical presentation of most families, “get us out of this mess but don’t make us change.” Milton Erikson’s (Erickson and Rossi, 1981) use of stories, riddles, and metaphors to indirectly inspire behavioral change heavily influenced this school.

Chloe Madanes (1981) posited that when children act out, their symptoms represent efforts to help the family. However, another consequence of children’s symptoms “helping” is that they also reverse the generational hierarchy, placing the child in a position that is superior to that of his or her parents. Madanes advocated using paradoxical techniques to reassert the parents’ authority. For example, she might invite the parent to ask the child to pretend to have the problem or pretend to help out. In both instances, these strategies put the parents back in charge while allowing the child a playful way to be helpful.

Systemic Family Therapy The Theory: Change occurs when beliefs are changed or the meaning of behavior is altered. Solutions, as well as the power to change, lie within the family. The therapist rejects any preconceptions as to what a family should look like at the end of successful treatment. The therapist denies knowledge of possessing the right truth to help a family. There is no one truth; rather, some ideas prove more useful than others. The systemic therapist believes that the family is constantly evolving. The therapist identifies redundant interactional sequences and introduces new information to the family without a plan for the family’s response. Progress takes place in leaps rather than in incremental steps. The systemic therapist introduces new information to effect systemic change, postulating that families only register information that comes from making comparisons. One technique of choice is the use of circular questions, which are aimed at surfacing differences around time, perception, ranking of a characteristic, and alliances within a family (e.g., “Who is most concerned about mother’s depression? Then who? Then who?”). This is in contrast to linear questions (e.g., “What made you depressed?”) that ask family members about cause and effect. Circular questions place problems within the web of family relationships, eliciting hidden comparisons and usable information. Systemic therapists employ two additional kinds of interventions, the reframe and the ritual. Re-framing offers novel positive or neutral interpretations of problematic behaviors that connect everyone in the family. Presenting problems are re-defined to encourage cooperation, to introduce the idea of volition when behaviors have been regarded as outside of anyone’s control, and to introduce confusion as a means to stimulate new thinking around tightly held beliefs. A ritual is introduced as an experiment (Imber-Black and Roberts, 1988). This therapist does not care if the ritual is carried out exactly. It is the ideas contained

in the ritual that contain the power to create change. For example, when families enact two inconsistent behaviors simultaneously, such as infantilization of, and demands of autonomy from, the same individual, a ritual can introduce time into this paradoxical system. The therapist would ask the family to adhere exclusively to one behavior or its opposite based purely on the day of the week. In this way, parents are given the opportunity to collaborate on a shared view of their son, first as a child, then as a young adult. The Practice: This therapist, working either with or without a team, generates a few hypotheses to be confirmed or discounted using circular questions (Penn, 1982). The therapist pays attention to both the verbal responses of each family member and to the non-verbal signs of interest in the questions to assess the validity of these hypotheses. If family members seem interested in one another’s responses and if their answers are thoughtful rather than automatic, the therapist would then craft an end-of-session intervention based on circular questions that seemed to most spark family interest and resulted in spontaneous rather than familiar responses. The Proponents: Systemic family therapy was developed by a quartet of psychoanalysts (Drs. Mara Selvini Palazolli, Luigi Boscolo, Gianfranco Cecchin, and Giulana Prata) who practiced from 1971 and 1980 in Milan, Italy; they invented a multi-part team approach and used a one-way mirror to observe interactions. In the first “presession,” the team generates initial hypotheses that are based on their experience and the referral information (e.g., “Who made the call?; “What was the emotional tone on the phone?”). Next, one clinician interviews the family while the remainder of the team watches from behind a one-way mirror. The interviewing therapist confirms or refutes the team’s hypotheses by use of circular questions. Finally, in the “intersession,” the team members create an intervention in the form of a re-frame or ritual that aims to connect everyone in the family. These messages are succinct, enigmatic, hypnotic, and intended to introduce enough new information that will catalyze change. The Milan school introduced the notions of circularity and neutrality. Circularity refers to thinking that emphasizes context, patterns, and recursiveness. Circular questions allow the therapist to be curious to uncover patterns of interaction in a family that are destructive to everyone, without blaming any one individual. The therapist conveys respect and acceptance by taking a non-evaluative stance of neutrality.

Narrative Family Therapy The Theory: The transformative power of new language to create change drives narrative family therapy. Families get “stuck” because they have become constrained by a problem-saturated story and by constricted ways of conversing. Dominant stories that limit the family’s possibilities are identified. Minor or undiscovered narratives that contain more hope for change are then amplified in response. Dominant stories include beliefs that may be held by the family (e.g., “You don’t talk about the family with outsiders”) or the culture (e.g., adolescents can only become adults through rebellion and rejection of their parents). These therapists separate problems from the people who experience them and then help families to rewrite the stories that they tell about their lives. The technique of externalizing the problem exemplifies the process of narrative therapy (White, 1988). The therapist and the family create a name for the problem and attribute negative intentions to it so that the family can band together against the problem, rather than against the individual who has the problem. The therapist also inquires about “unique outcomes,” or times when the patient was free of the problem. The family is asked to ponder how the strength was found during those times to resist the problem. These unusual moments of resistance are then amplified and added to by more stories that feature the patient as competent and problem-free (Combs and Freedman, 2004). Narrative therapists have also developed the concept known as the reflecting team (Friedman, 1996; Andersen, 1987). A group of clinicians observe an interview through a one-way mirror, and then speak directly to the family, offering ideas, observations, questions, and suggestions (Fishel et al, 2010). These comments are offered tentatively and spontaneously, encouraging the family to choose what is useful from among the team’s offerings and reject the rest. The reflecting team assumes that (Miller and Lax, 1988): the abundance of ideas generated by the team will loosen a constricted story held by the family; the relationship between the therapist and the patient should be non-hierarchical (sharing, rather than giving information); people are more willing to change under a positive connotation; and that ideas presented are not right or wrong, but more or less helpful to a family. The Practice: This therapist might begin by asking how would a family know when the therapy was over? Consider the De Shayzer (1994) miracle questions: “If there were a miracle that took place, what would be different? How would the family be different?” The therapist would also deconstruct the present

problem by externalizing it (e.g., “What tricks has depression used to keep you shut down?”; “When was a time that you were able to outsmart depression to accomplish something important to you?”). Another narrative tact is to ask about the influence of culture on the presenting problem (e.g., “Does your family subscribe to the common cultural notion that depression is an excuse for laziness, or weakness of character?”). The Proponents: Michael White, in Australia, and David Epston, in New Zealand (1990), are the best-known theorists of the narrative approach. In addition to their ideas of deconstructing the problem through externalizing and re-authoring, they have situated their work within a political and social context. Building upon the work of Foucault, their approach is a critique of the professional’s linkage of power and knowledge. They neither make diagnoses nor rely on medical records kept private from their patients. A letter to a patient at the end of the session can equally serve as the note for the medical record. The record can be given to the patient and/or, with permission, shared with other patients in similar circumstances. Tom Andersen and his colleagues at the Tromso University in Norway are credited with the invention of the reflecting team in 1985. Andersen (1996) found that therapists often followed a pessimistic view of the family, regardless of re-framing questions that were phoned in by a team behind a mirror. In response, he “launched the idea to the family and the therapist that we might talk while they listened to us.” With the team speaking directly to the family, presenting multiple ideas in an unrehearsed and tentative way, the concept of the reflecting team took root.

Behavioral Family Therapy The Theory: Behavioral family therapy (Zinner and Shapiro, 1972; Scholvar and Schwoeri, 2003; Lebow, 2005; Carr, 2000) derives from social learning theory. Empirical evidence justifies its interventions. Family systems comprise individuals’ best attempts to achieve personal and mutual rewards while avoiding negative consequences. Maladaptive behaviors’ persistence is dependent upon continued modelling or reinforcement. The therapist and the family collaborate to identify problematic behavioral patterns and the therapist employs varied, empirically supported behavioral techniques to promote new adaptive behaviors while extinguishing their problematic predecessors. The Practice: Behavioral family therapy relies upon a detailed, functional behavioral analysis. The therapist assesses the thoughts, feelings, and behaviors

of each individual family member as they relate to the presenting problem. The therapist then works with the family to detail representative sequences of distressing behaviors, considering factors that both precipitate and relieve the problem. Ultimately, a hypothesis is generated as to how each problematic behavior is reinforced, and what interventions might result in its extinction. The therapist then acts as a collaborative teacher, designing experiments that will test for behavioral changes. These can be conducted within the session and/or as homework. Results of these experiments are analyzed with the same rigor of the initial assessment. Objective benefit is the only assurance of an intervention’s efficacy. Techniques include contingency contracting (e.g., each parent must express reciprocal positive regard at least daily) and other operant reinforcement strategies (e.g., when an adolescent commits to completing a desired task by a certain time, parents refrain from reminding or nagging within that period). Behavioral family therapy techniques have established empiric support across a broad range of conditions (Birnmaher et al, 2000; Barrett et al, 2004; Cobham et al, 1998; Robin et al, 1999; Sanders et al, 2000; Bor et al, 2002; Waldron et al, 2001; Epstein et al, 1990; Gustafsson and Kjellman, 1986). When the stress of a crisis exceeds the family’s current ability to effectively problem-solve, the behavioral therapist may take on a more directive role to assist in crisis management. The Proponents: Robert Liberman (1970) and Lawrence Weathers (1975) have made major contributions to the field of behavioral family therapy, particularly in their application of contingency contracting. In the contingency contract, family members agree to undertake structured interactions designed at improving positive exchanges, countering the aversive exchanges typical of families in distress. Gerald Patterson (1982), and Marion Forgatch (Patterson and Forgatch, 1987) have explored the way family systems reinforce aggressive behavior in adolescents through intermittent punishment, empty threats, and parental irritability.

Psychoeducational Family Therapy The Theory: Psychoeducational family therapy (Scholvar and Schwoeri, 2003; Lebow, 2005; Carr, 2000) originated to assist families caring for a severely mentally ill and functionally-impaired family member. Family dysfunction is formulated as deficits in acquirable skills and knowledge. Families and patients are empowered to effect their own change through education and focused skills training. Deficiencies present in several key domains including communication,

problem-solving, coping, and understanding of the illness. The therapist is also vigilant in identifying relationships that appear over-involved or hypercritical, as these predict increased likelihood of relapse and exacerbations of the affected member’s illness. The therapist creates an environment that is more deliberate in its fostering of mastery and recovery. The Practice: Psychoeducational family therapy is performed with individual families and with family groups. Treatment typically takes place in discrete phases that are often manualized for various disorders and contexts. The first phase, engagement, seeks to establish an alliance with the family while evaluating their approach to crisis management. The therapist acquires detailed information regarding family communication styles and coping strategies while monitoring alliances and divisions. The therapist offers appropriate reassurance to set the stage for their participation in her treatment as effective agents of change. Following engagement, the family would be invited to an educational workshop along with a group of other families in a similar situation. Families would be provided with essential information to inform their understanding of the diagnosis, treatment, and prognosis of a given condition. Warning signs of future relapses would be emphasized so that family members could anticipate when to seek extra support and intervention. The next phase is marked by the process of re-entry into the community. The therapist would offer methods designed to achieve goals deemed appropriate during this period. These include the maintenance of good interpersonal boundaries despite heightened anxiety and protectiveness, medication and appointment compliance, and surveillance for signs of relapse. The final phase, rehabilitation, focuses on the family’s task of encouraging the slow, progressive increase of independence and responsibility in the identified patient. The Proponents: The origins of psychoeducational family therapy lie in the treatment of schizophrenia. Ian Falloon’s (1981) attention to levels of expressed emotion within families has informed both the behavioral and psychoeducational schools of family therapy. Carol Anderson (1980) developed a psychoeducational model for schizophrenia, which she later adapted to affective disorders. William McFarlane (1991) is responsible for the psychoeducational model illustrated in the above example that emphasizes different phases of treatment. This model was similarly designed for families coping with schizophrenia (Dyck et al, 2000; Lucksted et al, 2012). Several families who have someone with schizophrenia would meet for psychoeducation in this

model. Psychoeducational methods continue to find increasing empiric support for additional conditions outside of the formal thought disorders (Long et al, 1992), such as for depression (Luciano et al, 2012).

Conclusion The field of family therapy has tended to value the distinctiveness of its different models (Shadish et al, 1995). The earliest years of the field were not driven by research, but rather by innovative theory, creative technique, and the dynamic maverick clinicians who were the founding mothers and fathers of family therapy. These rogue theorists defied a prevailing notion that social beings, fundamentally organized around—and functioning in—kin groups, could be adequately assessed and treated in isolation. To date, there are no research studies comparing the efficacy of each of the major schools, though many studies have looked at process variables and outcome measures within the behavioral (Birnmaher et al, 2000; Barrett et al, 2004; Robin et al, 1999; Waldron et al, 2001; Epstein et al, 1990; Gustaffson and Kjellman, 1986) and psychoeducational models (McFarlane, 1991; Dyck et al, 2000). In an extensive meta-analysis of marital and family therapy, Shadish et al (1995), concluded that “no orientation is yet demonstrably superior to any other.” The most effective approaches tend to be multi-disciplinary or integrative. Many studies have been conducted that support the power of common factors to account for therapeutic change, regardless of the theoretical model. As with individual therapy, Sprenkle et al (1999, 2009) posited that the following factors likely accounted for most of the change that transpires during family therapy: patient factors (such as higher socioeconomic status, the shared cultural background between patient and therapist [Goldstein and Miklowitz, 1995], and the family’s ability to mobilize social supports); relationship factors (particularly the presence of warmth, humor, and positive regard in the therapeutic relationship) (Alexander et al, 1977); and, the family therapist’s ability to engender hope and a sense of agency in family members. Other common factors unique to explaining change in family and couples therapy have been identified (Sprenkle et al, 2009): framing problems in relational terms rather than using an individual diagnosis to locate the difficulty within one person; disrupting dysfunctional relational patterns (Davis and Piercy, 2007); expanding the direct treatment system to include key players involved in the presenting problem; and inviting feedback from clients about the therapy. More generally, when a clinician feels “stuck,” or overwhelmed by an individual

patient’s presentation, it may be prudent to consider that patient’s wider context and “bring in the family.”

Suggested Readings 1. Alexander JF, Barton C, Schiavo RS, et al: Systems-behavioral intervention with families of delinquents: Therapist characteristics, family behavior, and outcome. J Consulting and Clin Psychology . 1977; 44: 656–664. 2. Anderson CM, Hogarty GE, Reiss DJ: Family treatment of adult schizophrenic patients: a psychoeducational approach. Schizophrenia Bull. 1980; 6: 490–505. 3. Andersen T: Reflecting processes: Acts of informing and forming. In: The Reflecting Team in Action. ed. Friedman S. New York: Guilford; 1996, p 17. 4. Andersen T: The reflecting team: Dialogue and meta-dialogue in clinical work. Family Process. 1987; 26; 415–428. 5. Barrett PM, Healy-Farrell L, March JS: Cognitive behavioral family treatment of childhood obsessive-compulsive disorder: a controlled trial. J Am Acad Child and Adolescent Psychiatry. 2004; 43: 46–62. 6. Birmaher, B, Brent DA, Kolko D, et al: Clinical outcome after short-term psychotherapy for adolescents with major depressive disorder. Arch Gen Psychiatry. 2000; 57: 29–36. 7. Bor W, Sanders MR, Markie-Dadds C: The effects of the Triple P-Positive Parenting Program on pre-school children with co-occurring disruptive behavior and attentional/hyperactive difficulties. J Abn Child Psychology. 2002; 30(6): 571 –587. 8. Boszormenyi-Nagy I: Invisible Loyalties. New York: Harper & Row; 1973. 9. Bowen M: Family Therapy in Clinical Practice . New York: Jason Aronson, 1978. 10. Carr A: Family Therapy: Concepts, Process and Practice . Baffins Lane, England: John Wiley & Sons Ltd., 2000. 11. Cobham VE, Dadds MR, Spence SH: The role of parental anxiety in the treatment of childhood anxiety. J Consulting and Clin Psychology. 1998; 66: 893–905. 12. Combs G, Freedman J: A post-structuralist approach to narrative work, In:

13.

14. 15.

16.

17. 18.

19.

20. 21. 22.

23. 24. 25.

Angus L, McLeod J, eds. The Handbook of Narrative and Psychotherapy Practice, Theory, and Reseacrh . Thousand Oaks, CA: Sage, 2004. Davis SD, Piercy FP. What clients of couple therapy model developers and their former students say about change, part 1: Model-dependent common factors across three models. Journal of Marital and Family Therapy. 2007; 33:318–343. De Shazer S: Words were Originally Magic . New York: Norton; 1994. Dyck DG, Short RA, Hendryx MS, et al: Management of negative symptoms among patients with schizophrenia attending multiple-family groups. Psychiatric Services. 2000; 51(4): 513 –519. Epstein LH, McCurley J, Wing RR, et al: Five-year follow-up of familybased behavioral treatments for childhood obesity. J Consulting and Clin Psychology. 1990; 58(5): 661 –664. Erikson MH, Rossi EL: Experiencing Hypnosis: Therapeutic Approaches to Altered States. New York: Irvington; 1981. Falloon IR, Liberman RL: Behavioral therapy for families with child management problems, in Helping Families with Special Problems . ed. Textor MR. New York: Jason Aronson. 1981; pp. 121–147. Fishel A, Ablon S, Craver J: The couple’s reflecting team: How spoken and written reflections, gender and stage of therapy impact perceived helpfulness. Journal of Couples and Relationship Therapy. 2010; 9: 344– 359. Framo J: Family of origin as therapeutic resource for adults in marital and family therapy. Family Process. 1976; 15: 193–210. Friedman S, ed.: The Reflecting Team in Action. New York: Guilford; 1996. Goldstein MJ, Miklowitz DJ: The effectiveness of psychoeducational family therapy in the treatment of schizophrenic disorders. J Marital and Family Therapy. 1995; 21: 361–376. Gustafsson PA, Kjellman NI: Family therapy in the treatment of severe childhood asthma. J Psychosom Res. 1986; 30(3): 369–374. Haley J, Hoffman L, eds.: Techniques of Family Therapy. New York: Basic Books; 1967. Imber-Black E, Roberts J: Rituals in Families and Family Therapy. New York: Norton; 1988.

26. Lebow J: ed.: Handbook of Clinical Family Therapy. Hoboken, NJ: John Wilely & Sons; 2005. 27. Liberman RL: Behavioral approaches to family and couple therapy. Am J Orthopsychiatry. 1970; 40: 106–119. 28. Long P, Forehand R, Wierson M, et al: Does parent training with young non-compliant children have long-term effects? Behaviour Research and Therapy. 1994; 32:101–107. 29. Luciano M, Del Vecchio V, Giacco D, De Rosa C, Malangone C, Fiorillo A: A ‘family affair?’ The impact of family pyschoeducational interventions on depression. Expert Review of Neurotherapeutics. 2012; 12(1): 83–92. 30. Lucksted A, McFarlane W, Downing D, Dixon L, Adams C: Recent developments in family psychoeducation as an evidence-based practice. Journal of Marital and Family Therapy. 2012; 38(1): 1010–121. 31. Madanes C: Strategic Family Therapy. San Francisco: Jossey-Bass; 1981. 32. McFarlane W: Family psycho-educational treatment, In, Gurman AS, Kniskern DP, Eds. Handbook of Family Therapy. Vol. 2. New York: Bruner/Mazel, 1991. 33. McGoldrick M, Gerson R, Petry S: Genograms: Assessment and Interventions. 3rd ed. New York: Norton; 2008. 34. McGoldrick M, Preto NG, Carter B, eds. The Expanding Family Life Cycle: Individual, Family, and Social Perspectives. 5th ed . New York: Pearson Education, Inc; 2016 35. Miller D, Lax WD: Interrupting deadly struggles: a reflecting team model of working with couples. J Strategic and Systemic Therapies. 1988; 7(3): 16–22. 36. Patterson G, Forgatch M: Parents and Adolescents Living Together: The Basics . Vol.1. Eugene, OR: Castalia, 1987. 37. Patterson G: A Social Learning Approach to Family Intervention: Coercive Family Processes. Vol. 3. Eugene, OR: Castalia, 1982. 38. Penn P: Circular questioning. Family Process. 1982; 21(3): 267–280. 39. Robin AL, Siegel PT, Loepke T, et al: A controlled comparison of family versus individual therapy for adolescents with anorexia nervosa. J Am Acad Child and Adolescent Psychiatry. 1999; 38: 1482–1489. 40. Sanders MR, Markie-Dadds C, Tully LA, et al: The triple P-positive

41.

42.

43.

44.

45.

46. 47. 48. 49.

parenting program: a comparison of enhanced, standard, and self-directed behavioral family intervention for parents of children with early onset conduct problems. J Consulting and Clin Psychology . 2000; 68(4): 624 – 640. Scholvar GP, Schwoeri LD, eds: Textbook of Family and Couples Therapy: Clinical Applications. Washington, DC: American Psychiatric Publishing, Inc.; 2003 Shadish WR, Ragsdale K, Glaser RR, et al: The efficacy and effectiveness of marital and family therapy: A perspective from meta-analysis. J Marital and Family Therapy. 1995; 21: 345–360. Sprenkle D, Davis SD, Lebow JL: Common Factors in Couple and Family Therapy: The Overlooked Foundation for Effective Practice. New York: Guilford Press; 2009 Sprenkle DH, Blow A, Dickey M: Common factors and other nontechnique variables in marriage and family therapy. In: The heart and Soul of Change: What Works in Therapy . Eds. Hubble MA, Duncan BL, Miller SD, Washington, DC: American Psychological Association; 1999. Waldron HB, Slesnick N, Brody JL, et al: Treatment outcomes for adolescent substance abuse at 3- and 7-month assessments. J Consulting and Clin Psychology. 2001; 69: 802–813. Weathers L, Liberman RL: Contingency contracting with families of delinquent adolescents. Behavior Therapy. 1975; 6: 356–366. White M, Epston D: Narrative Means to Therapeutic Ends . New York, Norton; 1990. White M: The externalizing of the problem and the reauthoring of lives and relationships. Dulwich centre newsletter. Summer, 1988. Zinner J, Shapiro S: Projective identification as a mode of perception and behavior in families of adolescents. Int J Psychoanal. 1972; 53: 523–530.

CHAPTER 66 Group Psychotherapy KATHLEEN H. ULMAN, PHD AND ANNE ALONSO, PHD

KEY POINTS Overview A therapy group is a collection of patients selected and brought together by the leader for a shared therapeutic goal. Therapeutic aspects of groups: – Group therapy rests on the assumption that there are healing factors that emerge and operate in all groups. – Groups can have a positive influence on distorted perceptions of others, difficulties in communication, stereotyped behaviors, impulsive actions, inadequately discharged affect, and alienation. – Some of the healing factors that apply to all group models are universality, hope, identification, catharsis, imparting of information, contagion, amplification of affect. Goals of Groups To re-establish pre-morbid levels of functioning, to support targeted patient populations, to provide relief from certain symptoms, and to encourage and stimulate character change. Conduct of Therapy Groups The success of the group depends on the ability of the therapist to provide a safe context and meaning for the group. This involves designing a contract around the group goal, carefully selecting patients, and developing cohesion in the group. Cohesion is highly correlated with patient satisfaction and positive therapeutic effects. The Role of the Group Leader The leader must decide on the therapeutic underpinnings, membership, and logistics, including co-therapy, concurrent therapy for the patient, and confidentiality.

– The leader’s stance must be consistent with the goals of the group. – The investment of sufficient time in the preparation of patients for a group will improve the chances of a successful entry into the group. – The group leader should explore the patient’s fantasies and fears and past and current relationships, explain how the group works, and define the role of the therapist and the patients. Group Agreements Agreements include expectations about regular attendance, the duration of the group, the context of patients’ discussions, confidentiality, and financial responsibilities. Authority and Group Leadership The leader must exercise authority over each part of the agreement if the group is to be safe and containing. The leader is in charge of administrative functions, such as inclusion/exclusion and finances. The clearer the leader is about boundaries the safer it is for the group members to work in the group. The leader is not a group member. The leader must maintain a stance of neutrality, restraint, warmth, and acceptance. Patient Selection Psychodynamic groups should have a similar level of ego development. Specific symptom groups define the membership of the group. Support groups are used to re-establish pre-morbid levels of functioning. These are often used in psychiatric inpatient units and partial hospitalization programs. There are groups for specific populations (e.g., patients with cancer, diabetes, or acquired immunodeficiency syndrome). Groups exist for specific symptoms and conditions (e.g., anxiety, depression, eating disorders). Contraindications to Groups Patients who are schizoidal, paranoid, or actively manic.

Confidentiality While the leader is bound by confidentiality, group members not; however, the leader can ask for it. Training and Supervision Formal training is essential to lead all types of therapy groups. Supervision is important for newly-trained group therapists. Consultation important for all group therapists.

Overview People thrive in a community that values their participation and protects their dignity. The stresses that impinge on individuals are defined in part by their biology, in part by their family dynamics, and also by the culture in which they live. The integration of mind, body, and social context is vulnerable to assault from problems in any one of these dimensions. Group psychotherapy offers the opportunity for purposefully created, closely observed, and skillfully-guided interpersonal interaction. Such interactions can positively influence the countless varieties of human distress and malfunction. Distorted perceptions of others, insufficient communications, inadequately-discharged affects, stereotyped behaviors, impulsive actions, and alienation can all be addressed and modified within a therapeutic group.

Therapy Groups: Definition A therapy group is a collection of patients selected and brought together by the leader for a shared therapeutic goal.

Common Therapeutic Assumptions Group therapy rests on some common assumptions across the whole panoply of therapeutic groups. A universal and primary need for attachment: The need for attachment is seen as primary by a whole host of group theorists; the press for belonging is that which yields a sense of cohesion that can help the individual stay with the anxious new moments in a group of strangers.

Contagion: For better and for worse, people who want to belong to a cohesive community are apt to mimic and identify with the feelings and beliefs of other members of that community. At its best, this process allows for new interpersonal learning; at its worst, it raises the specter of dangerous mobs. Amplification: An increasing exposure to feelings, needs, and drives increases the individual’s awareness of his or her own passions and allows for a more direct and conscious management of those impulses. Intimate exchanges: Of necessity, the members of a cohesive group experience their own approaches to intimacy with others and with the self, and receive immediate feedback on the impact they have on important others in their surround.

Intimate Exchanges: Healing Effects Close interactions between the members of a group yield beneficial effects by generating interpersonal situations that reduce isolation, diminish shame, evoke early familial interactions and feelings, expand the individual’s emotional and behavioral repertoire, provide support and empathic confrontation, and help people grieve.

Therapeutic Aspects of Groups Whatever the model, group therapy rests on the assumptions that there are healing factors that emerge and operate in all groups, and that some of these can be brought into play to allow the individual within the group to grow and develop beyond the constrictions in life that brought that person into treatment. Whereas some group theorists rely on a cluster of factors relevant to their models of the mind and of pathology, all utilize some of the whole group of therapeutic factors identified in Tables 66-1 and 66-2. Table 66-1: Comparison of Different Types of Group Psychotherapy Day Hospital/ Inpatient Supportive Psychodynamic Parameters Group Group Therapy Group

CognitiveBehavioral Group

Frequency

3–5 times/week

Once/week

1–3 times/week

Once/week

Duration

1 week to 6 months

Up to 6 months or more

1–3+ years

Up to 6 months

Indications

Acute or chronic Shared universal major mental illness dilemmas

Neurotic disorders and borderline states

Phobias, compulsive problems, etc.

Pre-group screening

Sometimes

Always

Usually

Usually

screening Content focus

Extent and impact of illness; plan for return to baseline

Transference

Therapist activity

Symptoms, loss, life management

Present and past life situations; intra-group and extra-group relationships

Cognitive distortions, specific symptoms

Positive institutional Positive transference encouraged encouraged to promote improved functioning

Positive and negative to leader and members, evoked and analyzed

Positive relationship to leader fostered; no examination of transference

Empathy and reality Strengthen existing testing defenses by actively giving advice and support

Challenge defenses, reduce Create new options, active shame, interpret and directive unconscious conflict

Interaction Encouraged outside of group

Encouraged

Discouraged

Variable

Goals

Better adaptation to environment

Re-construction of personality dynamics

Relief of specific psychiatric symptoms

Re-constitute defenses

Table 66-2: Some Therapeutic Factors in Group Psychotherapy Factor

Definition

Acceptance

The feeling of being accepted by other members of the group; differences of opinion are tolerated, and there is an absence of censure.

Altruism

The act of one member’s being of help to another; putting another person’s need before one’s own and learning that there is value in giving to others. The term was originated by August Comte (1798–1957), and Freud believed it was a major factor in establishing group cohesion and community feeling.

Cohesion

The sense that the group is working together toward a common goal; also referred to as a sense of “weness;” believed to be the most important factor related to positive therapeutic effects.

Contagion

The process in which the expression of emotion by one member stimulates the awareness of a similar emotion in another member.

Corrective familial Experience

The group re-creates the family of origin for some members who can work through original conflicts psychologically through group interaction (e.g., sibling rivalry, anger toward parents).

Empathy

A capacity of a group member to put himself or herself into the psychological frame of reference of another group member and thereby understand his or her thinking, feeling, or behavior.

Imitation

The conclusion emulation or modeling of one’s behavior after that of another (also called role modeling); also known as spectator therapy, as one patient learns from another.

Insight

Conscious awareness and understanding of one’s own psychodynamics and symptoms of maladaptive behavior. Most therapists distinguish two types: (1) intellectual insight—knowledge and awareness without any changes in maladaptive behavior; (2) emotional insight—awareness and understanding leading to positive changes in personality and behavior.

Inspiration

The process of imparting a sense of optimism to group members; the ability to recognize that one has the capacity to overcome problems; also known as instillation of hope.

Interpretation The process during which the group leader formulates the meaning or significance of a patient’s resistance, defenses, and symbols; the result is that the patient develops a cognitive framework within which to understand his or her behavior. Learning

Patients acquire knowledge about new areas, such as social skills and sexual behavior; they receive advice, obtain guidance, attempt to influence, and are influenced by other group members.

Reality testing

Ability of the person to evaluate objectively the world outside the self; includes the capacity to perceive oneself and other group members accurately.

Ventilation

The expression of suppressed feelings, ideas, or events to other group members; the sharing of personal secrets that ameliorate a sense of sin or guilt (also referred to as self-disclosure)

Creation and Goals of Groups Planning and Organizing a Group Before approaching the concrete work of planning and organizing a psychotherapy group, the goals of the group must be clearly understood and developed by the leader. These goals in turn will be dependent on the setting, the population, the time available for treatment, and the training and capacity of the leader(s).

Goals of Groups Therapists form groups for a wide range of therapeutic purposes. Several are worth noting.

Re-Establish Pre-Morbid Levels of Functioning People in acute distress often find support in groups that have as their main goal a re-establishment of a person’s equilibrium. Patients who have suffered a breakdown of their lives and who have needed hospitalization can utilize groups within an inpatient or partial hospital setting. These groups have as their primary focus the re-structuring of a patient’s sensorium, the management of acute distress, and planning for a return to the community. These patients also need help in dealing with the shameful consequences of hospitalization, and with the sometimes-elusive process of establishing outpatient treatment that will support them upon discharge. A benevolent inpatient or partial hospital group experience will be of special value with the latter problem because affordable treatment will be primarily offered in group therapy for the foreseeable future. Many patients who have been hospitalized after an acute illness, or who attend partial hospital programs need to re-gain equilibrium, deal with the shame inherent in losing the ability to live independently, and prepare to reenter the world outside of a therapeutic environment.

Support-Targeted Patient Populations Since the time that Dr. Pratt offered his “classes” for tubercular patients at the Massachusetts General Hospital in 1905, people have come together to commiserate with one another around common problems, to share information, and to learn how to deal with the impact of those problems on their lives. Groups have been organized around medical illnesses (e.g., cancer, diabetes, acquired immunodeficiency syndrome [AIDS]); around psychological problems (e.g., bereavement); and around psychosocial sequelae of trauma (e.g., war or natural disasters). The goals of such groups are to provide support and information embedded in a socially-accepting environment with people who are in a position to understand what one another are going through. The treatment can emerge from cognitive-behavioral principles, psychodynamic principles, or psychoeducational ones. Frequently, these groups tend to be time limited; members often join at the same time and terminate together. The problems addressed in these groups are found in a broad variety of patients, from the very healthy to the more distressed, and cut across other demographic variables, such as age and culture. Increasingly, research data has shown that involvement in these groups can have positive effects on medical illness, post-traumatic stress disorder (PTSD), and bereavement.

Provide Relief for Certain Symptoms Group treatment can target specific symptoms. This approach to psychopathology is congruent with categorical nosological systems such as presented in the Diagnostic and Statistical Manual of Mental Disorders . Diagnosis here is seen as symptomatic rather than developmental; treatment goals include alleviation of symptoms. For example, patients with eating disorders or specific phobias are clustered in groups that can then promote skills for self-monitoring and for replacing an automatic symptom with a more adaptive set of behaviors and cognitions. These groups can include members with a broad range of intrapsychic development, which is not the primary focus of the group. At the same time, some people who work successfully in these groups might want to continue the work of personality change in open-ended dynamic groups when their symptoms are relieved.

Encourage and Stimulate Character Change Character difficulties are tenacious for all human beings, from the healthiest neurotic to the most regressed patient. For all individuals, character problems are

outside of the patient’s awareness, syntonic and perceived as “who I am” when brought into awareness, and resistant to change even when the patient wants to make such a change (repeated compulsively until worked through). The neurotic patient will find intrapsychic conflicts emerging in the interpersonal field of a psychodynamic or interpersonal group, and make use of the group’s curative factors to overcome the resistances to newer intimacies. Some of the earlier literature on group treatment expressed doubts about the appropriateness of this “uncovering” kind of group for sicker patients. More recently, group theorists have argued that the distributed transferences in a group mitigate an overly-threatening regression for such patients. Character problems are difficult to re-organize in brief treatment. Instead, the process requires frequent regressions in the service of the ego, and attempts to work through the same characterological habits again and again. However, brief analytic and cognitive-behavioral group models have addressed aspects of personality difficulties with good effect.

Conduct of Therapy Groups The success of a group depends on the ability of the therapist to provide a safe context and meaning for the therapy group. This is done by designing a contract around the group goal(s), by creating a feeling of group cohesion and by carefully selecting members that are suitable for that group. For example in a symptom-specific group, members should have similar symptoms and concerns; in a more psychodynamic group, members should be selected from a fairly homogeneous level of ego development although their symptoms and character styles may differ along a spectrum.

Roles of the Group Leader Before the group begins, the leader must make several decisions that will have major implications for the entire enterprise. Beyond the obvious focus on the type, duration, and theoretical underpinnings, the leader must then decide on matters of membership; logistics (such as place, time, and fees); whether to work alone, or with a co-therapist; whether patients will be treated in group therapy alone or in some combination of group therapy, individual therapy, pharmacotherapy, or self-help group; and, managing records, and protecting confidentiality. In addition to the aforementioned logistical decisions, the leader’s stance needs to be consistent with the goals of the group. A leader of a psychodynamic openended group will probably be more likely to sit back and allow the group’s

associations to lead the way for the group’s work while he or she comments, like a critic at a concert. On the other hand, such a stance makes little sense for the leader of a cognitive-behavioral group, who is engaged in conducting desensitization exercises, and in providing cognitive re-structuring, including homework exercises to meet the goals of that therapeutic endeavor.

Preparing for a Group Both anecdotal and empirical evidence shows that investment of significant amounts of time in preparation of a patient for group therapy will improve the chances of a successful entry into a group. In addition to the usual historytaking, it is very helpful to examine the patient’s fantasies and biases about groups and to collect the history of their participation in all kinds of groups (e.g., family, school, sports, work, friendships). This is the time to discuss the group’s agreements and the rationale that underlies them, and to elicit the patient’s collaboration in the enterprise by making as much information available as possible. Patients are helped by knowing how the group works, by knowing what the leader’s role might be, and by knowing what they might expect for themselves. A typical agreement includes expectations about regular attendance, the duration of the group, the content of the patient’s discussions, and the commitment to confidentiality and to financial obligations. Beyond those, each specific group will have more particular expectations; for example, a cognitivebehavioral group might expect “home work” from the members, and a more psychodynamic group might encourage dream analysis.

Dealing with Authority and Group Leadership A group leader must exercise authority over each of the above factors if the group is to be safe and containing for its members. Whether a member who is difficult in the group stays or leaves or whether a new member enters must not be left to a vote, just as such decisions are not made within a family. The privilege and burden of administrative and inclusion/exclusion matters is a serious responsibility of the group leader, as is the question of single or coleadership. It is important to remember that the leader is not a member of the group, despite the ambivalent entreaties of the members to bring the leader into the group. The clearer the leader is about the boundaries, the safer are the members to indulge their fantasies of wanting to corrupt the process, or overcome the leader’s authority. The fiduciary responsibilities of the leader are better maintained to the extent

that the leader exercises restraint and relative neutrality in the sense of nonjudgmental listening and responding to the patient’s struggles. By remaining warm and neutral, the leader is in a position to listen non-judgmentally to all aspects of the entire group’s impulses and resistance, without taking sides or carrying the burden of somehow policing the group and deciding which are good feelings and interactions and which are not.

Dealing with the Incorruptibility of the Leader In a therapy group, as in any therapeutic work, the leader must remain as pure as Caesar’s wife; dual roles are unacceptable and no overly familiar incursions into the members’ personal lives (or those of the leader) are tolerated. No special fee arrangements that are not in the awareness of the group can be tolerated without damaging the integrity of the group boundaries. In short, all group business that cannot be conducted in the group ought not to be conducted at all. This refusal to hold secret any extra-group contacts sets a model that says the group is a safe therapeutic agent.

Dealing with the Question of Co-Leadership As in many clinical decisions, the question of leading alone or with a colleague depends in part on the model, in part on the context and setting, in part on the availability of an appropriate co-therapist, and the system’s support (administrative and otherwise), for committing two professionals to the same task at the same time. Inpatient or partial hospitalization groups tend to meet several times a week, and for those groups, co-therapy is a useful way to ensure continuity of leadership. On the other hand, some analytic group leaders avoid co-therapy due to the splitting of the patient-to-leader transferences. There are no rigid rules, but certain caveats must be observed. Co-leaders work best when they are truly co-therapists, of relatively equal status and experience. For cases in which a student and a supervisor work together, it is useful to acknowledge this reality); they share a common theoretical framework; they are willing to dedicate an hour or so per week to working out their collaborative problems and their perceptions of the group; and, they are comfortable in sharing the fee. Failure to observe these agreements can leave the patients low on the priority list of therapeutic concern while the co-therapists compete or otherwise undercut each other. On the more positive side, when co-therapy works well, both

clinicians and patients have the advantage of two professional heads and hearts working in concert for the benefit of all.

Patient Selection for Group Therapy Indications for Group Treatment In a psychodynamic group where early developmental conflicts and relationships are assumed to interfere with the here-and-now of the patient’s life, it will be important to organize a group that is reasonably homogeneous for the level of ego development and heterogeneous in every other regard. Mixing people of differing genders, cultures, and/or ages can be extremely useful so long as these patients emerge from a similar developmental spectrum. The differences among them can then be addressed and exploited to the advantage of the members in the group. However, when patients differ greatly in levels of ego development, group cohesion and universality will be compromised. For example, a group of patients who experience severe anxiety around loss consequent to serious abandonment throughout their lives will do well to work together in a group. On the other hand, to mix two or three such patients in a group of people who are conflicted around intimacy and sustained relationships can well result in two subgroups, neither of which has an easy empathic rapport with the other’s internal dilemmas. The specific symptom or population designation of other groups points the way, by definition, to patient selection.

Contraindications to Group Therapy Some patients are unable to make good use of group therapy without additional clinical interventions. For example, the actively manic patient might be more overstimulated than helped in a group. Another category of patients frequently referred to groups includes severely schizoidal people who have never developed sustained human relationships. To place these patients in a group overrides their capacity and sets them up for early failure. In general, severely paranoid patients do not do well in group therapy. Acutely disturbed patients might need and deserve individual attention prior to entry into an ongoing therapy group. In all of these cases, prior treatment, either psychopharmacological and/or individual supportive therapy can increase the likelihood of the patient succeeding in the therapy group.

Combination Therapies

Group Therapy Combined with Individual Therapy Occasionally , patients are treated in both individual and group therapy, either by the same therapist or by different ones. This option is useful for a variety of patients. The over-intellectualized patient: For some patients, insight becomes a way to avoid feeling. When it does, it is very useful to place these patients in a therapy group where they can see how they interact with others who will offer feedback and affective resonance. The patient who cannot tolerate the dyadic transference of individual treatment: Dyadic treatment can threaten the fragile ego boundaries of patients who are either very needy, or who are over-stimulated by the apparent promises of the individual work. These patients often flee treatment or regress to terrifying actions that can be life-threatening in what approaches psychotic levels of transference. Adding group therapy can distribute the transferences across all the members of the group and the group leader and might enable the individual and the group treatment to proceed more safely and more productively.

Collaboration Between Therapists It is crucial that the two therapists collaborate by frequent phone calls and by avoiding the patient’s likely attempts to split them. For the case in which the two therapists disagree or do not respect the other’s work, the patients are at risk of harm, or at least in a stalemate that is iatrogenic in origin.

Combined Treatment with the Same Therapist Patients will sometimes be seen both in individual and group therapy with the same therapist. There are many advantages and, as always, some costs to this treatment plan. It is illuminating to deal with the intrapsychic dimensions of the patient in the individual hour, and then observe the same patient express those internal dilemmas and live them out in the interactions with members of the group. For example, a mild and extremely gentle individual patient might startle his or her therapist by launching a very aggressive attack on one or more members of the group when the shy facade is challenged. For some patients, however, sharing the therapist’s attention can be so distressing that the work of therapy is stalled. It might be far better for that

patient to be referred to another leader’s group, or to defer group treatment to a more secure time.

Boundaries in Combined Treatment Clinicians struggle with how much to preserve the privacy of what they know about the patient from the dyadic hour when the patient enters the group, and how much to disclose. Although there are no hard-and-fast rules, consistency matters, as does the prior agreement with the patient about these issues. Many clinicians opt to protect the information while urging the patient to bring the problems into the group. One major exception is the case in which the group or one of its members is at risk; as usual, the rules of confidentiality are suspended when there is any threat to safety of any of the participants. It is very useful to agree that all treaters will be in regular contact with one another in order to work for the patient’s advantage.

Group Therapy: Primary or Adjunctive Treatment As in most treatments that adhere to the biopsychosocial model, psychosocial treatment has an impact on the biology of the patient as well as on the psychology and the social adjustment of that person. In cases of more severe distress, a combination of group treatment, psychopharmacological treatment, and occasionally, individual treatment, can be ideal. However, given the cost constraints that de-limit most mental health care, group therapy remains a very impressive primary treatment for a whole host of patient situations and needs.

Legal and Ethical Considerations in Group Therapy The Leader and Confidentiality The group leader is bound by the usual rules of confidentiality in the group as in any other clinical encounter with the patient. With the exception of a threat to a person or persons, this confidentiality holds and is usually elaborated in the Code of Ethics of the therapist’s professional organization. The same pertains to conduct of the therapist that violates the code of ethics relative to sexual or other extra-professional contact with a patient.

Group Members and Confidentiality The bigger challenge is confidentiality among members. Aside from stressing the importance of protecting the identities of patients in the group, there is little that the leader can do to ensure compliance, nor is it against the law for members

to break confidentiality. Group therapists worry about whether the group can become a pool of witnesses in the case of a subpoena. Some states extend the same protection to the members that they do to the leader, namely the patient– therapist privilege, but this has not been tested and might not apply with all professionals across the disciplines.

Research Outcome and Evaluation Research on group therapy has focused mostly on outcomes. More recently, measures have been developed that seek to relate the patient’s sense of belonging and feeling valued in the group with the effectiveness of the treatment. Studies continue to support the importance of group cohesion on group effectiveness; feeling valued is seen as a statement of cohesion. Research also indicates greater confidence in the efficacy of group treatment and shows no appreciable differences between individual or group therapy and pharmacotherapy. However, these studies remain problematic, given the problems that bedevil most social science research: it is difficult to control for therapist differences, and attempts to do so by providing manuals for intervention become different models than what happens in real life. Non-specific factors are elusive, but seem to indicate that patients progress when they feel cared about, when the leader is warm and somewhat structured, when the match with colleagues in the group is appropriate, and when the goal and direction of the group is clear and consistent. Researchers have moved beyond the question of whether groups work, to a closer look at how they work, in what circumstances, and for whom. Proper screening and preparation leads to a greater chance of staying in the group. Members who are at about the same level of ego-development do better in openended groups than they do in groups with a large disparity of ego levels of development. Short-term, focused groups are more successful if leaders are structured as to agenda and time boundaries, and if the patients are more homogenous with regard to the problem being addressed. Research instruments are useful for the measurement of patient satisfaction and for self-reports of increased well-being. The Clinical Outcome Results BatteryRevised developed by the American Group Psychotherapy Association is but one example; it utilizes such measures as the Outcome Questionnaire 45 (OQ45), Inventory of Personal Problems (IIP-32), Group Evaluation Scale (GES), Group Climate Questionnaire, TFI-Cohesion Scale, and Empathy Scale. A major shortcoming in group therapy research stems from the pragmatics of conducting research over a long time, and with more amorphous goals. Thus,

most of the data emerges from research on time-limited groups, usually within the cognitive-behavioral or interpersonal model. Although those findings are very important to secure, they have limited applicability for the more openended dynamic models of group treatment. That research remains to be enlarged upon.

Consultation and Supervision for Group Therapy It is often difficult for group leaders to ask for help because it is difficult for most professional helpers after they have gone beyond their formal training years. But failure to find help in group leadership can increase the strain on the leader exponentially given the number of people in the consultation room, and the multiplicity of countertransference vectors. A well-running group can look deceptively autonomous of the leader’s impact, but the truth is that the leader’s calmness and full attention is the platform on which the group grows. Occasional consultations and/or ongoing peer supervision is a safe, judicious practice. It is also a way for the leader to take advantage of his or her affiliative needs and to avoid using the patient group for dealing with the loneliness of the wellfunctioning group leader. In addition to departmental faculty with group therapy expertise, there are professional organizations that offer ongoing training and supervision for group leaders at all levels of seniority.

Suggested References 1. Alonso A, Swiller HI, eds.: Group Therapy in Clinical Practice . Washington, DC: American Psychiatric Press, Inc.; 1993. 2. Bion WR: Experiences in Groups, and other papers . London: Tavistock; 1961. 3. Bloch S, Crouch E: Therapeutic Factors in Group Psychotherapy . New York: Oxford University Press; 1985. 4. Brabender V, Fallon A: Models of Inpatient Group Psychotherapy . Washington, DC: American Psychiatric Press, Inc.; 1993. 5. Buchele BJ, Spitz HI, eds.: Group Interventions for Treatment of Psychological Trauma. New York: American Group Psychotherapy Association; 2004. 6. Burlingame GM, Strauss B, Joyce AS: Change mechanisms and

effectiveness of small group treatments. In: Lambert MJ, ed.: Handbook of Psychotherapy and Behavior Change . 6th ed. Hoboken, NJ: Wiley; 2013. 7. Burlingame GM: CORE Battery-Revised: An Assessment Tool Kit for Promoting Optimal Group Selection, Process and Outcome. New York: American Group Psychotherapy Association, Inc.; 2006. 8. Dolbeault S, Cayrou S, Bredart A, et al: The effectiveness of a psychoeducational group after early-stage breast cancer treatment: results of a randomized French study. Psycho-Oncology . 2009; 18 (6): 647–656. 9. Durkin HE: The Group in Depth. New York: International Universities Press; 1964. 10. Ezriel H: Psychoanalytic group therapy. In: Wolberg LR, Schwartz EK, eds.: Group Therapy: 1973, An Overview. New York: Intercontinental Medical Book Corp.; 1973: pp. 183–210. 11. Foulkes SH: Group processes and the individual in a therapeutic group. Br J Med Psychology. 1961; 34: 23–31. 12. Freud S: Group psychology and the analysis of the ego. In: Standard Edition of the Complete Psychological Works of Sigmund Freud. London: Hogarth: Institute of Psycho-Analysis; 1962. 13. Gans JS: Broaching and exploring the question of combined group and individual therapy. Int J Group Psychotherapy. 1990; 40: 123–137. 14. Glatzer HT: The working alliance in analytic group psychotherapy. Int J Group Psychotherapy. 1978; 28: 147–161. 15. Kaplan HI, Sadock BJ, eds.: Comprehensive Group Psychotherapy. 3rd ed. Baltimore, MD: Williams & Wilkins; 1993. 16. Kelly JA, Murphy DA, Bahr GR, et al: Outcome of cognitive-behavioral and support group brief therapies for depressed, HIV-infected persons. Am J Psychiatry. 1993; 150: 1679–1686. 17. Klein RH, Bernard HS, Singer DL, eds.: Handbook of Contemporary Group Psychotherapy: Contributions from Object Relations, SelfPsychology, and Social Systems Theories . Madison, CT: International Universities Press; 1992. 18. Klein RH, Schermer VL, eds.: Group Psychotherapy for Psychological Trauma. The Guilford Press, New York, 2000. 19. Kleinberg JL: Wiley-Blackwell Handbook of Group Psychotherapy.

Chichester, West-Sussex, UK: John Wiley and Son, Ltd; 2012. 20. Leszcz M: The interpersonal approach to group psychotherapy. Int J Group Psychotherapy. 1992; 42: 37–62. 21. MacKenzie KR, ed.: Classics in Group Psychotherapy . New York: Guilford Press; 1992. 22. MacKenzie KR: Time-Managed Group Psychotherapy: Effective Clinical Applications. Washington, DC: American Psychiatric Press, Inc.; 1997. 23. Malan DH, Balfour FHG, Hood VG, et al: Group psychotherapy: A longterm follow-up study. Arch Gen Psychiatry. 1976; 33: 1303–1315. 24. Pam A, Kemker S: The captive group: Guidelines for group therapists in the inpatient setting. Int J Group Psychotherapy. 1993; 43: 419–438. 25. Riester AE, Kraft IA, eds.: Child Group Psychotherapy : Future Tense. Madison, CT: International Universities Press; 1986. 26. Rutan JS, Stone WS, Shay JJ: Psychodynamic Group Psychotherapy . 4th ed. New York: Guilford Press; 2007. 27. Scheidlinger S: On the concept of the “mother-group.” Int J Group Psychotherapy. 1974; 24: 417–428. 28. Van Ingen DJ, Novicki DJ: An effectiveness study of group therapy for anxiety disorders. Int J Group Psychotherapy . 2009; 59 (2): 243–251. 29. Yalom ID, Leszcz M: The Theory and Practice of Group Psychotherapy. 5th ed . New York: Basic Books; 2005.

CHAPTER 67

Cognitive-Behavioral Therapy JOHN D. MATTHEWS, MD

KEY POINTS Overview Cognitive-behavioral therapy (CBT) addresses the interactions among thoughts, feelings, sensations, and behaviors. According to CBT, our distressing emotions, sensations, and maladaptive behaviors are a product of the meanings we attribute to our experiences. Core beliefs include lovability/acceptance, competency/worth, and control/helplessness. How we interpret the present is determined by the balance between adaptive and maladaptive core beliefs. Automatic thoughts become dysfunctional in the context of our maladaptive core beliefs that become activated in conscious awareness. Early in treatment, the goal of CBT is to identify cognitive distortions in the present and to modify them using cognitive and behavioral techniques. Enduring change of distressing emotions, sensations, and/or maladaptive behaviors involves focusing on modifying the underlying core beliefs that give rise to the dysfunctional automatic thoughts; this process is referred to as “belief work.” Belief work involves framing the underlying maladaptive core belief in less severe terms. Theoretical Basis Cognitive therapy is based on cognitive science, which is an information processing model. How we scan our environment and choose stimuli to attribute meanings is variable and determined by past experiences. According to cognitive science, our thoughts are subject to change with information.

Clinical Applications Randomized clinical trials have demonstrated that CBT is effective in mood and anxiety disorders, psychotic disorders, personality disorders, eating disorders, attention deficit hyperactivity disorder, sleep disorders, chronic pain, and substance use disorders.

Theoretical Basis Cognitive-behavioral therapy (CBT) is derived from the science of cognitive psychology, which is an information processing model. “Cognitive pertains to how individuals perceive, interpret, and explain their experience. The process by which individuals select stimuli to interpret, assign meanings to those stimuli, and respond affectively and behaviorally to them is variable and strongly influenced by prior learning and mental set.” (Beck and Weishaar, 1990) According to Beck et al (1979), psychological functioning and adaptation to environmental changes consist of meaning–making structures of cognition defined as “schemas.” In the process of meaning assignment to new internal and external information, schemas direct or control the psychological systems of attention and memory resulting in either a positive or negative impact on emotions, physiology, and behavior. Schemas evolve to serve survival and attachment. Schemas are determined by past experiences; thus, they influence present objectivity. Therefore, beliefs do not equal fact, but are subject to change with new information. Schemas are associated with specific content (beliefs/attitudes) and patterns of information processing. For example, depressive schemas process information in terms of loss/failure; whereas anxiety schemas process information in terms of overestimation of danger and underestimation of one’s ability to manage or cope in stressful situations. Schemas are usually adaptive and process information quickly and efficiently to determine the best course of action. However, persistent maladaptive schemas bias information processing negatively and are associated with psychiatric disorders. When activated, maladaptive schemas process new information into a form consistent with current maladaptive schemas, giving them more strength. Beck et al (1979) argues that cognitive therapy provides strategies for assessing new information before it is incorporated into maladaptive schemas, decreasing the strength of maladaptive schemas while increasing the development of more adaptive schemas.

Beck was among the first to develop theories as well as cognitive and behavioral interventions for most psychiatric disorders (Wright, Basco, Thase; 2006). Beck believed that cognitive therapy reduces excessive emotional reactions and self-defeating behaviors by modifying erroneous thinking and maladaptive schemas that underlie these reactions (Beck et al, 1979). In psychopathology, these corrective functions are impaired because of the maladaptive schemas that direct the focus of attention, access to memories, and the utilization of errors in logic (Beck and Weishaar, 1990). Thus, CBT is based on the interplay of cognition, mood, physiological responses, and behavior. CBT assumes that all psychopathology is, in part, the product of distorted thinking or information processing, which in turn has a negative impact on mood, physiology, and behavior. CBT not only addresses the impact of cognitions on mood, physiology, and behavior, but also the impact of mood, physiology, and behavior on cognition. For example, studies have shown that a depressed mood interferes with access to pleasant memories and past successes. CBT identifies four problematic aspects of cognition (dysfunctional automatic thoughts, maladaptive core beliefs, maladaptive intermediate beliefs, and errors in logic). Dysfunctional automatic thoughts are unpremeditated misinterpretations associated with specific situations in the present. They are responsible for an individual’s current negative emotional reactions. One of the tasks early in treatment is to help the patient to identify these negative interpretations by asking the question “What is going through my mind” at the time he or she is experiencing negative emotions. According to Beck (2011), core beliefs are the central ideas a person has about one’s self; they are rigid, global, and independent of time. Core beliefs differ from schemas in that schemas represent cognitive structures of the mind that direct attention and access memories, whereas core beliefs represent the schema content. Core beliefs are the product of long-term experiences associated with individuals and situations. Because people are exposed to both positive and negative experiences, one develops both adaptive and maladaptive core beliefs. The balance between adaptive and maladaptive core beliefs determines how one functions in stressful situations. Maladaptive core beliefs tend to be dominant in conscious awareness and this determines how one interprets situations in the present; they are the driving forces for the content of dysfunctional automatic thoughts. Maladaptive core beliefs are generally categorized into three major themes by virtue of whether he or she believes they are unlovable/unacceptable,

incompetent/worthless, or helpless/no control. The final task of CBT is to identify and challenge the validity of the maladaptive core beliefs and to replace them with more adaptive core beliefs to achieve enduring change of problematic emotions and behaviors. Because of the emotional distress that is triggered by awareness of one’s maladaptive core beliefs, he or she develops cognitive coping strategies, or maladaptive intermediate beliefs, in the form of rules and assumptions. These rules and assumptions are developed and implemented with the task of preventing the distressing maladaptive core beliefs from being realized. These rules or assumptions are “if…then…” statements that take on either positive or negative forms. For example, a patient with the core belief, “I am incompetent” might develop a maladaptive intermediate belief, “If I avoid making mistakes, my weaknesses will not be seen” (positive form) or “If I do not perform perfectly, I will fail” (negative form). The negative forms are more operational under intense distress. From the CBT perspective, it is important to identify these compensatory strategies given that they also contribute to an individual’s maladaptive approach to his or her problems. Errors in logic present in a variety of forms: all-or-nothing thinking (events are seen in one of two mutually-exclusive categories); over-generalization (a specific event is seen as characteristic of life); mind reading (an individual assumes that others are reacting negatively without obtaining the necessary evidence); catastrophic thinking (negative experiences are interpreted as intolerable or in terms of the worst possible outcome); and personalization (an individual automatically assumes responsibility for a negative event without considering other contributing factors). Errors in logic also contribute to misinterpretations of situations in the present. The therapist instructs his or her patient to identify and monitor their use of these errors in logic to achieve a more balanced view of a stressful situation.

Principles of CBT (Modified from Judith Beck, 2011) CBT focuses on subjective experience, the centrality of self, and meaningmaking processes (information processing). Conscious processes are believed to cause psychopathology and are used for correcting psychopathology. In contrast to psychoanalysis, there is no focus on making the correct interpretation or assuming the existence of motivated forgetting or repression. For CBT, all emotional responses are based on attributed meanings of the experience rather than in terms of hypothetical causes (e.g., castration fears).

CBT conceptualizes patient’s negative emotions and problematic behaviors in cognitive terms. This conceptualization is based on a comprehensive assessment conducted during the first few sessions and is modified, based on new information. Initially, the therapist demonstrates the relationships among distorted thinking, negative emotions, and problematic behaviors, and describes how such faulty thinking perpetuates distress. CBT uses a collaborative approach. The therapist and patient work together to determine the goals for therapy, the agenda for each session, the homework assignments, the frequency of meetings, and how long to continue therapy. The therapist guides the therapy based on the patient’s needs, priorities, and capabilities. The technique used by the therapist to achieve these ends is guided discovery . Using guided discovery, the therapist asks appropriate questions that enable the patient to gain a better understanding of his or her problems, explore possible solutions, and develop strategies to resolve the problems. It is important that the therapist not be viewed as having the answers or to impose his or her beliefs on the patient. CBT requires alliance building. Although CBT uses a variety of cognitive and behavioral techniques, effective treatment relies on a positive relationship between the therapist and patient. The therapist must be competent, caring, and empathic. Empathy enables the therapist to understand the patient from the patient’s point of view and thus gain insight into the belief systems and rules of logic that determine thoughts, feelings, and behaviors. CBT is problem and goal-oriented. The therapist assists the patient in identifying the specific problems that brought the patient to therapy, prioritizing which problems are most important and most accessible for immediate success, and operationalizing the expected outcome. CBT initially focuses on the present rather than on the past. Dysfunctional automatic thoughts are generally more accessible to conscious awareness in the here-and-now than are core beliefs, which are a product of the past. Thus, one of the first tasks in CBT is to identify patterns of dysfunctional thinking in the present that can provide insight into the underlying maladaptive core belief. After patterns of dysfunctional thinking are identified, the therapist generates hypotheses about possible underlying maladaptive core beliefs. The past is addressed later in therapy to assist the patient in understanding how the core beliefs developed. CBT is generally time-limited. In treating crisis situations (e.g., job loss, divorce) or an Axis I disorder, CBT is considered to be “brief psychotherapy,”

which can include 8 to 20 sessions. For Axis II disorders or other chronic conditions, the therapy can last 1 to 2 years. CBT sessions are structured. The therapist and the patient at the beginning of each therapy session set an agenda. Elements of the agenda include: reviewing of the patient’s clinical condition (including ratings of symptom severity); reviewing significant events that occurred since the last therapy visit; obtaining feedback from the previous session; reviewing of the patient’s homework from the previous session; discussing new problems; developing new homework; and providing feedback from the present session. CBT teaches the patient a method and skills that will enable the patient to become his or her own therapist. To accomplish this task, the therapist first teaches the patient about the nature of the disorder and the CBT model. The therapist teaches the patient the same skills he or she was taught. By the end of therapy, the patient will possess a strategy and a set of tools to confront problematic situations. CBT uses both cognitive and behavioral techniques to bring about changes in thoughts, feelings, and behaviors. The patient is taught to challenge his or her dysfunctional thoughts and beliefs by looking for evidence for and against them. Behavioral techniques can enable the patient to further test the validity of the faulty thoughts or beliefs. The choice of techniques depends on the patient’s specific disorder. CBT teaches relapse prevention. The last two or three therapy sessions are devoted to relapse prevention. The therapist encourages the patient to identify potential problem areas that he or she might encounter after therapy and to think of possible solutions based on knowledge learned from therapy. CBT is data-based. CBT treatment techniques have been empirically validated, and the body of research on CBT is large and growing. Treatment is also driven in large part by patient self-report data (e.g., rating scales, diaries, homework assignments).

The Application of CBT The therapist and patient agree on the goals of treatment based on the therapist’s conceptualization of the patient’s presenting problems. To help the patient achieve his or her goals, the therapist teaches the patient several cognitive and behavioral techniques.

Cognitive Techniques

Identification and Modification of Negative Automatic Thoughts Negative shifts in mood provide an excellent opportunity to identify negative automatic thoughts. During the session, the therapist monitors for strong emotional reactions and, when identified, asks the patient, “What went through your mind just then?” Patients are generally aware of their intense negative emotions but unaware of the corresponding negative automatic thoughts. Guided discovery is a technique by which the therapist asks the patient a series of inductive questions to identify negative automatic thoughts. The questions also help develop dissonance about the validity of the patient’s negative automatic thoughts. In a highly self-critical patient who acknowledges that he would show more compassion for a friend who might have made the same mistake, the therapist might ask, “Why do you treat yourself differently” or “How would your life be different if you treated yourself with compassion”? Examination of the evidence is basic to modifying distorted negative automatic thoughts. The therapist teaches the patient to treat the negative automatic thought as a hypothesis; then, together they search for evidence both for and against the hypothesis. The final interpretation is based on the outcome of this “examiningthe-evidence” exercise. Re-attribution techniques are used to help patients reassess their degree of responsibility for the occurrence of problematic events. A depressed patient, in particular, is more apt to have problems with negatively biased attributions regarding self, the environment, and the future. For example, a depressed patient might take on responsibility for a situation that is only minimally attributable to him or her. The therapist can help the patient recognize that other relevant individuals might have contributed more to the problem. This realization by the patient can help diminish negative emotions such as guilt and anger. The Dysfunctional Thought Record (DTR) combines many of the techniques noted above. The DTR is used to help the patient identify and modify negative automatic thoughts. The patient is asked to write down, in three separate columns, a stressful situation, the corresponding negative emotions, and negative automatic thoughts. The patient also rates, from 0 to 100, the severity of the negative emotions and the strength of his or her belief in the negative automatic thoughts. This teaches the patient the relationship between emotions and thoughts. In a fourth column, the patient records alternative thoughts or evidence against the original negative automatic thoughts. This technique challenges the original negative automatic thoughts and helps the patient gain a more realistic perspective. In a final fifth column, the patient rerates his or her belief in the

original negative automatic thoughts. If the alternative thoughts rate high in believability or if the evidence accumulated against the original negative automatic thoughts is convincing, the patient’s belief in the original negative automatic thoughts will be diminished, and the intensity of the negative emotions should be correspondingly reduced.

Identification and Modification of Maladaptive Core Beliefs Core beliefs are difficult to access because they are often unavailable to awareness. As the patient identifies a series of negative automatic thoughts across several stressful situations, certain patterns of thinking will emerge that will suggest possible underlying maladaptive core beliefs. After the patient has identified maladaptive core beliefs, the therapist asks the patient to perform a pros–cons analysis using a double-column procedure. In one column, the patient writes down all of the evidence that supports the core belief and, in the other column, all of the evidence that argues against the maladaptive core belief. This will enable the patient to examine the validity of the maladaptive core belief. Advantages and disadvantages analysis allows the patient to assess the full range of effects of one’s maladaptive core beliefs. On a four-cell grid, the patient writes the advantages and disadvantages of having, or not having, the maladaptive core beliefs. Some maladaptive core beliefs have few or no advantages (e.g., “I am a loser), whereas other maladaptive core beliefs have both positive and negative aspects (e.g., “If I do a perfect job, people will not see my weaknesses and accept me”). In the latter example, doing a perfect job has certain rewards; however, there is a price to pay because of the added effort and stress in doing a perfect job. This analysis will underscore the negative impact of maladaptive core beliefs on the patient’s life and thus provide motivation to look for alternative core beliefs. Generating alternative core beliefs is facilitated by the therapist using a “brainstorming attitude” (Wright and Beck, 1994), guided discovery, role-play, and imagery. First, the patient is asked to re-frame his or her maladaptive core belief in less-severe terms. For example, the re-frame of the core belief “I am incompetent” could be, “Having weaknesses does not mean I am a failure.” For homework, the patient is asked to identify evidence that is against the old core belief and supports the new core belief; “My evaluations at work are good, but not perfect.” Finally, the patient is asked for evidence for the old belief with a reframe; “Although I have deficiencies, I am more than my weaknesses.” The

therapist and patient then address the impact of the revised core beliefs on his or her life. The patient practices multiple times, both in therapy and outside of therapy, to reinforce learning of the new core belief.

Behavioral Techniques Techniques to Identify and Modify Maladaptive Cognitions Behavioral experiments directly test the validity of automatic thoughts and beliefs. The therapist and patient clearly identify the belief to be tested and then they collaboratively design an experiment to test the belief. The power of this technique is realized when the patient personally experiences evidence that contradicts the validity of his or her view. For example, as a homework assignment, a mother finally developed the courage to set limits with her neighbors who, at the last minute, would take advantage of her willingness to take care or their children while they went on shopping sprees. After requesting that her neighbors provide her 24 hours notice, to her surprise, she discovered that they understood her frustration and subsequently showed her more respect, rather than confirming her prediction that they would reject her for not being available. Bibliotherapy is used by the therapist to consolidate certain points during the therapy. The therapist must monitor the patient’s understanding of the material. This technique is consistent with the psychoeducational approach to CBT. Role-play is effective in helping the patient to identify automatic thoughts, to rationally respond to distorted automatic thoughts, and to modify maladaptive core beliefs. This technique allows for the activation of specific emotional experiences that may make distressing thoughts and beliefs more accessible to conscious awareness.

Techniques to Change Dysfunctional Behaviors Graded exposure is a technique to address the tendency of a patient to become overwhelmed with a task and thus avoid working on it at all. The therapist helps the patient break down the task into smaller steps and then encourages the patient to focus on the current step rather than the goal. Scheduling activities is useful for dealing with time-management problems and difficulty with prioritizing tasks. The therapist has the patient write down activities for the week on a grid. The therapist may ask the patient to write down ratings for mastery, pleasure, and mood for each task. These ratings provide

important data that can be used by the patient and the therapist to modify the patient’s behavior. Problem-solving is a technique to assist a patient who did not develop this skill in the process of development. The patient learns to specify a problem, identify alternative solutions, examine the pros and cons of each potential solution, select a solution, devise a plan for implementation, implement the plan, and assess the effectiveness of the results.

The Application of CBT to Specific Disorders Depression Conceptualization . According to Beck, a depressed individual views himself or herself as defective or worthless, views the world as unsupportive or making too many demands, and views the future as hopeless because he or she does not believe he/she has the internal or external resources to solve his problems. These negative views are referred to as Beck’s cognitive triad . The resulting depressed mood has an impact on the patient’s ability to recall positive experiences and past successes, resulting in impaired problem solving and a further worsening of depression and sense of hopelessness.

Treatment of Depression Behavioral Techniques Activity Scheduling: During the early phase of treatment, a depressed patient might experience significant psychomotor retardation and/or fatigue; this condition can make it difficult for the patient to cooperate with cognitive strategies. Increasing activity often has a positive effect on improving mood, which, in turn, enables the patient to work more effectively on tasks requiring cognition. In addition, avoidance and isolation prevents a depressed person from having the opportunity to challenge his or her distorted thinking.

Cognitive Techniques Daily Thought Records: This technique helps the patient to systematically challenge his or her negative views of self, environment, and future. After the negative automatic thoughts are identified, the patient, in collaboration with the therapist, identifies alternative views and searches for evidence to support them.

Belief Work: Although the correction of negative automatic thoughts is effective in resolving an acute episode of depression, it is crucial to identify and correct the dysfunctional core belief system that is responsible for the distorted views of self, environment, and future. The core beliefs are accessed through the discovery of patterns of negative automatic thoughts in given situations. The therapist, with the patient, identifies the core beliefs by working backwards from the cognitive themes observed in the present. Specific dysfunctional core beliefs tend to generate specific negative automatic thoughts. After the dysfunctional core beliefs are identified and corrected, the patient is less likely to relapse. In outcome studies of the acute treatment of outpatients with mild to moderate major depression, CBT is comparable to antidepressants for symptomatic relief. In preventing relapse, follow-up studies 1 to 2 years after termination of treatment demonstrate relapse rates of 20% to 30% for CBT and 65% to 78% for antidepressants. Thus, CBT exhibits durability post-treatment in comparison to antidepressants.

Panic Disorder Anxiety is a normal emotional response when an individual is facing a dangerous situation; however, anxiety is an abnormal response if it occurs in the absence of real danger, or if the anxiety response is out of proportion to the dangerousness of the situation. According to CBT, patients with an anxiety disorder are preoccupied with danger. The threats might be physical, psychological, or social. Maladaptive core beliefs contribute to the interpretation of dangerousness. A patient with an anxiety disorder is more likely to have maladaptive core beliefs of being inadequate, incompetent, or helpless. According to Freeman et al (2004), some of the errors in logic commonly found in anxious patients include: catastrophizing, personalizing, over-generalizing, magnifying, and minimizing. Perceived danger is maintained by avoidant behaviors and by focusing on both internal and external stimuli that contribute to the anxiety. Avoidant behaviors prevent the patient from testing the validity of his or her misinterpretations; at the same time, the patient tends to focus his or her attention on the stimuli that contribute to anxiety, thus intensifying the anxiety response. A patient with panic disorder misinterprets normal anxiety or bodily sensations in a catastrophic way. Signs and symptoms include rapid heart rate, shortness of breath, diaphoresis, paresthesias, dizziness, and palpitations; these are

interpreted as having life-threatening consequences. The triggers for panic attacks can be external (e.g., being in a crowded shopping mall) or internal (e.g., having a physical sensation, an image, or memory of an anxiety-provoking event). Avoidant behavior, such as agoraphobia, often develops as a coping strategy when certain external situations tend to trigger panic attacks. According to Clark (2010), panic disorder is maintained by the patient’s tendency to become hypervigilant for bodily sensations and to develop “safety behaviors” as a means of protecting himself or herself from either having a panic attack or experiencing the feared consequence of having a panic attack (e.g., heart attack). Both the hypervigilance and “safety behaviors” interfere with the patient’s opportunity to challenge his or her catastrophic thinking.

Treatment of Panic Disorder Treatment begins with teaching patients coping skills, then using cognitive strategies to challenge the validity of their catastrophic thinking, and finally developing behavioral experiments to test the validity of their catastrophic thinking.

Coping Strategies Coping skills are particularly helpful in the early phase of a panic attack. Diaphragmatic breathing helps to reduce arousal and to slow down bodily processes, such as heart rate. The patient is instructed to breathe in slowly over 5 seconds and then to exhale over 10 seconds. Each breathing sequence should take about 20 seconds. Muscle relaxation involves tensing and relaxing different muscle groups. One strategy is to begin at the feet and then to work up the body to the head. The patient tenses a particular muscle group, holds it, and then releases the tension. Distraction is a technique to help the patient avoid focusing on his or her physical symptoms, which tends to worsen anxiety. The patient is instructed to focus on external objects and to pay attention to as much detail as possible. This technique should not be viewed as avoiding the problem but as a means to get more reality focused.

Cognitive Strategies Psychoeducation about panic attacks is provided early in the treatment. The patient is told that people do not die from panic attacks despite having the feeling that it can feel like a myocardial infarction. The patient first makes a list of symptoms that occur during a panic attack and then identifies the negative

automatic thought associated with each symptom. Examples of negative automatic thoughts include, “I’ll faint,” “I’ll have a heart attack,” “I’ll look stupid,” and “I’ll go crazy.” The patient and therapist together challenge the validity of the negative thoughts.

Behavioral Strategies Interoceptive exposure is a technique that allows the patient to challenge the feared symptom by having the patient artificially create the symptom in a safe environment and then realize that there is not a catastrophic outcome. Examples include having the patient spin around in a chair to create dizziness, hyperventilating to create paresthesias, and running up a flight of stairs to induce tachycardia. Each of these induced symptoms can be symptoms of panic disorder. Before initiating the more strenuous techniques, the patient’s needs to be medically stable. Exposure experiments are important to help the patient resist “safety” and avoidant behaviors, which are a product of panic attacks and which prevent the patient from learning that his or her symptoms are not dangerous. A patient who fears that he or she might be having a myocardial infarction might avoid exercise. The therapist would have the patient exercise when the feared sensation was present during a therapy session and then again later as homework.

Other Applications Substance Use Disorders CBT addresses relapse prevention. It teaches that urges to use are the product of addictive beliefs that are triggered by internal (e.g., emotions) and external (e.g., people, places, things, situations) cues. Examples of addictive beliefs include, “I cannot have fun without cocaine,” or “The only way I can relax is to have a drink.” Cognitive therapists help the patient challenge the validity of these beliefs and identify alternative ways of dealing with the cues that trigger the beliefs. When the patient experiences cravings, permissive beliefs are activated such as, “I deserve a drink for all my stress,” or “I can stop after just one drink.” The permissive beliefs lead the patient to begin thinking of strategies to get the substance, which results in a lapse or relapse. Each step in the process toward using a substance is an opportunity to intervene either cognitively or behaviorally. Patients are also encouraged to look at the disadvantages of using substances given that they tend to focus only on their benefits. Also, the technique of having patients look at the advantages and disadvantages of using

and not using enables them to identify the positive reinforcers (i.e., factors that increase the risk) and the negative reinforces (i.e., factors that decrease the risk) of using the substance. With the identification of the positive reinforcers, patients can work on identifying alternatives to using the substance to achieving a given effect while identifying negative reinforces provides motivation for stopping the use of the substance.

Psychosis Cognitive therapy addresses several aspects of psychotic experiences including: misunderstanding the illness and its treatment; failing to adhere to treatment; appreciating the impact of the illness on self-esteem; challenging the validity of delusions and hallucinations; assisting in the development of better coping strategies; and identifying triggers and early signs of relapse. Techniques used include psychoeducation, problem-solving, stress management, and the identification of evidence that contradicts the psychotic symptoms (cognitive restructuring). However, prior to applying the technique of cognitive restructuring, treatment with antipsychotic medications is necessary to reduce the salience, and the associated emotional distress, of the psychotic symptoms (Kapur, 2000). Pre-clinical studies have demonstrated that the mesolimbic dopamine system is the salience center of the brain. Normally, the dopamine activity in mesolimbic dopamine system is context driven (i.e., based on experience); however, in psychosis, the mesolimbic dopamine system is overactive and thus is not context-driven. This results in the attribution of importance to internal and/or external experiences that are not currently important based on experience. Kapur (2000) argues that by blocking dopamine activity with antipsychotic medications, distress levels by reducing the salience of internal and external experiences associated with psychosis. After this is achieved, patients are more amenable to cognitive restructuring.

Eating Disorders The main problem areas in anorexia nervosa include a distorted body image, low weight, and abnormal eating behaviors. Cognitive techniques address the beliefs that body shape and appearance determine acceptance. In addition, there is the common belief among these patients that any compromise with the extreme standard of very low weight will result in total loss of control. Behavioral techniques are used to normalize the eating pattern (e.g., eating balanced meals at specific times) and to provide psychoeducation about the medical risks of the abnormal eating behaviors to help motivate change. Because

eating disorders are often seen as a coping strategy to deal with more fundamental belief systems, cognitive therapy can also address the issues of low self-esteem and negative self-image.

Personality Disorders Beck (2004) and others believe that there are four main areas of idiosyncratic cognitions that are unique for each personality disorder: core beliefs; view of self; view of others; and strategies for interpersonal interactions. For example, patients with borderline personality disorder might view themselves as “defective” or “totally undesirable,” and view others as rejecting and malevolent. Their social interactions consist of extremes including idealization and rejection. Because personality-disordered patients have a predominance of maladaptive core beliefs, therapy tends to be long-term and focuses on constructing a repertoire of adaptive core beliefs, which are deficient or lacking due to a deprived and invalidating environment early in their development.

New Developments in the Spectrum of CognitiveBehavioral Therapies Mindfulness-based cognitive therapy (MBCT ) was developed by Zindel Segal, Mark Williams, and John Teasdale (2002) and combines mindfulness meditation with elements of traditional CBT. MBCT was initially developed as a costeffective approach for reducing relapse rates in patients with recurrent major depressive disorder (MDD). Mindfulness as defined by John Kabat-Zinn is “a particular way of paying attention: on purpose, moment-by-moment, and without judgment.” This approach allows the patient to reduce his or her distress by not trying to resist a painful condition for which there are no immediate solutions. It teaches how ruminations about the past and worries about the future perpetuate the patient’s distress rather than resolve it. By focusing attention on the moment while broadening the patient’s awareness of what is consciously available in the moment, suffering can be reduced. Studies have shown that patients with a history of recurrent MDD tend to ruminate and worry, even when they are no longer depressed. Ruminative thinking has been associated with relapse of MDD. There are now several controlled trials demonstrating that MBCT can reduce relapse rates by 40% to 50% in patients with MDD and who have had at least three previous episodes. (Ma and Teasdale, 2004; Teasdale et al, 2000) More recently, MBCT has been shown effective in reducing symptoms of

depression in patients who are acutely depressed and who have a history of recurrent episodes. (van Aalderen et al, 2012)

Acceptance and Commitment Therapy Acceptance and commitment therapy (ACT), along with dialectic behavioral therapy (DBT) and MBCT, are considered the third wave of CBT. Behavioral therapy was the first wave and developed from classical and operate conditioning in the 1950s and 1960s. The focus of treatment in classical conditioning is on exposure to reduce disturbing thoughts and emotions through extinction. The focus of treatment in operant condition is on identifying positive and negative reinforcers of maladaptive behaviors; positive reinforcers increase whereas negative reinforcers decreased the risk of engagement in maladaptive behaviors. Cognitive therapy was the second wave and developed from cognitive science in the 1970s; it brought an information processing perspective to internal and external experiences. The focus of treatment with cognitive therapy is on identifying and challenging irrational and dysfunctional thoughts/beliefs and replacing them with more realistic and more adaptive interpretations of internal and external experiences. ACT had its beginnings in the 1980s and was primarily developed by Steven Hayes (2012). The aim of ACT is to encourage a meaningful, purposeful, and vital life while accepting associated painful internal experiences (thoughts, emotions, physical sensations, images, or memories) for which there is no control or immediate solutions. In contrast to CBT, ACT does not focus on changing the content of one’s thinking but instead on changing one’s relationship to his or her thoughts, emotions, physical sensations, images, and memories. ACT makes use of mindfulness strategies to enhance acceptance of one’s situation, which then enables the individual to direct his or her attention to current values to commit to value-based goals. According to ACT, commitment to actions that are uniquely value-based is the basis of quality living. Acceptance does not mean one is giving up or satisfied with one’s distressing thoughts, feelings, physical sensations, images, or memories; acceptance is only pursued if control of the internal distress is not possible or if the strategies to control it interferes with achieving value-based goals. The assumption of ACT is that human suffering is rooted in language. On the positive side, language allows us to learn, create, and communicate; however, language contributes to harsh judgments, self-criticism, painful comparisons, self-hatred, ruminations about painful past events, worries about the future, and

negative self-concepts, to name a few. “Thanks to human language, wherever we go, whatever we do, we can experience pain instantly. In any moment, we can relive a painful memory or get lost in a fearful prediction of the future. Or we can get caught up in unfavorable comparisons or negative self-judgments.” (Harris, 2009) Because of language, one normally constructs “stories” or constructs about self, others, or situations to make sense of internal or external experiences. The degree of distress experienced is determined by how tightly one becomes attached to the stories; the more fused with the stories, the greater the distress. Because of the resulting distress, one responds by wanting to avoid, to escape, or to get rid of the associated negative thoughts, feelings, physical sensations, images, and/or memories. ACT refers to these responses as experiential avoidance. According to ACT, psychopathology is a product of fusion with the stories or maladaptive constructs of one’s internal or private experiences followed by experiential avoidance. The combination of fusion and experiential avoidance leads to other pathological processes as well that contribute to psychological inflexibility, a response repertoire that is limited. Psychological flexibility is defined as being fully aware and open (without judgment) of the present moment, while taking actions that are directed by one’s values. Psychological inflexibility is the product of fusion with maladaptive constructs, experiential avoidance, inflexible attention (focus on the past and future rather than the present), attachment to the conceptualized self (overidentification with one’s construct of self or self-story), lack of clarity or contact with one’s values, and inaction or acting inconsistently with one’s values. ACT argues that these six pathological processes are all interactive. The focus of ACT treatment is on three response styles: opening one’s experience in the moment by enabling the defusion from self-constructs that interfere with valued living and accepting painful experiences as an opportunity to observe and learn; centering on the present moment with flexible attention to enhance defusion and acceptance skills or enabling the engagement in value-based actions; and, engaging in value-based committed actions in the present. ACT has been effective across a variety of psychiatric disorders and clinical conditions. There are controlled studies showing efficacy in depression, anxiety disorders, substance use disorders, borderline personality disorder, psychosis, adjustment to cancer, epilepsy, chronic pain, and diabetes management to name a few. The efficacy of ACT in so many conditions speaks to it meeting the scientific requirements of being a model that is unified and transdiagnostic. (Hayes et al, 2012)

Suggested Readings 1. Beck AT, Freeman A, Davis DD: Cognitive Therapy of Personality Disorders. New York: The Guilford Press; 2004: pp. 17–51. 2. Beck AT, Rector NA, Stolar N, et al: Schizophrenia Cognitive Theory, Research, and Therapy . New York: The Guilford Press; 2009: pp. 62–232. 3. Beck AT, Rush AJ, Shaw BF, et al: Cognitive Therapy of Depression . New York: The Guilford Press; 1979: pp. 1–33. 4. Beck AT, Weishaar ME: Suicide risk assessment and prediction. Crisis . 1990; 11(2); 22–30. 5. Beck AT, Wright FD, Newman CF, et al: Cognitive Therapy of Substance Abuse . New York: The Guilford Press; 1993: pp. 22–41. 6. Beck JS: Cognitive Therapy: Basics and Beyond . New York: The Guilford Press; 2011: pp. 1–24. 7. Blackburn IM: Severely depressed in-patients. In: Scott J, Williams JMG, Beck AT, eds. Cognitive Therapy in Clinical Practice: An Illustrative Case Book . London: Routledge; 1989: pp. 1–24. 8. Clark DA, Beck AT: Cognitive Therapy of Anxiety Disorders . New York: The Guilford Press; 2010: pp. 31–57. 9. Freeman A, Pretzer J, Fleming B, et al: Clinical Applications of Cognitive Therapy . New York: Plenum Press; 2004: pp. 3–93. 10. Harris R: ACT Made Simple . Oakland, CA: New Harbinger Publications, Inc.; 2009: pp. 1–39. 11. Hayes SC, Strosahl KD, Wilson KG: Acceptance and Commitment Therapy: The Process and Practice of Mindful Change. New York: The Guilford Press; 2012. 12. Kapur S: Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and psychopharmacology in schizophrenia. Am J Psychiatry . 2003; 160(1); 13–23. 13. Kingdon DG, Turkington, D: Cognitive Therapy of Schizophrenia. New York: The Guilford Press; 2005: pp. 55–137. 14. Kleifield EI, Wagner S, Halmi KA: Cognitive-Behavioral Treatment of Anorexia Nervosa. In: Yager J, ed.: The Psychiatric Clinics of North

America . 19:4. Philadelphia; 1996: 715–737. 15. Ma SH, Teasdale JD: Mindfulness-based cognitive therapy for depression: Replication and exploration of differential relapse prevention effects. J Consulting Clin Psychology . 2004; 72: 31–40. 16. Mitchell JE, Peterson CB: Cognitive-behavioral treatment of eating disorders. In: Wright JH, Thase ME, eds.: Cognitive Therapy . Washington DC: American Psychiatric Press, Inc.; 1998: pp. 107–133. 17. Scott J, Wright JH: Cognitive therapy for chronic and severe mental disorders. In: Wright JH, Thase ME, eds.: Cognitive Therapy . Washington DC: American Psychiatric Press, Inc.; 1998: pp. 135–170. 18. Segal ZV, Williams JMG, Teasdale JD: Mindfulness-Based Cognitive Therapy for Depression . New York: The Guilford Press; 2002: pp. 9–78. 19. Teasdale JD, Segal Z, Williams JMG, et al: Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consulting Clin Psychology . 2000; 68: 615–623. 20. van Aalderen JR, Donders ART, Giommi F, et al: The efficacy of mindfulness-based cognitive therapy in recurrent depressed patients with and without a current depressive episode: a randomized controlled trial. Psychological Med . 2012; 42: 989–1001. 21. Wright JH, Basco MR, Thase ME: Leaning Cognitive-Behavioral Therapy . Washington, DC: American Psychiatric Publications, Inc.; 2006: pp. 1–26. 22. Wright JH, Beck AT: Cognitive therapy. In: Hales HE, Yudofsky SC, Talbott JA, eds.: The American Psychiatric Press Textbook of Psychiatry . 3rd ed. Washington DC: American Psychiatric Press, Inc.; 1999: pp. 1205– 1241.

CHAPTER Mind–Body Medicine 68 JONATHAN P. ZEBROWSKI, MD; MICAELA B. OWUSU, MD MSC; GREGORY L. FRICCHIONE, MD; AND JOHN W. DENNINGER, MD, PHD

KEY POINTS Overview Mind–body medicine adapts ancient medical/spiritual practices to clinical practice. Evidence-based interventions deriving from these practices are utilized for treatment of chronic mental and physical conditions, and for improving baseline well-being. Theoretical Basis Mental processes directly affect physical processes, and vice versa . Chronic or intense stress over-activates physiologic pathways that lead to cellular damage. Mind–body methods induce the Relaxation Response to dampen over-active stress responses. Decreasing reactivity to stress and improving resiliency via mind–body techniques improves disease processes, reduces physiologic disarray, and decreases susceptibility to illness. Classification of Methodology Sub-types Mind–body techniques can be categorized as using mindfulness, mindful movements, and manualized therapies. Indications Indications for mind–body medicine include: wellness and resiliency enhancement; symptoms of depression/anxiety; chronic pain; chronic illness (e.g., cardiovascular disease, cancer); and disease prevention.

Clinical Applications Individual or group meditation or mindful movements: – Target improving baseline wellness and decreasing reactivity to stress. Mindfulness-Based Stress Reduction: – Serves patients coping with chronic illness, chronic pain, or high ongoing stress. Mindfulness-Based Cognitive Therapy: – Targets symptoms of depression. Integrated Treatment/Prevention Programs (i.e., SMART-3P) – Unifies medical care with methods to lower stress reactivity and increase resiliency. Important Historical Proponents of Mind–Body Medicine Herbert Benson: discovered the Relaxation Response. Jon Kabat-Zinn: applied mind–body techniques to the treatment of chronic pain and other illnesses and developed Mindfulness-Based Stress Reduction (MBSR).

Overview Mind–body medicine can be broadly defined as an approach both to illness and to wellness that is based on the reciprocal interaction between mental processes and physical health. Many modalities employed by the field originated within the medical or spiritual systems of ancient Eastern civilizations. Although there are some patients who identify closely with the religious or philosophical underpinnings of mind–body techniques, the field relies on evidence-based interventions that are effective in improving health irrespective of patients’ belief systems. Some widely known examples include meditation, yoga, biofeedback, and tai chi . Mind–body modalities exert their effects by dampening physiologic stress responses. These interventions have demonstrated efficacy in treating a wide range of illnesses, and they might also play a role in primary prevention by improving baseline functioning and reducing susceptibility to illness.

Historical Perspective

Several ancient cultures, primarily those in the Eastern hemisphere, developed religious and medical traditions that viewed thoughts, emotions, senses, and one’s body as representations of different aspects of the same process. On the Indian subcontinent, Ayurveda medicine conceptualized wellness as an equilibrium between body, mind, and spirit. Traditional Chinese medicine understood humans as directly connected with the universe, and wellness resulted from a balance of the opposing existential forces of yin and yang . The healing tradition in Buddhist cultures identified the mind as the creator of wellbeing and illness, as all phenomena including the body could only be experienced in the mind. As a result, all of these systems developed methods to heal the body by focusing or calming the mind. Simultaneously, they upheld the use of natural products and invasive procedures as treatments for specific illnesses, recognizing that affecting the physical body via external means was also necessary in many cases. In contrast, Western civilizations have generally split the two concepts. In ancient Greece, Plato, Aristotle, and others argued that the soul was an independent entity that happened to be attached to a body. In the 1600s, French philosopher René Descartes restated this duality as the often-quoted phrase “I think, therefore I am.” This idea, which aligned with Christian religious beliefs, held that mind was an entirely different type of matter altogether and was essential to being human. The body, conversely, was made of ordinary matter and could be manipulated only by physical means. As Western medicine evolved, treatments for mental and physical illnesses paralleled this philosophical divide. In the United States, it was not until the 1960s and 1970s that biomedical research, first conducted by Herbert Benson, demonstrated that mental states could have a direct effect on physiologic functions. As evidence grew, Jon Kabat-Zinn and others adapted and popularized ancient techniques as treatments for specific illnesses, and mind–body concepts began to be incorporated into Western medical systems.

Consequences of Stress Mind–body interventions rely on modification of physiologic and psychological reactions to stress. A stressor is any stimulus that both disturbs one or more aspects of an organism’s homeostasis and triggers a compensatory response. There are two types of stress: eustress and distress. Eustress results from a stimulus that is relatively brief and requires a response within the range of routine functioning. This is also known as positive stress, because the

resultant response can be motivating, pleasant, or enhance function. In contrast, distress results from a stimulus that requires a response exceeding the range of routine functioning or that overwhelms attempts at response. Distress can be caused by an acute stressor or the ongoing demands of a chronic stressor that might have initially resulted in eustress. Multiple physiologic pathways, collectively referred to as the stress response, are involved in causing changes within the organism to result in maintenance of homeostasis. These pathways become over-activated in settings of distress, leading to accumulation of damage at the cellular level. The stress response confers an evolutionary advantage by allowing organisms to adapt to a wide range of stimuli. However, these systems likely evolved in an environment of predominantly acute and time-limited stress, in contrast to the predominantly chronic stress most human beings face in modern society. Chronic stress not only causes further damage to the body through persistent high-intensity stress responses, but also prevents the return to a more normal physiologic state that could allow repair of damage. The earliest identified stress response pathway is the autonomic nervous system, which is composed of inversely acting sympathetic and parasympathetic components. Multiple brain regions involved in stimulus processing, including the amygdala and hypothalamus, regulate the relative output of these two components. The sympathetic nervous system is activated in response to homeostatic disturbances that require a higher level of energy utilization to overcome. This results in increased cardiac output, respiratory capacity, muscle contractility, and attentional focus. Chronic sympathetic activation can contribute to the development of disease in the multitude of organs controlled by the autonomic nervous system, including the heart, lungs, kidneys, gastrointestinal tract, and endocrine structures. In contrast, activation of the parasympathetic nervous system decreases the activity of these systems, restoring the energy distribution of the body to support normal functioning. Parasympathetic output can have a protective effect against conditions caused by sympathetic overload. Another key component of the stress response pathway is the hypothalamicpituitary-adrenal (HPA) axis. Similar to the autonomic nervous system, increased output by this axis is triggered when a stressor leads to increased energy requirements. The predominant terminal output of this pathway is increased circulating cortisol, which results in increased turnover of glycogen and other energy stores in the liver, impaired activity of the innate immune system, slowed

growth of muscle and bone, and decreased mood. Differences in function of this axis are a major contributor to observed variations between individuals in their capacity to recover from major stressors. Homeostatic disturbances also directly activate the immune system, likely as an evolutionary adaptation to an increased microbial burden that can be associated with stress. The innate immune system in particular responds by rapidly upregulating transcription factor NF-κ B, which in turn stimulates circulating levels of pro-inflammatory cytokines. Activity of these cytokines causes oxidative stress that leads to widespread cellular damage throughout the body, and specific cytokines have been shown to be directly toxic to brain tissue, resulting in neuronal apoptosis or demyelination. The increased cortisol release associated with stress directly inhibits NF-κ B, dampening the destructive effects of innate immune responses. Notably, in settings of chronic stress, the innate immune system becomes increasingly resistant to suppression by cortisol. The changes induced in this system by chronic stress have been linked to more susceptibility to infection, increased flares of autoimmune conditions, and greater risk of coronary artery disease and Alzheimer’s disease.

Mechanisms of Mind–Body Interventions The theoretical foundation of mind–body medicine involves several key concepts. First is the understanding that mind and body are unified, with changes in one directly affecting the other. Therefore, psychological and social stress, through the excess activation of the aforementioned pathways, results in accumulation of cellular damage in the body. This cellular damage in turn drives susceptibility to physical and mental health conditions, separate from any underlying genetic or environmental predispositions. Finally, by decreasing cellular damage resulting from stress, the likelihood of manifesting a disease process might be reduced. Research has extended this model to show that mind– body techniques can also alter genetic expression, reducing not only risk conferred by cellular dysfunction, but also risk conferred by genetic inheritance. This understanding is unified within the Mind–Body Medicine Equation, which is a simple ratio in which the numerator is the level of stress and the denominator is resiliency. Resiliency is a concept that represents an individual’s overall capacity to recover from the negative effects of stressors with minimal damaging effects on the mind and body. Lowering stress and increasing resiliency tips the balance of the equation toward wellness and resistance to

disease. Mind–body medicine targets both halves of the equation, through interventions designed to initiate a process known as the relaxation response. The relaxation response is a physiologic state defined by decreased heart rate, vascular tone, respiratory rate, and oxygen consumption. It directly opposes the aforementioned stress responses and, over time, improves resiliency. This state is achieved by focusing the mind on an activity while concurrently slowing or dissipating the automatic mental processes that automatically occur. It was first reported as a physiologic effect in individuals engaged in long-term meditation practice and has since been shown to be brought about by regular practice of many varied techniques that are the foundation of mind–body treatment and are described in further detail in the sections that follow.

Primary Mind–Body Techniques Meditation The general principle behind meditation is establishment of a mental state known as mindfulness, which refers to the ability to focus the mind on the present and maintain that focus despite varied sources of distraction. Although entering a state of mindfulness may result in some benefit at that time, the main positive effects of meditation are achieved cumulatively with ongoing practice. A multitude of meditation formats have evolved over thousands of years, varying in both position (walking, standing, or sitting) and mental processes employed. In focused attention meditation, awareness of the present moment is directed toward a specific object or repetitive process, such as the breath. In mantra recitation, focus is trained on the repetition of a word or sound. Open monitoring practice involves awareness of all thoughts and sensations that arise and fade, without holding on to any phenomenon. Loving-kindness meditation emphasizes directing feelings of warmth and joy toward oneself and others. Other variations include solo versus group meditation, and presence versus absence of verbal guidance by an instructor.

Mindful Movement By extending conscious awareness beyond mental processes and onto physical experience, mindful movement techniques reinforce the interrelatedness of brain and body. The most commonly employed modalities in mind–body medicine were developed over millenia as adjuncts to mindfulness practices and as primary forms of maintaining physical health. They all involve deliberate, controlled, and often slow transitions between specifically-prescribed

configurations of torso or limbs. Yoga , which originated in the Hindu tradition, emphasizes maintenance of full-body postures in combination with control of breath. The two other widespread formats of mindful movement originated in China, utilizing predominantly limb movements as means of moving energy (qi or chi ) through the body. Tai chi , which can also be considered a martial art, involves proceeding through specific patterns of relatively complex movements. Qi gong employs less complex movements and emphasizes a wider variety of patterns adapted to an individual’s style of motion.

Manualized Therapies As mind–body techniques began to gain momentum in the West, structured programs were created to provide a framework for individuals interested in integrating mindfulness and mindful movement into their medical treatment or health maintenance regimens. In the 1970s, Jon Kabat-Zinn developed Mindfulness-Based Stress Reduction (MBSR ), an eight-week program that combined mind–body modalities with formal education and daily exercises. MBSR is designed primarily for individuals coping with serious illness or experiencing high levels of stress. Mindfulness-Based Cognitive Therapy (MBCT), a similar program that also incorporates cognitive-behavioral interventions, is intended as a treatment program for symptoms of depression. The Stress Management and Resiliency Training Relaxation Response Resiliency Program (SMART-3RP) at the Benson-Henry Institute for Mind– Body Medicine at the Massachusetts General Hospital (BHI) combines meditative and other techniques that elicit the relaxation response, stress awareness, cognitive restructuring and positive psychology exercises, and a focus on healthy lifestyle changes to reduce stress and improve resiliency.

Efficacy A wide variety of mind–body techniques have been studied as treatments for a range of medical illnesses. Though research in the field can vary in reliability and rigor, a robust body of evidence now exists for the effectiveness of these methods on specific disease categories. These include cardiovascular diseases, certain pain conditions, insomnia, depression, and anxiety. At a molecular level, techniques that elicit the relaxation response have been shown to induce epigenetic changes that alter expression of genes involved in inflammation and metabolism. Mind–body modalities also decrease oxidative stress and, via this effect, slow the shortening of telomeres. On a physiologic scale, long-term practice leads to sustained reduction in blood pressure and oxygen demand.

Financial benefits have also been demonstrated, as adoption of these techniques can result in more rapid improvement of illness and decreased utilization of medical resources.

Clinical Practice Integration Though mind–body medicine represents a specific set of interventions and orientations toward symptoms, its treatments are applicable to a wide spectrum of conditions. As such, it is not a separate medical specialty; rather, it is a body of understanding that can be integrated into any practice setting. Many formal training courses exist, including certifications in structured therapies such as MBCT, MBSR, and SMART-3RP. It is recommended that providers intending to directly guide patients in a mind–body intervention first engage in direct practice in that modality themselves, whether or not certification is sought, as this increases clinicians’ ability to direct patients through these treatments. If incorporating direct treatment within a current practice model is not feasible, identifying local mind–body groups or individual experts will aid in ability to refer patients. An understanding of mind–body medicine might also increase rapport with patients who seek holistic approaches to treatment, when framed as an adjunct to other forms of care.

Precautions Mind–body interventions are adaptations or direct applications of techniques that have been safely and effectively utilized for thousands of years. In general, they involve minimal risk of adverse effects. Nevertheless, patients should be assessed individually for any characteristics that could increase risk, some of which we address in this section. Persons with the potential for increased risk might still be able to utilize mind–body techniques in modified forms or with specialized supervision. Mindful movement techniques emphasize gentle and focused motions or maintenance of postures. They are not intended as aerobic exercise, strength training, or flexibility enhancement. These techniques should be performed well within limits of an individual’s physical capabilities. Patients with connective tissue disorders, musculoskeletal injury, neurologic deficits, or other conditions that might limit range of motion or balance might need to avoid specific modalities or utilize modified techniques. Individuals with respiratory or cardiovascular co-morbidities should be assessed for their ability to tolerate exercise. Mindfulness techniques involve application of mental capacity to focus on the

present experience and to engage in introspection. Some modalities might additionally require sitting in silence or embarking on other forms of prolonged non-interaction. These aspects are generally well tolerated, but individual reactions can be idiosyncratic. Certain situations require caution or might even represent a contraindication to mindfulness practice. Patients who experience high levels of anxiety, rumination, a poor sense of self, or dissociation can become overwhelmed by attempts to observe their mental processes. Patients who experience over-identification with oneself or lack empathy, including those with severe personality disorders, might undergo reinforcement of maladaptive self-constructs. Finally, mindfulness practice should be approached with caution in patients with major difficulties in reality testing or with any history of developing psychosis during introspective or isolating activities.

References 1. Benson H, Beary JF, Carol MP: The relaxation response. Psychiatry . 1974; 37: 37–46. 2. Bertisch SM, Wee CC, Phillips RS, et al: Alternative mind-body therapies used by adults with medical conditions. J Psychosom Res . 2009; 66: 511– 519. 3. Bower JE, Irwin MR: Mind-body therapies and control of inflammatory biology: A descriptive review. Brain Behav Immun . 2016; 51: 1–11. 4. Chang BH, Dusek JA, Benson H: Psychobiological changes from relaxation response elicitation: long-term practitioners vs. novices. Psychosomatics . 2011; 52: 550–559. 5. Chrousos GP: Stress and disorders of the stress system. Nat Rev Endocrinol . 2009; 5(7): 374–381. 6. Cohen S, Tyrrell DA, Smith AP: Psychologic al stress and susceptibility to the common cold. N Engl J Med . 1991; 325: 606–612. 7. Dusek JA, Otu HH, Wohlhueter AL, et al: Genomic counter-stress changes induced by the relaxation response. PLoS One . 2008 Jul: 3(7): e2576. 8. Feder A, Nestler EJ, Charney DS: Psychobiology and molecular genetics of resilience. Nat Rev Neurosci . 2009; 10: 446–457. 9. Fox KC, Dixon ML, Nijeboer S, et al: Functional neuroanatomy of meditation: A review and meta-analysis of 78 functional neuroimaging

investigations. Neurosci Biobehav Rev . 2016; 65: 208–228. 10. Gotnik RA, Chu JJ, Busschbach H, et al: Standardised mindfulness-based interventions in healthcare: an overview of systematic reviews and metaanalyses of RCTs. PLoS One . 2015; 10(4): e0124344. 11. Kabat-Zinn J, Lipworth L, Burney R: The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med . 1985; 8: 163–190. 12. McEwen BS: Protective and damaging effects of stress mediators. N Engl J Med . 1998; 338: 171–179. 13. Niles H, Mehta DH, Corrigan AA, et al: Functional genomics in the study of mind-body therapies. Ochsner J . 2014; 14(4): 681–695. 14. Samuelson M, Foret M, Baim M, et al: Exploring the effectiveness of a comprehensive mind-body intervention for medical symptom relief. J Altern Complement Med . 2010; 16: 187–192. 15. Wolsko PM, Eisenberg DM, Davis RB, et al: Use of mind-body medical therapies. J Gen Intern Med . 2004; 19: 43–50.

CHAPTER Geriatric Psychiatry 69 M. CORNELIA CREMENS, MD, MPH AND JAMES M. WILKINS, MD, DPHIL

KEY POINTS Overview As the population of older adults is increasing there is a greater need for physicians, particularly in psychiatry, to develop a broader knowledge of psychiatric and medical syndromes specific to older adults. Older adults now account for 14.5% of the United States population and the number of psychiatrists caring for this population is inadequate to care for them. Changes Specific to Older Adults Metabolic changes in aging patients involve both pharmacokinetics and pharmacodynamics. While the brain demonstrates remarkable functional compensation for neuronal loss the loss of brain-differentiated neurons is permanent. Evaluation of Older Patients The atypical presentations of both medical and psychiatric illness are challenging. Drug-drug interactions, memory loss, and a decline in functional ability contribute to clinical complexity. Screening tools help to quantify memory problems. Suicide is common (especially in older men) and must be considered during the initial evaluation. Common Syndromes and Diagnoses Depression and delirium, often in the setting of memory loss, are the most common psychiatric diagnoses in the elderly.

Frailty in older adults complicates assessment of medical and psychiatric conditions. Substance use is often over-looked in older adults; however, it requires careful assessment. Elder abuse can be subtle and go undiagnosed in older adults, in part due to overwhelmed caregivers or life-long familial patterns.

Introduction The population of older adults (i.e., over 65) is increasing rapidly as the Baby Boom generation (people born between 1946 and 1964) is getting older; this will result in a greater need for care of psychiatric, neuropsychiatric, and co-morbid medical problems. According to the United States Census Bureau, older adults were estimated to number 46.2 million in 2014, accounting for approximately 14.5% of the United States population (or more than one in every seven Americans). Of those, approximately 25.9 million were women, and 20.3 million were men. Since 2010, the number of older Americans has increased by 14.2%, whereas those under the age of 65 increased by only 1.4%. Indeed, by the year 2040, it is estimated that older adults will account for 21% of the American population.

Metabolic Changes Associated with Aging The altered pharmacokinetics and pharmacodynamics of aging affects numerous metabolic functions; as a result, determining the appropriate medication and its dosage is a complex task. Hepatic function (with a decreased first-pass effect) in the elderly declines due to reduced blood flow and cardiac output. In addition, enzymatic function is reduced; demethylation and hydroxylation are notably effected. Absorption is decreased due to reductions in gastric blood flow, acidity, motility, and surface area. Renal excretion is delayed due to reductions in glomerular filtration rate, tubular excretion, and blood flow. Protein binding and albumin are also decreased. The volume of distribution is increased due to reductions in muscle mass, total body water, and cardiac output. Total body fat increases relative to total body weight and lipophilic drugs will be diluted due to their greater distribution in peripheral tissues. The brain demonstrates a remarkable functional compensation (e.g., with dendritic arborization and compensatory dendritic proliferation) for neuronal

loss and functional decline in response to the central nervous system (CNS) changes associated with aging (e.g., age-related loss in neurons, enzymes, neurotransmitters, receptors). Unfortunately, the loss of brain-differentiated neurons is permanent; whereas these cells do not divide or proliferate, glial cells can divide. Dendritic arborization and compensatory proliferation allow neuronal pathways to maintain contact despite neuronal loss. Levels of neurotransmitters and enzymes change with aging, resulting in increases in monoamine oxidase, and decreases in acetylcholine and dopamine. With advancing age, receptors decrease in number and increase in resistance to drug diffusion. Approximately 10% to 60% of neuronal cell loss normally occurs in the neocortex, the cerebellum, and the hippocampus, with less loss in the subcortical areas (with the exception of the locus coeruleus). This loss usually does not affect ordinary functions of living or occupation until after the age of 75.

Evaluation of the Older Patient Illnesses often present atypically (e.g., with vague complaints, falls, cognitive deficits, functional losses, behavioral changes) in the elderly. Physicians, in busy primary-care settings, poorly document these atypical findings; this often leads to misdiagnosis. Observation of the patient when he or she enters the room begins the evaluation process. The patient’s presentation, interaction with the family, and approach to the physician are critical in the assessment. Psychiatric assessment includes evaluation of affect, behavior, and cognition. Symptoms of disordered mood and affect (which are often subtle in the elderly) should be addressed first. Sleep disturbance is either increased or decreased and can be altered by use or discontinuation of medications. Interests might be decreased due to medical illness as well as loss of family or friends. Guilt is often prominent, as are ruminations and regrets. Energy might be reduced and confounded by illnesses or medication side effects. Concentration can be impaired and present as distraction or inattention. Loss of appetite and weight can be harbingers of a neurocognitive disorder, depression, or a medical illness. Psychomotor agitation or retardation can be confused with the manifestations of neurological illnesses, such as Parkinson’s disease. Several screening tools are available for the assessment of cognition. The most frequently used screen is the Mini-Mental State Examination (MMSE)

developed by Folstein and associates. It can be rapidly administered and can be incorporated within the context of the evaluation process. However, the Montreal Cognitive Assessment (MoCA) Test is more sensitive for milder cognitive impairment and it provides a more inclusive screen with regard to neurocognitive disorder due to Alzheimer’s disease (AD) and frontotemporal lobar degeneration. These tests screen only for dysfunction; they do not fully address the complex neuropsychiatric deficits that more formal neuropsychiatric testing can detect. Suicide is common in the elderly; the suicide rate appears to be highest in men older than 80 (accounting for 45 deaths by suicide per 100,000 in 2014), which appears to be driven primarily by Caucasian men(49 deaths by suicide per 100,000 in 2014). Roughly 1 in 9 suicide attempts in the elderly result in death. The risk of death after a suicide attempt in those older than 65 is double that of the United States population at large. Indeed, although older adults (i.e., those older than 65) comprise only 14.5% of the population in 2014, they accounted for approximately 18% of the deaths by suicide. Moreover, because statistics report completed suicide and not passive efforts to die, suicide in the elderly is probably under-reported. Predictors of suicide risk include: advanced age; male sex; being separated, isolated, or divorced; having a debilitating illness; and abusing alcohol. Psychosis (with hallucinations, paranoia, or delusions) is common in psychiatric disorders of the elderly, often related to medical, neurological, and psychiatric illnesses. Any pathological process (e.g., medical, neurological, psychiatric) that affects the brain is apt to result in delirium or a neurocognitive disorder. Clinicians should remember that hallucinations (visual, auditory, olfactory, gustatory, and tactile) can be manifest in a variety of illnesses, not just psychiatric conditions.

Functional Assessment Assessment of activities of daily living (ADLs) is crucial; this includes determination of the ability to transfer independently, dress oneself, bathe, maintain hygiene, feed oneself, use the bathroom, and maintain bladder and bowel continence. Assessment of instrumental activities of daily living (IADLs) includes determination as to whether the patient can live independently, go shopping for food, cook meals, use the telephone, do light housekeeping, manage medications, handle finances, and arrange transportation.

Clinicians should obtain a complete medical history, and review the medical records. Asking the family to summarize the history of the patient’s function over the past several years is helpful; if possible, they should have them provide a written summary. History is very important to document, and it might not be accurately obtained from the patient. Clinicians should perform a baseline mental status examination (MSE) and a neurological examination (using either the MoCA or the MMSE). A thorough physical examination should be performed, and the records from the primary-care physician (PCP) reviewed. Imaging studies (e.g., computerized tomography [CT] or magnetic resonance imaging [MRI]) and an electroencephalogram (EEG) should be considered, if indicated by the history. Additional laboratory testing can be ordered, if indicated, after a review of the records and an evaluation of the patient has been completed. The patient’s living situation should be assessed carefully (e.g., does the patient live alone, is he or she safe at home, does the patient live with the family and/or depend on the family, or does the patient’s family depend the on elder for money or other financial benefits).

Depression in the Older Patient Although the diagnosis of depression in the elderly is not difficult to make, it is often overlooked due to impaired cognition, sadness, grief, confusion, and a general decline in function or to a failure to thrive (FTT). In addition, medical and neurological complications and side effects of medications can obscure the diagnosis of a psychiatric illness. It should be noted that in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the bereavement exclusion has been removed such that a diagnosis of a major depressive episode can be made within two months of the death of a loved one during a period of bereavement. Depression lowers the life expectancy of the elderly (from suicide and from medical co-morbidity). Rates of suicide increase as isolation increases. Lateonset depressive illness is associated with a higher rate of physical illness; depression also leads to psychiatric hospitalization in 50% of those afflicted. Approximately 30% of those with a major neurocognitive disorder have comorbid major depressive disorder (MDD), and those with a history of stroke, Parkinson’s disease, or multiple sclerosis are also vulnerable to depression. Grief and loss also contribute to depression. Nearly 60% of depressed patients have co-morbid anxiety; roughly 40% of anxious patients have co-morbid depression

related to medical illness (e.g., cardiac conditions [such as myocardial infarction], renal failure, cancer, endocrine disturbances, infections) and neurologic illness (e.g., stroke, Parkinson’s disease, cerebral neoplasm, multiple sclerosis). It is crucial to recall that undiagnosed medical illness can present as depression. Epidemiological studies of the elderly reveal a one-month prevalence of all affective disorders of 2.5%. Unfortunately, although depressive symptomatology is recognized in 10% to 25% of the elderly, the disorder is rarely diagnosed. Women meet criteria for MDD more often than do men. Rapid assessment and treatment of depression is essential to prevent a FTT syndrome, progressive deterioration, and treatment-refractory depression. Factors (such as illness, use of medications, and psychosocial problems) should be addressed at their onset and treatment initiated (see Table 69-1). Several collaborative care models, such as the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) trial and the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) have been shown to be effective in treating late-life depression in the primary-care setting. These models utilize mental-health-care managers embedded within the primary-care practice and have been shown to reduce the severity of depression symptoms and provide higher rates of remission. Table 69-1: Common Classes of Drugs Causing Symptoms of Depression Analgesics Narcotics NSAIDs Antihypertensives Antipsychotics Anxiolytics Alcohol Benzodiazepines Chemotherapeutic agents Anti-neoplastics Diuretics Thiazides H2 blockers Sedative-hypnotics Steroids

Polypharmacy is a significant problem for the elderly. Therefore, when considering the use of medications (see Table 69-2), the risks and benefits should be weighed while monitoring the interactions with medications prescribed by other doctors. The addition of even one new drug can disrupt a tenuous balance of an established drug regimen. One should begin with a complete review of current medications and include a review of all drugs, including over-the-counter (OTC) and homeopathic remedies. The patient and/or family members should bring in all of the medication bottles and OTC medications. Table 69-2: Treatments Recommended for Depression in the Elderly Drugs

Dose Range (mg/d)

Comments

Tricyclic Antidepressants Nortriptyline

10–150

Desipramine

10–250

Reliable blood levels, minimal orthostasis, mildly anticholinergic

Monoamine Oxidase Inhibitors Tranylcypromine

10–30

Selegiline patch

6–12

Orthostasis (can be delayed), pedal edema, weakly anticholinergic, dietary restrictions needed

Stimulants Dextroamphetamine 2.5–40 Methylphenidate

Agitation, mild tachycardia

2.5–60

Selective Serotonin Re-uptake Inhibitors Fluoxetine

5.0–60

Sertraline

25–200

Paroxetine

5–40

Fluvoxamine

25–300

Citalopram

5–20

Escitalopram

5–40

Akathisia, headache, agitation, GI complaints, diarrhea/constipation

Serotonin/Norepinephrine Re-uptake Inhibitors (SNRI) Venlafaxine

25–300

Duloxetine

20–60

Increase in systolic BP, confusion

α 2 Antagonist/Selective Serotonin

Mirtazapine

15–30

Sedation, weight gain

Serotonin Antagonist and Re-up-take inhibitors Trazodone

25–250

Sedation, orthostasis, incontinence, hallucinations, priapism

Nefazodone

50–600

pedal edema, rash

Norepinephrine Dopamine Re-up-take Inhibitors Bupropion

75–450

Seizures, less mania/cycling headache, nausea

An initial diagnostic formulation should be proposed and a time-limited medication trial considered (with clearly identified target symptoms). The patient’s response should be re-evaluated often, and the drugs should be given for an adequate period before discontinuing them. Adverse drug–drug effects should be avoided if possible by starting with the lowest possible dose of a medication and increasing it slowly. In a frail, medically ill, or extremely old person, clinicians should start lower and go slower. When adverse side effects appear, it is prudent to discontinue the drug; remember that the elimination halflife is longer in the elderly and it can complicate the effects caused by the addition of a second drug. The side effect profile of a drug should be used advantageously, e.g., inducing sedation in a patient with insomnia, or weight gain in a patient with significant weight loss. It is wise to begin one drug at a time, and change one element at a time; too many changes will confound the result. Aggressive treatment is indicated when psychosis or thoughts of suicide are prominent features; if depression is life-threatening, hospitalization and/or use of electroconvulsive therapy (ECT) should be considered. Therapeutic trials should be re-evaluated at frequent intervals. When symptoms remit, the current dose should be continued for at least one year before discontinuing the medication. If symptoms have partially resolved, clinicians can continue and increase the dose or add an adjunctive medication to boost the initial response. When there is no response, clinicians can start another medication, possibly even one within the same class. Adjunctive medications should be considered only if an initial response was noted. Recent evidence suggests that the addition of aripiprazole to the antidepressant regimen of an older adult with treatment-resistant depression is effective in achieving and sustaining remission. The question inevitably arises as to when the medication can be discontinued; remember, the risk of relapse and recurrence is greater in the elderly, and a trial off medications can be fraught with complications. If there is no

contraindication, clinicians should maintain the medication to prevent recurrence. Psychotherapy is effective alone or in combination with medications. Structured individual therapies can be successful, but are best when used in combination with medications. Individual therapies include: supportive, cognitive, behavioral, interpersonal, and psychodynamic treatment. All modalities have shown efficacy in the older population. Group therapy is very successful; specific themes for a group allow discussion of issues that might be more difficult to identify, e.g., depression, grief, and anxiety. Support for both patient and family is typically needed. Family therapy can be informative and information-gathering, or it can deal with family dynamics, understanding, and conflict resolution.

Bipolar Illness Although not rare in the elderly , the first onset of symptoms of mania and hypomania is uncommon; most patients have had at least one episode earlier in their life. New-onset mania in the elderly should elicit a search for an underlying medical or neurological illness. Complicating the diagnosis of bipolar disorder is a secondary mania due to a medical condition or neurological disorder.

Anxiety Anxiety is frequently diagnosed in older patients, and symptoms of anxiety are found in 10% to 20% of older patients. The prevalence is higher in women than in men. Anxiety and depression are often associated with physical illness and can present prior to the diagnosis of a medical illness. Symptoms of anxiety include worry, fear, apprehension, concern, and foreboding, as well as somatic complaints (tachycardia, sweating, abdominal distress, dizziness). Worries, fears and concerns often center on financial issues, illness, loneliness, dependency, and cognitive function. Substances (such as caffeine, ephedrine, stimulants), can precipitate anxiety in the elderly. Withdrawal from benzodiazepines, alcohol, or barbiturates can resemble anxiety disorders and require aggressive treatment. Treatment of anxiety with medications and/or therapy is similar to that seen in younger patients. Initiation of antidepressants as initial therapy is done cautiously, and judicious use of benzodiazepines can be effective. However, complications related to use of these medications include daytime somnolence, confusion or cognitive impairment, unsteady stance or gait, paradoxical effects,

memory disturbance, withdrawal, abuse, dependence, and respiratory compromise. Cognitive-behavioral therapies are increasingly used to avoid medication side effects.

Major Neurocognitive Disorder In the DSM-5 , the term major neurocognitive disorder has been offered as an alternative to the term dementia and a differentiation has been made between a major neurocognitive disorder and a minor neurocognitive disorder based on the severity of symptoms as well as its impact on independent functioning. A major neurocognitive disorder involves a chronic and substantial decline in at least one cognitive domain (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition). A major neurocognitive disorder is the most common cause of cognitive impairment or decline in the elderly. Age-Associated Memory Impairment (AAMI ) or age-related cognitive decline is common in those older than age 65. Although patients and family members worry that symptoms of AAMI might be a harbinger of a major neurocognitive disorder, affected individuals tend not to develop a major neurocognitive disorder even after many years. Mild neurocognitive disorder signifies a more serious concern for significant memory loss but does not necessarily imply progression to a major neurocognitive disorder. Although current understanding of mild neurocognitive disorder and major neurocognitive disorder is informed by earlier diagnostic criteria (e.g., mild cognitive impairment and dementia, respectively), these diagnostic entities are not necessarily equivalent. Using older diagnostic criteria, it was found that approximately 20% to 30% of individuals with minor cognitive impairment progressed to dementia, although percentages varied by population and symptom cluster. Establishing a baseline of cognitive impairments is of benefit for two reasons: future testing will be compared to the original presentation to assess deterioration in a standardized format and to strategize and find useful tools to enhance weaker areas and to implement safety. Providing for safety when any memory disorder is present is paramount. A major neurocognitive disorder tends to present with a chronic persistent decline, albeit subtle, over several years. Most major neurocognitive disorders have an insidious, slow, and progressive course. In 2014, it was estimated that approximately five million people in the United States had a major neurocognitive disorder due to AD with an expected increase to approximately

14 million by 2050. Of the approximately 1.4 million residents occupying nursing home beds in this country, approximately 48.5% carry the diagnosis of a major neurocognitive disorder according to the Centers for Disease Control and Prevention (CDC). Major neurocognitive disorder due to AD is ultimately a histopathologic diagnosis at autopsy. The basic criteria are outlined in the NINCDS-ADRDA criteria for clinical diagnosis of probable AD. The criteria include deficits in memory , language , perceptual skills , attention , constructive abilities, orientation , problem-solving , and functional abilities. The course is slow; over time there is worsening of memory and other cognitive functions in the presence of a clear consciousness. Reversible causes should be ruled-out and a complete neurological evaluation conducted considering further testing (such as a positron emission tomography [PET] scan or cerebrospinal fluid analysis). A brief synopsis of the stages of decline include: no cognitive decline; very mild decline (aware of deficits); moderate decline (with clear deficits, e.g., getting lost); moderately severe (requiring assistance and reorientation); severe (e.g., unaware, apathetic, agitated, abulic, violent, with a sketchy memory of the past, and marked personality change); and very severe (unable to communicate, incontinent, with focal neurological signs and needing assistance most of the time). Major neurocognitive disorder due to Lewy body disease (LBD) is often misdiagnosed as major neurocognitive disorder due to AD and it can complicate the use of medications. Patients with a major neurocognitive disorder due to LBD have more hallucinations and a greater sensitivity to the side effects of antipsychotic medications, both typical and atypical, than do patients with a major neurocognitive disorder due to AD. Major neurocognitive disorder due to LBD is characterized by widespread distribution of Lewy bodies in the brainstem, basal forebrain, and cortex. Reported as a common form of a major neurocognitive disorder, it is characterized by fluctuating cognitive impairment, transient episodes of marked confusion, prominent behavioral changes, a high incidence of visual and or auditory hallucinations and delusions, and a movement disorder similar to that of Parkinson’s disease. Extrapyramidal signs are present and there is an exquisite sensitivity to antipsychotic medication. Major neurocognitive disorder due to frontotemporal lobar degeneration (FLD) manifests prominent symptoms of disinhibition, self-neglect, compulsive behaviors, apathy or euphoria, neglect of personal hygiene and self-

destructiveness. Patients are often unaware or unconcerned that any problem or deficit exists (e.g., of language and speech symptoms and movement disorders). Major neurocognitive disorder due to vascular disease usually presents with a stuttering course and the losses that are more focal in the territory of the damage. The ratio of major neurocognitive disorder due to vascular disease to major neurocognitive disorder due to AD is about 1:5. Risks associated with major neurocognitive disorder due to vascular disease are hypertension, cardiac disease, diabetes, smoking, alcohol use disorder, and hyperlipidemia. The incidence of major neurocognitive disorder in patients with risk factors and following a stroke is about 25% to 30%. Major neurocognitive disorder due to alcohol use gradually damages the dorsal inferior frontal lobe; symptoms are often similar to those with frontal lobe lesions. When alcohol use is stopped, cognitive losses should stabilize. The damage done can be permanent, as in Korsakoff’s and Wernicke’s syndromes, without immediate nutrition and replacement of the deficient vitamins. A variety of issues should be discussed with family members, friends, and caregivers; education around the diagnosis of a major neurocognitive disorder should begin early on in the course of the disease. Rapid changes in a patient’s behavior or cognition can be related to medical illness or side effects from medications. Onset of urinary or even fecal incontinence, often develops later and can be related to an underlying infection. Driving should be evaluated, and if a patient is unable to drive safely or becomes lost frequently, alternative transportation should be arranged. The discussion around driving is often contentious; families struggle with limiting the independence that driving affords. Families will hide car keys, disable, or remove the vehicle. Cooking should always be supervised; disabling the stove by turning off the gas or electricity might be necessary. Assistance should be given to the family and patient to stop smoking (and not let the elderly have matches available for any reason). Firearms should be removed from the home and then locked securely in a safe location. Caregiver support is essential; on-line support groups and information are of great benefit. The Alzheimer’s Association on-line website and the numerous local support groups alleviate isolation and increase confidence. Senior daycare centers that specialize in the care of those with memory disorders are beneficial for both the patient and the caregiver. Legal assistance is important early in the process (prior to a crisis) with attention paid to financial and estate planning, future needs, and long-term care.

Clinicians should establish a health-care proxy, durable power of attorney, and care plan early on, when the patient can participate in the process.

Delirium Delirium is often under-recognized, under-reported, or inadequately documented by physicians. Signs and symptoms of delirium are documented in fewer than 50% of cases; 10% to 20% of all hospitalized patients manifest some degree of delirium. Elderly patients are at high risk for delirium. The elderly are at greater risk for delirium due to age-related sensitivity to medications, and to co-morbid illnesses. Life-threatening condition must be treated swiftly and the under-lying cause ameliorated. Medical illness is often the culprit and medications add a second dimension to the problem. Drug-induced delirium can be precipitated by any medication; scrutiny of all medications is essential. The presentation of delirium is variable and therefore it is difficult to diagnose with certainty. Clinical features of delirium include a prodrome, a rapidly fluctuating course, decreased attention, altered arousal, psychomotor abnormalities, sleep– wake cycle disturbances, impaired memory, EEG abnormalities, and affective features (of intense anger, fear, sadness, rage, apathy, anxiety, or panic). Management of delirium is complex and involves accurate diagnosis, treatment of the underlying cause, and elimination of contributing factors. Supportive care is helpful as is maintenance of an adequate fluid balance, nutrition, sedation, rest, comfort, good nursing care, and encouragement of a family presence, frequent reorientation, optimal stimulation, a well-lit room, and appropriate use of eyeglasses and hearing aids. Helpful medications include use of high-potency antipsychotics, with attention paid to target symptoms (see Table 69-3). Haloperidol has been the drug of choice, but newer atypical neuroleptics are being used more frequently. The starting dose is always the lowest effective dose. Haloperidol, used intravenously, has the most rapid effect, starting with a low dose and titrating upward. Benzodiazepines can be synergistic with the antipsychotics, but can disinhibit the patient or cause paradoxical reactions. The course and prognosis needs to be monitored carefully because older patients are at a greater risk for death during the illness and for mortality six-months to a year after recovery. Table 69-3: Commonly Used Antipsychotics for the Elderly Mg Sedation Anticholinergic Extrapyramidal Equivalency

Low Potency thioridazine (Mellaril) 10–50 mg

high

high

low

95

medium

medium

medium

8

haloperidol (Haldol) 0.25–2 mg

low

low

high

2

thiothixene (Navane) 0.5–4 mg

low

low

high

5

fluphenazine (Prolixin) 0.5–2 mg

low

low

high

2

aripiprazole (Abilify) 2–30 mg

low

low

low

clozapine (Clozaril) 2.5–100 mg

high

high

very low

100

risperidone (Risperdal) 0.5–3 mg

low

low

low-mod

1–2

olanzapine (Zyprexa) 5.0–10.0 mg mod

mod

low-mod

quetiapine (Seroquel) 12.5–200 mg

low

low

Intermediate Potency perphenazine (Trilafon) 0.5–5 mg

High Potency

Atypical Antipsychotics

high

Substance Use Disorders Alcohol use disorder is often over-looked or minimized in the elderly. A lifelong pattern of daily use can be a problem and can lead to withdrawal. Comorbid psychiatric, neurologic, and medical illnesses can confound an accurate diagnosis. A careful history from family, friends, and caretakers is extremely important in this illness because alcohol use disorder is often characterized by denial. Prescription medications, including benzodiazepines and opioids, can also present challenges in older adults not only due to the side-effect profile, but also due to potential for misuse. For instance, benzodiazepine use in older adults has been associated with mood effects, cognitive impairment, and increased risk for falls, whereas opioid use in older adults is complicated by an increased risk for falls, an increased propensity for drug–drug interactions, and constipation. Although dependence and mis-use of these medications appear to be uncommon in older adults, careful prescribing in this population is essential, with particular attention paid to who else might have access to the medication. Indeed, opioids should be reserved for those with moderate to severe and persistent pain,

whereas medications like acetaminophen might be a more appropriate first-line choice for some patients.

Acute Behavioral Problems Patients with dementia, and delirium can exhibit acute behavioral problems, such as aggression, agitation, rage, wandering, and screaming. These symptoms are difficult to treat; patients are often over-medicated, yet are never successfully relieved of these problems. Indeed, the neuropsychiatric symptoms of a major neurocognitive disorder (e.g., agitation, depression, anxiety, apathy, sleep disturbances, psychosis) are very common (greater than 98% of patients will experience these symptoms in the disease course) and only modestly receptive to pharmacological approaches (e.g., use of antipsychotics and antidepressants). Non-pharmacological approaches are the recommended first-line intervention except in emergency situations or in routine clinical care.

Elder Abuse Every year an estimated 2.1 million older Americans are victims of physical, psychological, or other forms of abuse and neglect. Elder abuse can present subtly and is a complex problem. Family members or caregivers might be overwhelmed. It might not be new but the continuance of life-long patterns of behavior, family violence and emotional or physical abuse or neglect. Hotlines are available in every state and there is a national number for the Eldercare Locator who can serve as a referral source to the appropriate agency in the area to report the suspected abuse (1-800-677-1116 or www.eldercare.gov ).

Suggested Readings 1. Agronin ME, Maletta GJ: Principles and Practice of Geriatric Psychiatry . 2nd ed. Philadelphia, PA; Lippinott Williams & Wilkins; 2011. 2. American Geriatrics Society 2015 Beers Criteria Update Expert Panel: American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015: 1–20. 3. Appels BA, Scherder E: The diagnostic accuracy of dementia-screening instruments with an administration time of 10 to 45 minutes for use in secondary care: A systematic review. Am J Alzheimer’s Dis & Other Dementias . 2010; 25: 301–316.

4. Avari JN, Alexopoulos GS: Models of care for late-life depression of the medically ill: examples from chronic obstructive pulmonary disease and stroke. Am J Geriatr Psychiatry. 2015; 23: 477–487. 5. Camargos EF, Pandolfi MB, Freitas MP, et al: Trazodone for the treatment of sleep disorders in dementia. Arq Neuropsiquiatr. 2011; 69: 44–49. 6. Centers for Disease Control and Prevention. WISQARS: Web-based Injury Statistics Query and Reporting System. [accessed 3/1/2016]; http://www.cdc.gov/injury/wisqars/index.html . 7. Charney DS, Reynolds CF, Lewis L, et al: Depression and bipolar support alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Arch Gen Psychiatry . 2003; 60: 664–672. 8. Conwell Y, Van Orden K, Caine ED: Suicide in older adults. Psychiatr Clin N Am . 2011; 34: 451–468. 9. Cummings JL, Mackell J, Kaufer D: Behavioral effects of current Alzheimer’s disease treatments: A descriptive review. Alzheimers Dement . 2008; 4: 49–60. 10. Draper B, Ridley N, Johnco C, et al: Screening for alcohol and substance use for older people in geriatric hospital and community health settings. Int Psychogeriatr. 2015; 27: 157–166. 11. Dubois B, Feldman HH, Jacova C, et al: Research criteria for the diagnosis of Alzheimer’s disease: Revising the NINCDS-ADRDA criteria. Lancet Neurol . 2007; 6: 734–746. 12. Harris-Kojetin L, Sengupta M, Park-Lee E, et al: Long-term care services in the United States: 2013 overview. National Center for Health Statistics. Vital Health Stat . 2013; 3(37). 13. Huang AR, Mallet L: Prescribing opioids in older people. Maturitas. 2013; 74: 123–129. 14. Ismail Z, Rajji TK, Shulman KI. et al: Brief cognitive screening instruments: an update. Int J Geriatr Psychiatry. 2010; 25: 111–120. 15. Jeste DV, Blazer D, Casey D, et al: ACNP white paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology . 2008; 33: 957–970. 16. Juurlink DN, Herrmann N, Szalai JP, et al: Medical illness and the risk of suicide in the elderly. Arch Intern Med . 2004; 164: 1179–1184.

17. Kales HC, Gitlin LN, Lyketsos CG: Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multi-disciplinary expert panel. J Am Geriatr Soc . 2014; 62: 762–769. 18. Lader M, Tylee A, Donoghue J: Withdrawing benzodiazepines in primary care. CNS Drugs . 2009; 23: 19–34. 19. Lenze EJ, Mulsant BH, Blumberger DM, et al: Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet . 2015; 386: 2404–2412. 20. Lisanby SH: Electroconvulsive therapy of depression. N Engl J Med. 2007; 357: 1939–1945. 21. Mitchell SL: Advanced Dementia. N Engl J Med. 2015; 372: 2533–2540. 22. Newhouse PA: Use of serotonin selective re-uptake inhibitors in geriatric depression. J Clin Psychiatry. 1996; 57(suppl 5): 12–22. 23. NIH Consensus Conference: Diagnosis and treatment of depression in late life. JAMA. 1992; 268: 1018–1024. 24. Olfson M, King M, Schoenbaum M: Benzodiazepine use in the United States. JAMA Psychiatry . 2015; 72: 136–142. 25. Ong MK, Xu H, Zhang L, et al: Effect of Medicare Part D benzodiazepine exclusion on psychotropic use in benzodiazepine users. J Am Geriatr Soc . 2012; 60: 1532–1541. 26. Reynolds III CF, Dew MA, Pollock BG, et al: Maintenance treatment of major depression in old age. N Engl J Med . 2006; 354: 1130–1138. 27. Sachdev PS, Mohan A, Taylor L, Jeste DV: DSM-5 and mental disorders in older individuals: An overview. Harv Rev Psychiatry . 2015; 23: 320–328. 28. Sachs-Ericsson N, Blazer DG: The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment. Aging Ment Health. 2015; 19: 2–12. 29. Shorr RI, Robin DW: Rational use of benzodiazepines in the elderly. Drugs & Aging. 1994; 4: 9–20. 30. Small G: What we need to know about age-related memory loss. BMJ. 2002; 324: 1502–1505.

31. Tariot PN, Profenno LA, Ismail MS: Efficacy of atypical antipsychotics in elderly patients with dementia. J Clin Psychiatry. 2004, 65 Suppl 11: 11–15. 32. United States Census Bureau: 65+ in the United States: 2010. Washington, DC: U.S. Government Printing Office; 2014: pp. 23–212. 33. United States Census Bureau: Annual Estimates of the Resident Population for Selected Age Groups by Sex for the United States, States, Counties, and Puerto Rico Commonwealth and Municipios: April 1, 2010 to July 1, 2014. [accessed 3/1/2016]; http://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml? src=bkmk . 34. Whooley JD, Khan BK, Murthy NK, et al: The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: Rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry. 2011; 72: 126–133. 35. Wilkins JM, Forester BP: Update on SSRI treatment for neuropsychiatric symptoms of dementia. Curr Psychiatry Rep. 2016; 18: 14. 36. Work group on Alzheimer’s Disease and Related Dementias: Practice Guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. Psychiatric Practice section of the APA website at www.psych.org/20071-86 . 37. Wu LT, Blazer DG: Substance use disorders and psychiatric co-morbidity in mid and later life: a review. Int J Epidemiol. 2014; 43: 304–317. 38. Young RC, Klerman GL: Mania in late life: Focus on age of onset. Am J Psychiatry. 1992; 867–875. 39. Zyas EM, Grossberg GT: The treatment of psychosis in late life. J Clin Psychiatry. 1998; 59 (suppl): 5–10.

Special Topics in Psychiatry

S E C T I O N F I V E

CHAPTER 70 Psychiatric Epidemiology ALBERT YEUNG, MD, SCD AND TRINA CHANG, MD, MPH

KEY POINTS Overview Psychiatric epidemiology is the science that studies the frequency of psychiatric disorders and the distribution and determinants of disease frequencies; it informs the natural history, service needs, and etiology of psychiatric illnesses. Psychiatric epidemiology begins with case definition, which means how a specific psychiatric disorder is defined. Epidemiological studies frequently rely on assessment instruments to evaluate psychiatric disorders; however, before these instruments can be used for case identification their reliability (or consistency) and validity (or truthfulness) must be established. The frequency of psychiatric disorders can be expressed using different concepts, including cumulative incidence, incidence density, point prevalence, period (e.g., one-month) prevalence, and life-time prevalence, depending on the time-point being used and the method of case counting. Data from the National Co-morbidity Survey Replication Study (NCS-R), which utilized the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV, published in 1994), showed that the most common life-time disorders are nicotine dependence, followed by major depressive disorder and alcohol abuse/dependence; the next most common disorders are social and simple phobias. Almost one in three respondents report a life-time anxiety disorder, one in four report a lifetime impulse-control disorder, and one in five report a life-time mood disorder. About one-half of adults in the United States meet criteria for one or more psychiatric disorders during their lifetime. Nearly one-third have at least one disorder in the 12 months prior to the interview.

Introduction Epidemiology is the study of the distribution and determinants of disease frequency in human populations. It is about observing, counting, and comparing the occurrence of disease between different populations at a given time, between sub-groups of a population, or between different periods of a population. Because human disease does not occur at random, systematic investigation of the relationship of disease frequency and of the characteristics of populations can shed light on the etiology of the disease. By providing data on the distribution and frequency of diseases, epidemiological studies help to assess service needs in the community or in special institutions, and to describe the natural history of illness. To achieve these goals, epidemiological observation studies are conducted with large groups of individuals. The first step is often case recognition. This is especially challenging in psychiatric epidemiology due to the absence of pathognomonic laboratory abnormalities for diagnosing psychiatric disorders.

Assessment Case Definition In 1972, Cooper and colleagues published the United States/United Kingdom diagnostic study, which demonstrated the variability of diagnosis in psychotic disorders. It highlighted the importance of having explicit operational criteria for case identification. The use of diagnostic criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) in 1980 represented a great step toward the advancement of the reliability and validity of psychiatric diagnosis. The most recent revision of the DSM, DSM-5, was released in 2013.

Standardized Instruments for Case Assessment The clinical interview is generally used to diagnose psychiatric illness. However, differences in personal styles as well as in theoretical frameworks can affect the process and the outcome of the psychiatric interview. To increase interrater reliability, a variety of standardized instruments have been used. The first such instrument was the Present State Examination (PSE), which was used in the International Pilot Study of Schizophrenia sponsored by the World Health Organization (WHO). Because the PSE was intended for use by psychiatrists or by experienced clinicians, its use in epidemiologic studies has been limited, due

to the high volume of subjects involved in such studies. Based on other research instruments, including the Renald Diagnostic Interview (RDI), the St. Louis criteria, and the Schedule for Affective Disorders and Schizophrenia (SADS), epidemiologists at the National Institute of Mental Health (NIMH) developed the Diagnostic Interview Schedule (DIS), a fully structured interview that could be used by non-clinicians to assess large numbers of subjects according to DSM-III criteria. The DIS has been used extensively in the United States and many other countries for surveys of psychiatric illness. The WHO and the NIMH updated and modified the DIS and developed the Composite International Diagnostic Interview (CIDI), which is structurally similar to the DIS and provides both ICD-10 and DSM-IV diagnoses.

Reliability Reliability is the degree to which a measurement produces systematic or reproducible results. Use of explicit diagnostic criteria, a structured assessment instrument, and adequate training of raters, each enhance the reliability of making a psychiatric diagnosis. Reliability is a necessary, but not sufficient, condition for a valid diagnosis. The kappa statistic (κ ) is frequently used to measure the reliability between raters (see Table 70-1). It shows the degree of consistency between raters, with an adjustment of agreement due to chance. An important characteristic of the kappa statistic is that it is influenced by how common the particular condition is in the study sample. When the frequency of the disorder is very low, kappa statistics will be low despite having a high degree of consistency between raters. Therefore, the kappa statistic is not applicable for measuring the reliability for infrequent disorders.

where P o is the observed agreement, P c is agreement due to chance, Po = (a + d )/n and Pc = [(a + c )(a + b ) +(b + d )(c + d )]/n 2 . Table 70-1: Inter-Rater Reliability Rater A Rater B

Disorder Present Disorder Absent Total

Disorder present a

b

a +b

Disorder absent c

d

c +d

b +d

n

Total

a +c

Validity An instrument is considered valid if the instrument measures what it is intended to measure. Rater or instrument validity of a psychiatric diagnosis is ideally done by comparison of the tested rater or instrument with a well-known standard of truth. Unfortunately, in psychiatry, there is no absolute measure of a diagnosis. A criterion instrument (rater) is usually chosen as the truth and is used for comparison with the new instrument (rater) (see Table 70-2). Table 70-2: Validity of a New Instrument Truth (Criterion Instrument Results) New Instrument Disorder Present Disorder Absent Total Disorder present

a

b

a + b

Disorder absent

c

d

c + d

Total

a + c

b + d

N

Sensitivity, specificity, positive predictive power, and negative predictive power are frequently used to express the validity of an instrument. Sensitivity is a measure of the new instrument’s ability to detect the true cases of a disorder identified by the criterion instrument. Specificity is a measure of the new instrument’s ability to identify the true non-cases identified by the criterion instrument. Higher values of sensitivity and specificity are always desirable. For a given instrument, higher sensitivity is obtained by lowering specificity, and vice versa . The only way to improve both sensitivity and specificity without a trade-off is to improve the instrument itself. Positive predictive power is the proportion of apparent cases, as detected by the new instrument as true cases as determined by the criterion instrument. Negative predictive power is the proportion of apparent non-cases, as detected by the new instrument as true non-cases as determined by the criterion instrument.

Measurement of Disease Frequency Prevalence

Prevalence is the proportion of individuals in a population who have a disease at a specific instant; it provides an estimate of the probability that an individual will be ill at any point. Prevalence is determined by the rate at which the disease develops and by the duration of the disease. That is, with the same rate of development, a chronic disease will have a higher prevalence than an acute one. The prevalence rate is more useful for descriptive purposes. It has been used to describe the frequency of an illness in a community population. In addition, it reflects service needs:

Incidence Incidence quantifies the number of new events or cases of a disease that develop in a population of individuals at risk during a specified time interval. There are two specific types of incidence measures: cumulative incidence and incidence rate. Cu mulative incidence (CI) is the proportion of people who develop the disease during a specified period. It is calculated by the following equation: CI = Number of new cases of a disease during a given period Total Population In real life, some people enter a study at different times; others might become lost during the study and are no longer available for follow-up. When a person in the study becomes a case, he or she stops being at risk and no longer contributes to the denominator. To account for the variable durations for which people are at risk, in cidence rate (IR) is used; this is defined as follows:

For example, 100 subjects were studied, two were lost to follow-up at the end of 6 months, and eight developed a disease at the end of the 6th month; 90 subjects were disease-free at the end of 1 year. The person-years of observation was (90 × 1 year) + (2 × 0.5 year) + (8 × 0.5 year) = 95 person-years, and IR = (8 persons)/(95 person-years) = 8.42/100 person-years of observation. Incidence rates are more difficult to calculate than prevalence rates, and require more extensive data collection. Unlike prevalence rates, incidence rates are not affected by the duration of the disease. The incidence rate is more precise when measuring disease rate; it is useful in analytical studies of effects of risk factors.

Period Prevalence The period prevalence rate is used to summarize the number of cases of a disorder that exist at any time during a specified time period. Its numerator includes any existing cases at the start of the period plus any new cases that develop during the time period. For a 1-year period, the annual period prevalence rate is approximately equal to the point prevalence rate [(existing cases)/(population at the start)] plus the annual cumulative incidence rate [(new cases in a year)/(population at risk)].

Lifetime Prevalence The lifetime prevalence rate is a measure of persons considered at a point in time who have ever had the illness under study. It is a useful statistic to describe conditions that remit but often recur, such as maj or depressive disorder (MDD).

Study Designs Descriptive Studies Descriptive studies describe patterns of disease occurrence in relation to selected variables (e.g., person, place, time). They utilize census data, vital statistic records, and clinical records from hospitals, or national figures on consumption of goods, oil, or other products. There are three main types of descriptive studies: correlation studies, case reports or case series, and crosssectional surveys of individuals. Data from descriptive studies are useful for public health administrators who plan for health care utilization and resource allocation. They are also valuable for formulation of etiologic hypotheses. However, descriptive studies in general cannot be used for testing etiologic hypotheses. For hypothesis testing, analytic design strategies (cohort, casecontrol, or intervention studies) are needed.

Cohort Studies In cohort studies, or follow-up studies, a group of individuals (cohort) is defined on the basis of the presence or absence of exposure to a suspected risk factor for a disease. The rates at which they develop a certain disease or an outcome of interest are measured and compared. By nature of the design, individuals in such a study need to be disease-free at the beginning of the study. For a prospective cohort study, individuals are followed for a specified period and their outcome is compared. For a retrospective cohort study, information on risk factors is obtained from records collected in the past at the actual time of the

exposure, and the information on disease status is obtained at the time of the study. Rel ative risk (RR) is calculated to test for the possible association between exposure and outcome (disease). If the relative risk is greater than 1.0, the exposure is considered to be associated with the disease (see Table 70-3).

Table 70-3: Association Between Risk Factors and Disease in Cohort and CaseControl Studies New Cases Non-Cases Total a

a + b

Risk factor not present c

c + d

Risk factor present

Total

a + c

+ d

a + b + c + d

Case-Control Studies Subjects in case-control studies are selected on the basis of whether they do (cases) or do not (controls) have a particular disease under study. The groups are compared with respect to their proportions of having certain risk factors of interest. A case-control design is usually used for studying rare disorders. Instead of relative risk, an odds ratio is calculated to detect an association between the risk factor and the disease. If the odds ratio is greater than 1.0, the risk factor is considered to be associated with case-ness (see Table 70-3).

Intervention Studies In an intervention study, the investigator controls the allocation of subjects to different comparison groups and regulates the experimental conditions of each group. Study subjects are randomly assigned to comparison groups and followed over time to observe the outcome (e.g., decreased disease frequency or improved clinical condition, of the intervention). Clinical trials are the most common form of intervention studies. To ensure the comparability between groups and to obtain valid results, intervention studies employ three basic research strategies: randomization, placebo-control, and blinding.

The National Co-Morbidity Survey (NCS)

Overview The NCS was the first nationally-representative mental health survey in the United States to use a fully-structured research diagnostic interview to assess the prevalences and correlates of the DSM-III-R disorders. It sampled widely dispersed subjects who were representative of all people living in households in the continental United States. The survey was done by administering a face-toface structured diagnostic interview using a modified version of the CIDI, a state-of-the-art structured diagnostic interview based on the DIS (Robins et al, 1981). Previous validation studies have shown that patients with non-affective psychosis might not be able to report information accurately. In the NCS, respondents with any evidence of schizophrenia or other non-affective psychoses were reinterviewed by experienced clinicians using the Structured Clinical Interview for DSM-III-R and their diagnoses were based on clinical interviews. The survey was repeated in 2001 to 2003 with English-speakers as with the NCS-R, using diagnostic criteria from the DSM-IV. When the DSM-5 was in development, the researchers re-calculated prevalence numbers for mood and anxiety disorders in adults and adolescents combined to correspond with the expected presentation format of the DSM-5; they noted there were some small discrepancies between these numbers and earlier estimates due to improvements in data coding and weighting. Since the DSM-5 had not been finalized, however, they still used DSM-IV diagnostic criteria to define cases.

Results Data from the NCS-R based on DSM-IV criteria revealed that the most common life-time disorders were nicotine dependence, followed by MDD, and alcohol abuse/dependence. The next most common disorders were social and simple phobias. As a group, anxiety disorders and impulse-control disorders were somewhat more prevalent than affective disorders, with approximately one in every four respondents reporting a life-time impulse-control disorder and almost one in three reporting a life-time anxiety disorder. Approximately one in every five respondents reported a life-time affective disorder. The prevalence of other NCS-R disorders was considerably lower (Tables 70-4). Table 70-4: Prevalence Estimates (%) for Specific Mood and Anxiety Disorders in Adults and Adolescents Major depressive disorder

Life-time (%)

12-month (%)

14.4

7.1

Bipolar (I & II) disorders

2.5

1.8

Generalized anxiety disorder

4.3

2.0

Panic disorder

3.8

2.4

Social phobia

10.7

7.4

Specific phobia

15.6

12.1

Agoraphobia

2.5

1.7

Data drawn from the National Co-morbidity Survey Replication reanalysis by Kessler et al, 2012.

About one-half of adults in the United States reported symptoms that met criteria for one or more psychiatric disorders during their lifetime. Nearly onethird had at least one disorder in the 12 months prior to the interview. While there was no meaningful gender difference in the overall prevalence of NCS-R disorders, men were more likely to have impulse-control and substance use disorders than women, while women were more likely to have anxiety disorders and affective disorders than men (with the exception of bipolar disorder, for which there was no sex difference). One remarkable finding was that most psychiatric disorders had their first-onset quite early in life, raising the public health importance of early recognition and treatment of these disorders to prevent protracted courses of the disorders.

Epidemiology of Major Psychiatric Disorders Schizophrenia Prior to the introduction of the DSM-III, the prevalence of schizophrenia was estimated to range from 1% to 7%. In a review of studies from 1965 to 2002, McGrath and colleagues (2008) reported a median point prevalence rate of four per thousand. Genetic loading is a robust risk factor of schizophrenia (see Table 70-5). The prevalence of schizophrenia in a monozygotic twin of a person with schizophrenia may be as high as 50%; with a dizygotic twin it is 15%. The prevalence for a child with two parents having schizophrenia is 46.3%; for a child with one parent with schizophrenia it is 12.8%. Other factors associated with schizophrenia include being a member of a lower social class (possibly due to the effect of the illness on an individual’s ability to work), being born or raised in cities, having pregnancy or birth complications, having an older biological father, and being born during the winter months. Studies have also shown that stressful life events, high levels of “expressed emotions” (critical and

over-protective behavior and verbalizations toward the family member with schizophrenia), and substance use can precipitate psychotic episodes. Table 70-5: Recurrence Risk* for Schizophrenia in Biological Relatives Population

Recurrence Risk

General population

1

Children of two parents with schizophrenia

89

Children with a father with schizophrenia

10.7

Children with a mother with schizophrenia

10.3

Children with a sibling with schizophrenia

8.6

Monozygotic twin of a sibling with schizophrenia

50.0

First cousin of a person with schizophrenia

2.29

Data drawn from Lichtenstein et al, 2006, and Tsuang et al, 2011 * Recurrence risk: the morbidity risk of the illness in a given family member of the patient compared to the risk in the general population

Bipolar I Disorder Bipolar I disorder affects men and women equally. The NCS-R re-analysis reported a life-time prevalence of 0.6% and a 12-month prevalence of 0.4% in adults and adolescents combined. Bipolar I disorder occurs at much higher rates in first-degree biologic relatives of persons with bipolar I disorder than it does in the general population. Family, adoption, and twin studies clearly support the evidence that bipolar disorder is genetically transmitted. The concordance rate in monozygotic twins is 58% to 93%, while the concordance rate in dizygotic twins is 16% to 35%. The life-time risks of suffering from bipolar disorder in relatives of bipolar probands are 2% to 19% in first-degree relatives and 1.8% to 2.8% in adoptive relatives.

Major Depressive Disorder Based on the reanalysis of NCS-R data, the 1-year prevalence for MDD in adults and adolescents combined is 7.1%; the lifetime risk for MDD is 14.4%. Risk factors for MDD include being female, having a history of depressive illness in first-degree relatives, having prior episodes of MDD or other psychiatric disorders, having a two-week period of 2 concurrent depressive symptoms, and being divorced.

Panic Disorder The re-analysis of NCS-R data reported life-time prevalence rate of 3.8% and 1-year prevalence rate of 2.4% for panic disorder in adults and adolescents combined. Women and adults aged 18 to 64 years are at higher risks of having panic disorder. Other analyses have found that the differences among Hispanics, non-Hispanic whites, and blacks are small. Panic disorder most commonly develops in young adulthood; the median age of presentation is about 23 years, but panic disorder can develop at any age. It is associated with a higher risk for MDD.

Alcohol Use Disorders The NCS-R found that life-time prevalence rates for alcohol abuse and alcohol dependence as defined in DSM-IV were 17.8% and 12.5%, respectively. Yearly prevalence rates for abuse and dependence were 4.7% and 3.8%, respectively. Alcohol abuse/dependence is one of the most common psychiatric disorders. Alcohol dependence was correlated with male gender, younger ages, being never married, and low income. In a recent epidemiologic survey using the DSM-5 (the National Epidemiologic Survey of Alcohol and Related Conditions-III), the lifetime prevalence for alcohol use disorder was estimated at 29.1% and the yearly prevalence at 13.9%, with the highest rates found among men, whites, and Native Americans, those who were never married or previously married, and younger people (Table 70-6). Table 70-6: Prevalence Estimates (%) for Specific Substance Use Disorders (DSM-5 Criteria) Life-time (%)

12-month (%)

Alcohol use disorders

29.1

13.9

Drug use disorders

9.9

3.9

Data drawn from the National Epidemiologic Survey on Alcohol and Related Conditions-III

Suggested Readings 1. Cooper JE, Kendell RE, Gurland BJ, et al: Psychiatric Diagnosis in New York and London . London: Oxford University Press; 1972. 2. Gordis L: Epidemiology . Philadelphia, PA: Saunders Elsevier; 2014.

3. Grant BF, Goldstein RB, Saha TD, et al: Epidemiology of DSM-5 alcohol use disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. JAMA Psychiatry . 2015; 72: 757–766. 4. Kessler RC, Petukhova M, Sampson NA, et al: Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res . 2012; 21: 169–184. 5. Lichtenstein P, Björk C, Hultman CM, et al: Recurrence risks for schizophrenia in a Swedish National Cohort. Psychol Med . 2006; 36: 1417–1425. 6. McGrath J, Saha S, Chant D, et al: Schizophrenia: a concise review of incidence, prevalence and mortality. Epidemiol Rev . 2008; 30: 68–76. 7. National Co-morbidity Survey, http://www.hcp.med.harvard.edu/ncs/index.php . 8. Robins LN, Helzer JE, Croughan J, et al: National Institute of Mental Health Diagnostic Interview Schedule. Its history, characteristics, and validity. Arch Gen Psychiatry . 1981; 38(4): 381–389. 9. Tsuang MT, Tohen M, Jones PB: Textbook in Psychiatric Epidemiology . 3rd ed. Chichester, West Sussex, UK: Wiley-Blackwell; 2011. 10. Yeung A, Chang TE: Psychiatric epidemiology. In: Stern TA, Fava M, Wilens TE, et al, eds.: Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Elsevier; 2016: pp. 659–666.

CHAPTER Statistics in Psychiat ric 71 Research THOMAS H. MCCOY, JR., MD AND CHRISTINA BORBA, PHD

KEY POINTS Overview Statistical methods are at the heart of data analysis needed to making conclusions about large populations based on small samples. Statistics is a large field unto itself but basic familiarity is possible through mastery of a small number of straight-forward concepts. Roles of Data Statistical analysis follows readily recognized patterns. Variables to be analyzed have a role to play in the analysis—predictor or outcome. Predictors, or independent variables, are typically those variables that are manipulated to affect the outcome or are used to explain changes in the outcome. Outcome, or dependent variables, is the measure in which change is observed or explained. All variables have a level of measure based on the properties of the measurement and property measured. The level of measure is helpful in identifying the appropriate model to apply in a given circumstance. Statistical Inference As a matter of practicality, questions are typically asked in a small number of people (sample) and applied in a large number of people (population). After making measurements in the sample, the process of inferential statistics allows researchers to make comments about what is likely true about the population. Effect Size Statistical significance is concerned only with the inference from sample to

population itself. Statistically significant results can be clinically meaningless. To assess the size of the effect explained by an intervention or predictor, it is increasingly common to report effect sizes. These effect sizes give an approximation of how clinically important a result might be.

Introduction Statistics is the science of summarizing and presenting data and the relationships therein. Statistical literacy is required to critically read the psychiatric literature. In daily practice, probabilistic thinking is central to working with the uncertainty inherent in medical decision-making and testing.

Levels of Measurement The science of data is rooted in the taxonomy of data types. The Steven’s taxonomy of level of measurement is the most widely used. The Steven’s taxonomy is based on the informational content of the measured construct, not the form of the measurement. The levels are: Nominal: These measurements are differentiable only by name. A patient’s race is an example of nominal data. Race is not inherently numerical, it is not inherently rankable, and mathematical operations are meaningless on categorization of race. Ordinal: Ordinal measurements are orderable. A Likert scale, that provides options ranging from strongly agree to strongly disagree, is an example of ordinal data. Degree of agreement is rankable, but the distance between ranked items is meaningless. For example, we have no reason to believe that the difference between “strongly agree” and “agree” is the same size as that between “agree” and “somewhat agree.” Interval: These measurements have meaningful spaces between values but an arbitrary zero value. Celsius temperature is a classic example. The difference between 10 and 20 degrees is the same as that between 20 and 30 degrees; however, 20 degrees is not twice as hot as is 10 degrees. If 0 degrees Celsius had been set to the temperature at which oxygen, instead of water, freezes “20 degrees” would be 4% not 200% warmer than “10 degrees.”

Ratio: Ratio measurements have meaningful continuous spacing and a meaningful zero point. Degrees Kelvin are the classical example, and human height is another. The distance between a 4- and 5-foot tall person is the same as that between a 5- and a 6-foot tall person. However, a 6-foot tall person is twice as tall as a 3-foot tall person. For most analytic approaches, interval and ratio can actually be lumped together as “continuous” variables. Nominal variables, on the other hand, can be decomposed into the special case of dichotomous (two named classes) and the general case of categorical (three or more classes). Physicians are often interested in time as a variable; for example, “How long does it take for something to happen.” Although time to an event is continuous, this is a variable of such interest and with particular practical characteristics that time-to-event is often treated as its own class of data. The other important taxonomy is that of a measurement’s role within a study. Two roles are of particular importance: Independent variable: The independent variable, or predictor , is the variable being manipulated by the investigator. Dependent variable: The dependent variable, or outcome , is the variable being observed to assess the impact of changes made to the independent variable. Identifying the level of a given measurement is an essential first step in selection of a summary statistic or test, whereas both the role and level are needed to do statistical inference.

Descriptive Statistics Descriptive statistics are used to summarize a large number of observations into a more workable, concise representation of the multiple observations. The most common features to summarize are the distribution of unique values, central tendency of those values, and the spread of the data around that center. Each of these is an example of univariate analysis, as they require only a single (“uni”) variable. The mean, median, and mode are the most commonly used measures of central tendency; which is used depends on the level of measure: Nominal: mode

Ordinal: mode or median Interval: mode, median, and mean (arithmetic) Ratio: mode, median, and mean (geometric, harmonic, or arithmetic) The range, inter-quartile range, and standard deviation are the most commonly used measures of spread around the center (or dispersion). Again, the level of measure dictates which can be used: Nominal: none Ordinal: range or inter-quartile range Interval or ratio: range, inter-quartile range, or standard deviation Many characteristics studied in the biomedical literature are measured with interval or ratio scales and are assumed to be “normally” distributed. In other words, if subjects’ scores are plotted on a histogram, as the number of subjects grows larger, the distribution will look more and more like a “bell-shaped curve” or ‘’Gaussian distribution,” with most subjects’ scores grouping toward the sample mean and fewer subjects’ scores falling toward the “tails” (or ends) of the distribution. This is convenient, given that any normal distribution can be described with its mean (measure of central tendency) and standard deviation (spread around that center) alone. Mean (a measure of the center of the distribution): The average score of a group of individuals. In a normal distribution, this is the best single estimate of the ‘’true” score of a group of individuals. The theory is that the mean of a group of individuals represents the “true” score, and the deviation of each individual’s score from the mean is caused by random errors. Standard deviation (a measure of the spread around the mean of the distribution): The average spread of each score from the mean of its group. The smaller the standard deviation, the closer each score is to the mean, and thus there is less spread in the scores. If all individuals had the same score, the standard deviation would be zero because all scores would fall at the mean and there would be no spread. On the other hand, if the standard deviation is as large, or larger, than the mean of a group, there is extreme spread in the group, possibly indicating a severely non-normal distribution.

Bivariate descriptive statistics are also possible. The most common bivariate description is the correlation coefficient (a measure of how two characteristics are related within individuals): a single number that summarizes the correlation of two measures in a group of individuals. Graphically, the correlation coefficient is the slope of the line that best fits a scatter plot of two measures (in standard scores). Correlation requires that variables A and B both be interval or ratio.

Inferential Statistics Inferential statistics are a framework used to infer the true value of a measurement on a full population of interest (typically not possible to perform) based on the measurements observed within a sample drawn from that population of interest. Inference is, to some extent, the reverse of sampling. Instead of shrinking a population of interest down to a tractable sample size, we now reverse the process and infer an interesting population result from a tractable sample. This process is necessarily imperfect. The goal of inferential statistics is to make estimates about the amount of error likely present in this inference about the population from the sample. Hypothesis testing is a statistical framework for assessing whether two samples were drawn from the same population. The less accurate but more useful formulation of this function is asking questions about group differences. This process begins with a null hypothesis stating that two groups are equivalent on some measure. Then, the data is reviewed to see how probable the observed difference between the groups would be as a result of random sampling of a single population. In populations for which the difference observed in the sample is thought to be extremely rare, the notion that the groups are drawn from a single population is rejected. This rejection is taken as evidence that the two samples are in fact from distinct populations. The particular statistical procedure used to assess the probability of the observed difference depends on the level of measure of the dependent and independent variables (Table 71-1). Table 71-1: Examples of Statistical Analysis Approach Selection in Terms of Data Taxonomy Dependent Variable Independent Variable Analysis Continuous

Dichotomous

t-test Wilcoxon rank test

Dichotomous

Time to event

Categorical

ANOVA Linear regression

Continuous

Correlation Linear regression

Dichotomous

Chi-square test Logistic regression

Continuous

Logistic regression

Dichotomous

Log-rank test

Rejection of a statistical hypothesis is open to error in two directions: false– positive and false–negative . A Type I error, or false–positive error, is the error of believing the samples were drawn from distinct populations when in truth the observed difference was merely the result of random variation in sampling. When a study makes a Type I error, the sample randomly happened to be such that a large difference was observed despite the lack of a true difference. In reporting and designing analytic plans the tolerated Type I error rate is called the alpha-level . Typical alpha levels are 0.05 or 0.01 (expected Type I error rates of 1 in 20 and 1 in 100 studies, respectively). Observed results thought to be rarer than one of these preselected alpha levels are said to be statistically significant . A Type II error is the false–negative result, or the odds of sampling from two distinct populations and failing to detect the truly present difference between them. When a study makes a Type II error, the sample randomly happened to be such that, despite a large true difference, the observed difference was small. The inverse of a failure to detect a difference is the detection of a true difference. This detection of a true difference is called statistical power . Small studies often lack the power to infer distinct differences by virtue of their sample size alone. The basic framework of analyzing the odds that an observed difference, or larger one, would arise by random chance and assessing the risk of making Type I and II errors is common to inferential statistics. This process applies to many statistical tests. The simplest form of this procedure is the t-test , which assumes a dichotomous independent variable and an interval or ratio-dependent variable. Dichotomous variables are a special case of nominal measures (ordinal measures with only two values). The t-test is a test for the difference of means (recall the mean is only meaningful in interval or ratio data) between two (recall dichotomous variables have only two values) groups. For example, you could perform a t-test on the difference of mean Beck Depression Inventory (BDI) scores in men and

women presenting to a depression clinic. Here the null hypothesis would be that the means are equal, whereas the alternative hypothesis based on previous literature would be that the mean BDI score of women is higher than the mean BDI score of men. After collecting the data and calculating the mean score for men and women, the results would almost certainly not be exactly equal. This would leave the question: “Is the observed difference a fluke of who we sampled or is it more likely that male and female depression constitute distinct populations?” The t-test could help establish the probability of a difference of the size observed (or larger). This probability value is referred to as the p-value . The p -value is the probability of observing a difference of a given size, or larger, by chance. Recall from the discussion of Type I errors, that when the p -value is smaller than the preselected alpha (tolerability of false–negative), the result is said to be “statistically significant.” If the p -value was much larger than the preselected alpha level (suggesting that this result was more likely to be a fluke that was tolerable to the investigator), the question of power can be raised. Even if a large difference is present in truth, studies with few participants might have insufficient power to detect that difference reliably and thus the study will end in a false–negative conclusion (Type II error). Importantly, inferential statistics, even those that are “statistically significant,” can well be wholly irrelevant. To illustrate this point, imagine doing a study of the age (in years) of men and women currently on your patient panel. You sample 20 people at random, find a 1-year difference in mean age between men and women, preform a t-test which yields a p -value of 0.005, and thus you reject your null hypothesis that men and women are of equal ages within your clinic. You found a “statistically significant” result. Whether a one-year age difference has any importance depends on your practice and reason for answering the question. The t-test and p -value have no bearing on this.

Effect Size The effect size is a standardized measure of the strength of an observed phenomenon. One of the most common measures of effect size is the Cohen’s d , which uses the standard deviation to standardize mean differences, making them more readily comparable. In other words, this is a way of looking at the distances between the center point of two samples adjusting for how widely spread around the center the original samples were. The bigger the effect size, the more likely a difference is to be of clinical significance. Returning to the hypothetical study of patients on your panel, if you are a child psychiatrist, a

one-year age difference may be of greater interest than it would be to a general adult psychiatrist. Effect size captures this intuition. In a children’s clinic, the children (age range 0–18) are less widely distributed in age than the patients in an adult clinic (age range 18–…). As a result, a 1-year mean difference is likely to net a larger effect size in a pediatric clinic than it will in an adult clinic. Although effect size has no cut-off, it is a useful way of comparing studies and developing intuitions for whether a result strikes you as meaningful.

Missing Data Missing data , that is data that should have been collected from a sample but was not, can have a significant effect on the conclusions drawn from the data. There are three types of missing data: Missing completely at random (MCAR) Missing at random (MAR) Missing not at random (MNAR) MCAR refers to the probability that a missing variable is not related to any of the study variables. If data are MAR, missing data may be related to at least one other variable in the study but not to the outcome being measured. The third form of missingness , MNAR, arise when missingness is related to one or more of the outcome variables or that the missing data has a systematic pattern. In general, the threat to the internal validity from MCAR is smallest, whereas MNAR is greatest. This is unfortunate because MNAR is most common pattern. The amount of missing data for each of the variables is important to understand. The “missingness” versus completeness of a dataset is typically expressed as a portion of total data (e.g., “23 of 25 completed the survey”). Small percentages of missing data are generally better than large percentages. There is not clear cut-off for “small,” but 5% missingness is often used as a rule of thumb. In combination, the fewer datapoints that are missing and the more random the elements that are missing, the more representative the data is for analysis.

Epidemiological Statistics These statistics are used to describe the rate of occurrence of a disease in a sample of individuals. Because epidemiologists usually study dichotomous

outcome variables (e.g., disease present/absent, survival/non-survival) these statistics lend themselves to counts, which are then converted to ratios for greater interpretability. Examples include: incidence, prevalence, and odds ratios. Epidemiologists frequently study dichotomous, qualitative variables (such as presence/absence of a disease and survival/death from a disease). The result of a structured psychiatric diagnostic interview will also yield a series of dichotomous, qualitative data. Qualitative variables are analyzed by counting the occurrence of each category of the variable. To make the results more meaningful, these counts are generally converted into proportions or rates by dividing the count of subjects possessing the characteristic by the total number of subjects studied. The rate is then expressed as the rate per 100 (i.e., percent), or, in epidemiology, the rate per 1,000 or per 100,000, depending on the rarity of a disease. Two of the most common epidemiological statistics are the prevalence and incidence of a disease. Incidence describes the rate of occurrence of new cases of a disease in a given population at a given time. This rate is computed as the number of new cases of the disease over a particular time period, divided by the number of people at risk for (but not yet suffering from) the disease. If 2 of 100 adolescents never previously diagnosed with obsessive-compulsive disorder (OCD) had received their first OCD diagnosis in the past 6 months, the 6-month incidence in this population would be 2%. Incidence represents the risk of developing the disease over a given period of time. Prevalence describes how widespread a disease is in a given population at a given time. It is computed as the number of individuals with the disease divided by the total size of the population being studied. For example, if 21 of a group of 100 patients met criteria for major depressive disorder (MDD) at some point in their lives, this particular group would have a life-time prevalence of 21%. If 11 of the same patients had suffered from MDD within the past year, the 12-month prevalence would be 11%. Prevalence represents the risk of having the disease at a particular time. Prevalence is equal to the product of incidence and the mean duration of the disease. Epidemiologists are often interested in comparing the relative likelihood of the presence of a disease depending on exposure or non-exposure to various predictive factors (e.g., selective serotonin re-uptake inhibitor [SSRI] dosing,

smoking, or lack of exercise). The ratios are computed as the risk ratio and the odds ratio between the exposed group and the non-exposed group. The risk ratio is simply the ratio of the chance of having a disease for the group exposed to the risk to the group not exposed to the risk. For example, if 40% of smokers develop asthma, compared to 10% of non-smokers, the risk ratio of smokers to non-smokers is simply 0.40 / 0.10 = 4.0. That is, smokers in this sample would have four times the risk of developing asthma. Risk ratios cannot be calculated in a case-control design (see Chapter 70 ). This is intuitive because case and control are each defined with respect to the outcome of interest, the rate in the groups would be 100% and 0%, respectively. The more commonly used odds ratio (OR) defines the odds as p / (1 – p ), where p is the risk of developing a disease (i.e., the odds of having the disease divided by the odds of not having the disease). So, in the case of smokers, their odds of developing asthma would be .40 /.60 = .67. For non-smokers, their odds of developing asthma would be .10 / .90 = .11. The odds ratio would then be .67 / .11 or 6.09, with smokers having odds of developing asthma 6.09 times greater than non-smokers. Odds ratios are more common for reasons of mathematical and study design necessity. Unfortunately, odds ratios are somewhat counterintuitive and can be easily misinterpreted as the more intuitive risk ratios. Odds ratios approximate risk ratios in very rare diseases; however, in more common cases, the odds ratio is typically much larger than the risk ratio would have been if calculated. Odds ratios are the output of logistic regression and can be calculated in either case-control or cohort studies.

Sensitivity and Specificity Because epidemiology deals with the presence or absence of disease, it is frequently important to know the accuracy of the tests used to diagnose that particular disease. Commonly used measures of diagnostic accuracy are sensitivity and specificity of a medical test. Sensitivity indicates the proportion of true cases that score positive on the screening test. If every subject with a true diagnosis is “picked up” by the screening test, its sensitivity would be perfect, at 1.00. (For example, if a tuberculosis [TB] skin test is positive in 80 of 100 patients with a TB diagnosis confirmed by X-ray and other tests, the sensitivity of the skin test would be 0.80). Specificity indicates the proportion of non-cases that score negative on the screening test. If every subject without a true diagnosis is identified as a negative

by the screening test, its specificity would be perfect, at 1.00. (If a TB skin test is negative in 50 of 100 patients with absence of TB confirmed by X-ray and other tests, the specificity of the test would be 0.50). For many screening tests of serious diseases, high sensitivity (.80 or above) is desirable, so few true cases are missed, at the expense of lower specificity, since false positives will be detected at the next step of evaluation.

Conclusions Basic statistical literacy is required for engagement with the psychiatric literature. Although the field of statistics is vast, literacy requires familiarity with a few organizing principles of statistics and a willingness to learn as you go. Being able to organize data into the role played within a study and the level of measurement is typically sufficient to guide a successful search for additional relevant information. Of particular importance is understanding the role of inference in reversing the sampling process and allowing conclusions about populations to be drawn from a sample to specified degrees of certainty. Of, however, perhaps of greatest importance is thoughtful attention to the magnitude of an effect demonstrated (effect size) and not conflating the size of effect (d ) with the confidence in that effect (p ).

Suggested Readings 1. Cohen J: Statistical Power Analysis for the Behavioral Sciences . 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988. 2. Fleiss JL: The Design and Analysis of Clinical Experiments. New York: John Wiley; 1986. 3. Goldberg G: Clinical Biostatistics Made Ridiculously Simple. Miami, FL: Medmaster; 2011. 4. Little RJA, Rubin DB: Statistical analysis with missing data. 2nd ed. New York: John Wiley & Sons; 2002.

CHAPTER Psychiatric Research 72 Methodology THOMAS H. MCCOY, JR., MD AND DANA CHARLES MCCOY, PHD

KEY POINTS Overview Psychiatric research requires knowledge of methodologies that are common to the biomedical literature and those that are more particular to psychiatry. Familiarity with both the common and the unique aspects of the psychiatric literature is a prerequisite to evidence-based practice. The question, or hypothesis, is central to research methodology. The PICO framework provides a tool for asking appropriate questions by identifying a patient, an intervention, the control, and the relevant outcome. These are the defining traits of a given study and the key traits to match when applying the literature to one’s practice. Validity It is important to conduct and read research with attention to its validity. Internal validity is a property of study design. Studies with high internal validity can be confident that the variables in that study are related as the study suggests they are. Claims of causality require the most internal validity. External validity is the extent to which results generalize from the study to a larger population. Threats to Validity Bias in study designs limits the validity of the resulting work. Sampling—the selection of people to be studied—is one of the most important threats to validity. If the group studied was not as advertised, the conclusions drawn may well be incorrect.

Study Design The biomedical literature draws heavily on a small number of study designs. There are predictable limits to the strength of conclusion that can be drawn from each of these study designs. Randomized controlled trials allow the strongest conclusions. Non-experimental designs, like case series, allow limited conclusions to be drawn.

Introduction Psychiatric research requires knowledge of methodologies (e.g., study design, sampling, and reporting) that are common to the biomedical literature and those which are more particular to psychiatry (e.g., psychometrics). Familiarity with both the common and the unique aspects of the psychiatric literature is a prerequisite to evidence-based practice. Research , be it engagement with existing literature or production of new literature, begins with a question. The PICO framework is a common guideline for research question formulation: P atient problem (or population): for example, non-geriatric adults presenting with delirious agitation following cardiac surgery. I ntervention (or exposure): for example, doubling doses of intravenous (IV) haloperidol every 15 minutes. C ontrol (or comparison): for example, placebo. O utcome: for example, time to intensive care unit (ICU) discharge. Putting these pieces together, we are able to form a single, coherent research question: “Does doubling of doses of IV haloperidol every 15 minutes (versus a placebo administered on the same time-frame) affect time to ICU discharge in non-geriatric adults who present with delirious agitation following cardiac surgery?” Although particularly well suited to treatment studies, the PICO framework provides general guidance on the components of informative research questions. At the same time, even studies with specific research questions can suffer from biases that limit confidence in their conclusions. In the following section, we define several additional prerequisites to the conduct of high-quality research as

well as several core aspects of rigorous study design that can improve the odds of achieving these high standards.

Experimental Validity Validity is the extent to which a study’s conclusions are well founded with roots in the observable world. Two forms of experimental validity should be considered: internal and external validity. A high-quality study is high in both internal and external validity. Internal validity is the “truth” of the observed relation between candidate exposures and outcomes within a given study. That is, “Is what we think we observed in our study what actually happened in the real world?” By considering “threats to internal validity,” clinicians can assess the extent to which a randomized controlled trial (RCT; a “gold standard” study design) actually reaches “golden” (i.e., causal) conclusions. These threats are numerous and can occur as a result of both obvious and subtle errors in sampling, randomization, and measurement. In essence, what we care about when considering the internal validity of a study is the degree to which the research was done in the intended fashion and thus the relationship between the reported variables is as it appears to be. Most study designs are inherently limited in their internal validity. As we discuss below, however, one type of study design, the RCT, can allow for internally valid claims but only if it is conducted appropriately. As such, the consequences of failing to recognize a subtle threat to the internal validity are greatest in the context of a RCT because they can lead to the incorrect reporting of a causal relationship between a treatment and an outcome. External validity is the extent to which the results of a given study can generalize to other situations and people within the broader population of interest. Study conditions and practical clinical conditions often differ a great deal. Studies with high external validity are better able to bridge this gap and to offer meaningful clinical guidance. The “P” of the PICO framework captures the importance of this aspect of validity. The more subjects included in a given study and the more similar they were to your patient, the higher that study’s external validity. The extent to which study patients and your patients are similar is a question of sampling.

Sources of Bias

A number of features of a given study can affect the degree to which it can make appropriate claims of internal and external validity. In the following subsections, we highlight several of these features, including sampling, study design, and measurement.

Sampling Sampling is the process of identifying those who will be studied from within a larger population of interest. A population is a definable group of people, events, objects, or other study-able units (e.g., delirious, agitated, non-geriatric adults). A sample is a sub-group of the population chosen to represent the population in a given research study. Sampling is not inherently desirable; rather, it is a practical necessity (studying all adults with delirium would not be feasible). The realities of research are such that the population is rarely a directly addressable group; instead, only a portion of the theoretical population has the potential to be included in a study sample. This portion is called the sampling frame . Another way to think of the sampling frame is as the largest theoretical possible sample of the population in a study free of concerns about feasibility. In an ideal study, the sampling frame is exactly the population and the sampling methodology is such that all members of the population have an equal chance of being selected for inclusion. There are many candidate sampling methodologies. These candidate methodologies fall into two categories: probability sampling and non-probability sampling. Probability sampling relies on any one of a number of random procedures for selection of the sample from the frame (e.g., simple, stratified, clustered). In other words, each individual within a particular sampling frame (or strata or cluster therein) would have an equal probability of inclusion within the final sample. Non-probability sampling relies on a non-random process (e.g., the next 100 people to present to clinic X). Sampling frames that poorly approximate the population and non-random sampling methodologies are sources of bias and thus weaken study representativeness (i.e., the external validity of a study).

Study Design A study’s design has important implications for the conclusions that can be drawn from it (see Figure 72-1). Whereas the study sample is relevant to the “P” of PICO, the study design is concerned with the strength of the claim we can make about the relationship between the “I” (versus the “C”) and the “O” (i.e., the internal validity of a study). As a general rule, study designs that allow stronger conclusions are more time-consuming and expensive (and thus, they are

rarer), whereas those that are less expensive and less time-consuming are more common.

Figure 72-1: Schematic of research methodology. The strongest conclusion that a study can draw is causality—that is, that the intervention has caused the observed outcome. Following are the most basic requirements for a causal claim: The candidate intervention, selective serotonin re-uptake inhibitor (SSRI); administration, and outcome (remission of depression) must be associated. The candidate intervention must precede the outcome. The relationship between the candidate intervention and the outcome must not be confounded (that is, caused by an unobserved third variable that is correlated with both the intervention and the outcome).

When conducted appropriately, the RCT (typically a double-blinded and placebo-controlled trial) provides the strongest form of clinical evidence because it meets these three demands. The random assignment of participants to intervention versus control status (typically active drug versus placebo) evenly distributes all possible confounds within the sample so that we can have confidence that differences that arise over the study period are attributable to the experimental manipulation. In other words, random assignment ensures that the participants in the intervention and control groups are similar on average (e.g., in terms of their demographic backgrounds, access to resources, health status). This addresses the problem of confounding such that an association between the candidate cause (SSRI administration) and the outcome (remission of symptoms) can be inferred as causal rather than being the byproduct of a meaningful, though potentially unobserved, difference between the two groups. Cohort studies sample subjects exposed to a candidate cause of interest (e.g., psychiatric hospitalization) and then follow this group over time, waiting for the outcome (e.g., psychiatric re-admission) to develop. For events that are very rare or that take a very long time to develop, these studies are prohibitively expensive and time-consuming. However, because the sampling occurs based on known exposure (e.g., being in the hospital), the participants are of known interest; thus, regardless of how rare the exposure, their outcome status can be rigorously measured based on study intent. As such, any association between the exposure and outcome and the order in which they occurred can be known with confidence. At the same time, confounding problems can still exist within cohort studies because the exposure has not been randomly assigned. Subjects who are “lost to follow-up” during a cohort study are an important source of confounding bias in cohort designs as those who drop out of the study are likely to differ in meaningful ways from those who remain in contact. Case-control studies sample subjects known to have an outcome of interest (e.g., schizophrenia) and then match these subjects to participants without the outcome of interest. Rather than looking forward in time (as is done in a cohort study), these studies then look backward to identify candidate exposures (a “frozen mother”) that might have caused these outcomes. Case-control trials are important for studying rare outcomes and are typically less expensive, less timeconsuming, and difficult to perform than the aforementioned types of studies. At the same time, they are ill-suited to studying rare predictors and are easily biased and confounded. Differential recall of candidate causal exposures across individuals experiencing different outcomes is an important source of

confounding bias (e.g., a patient with schizophrenia might search his or her memory harder for adverse childhood experiences than a healthy control). Matching controls is notoriously difficult; if controls are matched to cases on all relevant variables, there are no variables left to study. In sum, case-control trials might be able to show that the candidate exposure preceded the outcome and that the two are associated, but, again, they cannot account for all potential confounds. Cross-sectional studies measure both candidate exposures and the outcome of interest at the same time. The studies are typically well suited to demonstrate associations between outcomes and candidate causes; however, such studies are definitionally unable to demonstrate the temporal ordering and have minimal protection from confounding beyond the inclusion of control variables in the analysis. Descriptive studies, such as case series , are studies that lack a group for comparison (i.e., a control group). These studies are unable to make causal claims because they are unable to demonstrate an association (as all participants have the same candidate exposure). In sum, the more rigorously a given study design addresses the requirements for causal claims, the more weight one should place on the internal validity of that study.

Measurement Psychiatric phenomena are often difficult to measure directly. This is less true in other areas of biomedical research in which directly measurable physical properties (e.g., blood pressure in mm Hg, ejection fraction) can serve as the variables of interest. Measurement tools (e.g., scales, indices) provide a means of indirectly operationalizing the interesting but inherently unobservable constructs. Psychiatry has many noteworthy measures, including the Beck Depression Inventory, which is used to approximate major depression. Psychometrics—the study of measures—is concerned with how reliable and valid a particular measurement tool might be. The reliability of a measure is the degree to which it is able to reproduce a particular individual’s score. There are many forms of unreliability and thus many ways of establishing reliability. For example: Inter-rater reliability: Do two psychiatrists administering the same scale to the same patient obtain the same result?

Test-retest reliability: If the same patient completes the same scale on two separate occasions spaced closely apart, will the scale yield the same result on both occasions? Internal consistency and parallel-forms reliability are also reported as indicators of a measure’s reliability. Although the details of these indicators are less intuitive, the generality is that the exact packaging of the scale does not drive the outcome and the individual questions on the scale all hang together. Reliability—either across time or across raters—is of particular importance because studies that allow for internally-valid claims typically require both. The validity of a measure is the degree to which it actually captures the unobservable construct it intends to capture. The conceptual problem of demonstrating an accurate measurement of the unmeasurable quickly becomes overwhelming if one considers it for any length of time. The easiest notion of validity is the extent to which a given measure is strongly correlated with an existing (typically more difficult or expensive-to-administer) gold standard test. This concept is known as criterion validity . In psychiatry, the structured clinical interview is often treated as just such a gold standard. If a new, patient-reported scale is able to reproduce the results of this more intensive assessment, then this new scale is said to show solid criterion validity and may be preferred moving forward for practical reasons. Psychometricians have developed guidelines for establishing validity de novo without reference to a gold standard. These typically include face , content , and construct validity , and focus, for example, on ensuring that a measure captures all constructs it intends to capture, but nothing further. Importantly, the psychometric notion of validity is distinct from, but conceptually related to, the question of diagnostic validity. Diagnostic validity is concerned with the extent to which the metric of diagnostic labels accurately reflects some independent truth in the world. The Feighner Criteria, reported by Feighner in the Archives of General Psychiatry in 1972, are one effort to define this. Although semantically similar, the concept of psychometric validity is distinct from the concept of experimental validity. At the same time, a lack of psychometric validity can have implications for experimental validity. For example, if a measure that lacks psychometric validity is used in a RCT, the systematic bias introduced by this measure becomes a threat to the internal validity of the RCT.

Reporting Because establishing the internal and external validity of a study is complex and nuanced, journal editors and evidence-based medicine advocates have developed guidelines and checklists for the reading and reporting of biomedical research. This effort is being driven by the EQUATOR (Enhancing the QUAlity and Transparency Of Health Research) Network . Important guidelines differ by study design. These guidelines are: CONSORT—for experimental randomized controlled trials STROBE—for quasi-experimental/observational studies CARE—for case reports Guidelines are also available for systematic reviews (PRISMA), qualitative research (COREQ), and preclinical studies (ARRIVE). In general, however, it is important to report all information that may be relevant for convincing a reader of a study’s internal and external validity, including full information regarding study sampling, design, and psychometric properties.

Conclusion Reading and contributing to the psychiatric literature requires familiarity with the issues inherent in all biomedical research, as well as those unique to psychiatric research. In this chapter, we have discussed several standards that are necessary for producing a high-quality psychiatric study; we summarize them here: As is true of the biomedical literature in general, whether one is consuming or producing psychiatric research, the process should begin with a clearly formulated and articulated research question. The PICO framework is particularly helpful when reviewing the treatment literature. The way that a study sample is selected from a broader population has critical implications for the study’s external validity, or generalizability. Probability-based sampling procedures improve confidence that the results of a study will be relevant for a broader population of interest. The internal validity of a study is largely dictated by the study’s design. Causality—that is, the claim that an intervention causes the outcome of

interest—is the strongest claim a study can make. This claim is only plausible in experimental (e.g., RCT) study designs. Although RCTs can allow for internally valid-causal claims in theory, in practice, they do so to varying degrees of success. Psychiatric constructs are particularly difficult to measure. Psychometrics is the study of a measure’s reliability and validity. In as much as measures are central to the psychiatric literature, their repeatability and relevance to constructs of interest are central to reading and using the psychiatric literature.

Suggested Readings 1. Brian Haynes R: Forming research questions. J Clin Epidemiology . 2006; 59: 881–886. 2. Fitzmaurice G: Measurement error and reliability. Nutrition . 2002; 18: 112–114. 3. Grimes DA, Schulz KF: An overview of clinical research: the lay of the land. The Lancet . 2004; 359: 57–61. 4. Grimes DA, Schulz KF: Bias and causal associations in observational research. The Lancet . 2002; 359: 248–252. 5. Grimes DA, Schulz KF: Cohort studies: marching towards outcomes. The Lancet . 2002; 359: 341–345. 6. Rothwell PM: External validity of randomised controlled trials: “To whom do the results of this trial apply?” The Lancet . 2005; 365: 82–93. 7. Sainani KL, Popat RA: Understanding study design. PM&R . 2011; 3: 573– 577. 8. Schulz KF, Grimes DA: Case-control studies: research in reverse. The Lancet . 2002; 359: 431–434.

CHAPTER Genetics and Psych iatry 73 TAMAR C. KATZ, MD, PHD; DANIEL H. EBERT, MD, PHD; CHRISTINE T. FINN, MD; AND JORDAN W. SMOLLER, MD, SCD

KEY POINTS Overview Genetic variants can disrupt a gene itself (coding DNA) or disrupt promoters or enhancers that regulate gene expression (non-coding DNA) and increase risk for psychiatric disorders. Several types of polymorphisms including single nucleotide polymorphisms, copy number variants, and rare variants differ between individuals and are linked to psychiatric illness. The genetics of psychiatric disorders is complex; whereas some are linked to a single gene mutation, others are due to the combined effect of many genes that each contribute only a small effect size. Most psychiatric diseases are thought to arise from the interaction of genetics and environment. Understanding the genetic causes of psychiatric illness can help elucidate mechanisms of illness, allow for targeted therapies that interrupt the genetic pathway of interest, identify family members who may be at risk, and allow for increased surveillance of symptoms. Theoretical Basis of Genetic Mapping Scientists use patterns of inheritance and sequencing technology to create genetic maps, detailed outlines of the location of each gene on every chromosome within a species. The genetic map for a species will be similar between all healthy members of that species, and the loss or mis-patterning of genes within the map sheds light on causes of illness. Genetic mapping can be done using blood or tissue samples from family members who carry a prominent disease and comparing it to the DNA of

healthy family members. Dominant, recessive, and X-linked patterns of inheritance have been linked to psychiatric illness. Mutations in high-risk genes can be inherited from one or both parents, or might emerge as de novo , or new, genetic mutations that can arise at any stage of genetic development. Variations within the same gene can be a risk factor for multiple psychiatric disorders. Tools of Psychiatric Genetics Family studies, twin studies, and adoption studies are used to determine the heritability of a disorder and the relative contributions of genetic and environmental causes. Popular molecular techniques include the candidate gene approach, whole genome approach, genome wide association studies (GWAS), linkage studies, and fluorescence in situ hybridization. The goal of molecular approaches is to identify the genes that cause a disorder so that targeted therapies can be designed to interfere with the genetic pathways and thus correct symptoms. GWAS in particular can identify novel mutations involved in psychiatric illness, though these studies often require thousands of subjects to reach statistical power. Some molecular techniques are leading to “personalized genomics” that allow an individual to know what genes he or she carries that might place him or her at risk. Genetics of Psychiatric Disorders and Clinical Applications Many psychiatric disorders have been shown to have high genetic heritability, including attention deficit hyperactivity disorder, autism spectrum disorders, mood disorders, anxiety disorders, dementia, schizophrenia, and substance use disorders. Many genetic syndromes and inborn errors of metabolism also manifest with psychiatric symptoms which may be the earliest evidence of the disease— examples include Huntington disease, Trisomy 21, Prader-Willi syndrome, and tuberous sclerosis among many others. Genetic syndromes and metabolic illnesses may be associated with a history of food intolerance, loss of developmental milestones, seizures, or other neurological findings. Psychiatrists must be familiar with clinical findings that raise suspicion for the

presence of genetic illness as accurate early diagnosis allows for improved surveillance and treatment. The possibility of a genetic syndrome should be considered in patients with congenital anomalies, co-morbid intellectual disability, or a familial pattern of illness.

Introduction The impact of genetic research and genetic medicine on psychiatry is growing due to advances in our understanding of the genetic basis of common psychiatric disorders, neuropsychiatric manifestations of genetic and chromosomal diseases, and the development of new genomic-sequencing technologies. This chapter reviews both the genetic aspects of psychiatric disorders and the psychiatric aspects of genetic disorders.

Basic Principles of Genetics and Gene Mapping The Human Genome The human genome encompasses 22 pairs of homologous chromosomes and one pair of sex chromosomes (X and Y) that together contain approximately 3.2 billion base pairs. Almost all (98%) of these bases comprise non-coding DNA , stretches of DNA that do not code for proteins but contain sequences essential for healthy gene functioning, including promoter and enhancer elements, regulatory RNAs, origins of DNA replication, centromeres, and telomeres, among others. The remaining 2% of the human genome, or coding DNA, contains approximately 21,000 genes that encode the estimated half million proteins that enable all human functions. Psychiatric disorders have been linked to genetic variations in both coding and non-coding DNA. Genetic variants can disrupt a gene itself (coding DNA) or disrupt promoters or enhancers that regulate gene expression (non-coding DNA) and increase risk for psychiatric disorders.

Genotypes and Phenotypes With the exception of egg and sperm cells, all healthy human cells contain two copies of each gene, one on each chromosome. The X and Y chromosomes are an exception to this and will be discussed later. These different forms of a gene are referred to as alleles , and the location of the gene on the chromosome is

known as the genetic locus . If the two alleles at a locus are the same on both chromosomes, an individual is said to be homozygous at the locus. If the alleles differ, the individual is heterozygous . The complete sequence of all genes contained within an individual is known as a genotype ; the observable traits that arise from expression of these genes is referred to as an individual’s phenotype. The genotypic similarity among members of a species accounts for the phenotypic similarity observed; for example, on average, all humans are 99.5% genetically similar to all other humans. Genes that are preserved between individuals within a species are said to be fixed , meaning that only a single allele of that gene is present in healthy members of the population. In contrast, genes with multiple variants within the population are referred to as polymorphisms . Polymorphisms, together with the exchange of genetic material during meiosis and random mutational events account for differences between individuals. Many polymorphisms exist as single base pair changes between alleles of the same gene, known as single nucleotide polymorphisms (SNPs ). SNPs occur normally throughout the genome, once every 300 nucleotides on average, which means there are roughly 10 million SNPs which account for normal variation between individuals. Some SNPs, however, occur in genes that are associated with causing illness, and the SNPs themselves might play a role. Rare variants are alternative forms of a gene that are present with a minor allele frequency of less than 1% and are often associated with causing disease.

Genetic Mapping Scientists use these patterns of inheritance and the relative locations of genes along a chromosome to create genetic maps , detailed outlines of the location of each gene on every chromosome within a species and within an individual. The genetic map for a species will be similar between all healthy members of that species, and the loss, misplacement, or mis-patterning of genes within the map sheds light on causes of illness. Genetic mapping may be done using blood or tissue samples from family members that carry a prominent disease and comparing it to the DNA of healthy family members. Two genes that are spatially close together on a chromosome are likely to be transferred between chromosomes on the same transmitted segment; thus, these genes tend to travel together and are said to be linked . An individual with one gene is likely to carry the other gene, as well, and will often express both traits (classic examples include red hair and freckles, or blonde hair and blue eyes).

The degree of genetic linkage is expressed as a genetic distance (in centimorgans) or a physical distance (in base pairs). Loci that are separated by recombination in 1% of meioses are 1 centimorgan apart; this corresponds roughly to a physical distance of 1 million base pairs.

Genetic Architecture of Psychiatric Disorders In some instances, a single gene gives rise to a single phenotypic trait, such as in the case of blood type and sickle-cell disease. This type of gene expression, in which a trait arises as the product of a single gene, is known as Mendelian expression . Mendelian inheritance can be characterized as dominant , whereby a single copy of the gene is sufficient to impart a phenotype, recessive , whereby the combination of both alleles impart a phenotype, and X-linked , whereby the gene is carried on the X chromosome and expression therefore differs in males (XY) versus females (XX). Neuropsychiatric disorders due to single gene mutations include Huntington disease (autosomal dominant), Wilson disease (autosomal recessive), and Fragile X syndrome (X-linked). However, in contrast to these three diseases, most psychiatric disorders have a polygenic etiology; that is, they result from the combined action of many genes, and each single gene can contribute to only a small effect size. In some cases, the mechanism by which these genes work together to cause psychiatric illness is not well understood, and the contribution of any one gene to the overall picture is sometimes elusive. Such complexity complicates efforts to identify the genetic basis of psychiatric disorders. A sub-set of psychiatric phenotypes arises from rare variants. As opposed to a polygenic model in which many modest effect-size genes combine to produce a phenotype, in a rare variant model, an individual rare mutation gives significant risk for developing a disorder. An example of a rare variant includes copy number variants (CNVs), which are genetic mutations in which the number of copies of a particular gene varies from one individual to the next. These can include deletions (too few copies of a genetic sequence) or duplications (extra copies). CNVs can range from thousands to millions of base pairs, unlike SNPs, which affect only one single nucleotide base. Many psychiatric illnesses, such as schizophrenia and autism spectrum disorder (ASD) show an increased number of CNVs as compared to controls. Mutations in high-risk genes can be either inherited from one or both parents, or can emerge as de novo , or new, genetic mutations that can arise at any stage

of genetic development (including DNA replication, homologous recombination during meiosis, or RNA transcription). Although some mutations are benign, others are sufficient to induce serious illness if they occur in a gene of psychiatric importance. For several neuropsychiatric disorders, including ASD and schizophrenia, there is an increased prevalence of de novo mutations, including de novo CNVs. To further complicate this picture, variations within the same gene can be a risk factor for multiple psychiatric disorders. Often, a single gene can affect two or more phenotypic traits, a phenomenon known as pleiotropy. For example, there is evidence of genetic overlap between the genes involved in schizophrenia and bipolar disorder and between schizophrenia and ASD. Micro-duplications of 1q21.1 are associated with ASD and schizophrenia, and micro-duplications of 16q11.2 are associated with ASD, schizophrenia, and bipolar disorder, yet individuals who have any one of these disorders are unlikely to have all three. Many CNVs are associated with multiple psychiatric disorders. This can complicate the identification of genetic causes of psychiatric disorders.

Psychiatric Disorders that Arise from the Interaction of Genes and Environment For most psychiatric phenotypes, an individual’s genetic background is thought to provide a risk for development of a disorder though it might not be sufficient to cause illness without the input of environmental factors, such as stressful life events or infection. Some psychiatric illnesses, such as bipolar disorder, show a strong genetic component, with identical twins having 80% concordance for bipolar disorder even when raised in different environments. Other illnesses, such as unipolar depression, seem to have more even distribution of environmental and genetic risk factors. Studies of gene-environment interaction are relatively new in the field of psychiatry (over the past 15 years) and their utility remains to be determined. These studies are difficult to conduct because multiple simultaneous genetic and environmental risk factors are likely involved in the onset of disease in an individual. Additionally, even though the heterogeneity of individual responses to causal factors can be attributed initially to genetic difference, the response of the individual in turn affects future environmental experiences, which spurs epigenetic modifications in an ever-turning cycle. It might prove near impossible

to distinguish between pure genetic and pure environmental influence, or to isolate an individual cause of complex multi-factorial diseases.

The Tools of Psychiatric Genetics Genetic epidemiologists and molecular geneticists employ numerous techniques to determine whether a disorder has a genetic basis and, if so, to locate the genes involved. The emergence of new DNA-sequencing technologies in recent years is leading to exciting progress in this area.

Family Studies Family studies seek to determine if a disorder runs in families. The proband is defined as the individual through whom a family is ascertained. If relatives of affected probands have a higher incidence of the disorder than relatives of unaffected probands, the disorder is familial. One index of the strength of familiality is the recurrence risk ratio for first-degree relatives (λ 1), defined as the ratio of the risk of the disorder in a first-degree relative of an affected individual to the prevalence in the general population. This ratio can predict the strength of genetic influences on the disorder and the likelihood that genemapping studies will have the power to identify the genes involved. The riskratio depends on both the risk to relatives (numerator) and the base-rate of the disorder within the general population (denominator). Even when the relative risk of the disorder is high, the absolute risk to a first-degree relative can be low if the base-rate of the disorder is low. For example, siblings of probands with schizophrenia have a roughly 10-fold increased risk of the disorder compared with the general population. However, because the population prevalence is approximately 1%, the absolute risk of the disorder for the sibling is only about 10% (thus 90% probability of being unaffected). In contrast, the lifetime prevalence of major depression is approximately 15%, so even a 2-fold increased risk to siblings is associated with a 30% risk of being affected.

Twin and Adoption Studies A disorder can run in families for non-genetic reasons. For example, shared environmental experiences may produce the disorder in multiple family members. Twin and adoption studies can be used to estimate the contribution of genetic and environmental causes of familial aggregation. Twin studies can provide an estimate of the heritability of the disorder, which refers to the proportion of the phenotypic differences among individuals that can

be attributed to genetic variation. Twin studies compare concordance rates between identical twins (also known as monozygotic twins, with near identical DNA) and fraternal twins (who are also known as dizygotic twins and share approximately 50% of their alleles on average). A twin pair is concordant if both co-twins display the phenotype. If we can assume that both monozygotic (MZ) and dizygotic (DZ) twins are exposed to the same levels of environmental influences, then significantly higher concordance rates in MZ twins reflect the effects of genetic contribution. Similarly, adoption studies can further disentangle genetic and environmental influences on family resemblance by comparing rates of a disorder in biological family members (who are genetically related) with those in adoptive family members. For example, if an adopted child has a genetically-influenced disorder, the biological (genetic) parents should have a higher risk of the disorder than the adoptive (environmental) parents. Adoption studies provided the first convincing evidence that genes are important in the development of schizophrenia.

Molecular Genetics The growing awareness of the genetic basis of much psychiatric illness has helped drive development of new molecular genetic methods that scientists use to locate and isolate the specific genes that influence a disorder. The hope is that by identifying the genes or groups of genes that cause particular disorders, targeted therapies can be designed to interfere with the identified genetic pathways and thus correct the psychiatric symptoms. Although the full scope of genetic methods employed would exceed the limitations of this text, the most common approaches are outlined here. The candidate gene approach focuses on one gene or a small group of genes that are believed to play a role in causing disease states. Candidate genes are typically selected based on a priori knowledge or a strong hypothesis that a gene’s biological function is likely to be involved in a particular disease state. Candidate genes can be selected based on knowledge of the gene’s function, or based on that gene’s location in biologically-relevant regions of the genome. For example, the serotonin transporter gene might be considered a candidate gene for mood disorders because serotonergic function has been implicated in the physiology and treatment of these disorders. The candidate gene approach is often designed as a case-control study, with the goal to ascertain whether subjects with a specific genetic mutation are more likely to develop the disease than control subjects without the mutation. The advantage of utilizing a

candidate gene approach is that studies are targeted, faster, and often less expensive. The disadvantage, however, if that because the pathogenesis of most psychiatric disorders is poorly understood, it might be difficult to identify compelling candidate genes for testing. Additionally, because many psychiatric illnesses are polygenic (caused by more than one gene), a candidate gene approach in which single or small groups of genes are studied in isolation is often insufficient to fully capture the genetic causes of a particular illness. In contrast, in a whole-genome approach , greater than 95% of an individual’s genome is sequenced and all mutations within that genome are elucidated. Therefore, mutations that occur at a higher rate in affected individuals become targets of interest and grounds for further study. This approach has been touted as “personalized genomics” and in recent years has been a major breakthrough in molecular genetics. Using this information, clinicians can identify increases in disease risk for specific patients, and their likelihood to respond to certain treatments. Unlike the candidate gene approach, a whole-genome approach requires no prior knowledge of the function or location of the genes involved in the disorder. This is a mixed blessing: even though a whole-genome approach is more likely to identify all mutations involved in an illness, it also identifies many extraneous mutations of unclear clinical significance and therefore clouds treatment decisions. Additionally, whole-genome sequencing is time consuming and costly. The largest neuroscientific breakthrough in psychiatric genetics in the past decade has been the increased focus on genome-wide association studies (GWAS ). In these studies, hundreds or even thousands of genomes from individuals with and without the disease are sequenced and compared to one another using sophisticated computer algorithms to analyze whether variations in genes and intergenic regions are associated with a psychiatric disorder. Genomes can be compared between unrelated individuals and between parents and their children. These studies often analyze single-nucleotide polymorphisms (SNPs ). If a SNP is more common in affected individuals, that SNP is considered to be “associated” with the disease. In GWAS, DNA chip (microarray) technology can be used to genotype SNPs across the genome in unrelated cases and controls or in families. To get enough statistical power to see an association of a SNP with a psychiatric disorder, thousands of patients and controls are often required, and factors such as race/ethnicity, gender, and geographic distribution must be controlled for to reduce false positives.

In additions to SNPs, GWAS of CNVs are also providing insight into rare genetic variants that contribute to a subset of psychiatric illness. There are more than 1,000 CNVs in the genome, and studies show that some CNVs are enriched in patients with schizophrenia, ASD, and bipolar disorder and tend to occur de novo at higher rates in these illnesses. GWAS are also providing insight into indels , insertion–deletion sites, which are sites within the genome where base pairs of DNA have been deleted or extra base pairs have been inserted. The insertion or deletion of DNA base pairs is implicated in psychiatric illness because it not only disrupts a gene in question, but often causes frameshift mutations that affect downstream genes and lead to incorrect mRNA transcription. Linkage studies examine whether two or more genetic loci are co-inherited more often than expected by chance, and might help determine which genes are consistently inherited by individuals who go on to display the phenotype in question. In classical linkage analysis, the strength of the evidence in favor of linkage is calculated as a logarithm of the odds (LOD) score. The LOD score compares the likelihood of obtaining the observed results if the two loci are indeed linked, to the likelihood of observing the same results by random chance. Traditionally, a LOD score of 3 (corresponding to odds of 1,000:1 in favor of linkage) has been the threshold of declaring linkage. Fluorescence in situ hybridization (FISH) is a cytogenetic technique that uses fluorescent probes designed to bind to a complementary segment of DNA. These probes can be designed to bind to any gene of interest, and can localize where on the chromosome a gene is located, as well as any mutations within that gene. FISH can also be used to detect and localize specific RNA targets in cells.

Heritability Estimates Many of the above molecular techniques are used to study the heritability of psychiatric disorders, a topic that will be referenced repeatedly in the coming sections of this chapter. It is important to note that heritability is the extent to which differences in the appearance of a trait across a population can be accounted for by genetic factors. Heritability is measured on an index from 0 to 1; a heritability index of zero means that none of the variability between individuals in the population is due to genetic factors (implying a strong environmental contribution). Heritability does not predict the extent to which traits are passed down from parent to offspring, nor does it indicate the degree of genetic influence in the traits of a particular individual. For example, if the

heritability of schizophrenia is 0.8, this does not mean that 80% of the symptoms are inherited from one’s parents and 20% are environmental, nor that 80% of one’s offspring will have schizophrenia.

Disorders of Childhood and Adolescence Attention Deficit Hyperactivity Disorder Family Studies Attention deficit hyperactivity disorder (ADHD ) runs in families, and firstdegree relatives of ADHD probands have a 2- to 8-fold higher risk of the disorder than relatives of unaffected individuals. Family studies also suggest that ADHD and depression share familial determinants, and that ADHD with conduct and bipolar disorders may be a distinct familial sub-type.

Twin Studies and Adoption Studies Most heritability estimates for ADHD have ranged from approximately 60% to 90%. Adoption studies have demonstrated that the risk of ADHD is higher among biological relatives than among adoptive relatives.

Molecular Genetic Studies GWAS have failed to reveal loci associated with ADHD with genome-wide significance despite large sample sizes, though over 30 candidate genes have been identified and are currently being studied including PRKG1 on chromosome 10. GWAS studies have also revealed an increased burden of large and rare CNVs with ADHD patients as compared to controls. Duplications of 16p13.11 have been associated with ADHD. Rare CNVs affecting GRM1 , GRM5 , GRM7 , and GRM8 have also been associated with increased risk for ADHD; the GRMs are metabotropic glutamate receptors that modulate excitatory synapses, suggesting an important role for glutamatergic neurotransmission in ADHD pathogenesis. In one study, CHRNA7, a nicotinic acetylcholine receptor, showed six large duplications in ADHD-affected individuals and none in controls. The lack of statistically strong GWAS findings may be explained by the fact that ADHD may be a multi-factorial disorder caused by multiple variants with small effect sizes, or may be caused by low frequency alleles that are not well detected with common microarray methods. Alternatively, there might be multiple ADHD sub-types that have different genetic mechanisms; the heterogeneity of combining thousands of samples of different sub-types might dilute the genetic results.

Autism Spectrum Disorder Family Studies The risk of autism spectrum disorder (ASD ) to siblings of affected children is approximately 3% to 4%, which is more than 75-fold higher than the general population’s prevalence. These studies argue against a single gene hypothesis for ASD, as a risk of 25% to 50% would be expected if the disorder were due to a single gene. Advanced parental age (e.g., over the age of 40 years) has been associated with a modest increased risk of ASD among offspring.

Twin Studies Concordance rates for MZ twins are markedly higher than those for DZ twins, and the heritability has been estimated to be in the range of 60% to 90%.

Molecular Genetic Studies Research on ASD is rapidly evolving. Currently, ASD is thought to arise from several genetic mechanisms: 3% of ASD cases are thought to arise from rare de novo mutations that occur spontaneously during development and are not inherited from one’s parents while an additional 3% arise from rare inherited variants. Examples include rare mutations in NLGN4 (encoding neuroligin 4 ), NRXN1 (neurexin 1), SHANK3, and SHANK2 all of which code for proteins involved in the assembly and function of synapses. CHD8, a helicase-binding protein that represses transcription, has also been implicated. Mutations in CHD8 cause overgrowth of some synapses. Thus, inappropriate synapse development is highly implicated in ASD pathogenesis. CNV studies have also revealed a 10-fold increase in de novo CNVs in individuals with ASD. However, recent GWAS have suggested that close to 50% of cases of ASD arise from the combined effect of over 100 common inherited gene variations, dispersed among almost all chromosomes, many of which are common variants found in individuals without the disorder and include both SNPs and CNVs. In this model, each genetic variant increases the risk of developing an ASD only slightly, but taken together the combined effects of multiple variants have a substantial impact. Increasing numbers of variants can push an individual further along the spectrum and might explain the broad range of behavioral features seen in individuals with ASD. Many of these SNPs and CNVs occur in noncoding regions of the DNA and likely affect regulation of nearby genes though the mechanisms are unclear. The cause of the remaining 40% to 45% of cases of ASD remains unelucidated.

Tourette Disorder Family Studies Tourette syndrome has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance, though GWAS have not yet identified common variants associated with the disorder. First-degree relatives of Tourette disorder probands have an 8.7% risk of the disorder, 174-fold greater than that of the population’s prevalence. There is evidence for variable expression of the genetic liability for Tourette disorder, e.g., relatives of probands with Tourette disorder have a higher risk of obsessive-compulsive disorder (OCD) and chronic motor or vocal tics.

Twin Studies In the largest twin study, MZ concordance rates are 50% to 77%, exceeding DZ concordance rates of 10% to 23%.

Molecular Genetic Studies Association studies have lacked sufficient size and sample power to detect common variants associated with Tourette disorder. Cytogenic studies reveal disruptions of CNTNAP2 , Neuroligin 4X , and Neurexin 1 , genes also implicated in ASD and schizophrenia. These genes may be risk factors for multiple psychiatric disorders, and such pleiotropy often complicates our understanding of psychiatric genetics.

Dementia: Alzheimer Disease Family and Twin Studies Alzheimer disease (AD ) has both an early-onset sub-type (onset before age 60) and a late-onset AD sub-type (onset after age 60–65) and both have strong familial heritability. Having a first-degree relative with AD approximately doubles the risk of AD. A large twin study estimated the heritability of late-onset AD to be approximately 60%.

Molecular Genetic Studies The genetics of early-onset familial AD (EOFAD) has been relatively well established, and three specific genes have been shown to produce EOFAD with an autosomal dominant mode of inheritance: mutations in amyloid precursor protein (APP) 10%–15% of EOFAD), presenilin 1 (PSEN1, 30%–70% of EOFAD), and presenilin 2 (PSEN2, less than 5% of EOFAS). Additional cases

have been described of EOFAS with no identifiable mutations in PSEN1, PSEN2, or APP . It is therefore likely that additional genes are causative. Late-onset AD is far more common and has a more complex etiology. The apolipoprotein E (APOE) gene has been associated with late-onset AD. There are three common alleles of APOE (ε 2, ε 3, and ε 4), and it is the ε 4 allele that increases risk for late-onset AD. Unlike autosomal dominant genes involved in early-onset AD, APOE- ε 4 is a susceptibility allele that acts as a risk factor for the disease, but it is neither a necessary nor sufficient cause. A primary effect of the ε 4 allele is to reduce the age of onset of AD; individuals with two copies of the allele have the earliest age of onset compared with individuals with other APOE genotypes. GWAS of late-onset AD in recent years have implicated CLU , PICLAM , CR1 , BIN1 , EPHA1 , MS4A , CD33 , CD2AP , and ABCA7 as loci associated with risk for AD; these genes provide insight into the pathogenesis of AD. Genes CLU and CR1 encode regulators of the complement system, suggesting a role for inflammation, the immune system, and complement. Genes BIN1 , PICALM , and CD2AP encode proteins involved in endocytosis, a pathway important for APP processing and β -amyloid formation. EPHA1 encodes a member of the ephrin receptor sub-family that is involved in axon guidance and synaptic plasticity. Genes APOE , CLU , and ABCA7 encode proteins involved in cholesterol and lipid metabolism suggesting that cholesterol and lipid metabolism influence AD. Indeed, hypercholesterolemia is a known risk factor for AD. The high risk of AD among individuals with Down syndrome (trisomy 21) has been attributed largely to triplication of the amyloid precursor protein gene on chromosome 21. Onset of AD in these individuals ranges from 40 to 60 years old.

Psychotic Disorders: Schizophrenia Family Studies Family studies of schizophrenia have repeatedly demonstrated high heritability. Compared with the life-time risk of 1% in the general population, first-degree relatives have a 10-fold increase, or approximately a 10% risk. The risk drops to about 4% for second-degree relatives and 2% for third-degree relatives. A number of neurobiological phenotypes also appear to be more common among non-schizophrenic relatives of individuals with schizophrenia. These phenotypes include smooth-pursuit eye-tracking dysfunction, neuropsychological deficits (in

memory, language, and attention tasks), and abnormal P50 auditory-evoked potentials. Such phenotypes can be called “intermediate phenotypes” or endophenotypes because they reflect genetic heritability but manifest as lowlevel symptom vulnerability rather than acute illness.

Twin and Adoption Studies The heritability of schizophrenia has been estimated to be 70% to 89%. The concordance rate for MZ twins of 46% substantially exceeds that of DZ twins 14%. Adoption studies have demonstrated that the prevalence of schizophrenia is approximately 4-fold higher in biological relatives than in adoptive relatives, suggesting that while environment may play a triggering role, genetic susceptibility is a key factor in the development of the illness.

Molecular Genetic Studies The genetic risk is schizophrenia is conferred by a large number of common alleles of small effect that collectively impart heavy risk. GWAS have identified over 108 associated loci that meet genome-wide significance, 75% of which include protein-coding genes, with sample sizes in some studies exceeding 36,900 subjects. Though we cannot list all 108 genes here due to space constraints, many of the identified genes are involved in key regulatory functions that are impaired in individuals with schizophrenia, including DRD2 (D2 dopamine receptor gene), TCF4 (a transcription factor involved in neurogenesis), NRGN (a post-synaptic protein kinase substrate involved in learning and memory), and ZNF804A (a transcription factor involved in regulating neuronal connectivity). Multiple genes involved in glutamatergic neurotransmission and synaptic plasticity were also implicated, including GRM3, GRIN2A, SRR , and GRIA1 , as were genes which encode voltage-gated calcium channel sub-units such as CACNA1C, CACNB2 , and CACNA1 . Loci involving microRNAs and CNVs have also been associated with schizophrenia. A higher overall rate of de novo CNVs has been associated with schizophrenia as compared to controls. Recent studies have raised a possible connection between schizophrenia and aberrant immune-mediated processes in the brain, such as inflammation or autoimmunity. GWAS has identified increased expression of many immune-related genes including the major histocompatibility complex (MHC) locus in individuals with schizophrenia. The connection between immunity and mental illness is still being elucidated.

Mood Disorders Bipolar Disorder Family Studies Bipolar disorder has high familial transmission: first-degree relatives of bipolar probands have a 5% to 10% risk of developing bipolar disorder (7–10 fold increase above the general population), and a 10% to 20% risk of developing unipolar depression (2–5 fold increase).

Twin and Adoption Studies Concordance rates are substantially higher in MZ twins (39%–62%) than in DZ twins (0%–9%), and the heritability of bipolar disorder has been estimated to be approximately 60%–85%.

Molecular Genetic Studies GWAS of over 24,000 participants have identified more than 50 genome-wide significant SNPs implicated in bipolar disorder in five chromosomal regions. The data also provide strong evidence for additional risk loci, each of which may contribute a small effect to bipolar susceptibility. The largest number of significant SNPs were identified in ANK3 and TRANK1 (both involved in cytoskeleton stability and cell motility and contact), ODZ4 (implicated in reward processing in the amygdala and connectivity and myelination of axons), and the risk loci ADCY2 (a key enzyme in cAMP signaling) and POU3F2 (involved in development of the neocortex and regulation of corticotropin-releasing hormone). Thus, many of the most highly implicated genes are involved in neuronal architecture and connectivity.

Major Depression Family Studies First-degree relatives of probands with major depression have a higher risk of the disorder (15%–22%) than relatives of controls (5%–11%). Certain features of major depression (such as early time of onset, recurrent episodes, long duration of episodes, suicidality, and greater levels of impairment in the proband) have been associated with increased familial risk. Relatives of probands with unipolar depression do not have a substantially increased risk of bipolar disorder.

Twin Studies

Depending on the sample and diagnostic convention used, concordance rates have ranged from 23% to 69% for MZ twins and from 16% to 42% for DZ twins. The estimated heritability is 31% to 42%.

Molecular Genetic Studies A 2015 GWAS identified the first two genetic markers reproducibly linked to major depressive disorder (MDD): the first near the SIRT1 (sirtuin-1) gene, an enzyme involved in cellular regulation including reaction to stress and cell longevity, and the second in an intron of the LHPP gene, whose connection to MDD is not yet clear. This study was the first to find statistically significant loci after multiple other studies of over 17,000 participants failed to identify genetic candidates with genome-wide significance. The difficulty of GWAS to yield positive results might suggest heterogeneity within the illness, as large cohorts with varying severity of illness have failed to yield genetic targets. The 2015 study, the first to yield genetic markers, limited participation to a homogeneous sample of individuals with similar ethnicity (Chinese) and illness severity. Additionally, given the association between MDD and life stressors, MDD more than other illnesses might have a strong environmental contribution that may complicate genetic studies.

Anxiety Disorders Panic Disorder Family Studies The estimated risk of panic disorder in first-degree relatives of affected probands has ranged from about 8% to 31%, significantly higher than the risk to relatives of controls. As with several other psychiatric disorders, early-onset is associated with increased familial risk.

Twin Studies Concordance rates for panic disorder among MZ twins have ranged from 23% to 73%, compared with approximately 17% for DZ twins. The estimated heritability is approximately 40% to 45%.

Molecular Genetic Studies To date, GWAS have failed to detect genome-wide significant SNPs associated with panic disorder.

Obsessive-Compulsive Disorder Family Studies Available family studies have yielded mixed results, although the risk to firstdegree relatives of OCD probands has been higher than the population prevalence of the disorder in several studies. The risk of tic disorders (Tourette syndrome and chronic tics) is elevated in a sub-set of families of OCD probands, suggesting that these disorders share genetic influences. Likewise, studies have also documented an elevated risk of OCD among relatives of probands with Tourette syndrome.

Twin and Adoption Studies Though studies are limited, heritability estimates range from 47% to 68%, with early-onset disorder associated with increased heritability (closer to 68%).

Molecular Genetic Studies Using linkage analysis, a replicated candidate gene linked to OCD is SLC1A1 , which encodes a glutamate transporter, suggesting a role for glutamatergic pathways in OCD. Mouse models have provided insight into the genetics of OCD. Genetic deletion of Sapap3 from mice caused symptoms suggestive of OCD. Sapap3 encodes a protein located in excitatory synapses in the postsynaptic density. Based on these mouse model findings, cohorts of humans with OCD and related disorders have been sequenced and rare Sapap3 variants have been found in patients with OCD and grooming behaviors. This human genetic evidence is suggestive but not determinate and suggests a role for synaptic function in OCD. Mouse models with genetic deletion of Slirtk5 and Hoxb8 also have OCD behaviors. These results have been preliminarily supported by GWAS though GWAS have failed to reach genome-wide significance.

Substance Use Disorders Alcohol Dependence Family Studies Studies vary widely with regard to the risk of alcohol dependence in firstdegree relatives of an affected proband, with most studies measuring an approximately 6- to 10-fold higher risk of the disorder compared to relatives of unaffected individuals (range among all studies is 2.5–20 fold). Susceptibility to alcohol withdrawal also appears to be familial.

Twin and Adoption Studies Most twin and adoption studies of alcoholism have supported the role of genetic influences, though many favor a strong environmental influence, as well. Heritability estimates vary by the diagnostic criteria. Among studies demonstrating genetic influence, estimated heritability has ranged from approximately 50% to 60% though environmental influences are consistently implicated, as well. Several adoption studies have demonstrated an increased risk of alcoholism among adoptees who have an alcoholic biologic parent.

Molecular Genetic Studies Several studies, including GWAS, have identified candidate genes involved in alcoholism. Many of these genes are alcohol-metabolizing enzyme genes and are associated with a reduced risk of alcohol dependence. By altering the rate of alcohol metabolism, certain alleles of the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes can produce a build-up of acetaldehyde, causing an endogenous disulfiram-like flushing reaction. By discouraging alcohol consumption, these alleles can be protective against the development of alcoholism. These genetic association was first noted in subjects of Asian descent with variants of the gene ALDH2 . Genes that encode sub-units of the γ amino butyric acid (GABA) receptor, including GABRA2 , have been associated with alcohol dependence. This genetic evidence and the mechanism of action of alcohol as a GABA receptor agonist suggest the importance of GABA-ergic pathways in alcohol dependence.

Genetics of Personality and Temperament An alternative to searching for genes for psychiatric disorders is to identify genes that influence temperament and personality traits. Quantitative variations in these traits reflect individual differences in personality but may also reveal a predisposition to certain psychiatric disorders. These traits are typically measured with paper-and-pencil tests. Large twin studies have demonstrated that a variety of personality and temperamental constructs are moderately heritable. For example, heritabilities of neuroticism and introversion–extraversion are approximately 40% to 50%. In another example, a 2010 study linked the gene HTR2B , which encodes the serotonin2B receptor, to impulsivity, a human genetic finding that was confirmed with a mouse model. Other studies have shown that risk-taking behaviors may be associated with the dopamine receptor D4 (DRD4) gene, a gene with a large number of polymorphisms. This gene contains tandem

repeat sequences, with different alleles containing different numbers of tandem repeats—a “short form” (fewer than 6 tandem repeats) and a “long form” (more than 6 tandem repeats). Individuals who score high for risk-taking behaviors are more likely to have the long form of the DRD4 gene. For example, the long form is more prevalent in athletes who engage in extreme sports. Perhaps not surprisingly, the long form is also more prevalent in children with ADHD as these risk-taking and impulsive traits may predispose one to development of this psychiatric disorder. Of course, these data are complicated by the overlap of nature and nurture. It is widely accepted that both our genes and our environment, specifically childhood experiences, affect temperamental development. Additionally, most behaviors of complexity are likely to result from the interaction of multiple genes and higher level synaptic pathways. There is an extremely low likelihood that any one gene is responsible for complex traits, such as risk-taking, emotional security, extroversion, or intelligence.

Implications of Psychiatric Genetics There is reason to be both optimistic and cautious about progress in psychiatric genetic research. The benefits of identifying genes involved in psychiatric phenotypes may include any the following: an improved understanding of the biological basis of psychiatric disorders, an improved understanding of the role of gene-environment in psychopathology, improved diagnostic criteria for psychiatric disorders, or more targeted therapies if genetic insights can be used to predict maximal therapeutic response with minimal side effect profiles. Perhaps most important is that an increased understanding of gene-environment interactions might improve prevention efforts by identifying individuals at risk for psychopathology and effective prevention measures. These blossoming advances in genetic research raise important ethical and social challenges for clinicians and researchers. For example, information about genetic susceptibility could have adverse emotional and financial (e.g., insurability) consequences for some individuals. Awareness of gene-environment interactions may prompt clinicians and policy makers to extend their sphere of influence into individual’s private or family lives. As our genetic understanding of psychiatric illness grows, it will be incumbent on psychiatrists to weigh the benefits and limitations of genetic research.

Psychiatric Manifestations of Genetic Syndromes and

Inborn Errors of Metabolism A variety of genetic syndromes and metabolic illnesses are marked by prominent psychiatric symptoms; in some cases, these symptoms are the earliest evidence of disease. Psychiatrists must be familiar with physical findings and historical information that may raise suspicions for the presence of genetic illness. Accurate early diagnosis may provide opportunities for new treatments, allow for surveillance of associated medical issues, and help identify other family members at risk. In addition, understanding the causes of psychiatric symptoms in disorders where the genetic mechanisms of disease are known might shed light on the pathophysiology of psychiatric disorders. The possibility of a genetic syndrome should be considered in a patient with congenital anomalies, co-morbid intellectual disability or learning disabilities, or a familial pattern of illness that appears Mendelian. Metabolic illness can be associated with a history of food intolerance, decompensation with illness, loss of developmental milestones, seizures, or other neurological findings. Overall, referring a patient for consultation with a geneticist as well as a neurologist can be an important part of the care of psychiatric patients.

Disorders Due to Chromosomal Abnormalities Down Syndrome/Trisomy 21 Down syndrome , or trisomy 21, is the most common genetic cause of intellectual disability, occurring on average every 1 in 700 births. The risk of conceiving a baby with Down syndrome increases with maternal age from 1/385 at age 35 to 1/30 at age 45 due to the failure of homologous chromosomes to segregate properly during cell division in older eggs. Common physical features include a characteristic facial appearance of up-slanting palpebral fissures (eye openings), epicanthal folds, a flat nasal bridge, low-set ears, a protruding tongue, short neck, and brushfield spots on the iris. Short stature, a single palmar crease, congenital heart disease, duodenal atresia, and hypothyroidism are also characteristic. Intellectual disability is seen in almost all patients, with an average IQ in the 25 to 50 range. The intellectual disability associated with Down syndrome is thought to be a static process; decline in cognition or change in behavior in early or middle adulthood in patients with Down syndrome should raise suspicions for possible early-onset AD, which has an increased incidence in this population. AD is thought to be increased in Down syndrome patients because the amyloid

precursor protein (important in the etiology of early-onset AD) is located on chromosome 21. The typical age of onset of AD in these individuals is around 40 to 50 years. Other psychiatric symptoms include non-specific behavioral issues, depression, and anxiety. Diagnostic testing involves karyotype analysis of chromosomes, often by prenatal amniocentesis.

Turner Syndrome Turner syndrome is a condition in which females are missing part of all of an X chromosome. It is diagnosed based on karyotype analysis and affected individuals are designated as 45, XO. No environmental risks are known and all parts of the world are effected equally at 1 in 2,000 to 5,000 births. Turner syndrome may also occur in a mosaic fashion in which case the symptoms are fewer or absent. Patients with this condition are females, and show varying severity of physical features, such as short stature, excess skin or webbing of the neck, a broad or flat chest, congenital heart defects, hypothyroidism, and gonadal dysgenesis (resulting in infertility and failure to achieve complete secondary sexual characteristics). Psychiatric symptoms may include delayed social maturation, problems with peer relationships, ADHD, and specific learning disabilities, though many are of normal intelligence. No cure is known. Treatments include growth hormone replacement to increase height and estrogen replacement to promote breast development. Affected individuals have a slightly shorter life-span due to cardiac issues.

Klinefelter Syndrome Klinefelter syndrome is due to the addition of an extra X chromosome, and is designated as 47, XXY. Diagnosis involves karyotype analysis and is one of the most common chromosomal disorders, occurring in 1:500 to 1:1,000 live male births. However, Klinefelter syndrome usually occurs randomly and is not inherited from one’s parents. Patients with this condition are males who are characteristically tall with long legs and small penis and testes. Often, these patients first come to medical attention when low testosterone levels interfere with normal pubertal development or cause infertility. Psychiatric symptoms include average verbal IQ in the 85 to 90 range, learning disabilities, ADHD, and possible increased rates of depression. Although there is no cure, treatments include physical and speech therapy, testosterone replacement, and assisted reproductive technologies. Life expectancy is normal.

Prader Willi Syndr ome Prader-Willi syndrome (PWS ) is a rare disorder caused by the deletion or inexpression of a critical region of up to 7 genes on the paternally-inherited chromosome 15q11-13. The incidence of PWS is between 1/10,000 to 1/25,000 live births. This particular region on chromosome 15 undergoes the process of imprinting , which is the differential silencing of the region based on whether the chromosome is of maternal or paternal origin. In PWS, the maternal copy of the chromosome region is imprinted (silenced), however the deletion present in the paternal chromosome means that individuals with PWS have no expression of these genes. (Of note, the deletion of this same region from the maternallyderived chromosome results in Angelman syndrome, which is marked by seizures, severe intellectual disability, little to no speech output, abnormal ataxic gait, and characteristic behaviors.) Features of PWS include: a characteristic appearance with up-slanting, almondshape eyes; thin upper lip; down-turned mouth; light skin and hair coloring; small hands and feet; small external genitalia; prominent low muscle tone; and failure-to-thrive in infancy. A feeling of chronic hunger often leads to obesity. Hyperphagia develops in early childhood, but can be controlled with behavioral techniques. Psychiatric symptoms include: obsessive thoughts; compulsions; skin-picking; temper tantrums; depression; anxiety; and psychosis. Patients exhibit cognitive disability including a decreased IQ or specific learning disabilities, accompanied by areas of relative strength (e.g., ability to complete jigsaw puzzles). Diagnostic testing involves analysis of the critical region for methylation status, by PCR or Southern, and the detection of a micro-deletion by FISH techniques. Treatments involve behavioral techniques. The use of growth hormone has been beneficial for the growth and obesity issues seen in these patients, and it may also help with behavioral and cognitive aspects.

Velocardiofacial Syndrome/DiGeorge Syndr ome Velocardiofacial syndrome /DiGeorge syndrome (VCFS/DGS ) is due to a micro-deletion on one copy of chromosome 22q11, resulting in the loss of up to 30 genes. The syndrome occurs in approximately 1 in 4,000 live births. Most cases are sporadic, but it can also be transmitted in a dominant fashion from affected parents.

Associated features vary widely, and include: a characteristic facial appearance of a broad, squared nasal root; mid-face hypoplasia; short palpebral fissures; small chin; and cleft palate. Other characteristics include: congenital heart defects; thymic aplasia leading to immunological problems; absent or hypoplastic parathyroid glands leading to problems with calcium homeostasis; low tone; and scoliosis. Subtler palatal problems can manifest as velopharygnal insufficiency (nasal speech, speech difficulties). Psychiatric disorders are common, with 60% to 75% exhibiting significant psychosis, mood disorders, or anxiety. Reported rates of schizophrenia and schizoaffective disorder are as high as 25% to 30%. In addition, it is estimated that as many as 2% of those with schizophrenia may have this condition (undiagnosed), and that rates may be even higher in patients with early-onset schizophrenia. Learning disabilities, especially non-verbal learning disorder, are common. Diagnostic testing involves detection of the submicroscopic deletion by FISH technique.

Autosomal Dominant Conditions Huntington Dise ase Hungtington disease (HD ) is a neurodegenerative disorder that affects muscle coordination and leads to cognitive decline. It is caused by a mutation in either of an individual’s two copies of the Huntingtin gene on chromosome 4p16. Specifically, expansion of a CAG (cytosine-adenine-guanine) triplet repeat stretch within the gene results in an abnormal form of the protein which causes damage to nerve cells, though the mechanism is not fully understood. The number of CAG triplet repeats tends to increase in successive generations, a process known as anticipation, which results in earlier age of onset and increased severity in affected offspring. An affected individual has a 50% chance of passing the mutation to their child. Symptoms can manifest at any age though typical age of onset is 35 to 45. Physical findings include dysarthria and clumsiness initially, followed by progressive motor decline of voluntary and involuntary movements, and by the development of chorea. These symptoms are managed by use of high-potency neuroleptics, like haloperidol. Psychiatric symptoms are the first presenting features in up to one-third of patients, and may begin with prominent personality changes, with eventual

development of dementia and psychosis. A high suicide rate is reported in these patients. Diagnostic testing involves mutation analysis of the Huntington gene.

Tuberous Sclero sis Tuberous sclerosis complex (TSC ) is a rare genetic disease that causes benign tumors to grow in multiple organ systems, including CNS tubers, retinal hamartomas, cardiac rhabdomyomas, and renal angiomyolipomas. TSC is due to mutation in the TSC1 gene on chromosome 9q23 or TSC2 gene on chromosome 16p13.3. These genes typically serve as tumor suppressors; thus, a mutation allows for abnormal tumor growth. In addition to multi-organ tumors, common characteristics include skin findings, such as hypo-pigmented macules, ash leaf spots, shagreen patches, and angiofibromas. Dental pits, seizures, and high rates of ASD are common. Diagnosis is usually by clinical assessment, though diagnostic testing involves mutation analysis of the TSC1 and TSC2 genes.

Neurofibromatosis Type 1/Von Recklinghausen Dise ase Neurofibromatosis Type 1 (NF1 ) is due to mutation in the NF1 gene on chromosome 17q11.2, which is believed to lead to loss of tumor suppressor function. Physical findings in NF1 include abnormalities of skin pigmentation, such as café au lait spots, freckling in axilla or groin, as well as neurofibromas (often many), Lisch nodules on the iris, bony abnormalities, and acoustic neuromas. Complications vary depending on the number, location, and extent of the neurofibromas, and with development of malignant tumors. Psychiatric symptoms include learning disabilities and attention deficit disorder (ADD). Diagnosis is usually made based on clinical features, but confirmatory testing of the NF1 gene is available.

Williams Syndr ome Williams syndrome (WS ) is due to a microdeletion on one copy of chromosome 7q11, and includes loss of the elastin (ELN) gene. Physical findings include: a characteristic “elfish” facial appearance characterized by: a broad forehead with narrowing at temples; stellate pattern in iris; short nose with fleshy nasal tip; prominent ear lobes; wide mouth with full lips; and small jaw. Affected individuals also display short stature, cardiac

defects (especially supravalvular aortic stenosis), and connective tissue disease (e.g., joint laxity). Psychiatric features include mild-severe intellectual disability, ADHD, and anxiety. A friendly personality and good verbal skills are common although superficial relating abilities and social disinhibition can make relationships difficult to sustain. Diagnostic testing involves detection of the submicroscopic deletion by FISH technique or chromosomal microarray analysis.

Porphyria The porphyrias are a group of rare genetic diseases in which porphyrins, normally utilized in heme metabolism, are unable to be metabolized properly and accumulate at high levels within the body. One of the more common types of porphyria is acute intermittent porphyria (AIP) due to mutations in porphobilinogen deaminase (PBGD) , an enzyme that is part of the heme biosynthetic pathway. Porphyrias manifest with either neurological symptoms, cutaneous symptoms, or occasionally both. Acute porphyrias cause acute “neurovisceral attacks,” marked by abdominal pain and vomiting, generalized weakness, and diffuse body pain related to nerve involvement. Over time, demyelination may occur. Cutaneous porphyrias cause excessive sensitivity to sunlight because porphyrins react to light. Psychiatric symptoms are quite variable, and may include a change in mental status, delirium, psychosis, anxiety, or depression. Anecdotally, these patients are often described as having “histrionic” traits, or a distinct personality. Symptoms are worsened by medications that induce the heme synthetic pathway including those that up-regulate the P450 system (e.g., barbiturates, sulfonamides, alcohol); the severe reactions that may occur in these patients can cause them to be misdiagnosed as treatment-refractory. In addition, hormone changes associated with the menstrual cycle can precipitate attacks. Diagnostic testing involves the measurement of pathway byproducts in the urine (porphobilinogen, ∆ -amino-levulinic acid), measurement of decreased PBGD in blood, and DNA testing to detect the mutation in PBGD . Treatment can include carbohydrate loading and hemin, both of which repress hepatic delta aminolevulinic acid synthase and reduce porphyrin precursors. Offending agents that can precipitate attacks are avoided. Attacks are treated with supportive care.

X-Linked Genetic Syndromes Fragile X Syndr ome Fragile X Syndrome (FXS ) is caused by an increased number of triplet CGG repeats in the FMR1 gene located on chromosome Xq27.3. It is the most common inherited form of intellectual disability (although Down syndrome is more prevalent, the majority of cases of Down syndrome are not inherited, as neither parent carries an extra or abnormal copy of the Down syndrome critical region). In contrast to Down syndrome, Fragile X is inherited from a mother who passes on the abnormal gene. The syndrome is almost exclusively described in males, but findings may occasionally manifest in carrier females and may range from mild to severe. Physical features include: a large head with long face; prominent jaw and forehead; large ears; large testes (might not be apparent until puberty); low tone; and connective tissue disease. Psychiatric symptoms include moderate to severe intellectual disability, ASD, ADHD, and mood lability. Diagnostic testing involves detection of mutations in the FMR1 gene.

Rett Syndr ome Rett Syndrome (RS ) is due to a mutation in the MECP2 gene on chromosome Xq28. Girls with Rett syndrome appear normal at birth; however, beginning around 6 to 24 months, they develop a progressive loss of skills associated with acquired microcephaly. These children have loss of social engagement, communication disorders (often no verbal skills), stereotyped hand movements (with loss of purposeful hand movements), gait abnormalities (including total inability to walk in 50% of individuals), and seizures. Psychiatric symptoms include features of ASD, a high burden of mood anxiety symptoms, and screaming fits. Diagnostic testing involves mutation analysis of the MECP2 gene.

Autosomal Recessive Conditions/Inborn Errors of Metabolism Homocystinuria Homocystinuria is caused by impaired metabolism of the amino acid methionine. Homocysteine, a building block of methionine, accumulates in the blood of affected individuals and is excreted at high levels in the urine. Classic

homocystinuria is due to mutations of cystathionine β synthase (CBS) gene on chromosome 21q22.3, leading to deficient cystathionine β synthase enzyme activity. Preserved enzymatic activity, and less severe disease, can be seen with the pyridoxine (vitamin B6 )-responsive variant, and other enzyme cofactor deficiencies (folate or B12 ) can also lead to symptoms. Patients with homocystinuria are normal at birth, with onset of symptoms in childhood. High levels of homocysteine interfere with collagen cross-linking, resulting in joints with restricted range of motion, and disruptions to the vascular endothelium leading to thrombus formation and potential for vascular events. Many patients are described as “Marfanoid,” with long, thin limbs, high-arched palate, scoliosis, arachnodactyly, pectus excavatum, and lens dislocations. Psychiatric symptoms include intellectual disability and developmental delay, depression, OCD, and non-specific behavioral problems. Schizophrenia and psychosis occur at higher rates in these patients. Diagnostic testing involves the use of urine nitroprusside test for disulfides and measurement of elevated homocysteine and methionine levels in the blood. Treatment is centered on providing a diet that is low in methionine (the precursor to homocysteine) and supplemented by vitamin B6 and cysteine, which becomes an essential amino acid in these patients. Life expectancy is normal in treated individuals. In those untreated, early death is common due to thrombotic complications (e.g., heart attack).

Wilson Disease Wilson disease is due to a mutation in the ATP7B gene on chromosome 13q14.3-21.1, leading to decreased levels of copper transporting ATPase 2 and resultant copper deposition in the CNS and liver. Physical findings are due to abnormal organ function caused by the copper deposits and are most prominent in the liver (jaundice, hepatitis, and cirrhosis) and CNS (movement disorders, dysarthria, and seizures). Due to copper deposition in the cornea, many patients have brownish-green rings located in the iris, also known as Kayser-Fleischer rings, visible on slit-lamp examination. Psychiatric symptoms include cognitive decline, personality changes, and mood lability (some with pseudobulbar palsy), which can be the first indication of disease. Diagnostic testing involves measurement of reduced serum-bound copper and ceruloplasmin and elevated urine copper excretion. Deposition can be visualized by liver biopsy, or neuroimaging. Mutation analysis is available.

Treatment consists of chelation therapy (e.g., penicillamine), avoidance of copper rich foods (shellfish, liver, chocolate, mushrooms, and nuts), and supplementation with anti-oxidants. Patients may go on to require liver transplantation.

Metachromatic Leukodystrophy Metachromatic leukodystrophy is due to deficiency of aryl-sulfatase A, leading to storage of galactosyl sulfatide in the white matter of the central and peripheral nervous systems. There are three forms, presenting in infancy, childhood, and early adulthood. Physical findings include gait problems and ataxia, difficulty with speech, incontinence, and progressive deterioration of the nervous system. Psychiatric symptoms can be the first presentation of this disorder and include decline in school performance/cognition as well as changes in personality, and psychosis. Diagnostic testing involves measurement of low aryl sulfatase A levels in blood, elevated urine sulfatides, and characteri stic magnetic resonance imaging (MRI) findings that show white matter atrophy.

X-Linked Recessive Metabolic Conditions Lesch-Nyhan Syndrome Lesch-Nyhan syndrome is due to a deficienc y of hypoxanthine-guanine phosphoribosyltransferase (HPRT) with resultant hyperuricemia, caused by mutations in the HPRT1 gene located on chromosome X126-27.2. Due to its Xlinked inheritance, it is described in boys. Physical findings include pyramidal and extrapyramidal neurological findings and sequelae of urate crystal deposition in joints, kidney, and bladder. The hallmark of this syndrome is the development of self-injurious behaviors, such as lip-biting, finger-biting, and head banging. Other psychiatric features include developmental delay, aggression, and intellectual disability. Diagnostic testing involves the measurement of increased uric acid and excretion, decreased HPRT enzyme activity, and mutation analysis of the HPRT1 gene. Treatment is focused on decreasing the amount of uric acid through the use of allopurinol, as well as behavioral techniques to manage self-injurious behavior.

X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy is due to a deficiency of lignoceroyl-CoA ligase, caused by mutations of the ABCD1 gene on chromosome Xq28, leading to accumulation s of very long chain fatty acids (VLCFA) in cerebral white matter and the adrenal cortex. Due to its X-linked inheritance, the full syndrome is usually seen in boys, but female carriers can also show symptoms. Physical findings include abnormal gait, dysarthria, and dysphagia. Over time, progressive loss of motor skills, vision, and hearing occurs. Sequelae of adrenal dysfunction can occur. The earliest symptoms often result in a diagnosis of ADD, but cognitive decline is progressive. Diagnostic testing involves demonstration of elevated VLCFA in the blood, increased ACTH, and other indications of adrenal dysfunction, as well as characteristic MRI findings. The diagnosis is confirmed by mutation analysis of the ABCD1 gene. A key aspect of treatment involves correction of adrenal function, which does not improve neurologic abnormalities. In patients with early stages of cerebral involvem ent, hematopoietic cell transplantation (HCT) can be beneficial. There is also some evidence that “Lorenzo’s oil”, a 4:1 mixture of oleic acid and erucic acid, may normalize the accumulation of VLCFA in the brain and thereby halt the progression of adrenoleukodystrophy. Its efficacy continues to be studied.

Syndromes Caused by Teratogen Exposure Fetal Alcohol Synd rome Fetal Alcohol Syndrome (FAS ) involves a spectrum of findings associated with in-utero exposure to alcohol; the severity of the syndrome is dose-related, with more severe findings associated with increased alcohol intake and binge drinking. Of note, the possibility of in-utero exposure to other drugs must also be considered in patients being evaluated for FAS. Physical features include: microcephaly; flattened mid-face; epicanthal folds; flat philtrum (the space between nose and upper lip); thin upper lip; small jaw; pre- and post-natal growth deficiency; and cardiac abnormalities. Psychiatric symptoms can include intellectual disability, ADD, oppositional behaviors, depression, and post-traumatic stress disorder (PTSD) (due to associated social issues). Diagnosis is made by clinical assessment and a history of alcohol exposure during pregnancy. There is no confirmatory laboratory testing available.

Suggested Readings 1. Akil H, Brenner S, Kandel E, et al: Medicine. The future of psychiatric research: genomes and neural circuits. Science . 2010; 327: 1580–1581. 2. Ashmore, Cheng: Genome-wide association studies on attention deficit hyperactivity disorder. Clin Exp Pharmacol . 2013; 3:119–120. 3. Cai N, Bigdeli TB, Kretzschmar W, et al: Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature . 2015; 523: 588– 591. 4. Cichon S, Craddock N, Daly M, et al: Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry . 2009; 166: 540–556. 5. Comings DE, Gonzales N, Wu S, et al: Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am J Med Gen . 1999; 88: 358–368. 6. Estrov Y, Scaglia F, Bodamer OA: Psychiatric symptoms of inherited metabolic disease. J Inherit Metab Dis . 2000; 23: 2–6. 7. Gaugler, T, Klei L, Sanders SJ, et al: Most genetic risk for autism resides with common variation. Nat Gen . 2014; 46: 881–885. 8. Gejman PV, Sanders AR, Kendler KS: Genetics of schizophrenia: new findings and challenges. Annu Rev Genomics Hum Genet . 2011; 12: 121– 144. 9. Grados MA: The genetics of obsessive-compulsive disorder and Tourette syndrome: an epidemiological and pathway-based approach for gene discovery. J Am Acad Child Adolesc Psychiatry . 2010; 49: 810–819. 10. Guerreiro RJ, Hardy J: Alzheimer’s disease genetics: lessons to improve disease modelling. Biochem Soc Trans . 2011; 39: 910–916. 11. Hawi Z, Cummins TD, Tong J, et al: The molecular genetic architecture of attention deficit hyperactivity disorder. Mol Psychiatry . 2015; 20: 289–297. 12. Kendler KS: Twin studies of psychiatric illness. Current status and future directions. Arch Gen Psychiatry . 1993; 50: 905–915. 13. Kendler KS: Twin studies of psychiatric illness: an update. Arch Gen Psychiatry . 2001; 58: 1005–1014.

14. Lander ES: Initial impact of the sequencing of the human genome. Nature . 2011; 470: 187–197. 15. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium: mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry . 2013; 18(4): 497–511 . 16. Malhotra D, Sebat J: CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell . 2012; 148: 1223–1241. 17. Mattheisen M, Samuels JF, Wang Y, at al: Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry . 2015; 20: 337–344. 18. Moldavsky M, Lev D, Lerman-Sagie T: Behavioral phenotypes of genetic syndromes: a reference guide for psychiatrists. J Am Acad Child Adolesc Psychiatry . 2001; 40: 749–761. 19. Muhleisen TW, Leber M, Schulze TG, et al: Genome-wide association study reveals two new risk loci for bipolar disorder. Nature Commun . 2014; 5: 3339–3346. 20. Ripke, S, Neale BM, Corvin A, et al: Biological insights from 108 schizophrenia-associated genetic loci. Nature . 2014; 511: 421–427. 21. Ripke S, Sanders AR, Kendler KS, et al: Genome-wide association study identifies five new schizophrenia loci. Nat Genet . 2011; 43: 969–976. 22. Sklar P, Ripke S, Scott LJ, et al: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet . 2011; 43: 977–983. 23. State MW, Levitt P: The conundrums of understanding genetic risks for autism spectrum disorders. Nat Neurosci . 2011; 14: 1499–1506. 24. Stoel RD, De Geus EJ, Boomsma DI: Genetic analysis of sensation seeking with extended twin design. Behav Genet . 2006; 36(2): 229–37. 25. Thompson CJ, Hanna CW, Carlson SR, Rupert JL: The -521 C/T variant in the dopamine-4-receptor gene (DRD4) is associated with skiing and snowboarding behavior. Scand J Med Sci Sports . 2013: 108–113.

CHAPTER 74

Psychiatry and the Law III Malpractice and Boundary Violations RONALD SCHOUTEN, MD, JD

KEY POINTS Overview Claims of medical malpractice can arise from unintentional errors in the course of medical treatment or from intentional acts. Boundary violations are behaviors on the part of the physician that violate standards for appropriate relationships between doctors and patients. Sexual relationships with patients are the most notorious of these. Theoretical Basis Medical malpractice is a sub-set of personal injury law. It exists to provide compensation for those injured by the negligent acts of others. Boundary violations are considered to be a departure from the standard of care and, as such, can be the basis for a malpractice claim. Although they are considered departures from the standard of care, they are intentional torts, and most malpractice insurers have adopted provisions that might provide for defense of the allegations but not pay the damages. Clinical Applications To prove a claim of malpractice, the plaintiff claiming to have been injured must establish that the defendant physician was derelict in fulfilling a duty to the patient, and that directly resulted in damage to the plaintiff. There are recognized standards for the relationships between doctors and patients. Some of these standards are more flexible under some circumstances. For example, psychiatrists generally should not have business relationships with patients. However, in small communities, certain business relationships might be acceptable because of limited options. On the other end of the spectrum, sexual relations with patients are always

deemed to be unethical, are the basis for license revocation, are considered a criminal offense in some states, and are the basis for malpractice suits.

Overview The law related to malpractice litigation has had a significant effect on the practice of modern psychiatry. This chapter reviews the legal basics of malpractice litigation, some major topics in malpractice, and the important area of boundary violations.

Malpractice Law Malpractice cases are part of the general field of personal injury or tort law. Torts are defined as civil wrongs in which one person injures another, giving rise to a right to sue for damages. In comparison, crimes are offenses against society, as represented by the government. The penalties for a crime can be monetary, confinement or other restriction on freedom (like probation), or in some cases and jurisdictions, death; that is, capital punishment. There are two types of torts: intentional and unintentional. Intentional torts are those in which the purpose of the action is the harmful act itself; for example, sexual contact with a patient or physical assault on a patient (both of which involve purposeful physical contact with the victim). Unintentional torts arise when some harm occurs as a result of a person not exercising adequate care (referred to as negligence), such as where a patient is injured in the course of treatment, allegedly because the defendant practitioner did not exercise appropriate care; that is, medical negligence. Malpractice insurance is intended to cover acts of negligence (unintentional torts); however, it will also cover intentional torts that are a component of legitimate treatment, such as a complaint of assault and battery arising from physical restraint of an agitated patient. Where there is no clinical justification for the intentional act, such as in sexual misconduct, malpractice insurers might cover the cost of defending the case, but not any damages awarded if liability is found. To prove a malpractice claim, a plaintiff (the party who claims to have been injured and who is seeking damages) must establish the four elements (the “4 Ds”) of a malpractice claim. Dereliction of duty: The defendant was derelict in his or her responsibilities. This can be established either by showing that the treating clinician departed

from or ignored the standard of care, or by establishing that the treating clinician followed the standard of care but did so in an inept fashion. Duty: The defendant had a specific obligation or duty to the patient to act with reasonable care. The general duty of physicians is to possess and employ such reasonable skill and care as are commonly had and are exercised by respectable, average physicians in the same or similar community. Specialists are held to a higher standard of performance because they hold themselves out to the community as having special expertise. A physician who holds him or herself out as an expert in a specific area will be judged according to this higher standard, regardless of the actual credentials. The “School Rule”: Practice in accordance with the standards of a recognized school of thought or training will be judged according to the standards of that school to which the defendant physician is a member. For example, cognitivebehavioral therapists should be judged according to the standard of care for that school of treatment, not according to a psychoanalytic standard of care. However, all clinicians who hold themselves out to the public as being qualified to diagnose and treat illnesses are held to the same basic standard of care with regard to safety, assessment, and conduct. For example, a psychiatrist cannot excuse himself from failing to diagnose his patent’s myocardial infarction on the basis that he does not prescribe medication and only does psychotherapy. In addition to the duty to possess and employ reasonable care, physicians have a duty to consult, i.e., to get consultation when the limits of the physician’s knowledge and experience have been exceeded. Direct causation of damages: Direct causation has two separate components. (1) A mechanical notion assessed by the “But for” rule: “But for” the negligent behavior, the injury would not have occurred. (2) Proximate or legal causation: the harm that occurred was a “reasonably foreseeable” consequence of the negligent action. In proving causation, a plaintiff may invoke the evidentiary concept of res ipsa loquitur (the thing speaks for itself) when the cause of injury to the plaintiff was under the sole control of the defendant and the defendant alone has knowledge of the injurious event. In such cases, the presumption is that the defendant was responsible for the injury and the defendant must rebut that presumption. Damages must be proven: Unless damages can be proven, the malpractice suit will not succeed, even if there was negligent performance of a duty. Damages

can be of three types: economic damages (such as lost earnings, the cost of medical treatment for the injury, or the cost of paying for someone to perform household services the victim can no longer perform as a result of the injury); physical damages (such as loss of a bodily function); and emotional pain and suffering.

Selected Malpractice Issues Abandonment can be either intentional (e.g., the doctor decides he or she no longer wants to see a particular patient), or unintentional (e.g., while planning to do so, the doctor forgets to arrange for coverage during vacation). Abandonment is defined as the unilateral termination of the doctor–patient relationship, by the doctor, without consent or justification, where the termination results in harm to the patient. After there is a doctor–patient relationship, the physician has a duty to continue to provide care until one or the other party ends it. Physicians always have the right to end the treatment relationship; however, there is an obligation to give the patient an opportunity to find alternative care, to cooperate in the transition to a new caregiver, and to make the patient aware of options for emergency coverage. Ideally, from both the clinical and medical–legal perspectives, this transition takes place over time as part of a proper termination. There are situations, however, in which the physician is justified in unilaterally terminating the relationship, in some cases abruptly, and providing more limited support in the transition. These situations include: no-show patients who repeatedly fail to keep their appointments; assaultive or abusive patients; and non-compliant patients. When it is necessary to terminate the relationship, claims of abandonment can be avoided by providing a referral to another clinician or agency, access to emergency coverage, and medications between the time of termination and the time of the appointment with the new treater. Abandonment allegations can arise when the physician is absent for vacation or conferences and fails to provide coverage or provides sub-standard coverage. These allegations can be avoided by providing adequate coverage during absences. The physician is responsible for ensuring that the coverage is competent and available. For example, a physician can be held liable if harm occurs to a patient during his or her absence and he or she knows or should have known that the covering physician was incompetent. Vicarious liability is the imposition of liability on one party for the negligent acts of another.

Vicarious Liability Under the doctrine of respondeat superior (let the master answer), the “master” (employer) can be held liable for the negligent acts of a second person, the “servant” (employee), committed within the scope of the employment. A master, for these purposes, is one who has direct authority over the servant, as evidenced by the power to hire or fire and veto power over the servant’s decisions. A consultant is distinguished from a master or employer by being outside the direct line of responsibility for the acts of the second person, having no direct authority over the second person, and offering advice and direction on a “take it or leave it” basis. This concept applies to the supervision of residents as well as to the supervision of non-physicians. In addition, at times physicians might be asked by non-physician colleagues to write prescriptions or to sign disability forms for patients they have not evaluated. By signing the form as the attending of record, the physician can be held to the same level of responsibility for any harm that occurs, just as if he or she had personally evaluated the patient.

Confidentiality Confidentiality is the physician’s duty to keep information revealed by the patient in the course of treatment private and not disclose it to unauthorized parties. The Health Insurance Portability and Accountability Act (HIPAA) is a federal statute that imposes, among other things, requirements for maintaining the confidentiality of patient information, referred to as Protected Health Information (PHI). Those HIPAA requirements are pre-empted by state confidentiality laws that provide a higher level of protection. There are a number of exceptions to the general duty of confidentiality, both in state laws and in HIPAA, as discussed here: Emergency: This is defined as a situation when failure to breach confidentiality would result in a serious; for example, life-threatening deterioration in the patient’s condition, imminent risk to self, or others. Waiver of confidentiality: The patient or other appropriate decision-maker expressly waives confidentiality. Incapacity: When the patient is temporarily or permanently unable to make decisions, information can be released about the patient in order to provide

care. However, when a substitute decision-maker is identified, that individual can insist that the patient’s confidentiality be protected. Various state and federal laws provide exceptions to confidentiality, such as releases of information required during civil commitment proceedings, malpractice cases, bill collections, and litigation in which the patient puts his or her mental status at issue. Breaches of confidentiality might be required by statute or case law, such as obligations to report child abuse or neglect, or the duty to take steps to protect third parties from harm threatened by a patient (discussed in the next section). In the normal course of treatment, information about a patient can be shared with a limited group of individuals without getting the express permission of the patient. These are generally held to include the patient, co-treaters, consultants, supervisors, and facilities to which the patient is being admitted or transferred. Before information is released to family members, referring clinicians, lawyers, or law enforcement, the patient’s expressed permission should be obtained. In all cases for which confidentiality is to be breached, it should be breached to the least extent possible and with the patient being aware.

The Duty to Protect Third Parties: The Tarasoff Legacy Breach of confidentiality is ethically permissible when it is necessary to protect the patient or third parties: “Psychiatrists at times may find it necessary in order to protect the patient or the community from imminent danger, to reveal confidential information disclosed by the patient” (Principles of Medical Ethics with Annotations Especially Applicable to Psychiatry, Sec.4, Annotation 8). The legal obligation to act to protect third parties from one’s patient is generally framed as follows: there is a basic duty to protect/warn if a therapist knows or should know of a patient’s potential for substantial harm to an identified or readily identifiable individual. The key case in this area is Tarasoff v. Regents of the University of California , 551 P. 2d 334 (1976), in which the court held that: “When a therapist determines, or pursuant to the standards of his profession should determine, that his patient presents a serious danger of violence to another, he incurs a serious obligation to use reasonable care to protect the intended victim from such danger.”

Implications of the Tarasoff Decision Psychotherapists and patients have a special relationship that sets the stage for the therapist being held uniquely liable for some actions of the patient. The duty that was established by Tarasoff was to an identified victim, although subsequent cases expanded the duty to broader classes of individuals and in some cases to individuals who might be in a “zone of danger” around an intended victim. The “Tarasoff Duty” is not necessarily a duty to warn the intended victim or law enforcement, which would require a breach of confidentiality, but a duty to protect that can be fulfilled through a variety of other actions on the part of the treater. The duty to protect third parties has been rejected or modified by courts and legislatures in multiple states, in response to the rapid expansion of the duty in many jurisdictions. The American Psychiatric Association (APA) developed a model statute that provides for liability to third parties for the acts of a patient where there is: “Communication of an explicit threat to identified victim(s) with apparent intent and ability to carry out the threat, and reasonable steps are not taken; or the patient has a known history of physical violence, and the therapist has a “reasonable basis to believe that there is a clear and present danger that the patient will attempt to kill or inflict serious bodily injury against a reasonably identified victim or victims”; and reasonable steps are not taken.” Reasonable steps are defined in the model statute as one or more of the following: warning potential victim or victims; notifying law enforcement in the area; arranging for voluntary hospitalization; or taking appropriate steps to involuntarily hospitalize the patient.

The National Practitioner Data Bank The National Practitioner Data Bank (NPDB ) was authorized by the Health Care Quality Improvement Act of 1986 (HCQIA), the data base applies to physicians, dentists, and, as of 2010, all other health-care practitioners. The HCQIA requires health-care organizations to report the following to the central Data Bank: payments made to satisfy malpractice claims (including settlements); adverse privilege actions taken by health-care entities; and, actions taken on licensure. The practitioner who is reported to the NPDB must be notified and given an opportunity to respond.

In 2010, Section 1921 of the Social Security Act expanded the range of information to be collected by the NPDB to include negative actions or findings by State licensing agencies, peer review organizations, and private accreditation organizations against all health-care practitioners and organizations. Hospitals, including human resource departments and nurse recruitment departments, nursing homes, other health-care organizations, as well as Quality Improvement Organizations, can register and obtain access to all NPDB data.

Boundary Violations An Introduction to Professional Boundaries Boundaries between doctors and patients provide a set of rules and expectations that allow the patient to develop trust in the physician and to know what to expect from the relationship. Boundary crossings involve minor, but potentially important, blurring of the boundaries. Boundary violations involve more clear-cut transgressions of the accepted boundaries between doctor and patient. What constitutes a boundary crossing or violation is determined both by the nature of the action and the setting in which it occurs. For example, in a rural area it might be appropriate for the family doctor to spend time with patients at a social gathering, while the same socializing for a doctor in an urban practice might be considered a boundary crossing. The maintenance of professional boundaries has been the subject of both ethical and legal proscriptions, not to mention a source of malpractice lawsuits. The core principle underlying these constraints on physician behavior is that physicians have a fiduciary duty to their patients, i.e., an obligation to put the patient’s interests above his or her own. The Hippocratic Oath includes admonitions about maintaining appropriate boundaries, including maintaining confidences and avoiding sexual relations. In 1989, the American Medical Association Council on Ethical and Judicial Affairs passed an ethical rule that prohibits physician-patient sexual contact, regardless of specialty. Physician-patient sexual contacts, and other forms of physician exploitation of patients, are the basis for discipline by physician registration authorities in all states. The American Psychiatric Association has adopted an ethical guideline that declares it unethical for a psychiatrist to have a sexual relationship with a former or current patient.

A number of states have enacted laws that make it a criminal offense for a physician to have a sexual relationship with a patient. States that have criminalized this behavior vary as to whether they classify doctor-patient sexual contact as a misdemeanor or felony. Some statutes distinguish between first and repeated offenses. Although many of the statutes criminalize psychotherapist– patient sexual contact, the term psychotherapy is broadly defined in some statutes as “the professional treatment, assessment, or counseling of a mental or emotional illness, symptom, or condition.” Thus, many of these statutes would apply to primary care physicians who treat psychiatric conditions. Statutes also differ with regard to how they define “patient,” and whether and when the prohibition applies.

Selected Boundary Issues Business Dealings Between Doctor and Patient The physician–patient relationship is fundamentally a business relationship. The terms of the contract are that the physician receives a fee in return for helping the patient with medical problems. The arms-length nature of the relationship allows the physician to be objective in his or her dealings with the patient. Involvement in other business dealings can detract from the distance, objectivity, and empathy necessary for the physician–patient relationship to succeed and is prohibited except under special circumstances; for example, the psychiatrist lives in a small community where the patient operates the only hardware store. Even in this limited situation, the psychiatrist would be well advised to find another store in a neighboring town.

Social (Non-Sexual) Relationships with Patients In certain settings, e.g., small towns, social contact between physician and patient is unavoidable. Confidentiality and cordiality without undue familiarity can allow these treatment relationships to succeed. Close friendships between physician and patient can compromise the physician’s objectivity and lead to errors in judgment because of the physician’s emotional involvement. The same principles apply here as apply in the context of physicians treating family members.

Sex in the Treatment Relationship As indicated earlier, sexual relations with patients have been the subject of great attention in legal and ethical circles. The reasons why physicians get

involved in these relationships vary. They include predatory sexual behavior by physicians seeking to take advantage of the patient as well as infatuation on the part of physicians who are vulnerable to engaging in such violations because of their own life circumstances and psychological issues. Some patients can be seductive, or at least engage in behavior that might be interpreted by the physician as seductive. Nevertheless, it is always the physician’s responsibility to maintain appropriate boundaries. Failure to do so is always the fault of the physician. Sex with patients in the guise of treatment constitutes fraud and misrepresentation and can provide the basis for criminal prosecution in some states. Sexual relationships with patients in many cases result from the disparity in power and authority between doctor and patient. Such relationships are inherently coercive and without consent, and are clear examples of the violation of the physician’s fiduciary duty to the patient. Patients who have had sexual relationships with their physicians often suffer significant harm as a result. Such injury becomes a justifiable basis for a lawsuit against the physician. Even though involvement in a sexual relationship with a patient constitutes an intentional tort that would ordinarily not be covered by malpractice insurance, courts have held that it represents a mishandling of the transference and countertransference in the treatment relationship, thus putting it within the realm of malpractice.

Suggested Readings 1. Bloom JD, Notman MT, Nadelson CC, eds.: Physician Sexual Misconduct . Washington, DC: American Psychiatric Press, Inc.; 1999. 2. Brendel RW, Schouten R: Legal concerns in psychosomatic medicine. Psychiatric Clin North Am . 2007; 40(4): 663–676. 3. Drogin EY, Dattilio FM, Sadoff RL, et al, eds.: Handbook of Forensic Assessment: Psychological and Psychiatric Perspectives . Hoboken, NJ: John Wiley & Sons; 2011. 4. Johnson RS, Persad G, Sisti D: The Tarasoff rule: the implications of interstate variation and gaps in professional training. J Am Acad Psychiatry Law . 2014; 42: 469–477. 5. Prosser and Keeton on Torts . 5th ed. St. Paul: West Publishing; 1984.

6. Simon RI: Clinical Psychiatry and the Law . Washington: APA Press; 1987.

CHAPTER Psychiatric Consultation to 75 Me dical and Surgical Patients SEAN GLASS, MD; JOHN QUERQUES, MD; AND THEODORE A. STERN, MD

KEY POINTS Summary Although the frequency of psychopathology in the general hospital setting ranges from 10% to 50%, the average rate of referral for psychiatric consultation is estimated to be 1% to 3%. Common reasons for psychiatric referral include delirium, dementia, depression, suicidal thinking, incapacity to make medical decisions, and interpersonal difficulties between patients and medical–surgical teams. Speaking with the consultee and members of the treatment team helps to clarify the “real” reason for the consult and helps to establish the urgency for consultation. Reviewing the medical chart helps the consultant appreciate the relevant medical history. Close attention to recent changes in medications is crucial because medications added or discontinued can affect the patient’s current mental state. Consultants are advised to communicate their findings and recommendations in a clear, concise, and respectful manner, regardless of whether there is agreement in diagnostic findings or treatment recommendations. Stating the diagnosis as well as considering the differential diagnosis is helpful in the consultant’s report. Moreover, when feasible, indicating that the patient’s symptoms are not attributable to a certain psychiatric disorder can be very helpful for consultees. Psychopharmacological strategies in medically ill patients include: monitoring for possible drug–drug interactions, considering pharmacokinetic effects as a result of altered organ function, and recognizing the possible adverse effects of otherwise safe and well-tolerated medications in ill patients. Psychotherapy with hospitalized medically-ill patients is brief and presentoriented. Major goals for psychotherapeutic intervention in hospitalized medically ill patients include bolstering healthy defenses to help cope with

their illness and helping them with existential issues related to being ill. Finally, interventions, such as relaxation techniques and hypnosis, might help patients with over-bearing anxiety.

Overview Consultation–liaison (C–L ) psychiatry is a branch of psychiatry that entails: consultation to medically and surgically ill hospitalized patients; enhancement of non-psychiatric clinicians’ awareness of affective, behavioral, and cognitive disorders; education of students and clinicians of all disciplines about the psychosocial and psychiatric aspects of medical care; and research at the interface of medicine, surgery, neurology, and psychiatry. Rooted in psychosomatic medicine and psychobiology, C–L psychiatry has gradually widened its arena from the medical wards of large general hospitals in the 1930s, to critical-care units, to specialized centers that provide care for patients with cancer, transplanted organs, and human immunodeficiency virus infection. The mid-1970s marked a growth phase for the field, fueled by the return of the medical model and the provision of grant money by Dr. James Eaton, the director of the Psychiatric Education Branch of the National Institute of Mental Health, for the establishment of new C–L services and research activities. Whereas in the early 1970s only three-quarters of all psychiatry residency programs even offered an experience in C–L psychiatry, today such rotations are required. In 2003 the American Board of Medical Specialties approved C–L psychiatry as an official sub-specialty, re-naming it psychosomatic medicine. The first examination for certification in the new field occurred in June 2005.

Epidemiology The frequency of psychopathology in the general hospital ranges from 10% to 50%, depending in large part on the type and severity of underlying medical or surgical illness. Because psychiatric co-morbidity prolongs length of stay, increases costs, and worsens the course of medical illness, prompt recognition and treatment are essential. Despite this high frequency of psychiatric disturbance in general hospitals, the rate of referral for psychiatric consultation is estimated to be only 1% to 3%, varying across institutions based on differences in patient population, length of stay, nature and severity of illness, and personal

style of referring physicians and consulting psychiatrists. At the Massachusetts General Hospital (MGH), between 11% and 13% of all hospital admissions are seen by a psychiatrist. Reasons for which consultation is requested typically involve affective, behavioral, and cognitive derangements, including delirium, dementia, depression, suicidal thinking, incapacity to make medical decisions, and interpersonal difficulties between patients and medical–surgical teams.

Diagnostic Features and Differential Diagnosis Diagnoses assigned by psychiatric consultants fall into the following categories: Psychiatric presentations of organic disease or its treatment (e.g., hypothyroidism with depressive features) Psychiatric complications of organic disease or its treatment (e.g., steroidrelated psychosis) Psychological reactions to organic disease or its treatment (e.g., adjustment disorder after a diagnosis of cancer) Organic presentations of psychiatric illness (e.g., depression with multiple somatic complaints) Co-morbid, independent psychiatric and medical illness (e.g., schizophrenia and coronary artery disease [CAD])

Principles of Psychiatric Evaluation of Medical– Surgical Patients A request for consultation can belie a problem in the patient, in the medical– surgical staff as individuals or as a whole, and/or between patient and staff. An effective consultant recognizes the importance of each of these possibilities and considers each in an accurate formulation of the problem. The consultative process begins by speaking directly with the consultee to define the reason for the consultation and to establish its urgency. Even though the “real” reason for the consultation might not be obvious from the stated request, it can be discerned during this initial conversation. The consultant is most helpful when he or she understands the consultee’s question or concern and then specifically addresses that issue.

A review of the current and pertinent portions of the old record is essential for a thorough appreciation of the patient’s medical and psychiatric history and present state. However, in the era of electronic health records, one must be particularly careful not to perpetuate errors in the chart by simply “cutting and pasting” portions of old notes into new ones. Attention should be paid to the patient’s medications, both those taken at home and those ordered in the hospital, being especially vigilant for recently added and discontinued (purposely or inadvertently) agents that may be relevant to the current mental status. In collecting collateral information from family, friends, and staff, avoidance of premature closure and of championing one version of events or facts over another is critical. When interviewing the patient and performing mental-status, physical, and neurological examinations, the atmosphere is less formal and rigid than in the outpatient setting; nurses, other staff, and family frequently interrupt; roommates and their visitors are often present; timing and format are best left flexible; and an appropriate use of humor often helps defuse tension and otherwise intolerable affect. Brief, jargon-free notes should emphasize impressions and recommendations and plans for treatment. Because these sections are the most important to the consultee, it is especially critical to be clear and specific in these sections. “Note wars,” criticism of the consultee, and accusations of shoddy work should be avoided. If the consultee chooses a therapeutic course equally appropriate to the consultant’s preferred choice, an indication of agreement in the chart may be more prudent than rigid insistence on the consultant’s preference. Not all battles need to be fought, but neither should a consultant be a “rubber stamp” for an illadvised treatment. The consultation note includes all of the elements of a standard psychiatric note, beginning with a short summary of the patient’s medical and psychiatric history, the reason for admission, and the reason for consultation. A synopsis of the present medical illness and hospital course should demonstrate a basic appreciation for the medical issues material to the consultation rather than rehash data already present in earlier notes. Relevant physical and neurologic findings (both positive and pertinent negative) and current and important past laboratory results (rather than just an unculled electronic “pasting” of all data) is included. In addition to the most likely diagnosis and a brief consideration of differential diagnoses, an indication that the patient’s symptoms are not attributable to a certain psychiatric disorder is often very helpful. Recommendations or plans listed in order of decreasing importance, and divided

into diagnostics (laboratory tests, neuroimaging, projective testing, neuropsychological testing) and therapeutics (biological, psychological, social, behavioral), complete the note. The initial consultation ends by speaking with the consultee, nurses, and other relevant staff about your findings, opinion, and treatment proposal, highlighting the rationale and anticipated outcome of your recommendations. This step is especially important when diagnoses or recommendations are crucial or controversial (e.g., when a pre-operative patient is found to have the capacity to refuse surgery). It is most helpful to both speak with the consultee in person or on the phone and provide your diagnostic impressions and treatment recommendations in the medical record to enhance clear communication among providers. A key element of effective therapeutics is the provision of periodic (usually daily) follow-up visits until the patient is psychiatrically stable, is discharged, or dies. This allows the consultant to: gather further history from patient, family, friends, previous treaters, and other collateral sources; supplement findings of the initial mental-status examination, which provides only a cross-sectional snapshot of a patient’s mental functioning at a given time, with longitudinal data; refine diagnoses; monitor treatment and recommend appropriate changes; and engage in ongoing dialogue with the consultee and other staff. “Signing off” of stable cases is acceptable, but the consultant should be prepared to resume follow-up should matters destabilize.

Treatment Treatment should proceed along multiple lines: biological, psychological, social, and behavioral. When prescribing psychotropic agents for patients who are taking other medications for medical illnesses, the consultant must be vigilant for drug–drug interactions. Numerous medicines, including many psychopharmaceuticals, are metabolized in the liver by the cytochrome P-450 enzyme system. Many psychiatric medications inhibit this enzymatic pathway and thus raise serum levels of concomitantly-administered drugs. Recent discontinuation of medicines or other substances might also affect drug levels (e.g., smoking induces the metabolism of some medications such that, when hospitalized patients stop smoking, levels of these drugs increase). In addition, some psychopharmacologic agents are highly protein-bound. These drugs can displace other protein-bound medicines and thus raise their serum concentrations, potentially to dangerous levels. Lastly, certain adverse effects

that healthy patients tolerate can be troublesome or dangerous for patients undergoing treatment for active medical illness. These side effects might worsen the medical problem or the side effects of other treatments. For example, the gutslowing effect of tricyclic antidepressants can worsen post-operative ileus. Psychotherapy with hospitalized, medically ill patients is brief, presentoriented, and practical. The consultant’s goal is to identify and bolster patients’ defenses to help them better cope with illness and hospitalization and to explain these coping strategies to the medical–surgical team in simple, jargon-free language. To be an effective therapist, the consultant must appreciate the variable stresses that different diseases engender as well as the universality of the experience of: uncertainty in diagnosis, treatment outcome, and prognosis; and grief over disfigurement, disability, or imminent death. Consultants might instruct patients in the use of relaxation techniques, guided imagery, and hypnosis to quell anxiety and reduce stress. Consultants also help the medical–surgical team and patient make decisions about: end-of-life care (e.g., do-not-resuscitate [DNR] and do-not-intubate [DNI] decisions); disposition to an appropriate living situation (e.g., home with visiting nurses, skilled nursing facility, nursing home); and short-term disability after a protracted illness or hospitalization. Explanation for the medical–surgical staff of patients’ natural coping styles helps the treatment team better understand and care for patients. For example, an electrical engineer with obsessive-compulsive traits feels out of control when he is admitted to the coronary care unit (CCU) with chest pain. He questions the team frequently because information helps him to feel more in control, even though the team considers his questions bothersome and they begin to avoid him. If the CCU team understands this patient’s defensive structure, team members might be less hostile toward him, answer his questions appropriately, and provide him with information before he asks for it. The consultant might suggest that the patient decide the times of medication administration or physical therapy (e.g., within an hour or so of the usual time) to help the patient feel more in control. For patients who are agitated or likely to hurt themselves or others, the consultant might recommend physical restraints and/or constant observation. Consultants should be prepared to transfer patients who are psychiatrically unstable to an inpatient psychiatric unit after their medical and surgical issues are resolved. Patients who require psychiatric follow-up but can safely go home should be referred for outpatient care. It is of critical importance to distinguish those patients who might be psychiatrically unstable for medical and surgical

reasons (i.e., delirium or traumatic brain injury) and ensure that their conditions resolve before re-assessing the need for primary psychiatric follow-up.

Conclusions The C–L psychiatrist is an expert in the affective, behavioral, and cognitive disturbances of hospitalized, medically or surgically ill patients, with skill in rapid assessment and in biological, psychological, social, and behavioral treatments. First and foremost a competent and thorough physician, the C–L psychiatrist takes a panoramic view of the patient, the disease, and the interrelationships between the two. The effective C–L psychiatrist addresses the needs of both the patient and the medical–surgical team. Accessibility, excellent communication skills, and tolerance for unpredictability are essential attributes.

Suggested Reading 1. Bronheim HE, Fulop G, Kunkel EJ, et al: The Academy of Psychosomatic Medicine practice guidelines for psychiatric consultation in the general medical setting. Psychosomatics . 1998; 39: S8–S30. 2. Garrick TR, Stotland NL: How to write a psychiatric consultation. Am J Psychiatry . 1982; 139: 849–855. 3. Gitlin DF, Schindler BA, Stern TA, et al: Recommended guidelines for consultation-liaison psychiatric training in psychiatry residency programs: A report from the Academy of Psychosomatic Medicine Task Force on Psychiatric Resident Training in Consultation-Liaison Psychiatry. Psychosomatics . 1996; 37: 3–11. 4. Goldman L, Lee T, Rudd P: Ten commandments for effective consultations. Arch Intern Med . 1983; 143: 1753–1755. 5. Hackett TP, Cassem NH, Stern TA, et al: Beginnings: Psychosomatic medicine and consultation psychiatry in the general hospital. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010; 1–6. 6. Kontos N, Freudenreich O, Querques J, et al: Consultation psychiatrist as effective physician. Gen Hosp Psychiatry . 2003; 25: 20–23. 7. Kontos N, Freudenreich O, Querques J: Ownership, responsibility and

hospital care: Lessons for the consultation psychiatrist. Gen Hosp Psychiatry . 2008; 30: 257–262. 8. Kontos N, Querques J: Psychiatric consultation to medical and surgical patients. In: Stern TA, Fava M, Wilens TE, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby Elsevier; 2016; 599–607. 9. McIntyre JS: A new subspecialty. Am J Psychiatry . 2002; 159: 1961–1963. 10. Querques J, Stern TA: Approach to consultation psychiatry: Assessment strategies. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia. PA: Saunders Elsevier; 2010: 7–14. 11. Worley LLM, Levenson JL, Stern TA, et al: Core competencies for fellowship training in psychosomatic medicine: A collaborative effort by the APA Council on Psychosomatic Medicine, the ABPN Psychosomatic Committee, and the Academy of Psychosomatic Medicine. Psychosomatics . 2009; 50: 557–562. 12. Wei MH, Querques J, Stern TA: Teaching trainees about the practice of consultation-liaison psychiatry in the general hospital. Psychiatric Clin North Am . 2011; 34: 689–707.

CHAPTER 76 Organ Transplantation LAURA M. PRAGER, MD

KEY POINTS Psychiatrists or other mental health professionals are involved in many stages of the transplantation process, ranging from selection of candidates and their pre-operative evaluation to short- and long-term post-operative management of both recipients and their families. Potential donors undergo a comprehensive psychological evaluation, as well as a medical work-up to determine motivation and to ensure autonomy, informed consent, and absence of coercion. Organ transplant recipient criteria include the absence of disabling psychiatric symptoms such as acute psychosis, suicidal or homicidal ideation, active substance abuse, dementia, or a history of multiple suicide attempts. The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) can be used by any member of the transplant team as a way to determine patients’ psychosocial risk factors. A combination of psychopharmacologic and psychotherapeutic interventions usually works best for both pre- and post-transplant patients. Many medicines, depending on their route of metabolism, will require dose adjustments based on the presence of renal or hepatic failure. A good rule of thumb is to “start low and go slow.” Organic brain syndromes are common sequelae of transplantation. Etiologies of delirium include medication effects or medication withdrawal, metabolic changes, and infection.

Introduction Organ transplantation has become a reasonable and often successful intervention for patients with end-organ failure. Organs commonly transplanted include the heart, lungs, liver, kidney, pancreas, and small intestine. Transplantation now also provides hope to some with severed upper limbs; face transplantation offers new meaning to some who have suffered tragic

disfigurement. With advances in immunosuppressive therapy and in techniques for organ procurement, transplant recipients are living longer and more productive lives. Former contraindications to transplantation, such as HIV infection or a history of cancer, are no longer absolute impediments due to advances made in the treatment of infectious and oncologic illness. Psychiatrists or other mental health professionals are involved in many stages of the transplantation process, ranging from selection of candidates and their preoperative evaluation to short- and long-term post-operative management of both recipients and their families. Our skill at organ transplantation has progressed dramatically over the past few decades. Unfortunately, the available supply of donor organs does not parallel the increase in demand, and many transplant candidates continue to die while awaiting a transplant.

Overview of Transplantation The United Network for Organ Sharing In the United States, The United Network for Organ Sharing (UNOS) is the non-profit corporation endowed by Congress and reporting to the Department of Health and Human Services that regulates the allocation of organs. UNOS has the power to enforce its policies as federal regulations. UNOS is divided into two branches: Organ Procurement and Transplant Network (OPTN), and Scientific Registry. The OPTN divides the country into eleven distinct geographic regions, and allocation of organs is done by local priority. This is particularly important because the radius of distribution for each organ is dependent on the vulnerability of that organ to ischemic injury and the time required for air transport of the available organ. Donor hearts and lungs must be transplanted within 4 to 6 hours of procurement. Kidneys can tolerate 24 to 36 hours of perfusion preservation and can be transported across the continent. New research involves transport of heart, lung, or liver within a portable matrix that allows for continuing blood perfusion and offers the potential for a longer radius of distribution. The length of the waiting list for each organ differs among geographic regions. Time spent waiting is the primary determining factor for kidney transplantation candidates. Acuity of illness confers priority for heart, lung, and liver candidates. Liver candidates also receive additional points for certain diagnostic features, such as liver cancer. Pediatric candidates for kidneys and livers take precedence over adult candidates. Full HLA compatibility confers priority for kidney

transplantation. Ventilatory support is almost always a contraindication to transplantation for potential lung candidates but confers priority status to heart and liver candidates. In some centers, patients with acute respiratory failure have been placed on an extracorporeal membrane oxygenator (ECMO) as a bridge to transplant. Sepsis is a contraindication to transplantation for all solid-organ candidates.

Limitations to Transplantation: Access and Outcome Despite an increase in national attention to the need for organ donation, the gap between the number of people who need organ transplantation and the number of available organs continues to widen, primarily due to the shortage of available deceased-donor and living-donor organs. In the United States, the principle source of transplantable organs is cadaveric (brain dead) donors. Brain death is determined by hospital-specific criteria, usually requiring examination by a neurologist, intensivist, or surgeon. Diagnostic tests used to support a diagnosis of brain death can include an apnea test, an electroencephalogram (EEG), a transcranial doppler, a cerebral blood flow scan, or an arteriogram. Clinical criteria for brain death include fixed and dilated pupils, absent reflexes, unresponsiveness to external stimuli, and apnea. Transplant centers try to expand the donor pool by harvesting organs from donors after circulatory death (DCD) in addition to harvesting organs from those who have suffered brain death. Other sources of cadaveric donor organs include extended criteria donations (ECD) for kidneys, livers, and lungs. ECD organs include, for example, those for whom the donor exceeded the standard age limits or engaged in a higher-risk lifestyle. Potential recipients must consent to the use of ECD organs prior to transplantation. Scarcity of cadaveric organs has prompted consideration of related or “Good Samaritan” (un-related) living organ donors. (This is particularly important in Japan where there are no defined criteria for determination of brain death and few cadaveric organs are harvested.) This option is currently available for kidney, liver, and lung transplantation at some centers in the United States. In fact, in the United States, living donor transplantation currently exceeds deceased organ donation as a source of kidneys. Parent-to-child liver transplantation (of the left lateral lobe) is an option, as is adult-to-adult transplantation of the right hepatic lobe. Living-lung donation is also an option for carefully-selected candidates, but it requires a lower lobe from two different donors for each single potential recipient. Potential donors undergo a

comprehensive psychological evaluation, as well as a medical work-up to determine motivation and to ensure autonomy, informed consent, and absence of coercion. In an effort to avoid potential conflict of interest or unintended coercion, the Center for Medical and Medicare Services (CMS) now requires that transplant centers maintain separate evaluation teams for intended recipients and living donors. The source of the donated organ (i.e., from a deceased donor or living donor) does not affect recipient outcome. Living organ donation raises several ethical questions: What is true informed consent regarding both short- and long-term risks for the donor? Is the donor’s offer (be it from an emotionally-connected or un-related person) truly voluntary? It is difficult to determine what level of risk is acceptable for a healthy, altruistic donor. In 2015, there were approximately 30,000 transplants performed in the United States; approximately 25,000 from deceased donors and 5,000 from living donors. Kidney and liver transplants numbered about 18,000 and 7,000 respectively, with the remainder being heart, lung, and pancreas transplants. Recent changes in how deceased-donor kidneys are distributed—accounting for a candidate’s estimated post-transplant survival (EPTS) and creating a measure of kidney quality or the Kidney Donor Profile Index (KDPI )—have helped to increase the number of patients who are “difficult-to-match” getting a transplant. Several factors can compromise the success of organ transplantation. Allograft rejection and the complications of antirejection therapy continue to pose problems for recipients post- transplantation. In addition, these immunocompromised hosts are vulnerable to bacteria, viruses, and fungi that are not considered pathogenic in the normal population. The side effects of immunosuppressive medications that are used to manage rejection can be debilitating, disfiguring, or life threatening, and increase the risk for neoplasm, problems with bone metabolism, or cause a Cushingoid body habitus, nephrotoxicity, posterior-reversible encephalopathic syndrome (PRES), and the development of diabetes mellitus. Finally, non-adherence to post-transplant medication regimens or failure to follow other recommendations of the treatment team remains a significant contributor to allograft loss.

Transplant Recipient Selection The process by which patients are selected to receive an organ for transplantation has been the topic of continuous debate since the first successful kidney transplant between monozygotic twins was done by Murray in 1954.

Three precepts serve as a template: a rights-based approach (that includes all candidates who wish to be included); a utilitarian-based approach (in which worth to society is a criterion for candidacy); and, a medically-based approach (that offers candidacy to those who can physically benefit from transplantation).

Medical–Surgical Screening Members of a multi-disciplinary committee evaluate each candidate for transplantation. Such a committee usually comprises a nurse coordinator, transplant surgeon, medical specialist (nephrologist, hepatologist, cardiologist, or pulmonologist), social worker, financial advisor, nutritionist, and psychiatrist. Patients are encouraged to bring family members or friends to the initial evaluation so that those who might provide post-operative support can also learn about the process of transplant. During these meetings, patients have a chance to learn about outcome data at that particular center and to ask questions about both candidacy and transplantation. Transplant teams benefit from access to skilled interpreter services and must be aware of differences in health-care literacy among patients as well as be sensitive to religious beliefs and cultural practices that might compromise understanding. Other criteria for candidacy include: history of compliance with medical regimens; appropriate HLA typing; ABO blood group compatibility; negative urinary drug screening for recreational drugs, and cotinine; absence of disabling psychiatric symptoms (such as acute psychosis, suicidal or homicidal ideation, active substance abuse, dementia, or history of multiple suicide attempts); identification of an infectious disease profile including HIV, HBV, HCV, CMV; and risk of exposure to tuberculosis. Cardiovascular evaluation and dobutamine stress testing are standard for patients with history of coronary artery disease, arrhythmia, congestive heart failure, congenital heart disease, pulmonary hypertension, and valvular heart disease. Sometimes, kidney recipients require further assessment of peripheral vascular patency for intra-operative vascular anastomoses and detection of risk of a “steal syndrome” that could cause ischemic damage to a limb.

Psychiatric Screening Psychiatric care of patients undergoing transplantation requires clear knowledge of the unique challenges of this surgical sub-specialty. Many transplant centers rely on a general hospital psychiatric consultation service. Major academic centers frequently enlist dedicated transplantation psychiatrists, who are familiar with the unique needs and vulnerabilities of transplant patients.

In addition, social workers play a central role in identifying adequacy of access to the transplant center, and the depth, capacity, and reliability of the patient’s support network. Psychologists may assist by offering standardized psychometrics and/or neuropsychological testing. Experts in the treatment of substance abuse and addiction can be particularly valuable in the assessment and management of this population.

Pre-Transplant Psychiatric Evaluation Pre-transplant evaluation of candidates requires recognition of common psychological symptom clusters and syndromes. Informed consent, teaching, and pre-operative management help adherence compliance with the requirements of transplant teams and thus more favorable post-operative outcomes. Unfortunately, there are no uniformly-accepted psychiatric guidelines for acceptance or rejection of transplant candidates. Some centers routinely use selfreport questionnaires, like the Beck Depression Inventory (BDI); others rely on a dynamically-informed clinical interview. One of the most promising standardized psychosocial assessment tool is the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) developed by Maldonado et al (2008), which can be used by any member of the transplant team as a way to determine patients’ psychosocial risk factors and highlight current issues that might translate into problems post-transplant. Transplant centers differ regarding the importance they attribute to psychological issues and the degree of risk the team is willing to assume. Factors that complicate pretransplant evaluation include a lack of reliable and predictive data with respect to “suitability for transplant.” Some centers feel comfortable managing patients with a history of bipolar disorder, whereas others do not. Clinical experience suggests that candidates on methadone or suboxone maintenance for opioid addiction can do well following transplant, yet some centers continue to exclude such patients. Centers vary in the amount of time they require candidates to demonstrate abstinence from substances of abuse, and the current “six-month rule” remains controversial. The objectives of the psychiatric evaluation include screening potential recipients for the presence of significant Axis I diagnoses (e.g., mood, anxiety, and psychotic disorders, as well as substance abuse) and Axis II diagnoses (e.g., involving personality disorders). Evaluators must also assess cognitive impairment that might complicate management or interfere with the patient’s ability to comply with treatment recommendations. Determining whether a given

candidate will be able to collaborate with the transplant team in a joint effort to optimize medical care both pre-and post-transplant is essential. This includes assessment of motivation, compliance with previous recommendations by other caregivers, availability of social supports, and history of perseverance in the face of adversity. The psychiatric interview can also serve as a forum in which to educate patients about the risks and benefits of transplantation. Patients who present with severe mood or psychotic disorders are often able to qualify for transplant candidacy following treatment, stabilization, and plan for long-term professional support as required. Transplant programs with a designated psychiatric consultant can work successfully with patients who have bipolar disorder, schizophrenia, or who suffer from severe depression, posttraumatic stress disorder (PTSD), or anxiety states. In addition, candidates for transplantation must live within a support network that is robust enough to provide round-the-clock care in the immediate postoperative period and caregivers who can transport them back and forth to the numerous doctor appointments that follow transplant surgery. Without such support patients will not qualify as candidates for transplantation. Even though it is difficult to reject a potential transplant patient, there is no advantage to accepting those with insufficient resources, internal or external, to allow them to comply with requirements for sustained graft function. The Academy of Psychosomatic Medicine has a transplant psychiatry group that maintains a list-serve on the Academy’s website. It is common for transplant psychiatrists to share ideas through this online mechanism and to collaborate not only in regard to patient selection but also with questions regarding use of psychotropic medication and interventions for unusual post-transplant psychiatric complications.

Psychiatric Treatment Strategies As in other areas of psychiatry, treatment plans for the pre- and post-transplant patient are multi-faceted and usually consist of a combination of psychopharmacologic interventions and psychotherapeutic techniques. Psychiatric disorders (including depression, anxiety, adjustment disorders, PTSD, and substance abuse) are common in the pre-transplant candidate population, regardless of the type of end-stage organ failure. As many as 25% of dialysis-dependent patients with end-stage renal disease (ESRD) manifest symptoms of major depression. Disorders in endocrine function (e.g., hyperparathyroidism), and chronic anemia that are common in these patients can

also contribute to depression. Hepatic failure (e.g., from cirrhosis) can cause depression and sub-clinical or frank encephalopathy. Other disorders are unique to patients who suffer from a particular type of endorgan failure. For example, many patients with heart failure spend weeks or months in a hospital’s intensive care unit (ICU) attached to a cardiac monitor or an intra-aortic balloon pump (IABP); others live outside the hospital with a left ventricular assist device (LVAD). Likewise, years can go by while a patient with lung disease waits at home, sometimes far from a transplant center, becoming gradually sicker and more sedentary, all the while tethered to an oxygen tank.

Pharmacology Psychopharmacologic agents can and should be used when indicated. Choosing a medication regimen for a potential transplant recipient with end-organ failure can be challenging. Many medicines, depending on their route of metabolism, will require dose adjustments based on the presence of renal or hepatic failure. A good rule of thumb is to “start low and go slow.” Selective serotonin re-uptake inhibitors (SSRIs; e.g., fluoxetine, sertraline, paroxetine, citalopram) are often the first-line management for mood because of their benign side effect profile and anxiolytic effects. Rarely, they may cause hyponatremia and the syndrome of inappropriate anti-diuretic hormone (SIADH) secretion. Bupropion is more stimulating than other antidepressants but at doses lower than 450 mg it has a relatively benign side effect profile. It can also be helpful for patients who are struggling to remain abstinent from tobacco products. Tricyclic antidepressants (TCAs) are no longer a first-line treatment because of their potential for cardiac (quinidine-like) effects. However, they can be helpful when used in low doses for neuropathic pain. Stimulants, such as methylphenidate or modafinil, can also be used as adjuncts for the treatment of depression. Benzodiazepines can be invaluable in the management of anxiety although some transplant teams are unwilling to use them because of their addictive potential. Shorter-acting agents (e.g., lorazepam and oxazepam) are preferable. Alprazolam can be problematic because of its potential for rebound symptoms that are often indistinguishable from the symptoms of anxiety. Many long-acting agents (e.g., diazepam) have active metabolites that can accumulate, particularly in patients with hepatic dysfunction. Patients with chronic psychotic disorders can and should be maintained on their existing antipsychotics. Low-dose neuroleptics can be helpful in ameliorating

anxiety, particularly in patients who cannot take benzodiazepines because of the risk of abuse. Patients who require mood stabilizers (such as lithium, valproic acid, or carbamazepine) can be maintained on them prior to transplant. Lithium levels will need to be adjusted for patients with renal failure as valproic acid and carbamazepine will be for patients with hepatic failure. Gabapentin can be particularly helpful in the management of steroid-induced mood lability, but it must be used with caution in patients with a glomerular filtration rate (GFR) below 30.

Psychotherapy Psychotherapeutic interventions are often extremely important because candidates for transplant have a wide variation in their coping styles and in the strength of their support networks. Patients usually do best with supportive, cognitive, or behavioral approaches. Even the one-time psychiatric pretransplant evaluation can serve as a good opportunity for listening and for validation of a patient’s hopes and concerns. Common issues raised include loss of occupational status with secondary financial pressures, guilt over lack of ability to perform at pre-morbid level of functioning, change of role within the family system, cognitive blunting or impairment, inability to perform sexually, and denial of the progressive nature of disease. Substance abuse counseling is essential for those who are struggling to remain abstinent. It is inappropriate for the transplant team to monitor the patient (with, for example, urine toxicological screens) although many lung transplant programs check cotinine levels routinely. Transplant candidates who have a history of substance use or abuse are better served by a referral to such programs as Alcoholics Anonymous (AA) or Narcotics Anonymous (NA) and/or a formal substance abuse treatment program.

Psychiatric Care of the Post-Transplant Patient Post-operatively , some patients recover rapidly and are able to leave the hospital within 1 to 2 weeks. Others are less fortunate and can spend many weeks in an ICU before being transferred to the floor or to a rehabilitation facility. Organic brain syndromes are common sequelae of transplantation. Etiologies of delirium include medication effects or medication withdrawal, metabolic changes, and infection. Immunosuppressive medication including steroids can

precipitate delirium, as can the narcotics used for pain and the benzodiazepines that might be used to manage, for example, anxiety in the setting of weaning from mechanical ventilation. The calcineurin inhibitors, such as cyclosporine (CYS), FK-506 (tacrolimus), and steroids (e.g., solumedrol or prednisone), can produce a wide variety of neuropsychiatric symptoms that include tremulousness, agitation, seizures, polyneuropathies, psychosis, and delirium. Less frequently, these medications cause a relatively severe neurotoxic syndrome, PRES. PRES is also often associated with hemodynamic instability. The clinical syndrome will often remit following discontinuation of the immunosuppressive medication. Patients can then undergo re-challenge with a different immunosuppressive medication. Heart transplant patients are at risk for intra-operative cerebral ischemia that can cause psychosis in the early postoperative period. Management of delirium requires a hunt for the etiology, and treatment of the underlying disorder if possible. Judicious use of neuroleptics, such as haloperidol, can ameliorate the symptoms of agitation, hallucinations, and delusions. When using neuroleptics (such as intravenous [IV] haloperidol) in this setting, the team must carefully follow potassium and magnesium levels and keep the QTc to less than 500 milliseconds to minimize the risk of torsades de pointes. Some treatment teams also use dexmedetomidine, an α 2 agonist, to manage delirious patients. In the immediate post-operative period, patients can be vulnerable to mood and anxiety disorders. Medications (such as beta-blockers used to treat hypertension or arrhythmias), infections (particularly CMV), acute or chronic pain, and episodes of rejection can trigger new symptoms of depression or a recurrence of pre-morbid issues. High-dose steroids can precipitate hypomania or mania. Likewise, many medications can cause anxiety, as can rapid withdrawal from sedative-hypnotics or opioids. Some patients develop anxiety in anticipation of pain or of rejection of the allograft. In the long term, transplant patients have exchanged one set of problems, those of end-organ failure, for another set of problems, those that attend the side effects of immunosuppressive medications (rejection of the allograft and progression of systemic disease). Pre-morbid vulnerabilities can easily re-surface in the setting of un-met expectations and the inevitable medical setbacks. Depression following transplant is extremely common. Alteration in mood can be related to chronic medication effects, disappointment with the bodily changes (e.g., weight gain, acne, hirsutism that can be secondary to steroids, persistent

weakness, cognitive dulling), and reactions from family members who might either demand too much too soon or be unable to see the patient as less dependent and/or more capable. Treating pre-morbidly depressed liver transplant patients with antidepressants has been shown to decrease the incidence of cellular rejection. Anxiety can re-emerge in response to side effects of medication (particularly the calcineurin inhibitors), the potential for allograft rejection, and ongoing concern regarding inability to live up to one’s own expectations or those of others. Patients sometimes have difficulty separating from caregivers (particularly members of the transplant team) and adjusting to the loss of other tangible supports (such as dialysis or oxygen tanks). Many patients report signs and symptoms consistent with PTSD following ICU stays, in which they have experienced frightening hallucinations and delusions. Problems with substance abuse can also re-emerge following transplant even after the patient has had years of sobriety. Although transplant teams usually prescribe abstinence, many liver transplant recipients resume drinking alcohol and lung transplant recipients resume smoking marijuana. Relapse on alcohol or illicit drugs and/or associated non-compliance with medication regimens can severely compromise the allograft. Such behavior deserves an assessment for depression and suicidality as well as an exploration of possible causes of anger at, and disappointment with, the treatment team.

Treatment Strategies A combination of psychopharmacologic and psychotherapeutic interventions usually works best for both pre- and post-transplant patients.

Psychopharmacology Psychopharmacologic treatment of the transplant patient is complicated by the risk for multiple drug interactions and is often confounded by the neuropsychiatric effects of the immunosuppressive drugs. Some SSRIs, notably fluoxetine and paroxetine, can increase cyclosporine (CYA) levels through inhibition of cytochrome P450 enzyme system. Nefazodone can also produce significant competitive inhibition and its use (as well as that of duloxetine) is contraindicated in liver transplantation due to risk for hepatotoxicity. CYA can increase lithium absorption and lead to higher lithium levels. The mood stabilizers and anticonvulsants (carbamazepine and phenobarbital) may decrease the levels of the calcineurin inhibitors through hepatic induction.

FK506 (tacrilomus) is often used as a “salvage” therapy for patients who fail CYA. It can also cause neuropsychiatric symptoms (such as headache, insomnia, tremor, and visual hallucinations). It, too, is metabolized through the cytochrome P450 isoenzyme system, and its blood levels will likely increase with concomitant use of the SSRIs and decrease with the use of anticonvulsants. Corticosteroids continue to be a mainstay of immunosuppressive regimens, and most transplant patients remain on them (at lower and lower doses) for the rest of their lives. They have numerous side effects (including weight gain with fat distribution, easy bruising, osteoporosis, and hirsutism), as well as a tendency to cause emotional lability, hypomania, mania, irritability, and depression. At high doses, patients can manifest rapid-cycling and become psychotic. Benzodiazepines (such as clonazepam), or mood stabilizers (such as gabapentin) can be extremely helpful in ameliorating these symptoms. Low-dose antipsychotics can also be of benefit. Clinicians should not discount the potential for interaction among herbal remedies or over-the-counter (OTC) preparations with the post-transplant medications. For example, St. John’s wort will decrease the levels of calcineurin inhibitors. Echinacea, an OTC derivative of the flower plant with the same name, has stimulant properties that can lead to allograft rejection. Sometimes, when a patient’s depressed mood proves refractory to aggressive psychopharmacology combined with supportive psychotherapy, a transplant psychiatrist might recommend electroconvulsive therapy (ECT).

Psychotherapy The transplant patient can also benefit from supportive therapy. Pre-morbid issues, such as anxiety or depression, often thought to be a product of the endorgan failure, might not go away but might recur in a slightly different form. Other issues that can benefit from discussion with an informed therapist include the patient’s curiosity about the donor and the wish to meet with and thank the family. Some recipients believe that the donor organ has altered their personalities or their likes and dislikes; some worry that they have lost an integral part of themselves when the diseased body part was removed. Other treatment modalities (such as cognitive-behavioral strategies for persistent anxiety or family work in the case of intra-familial conflict) can also be extremely helpful. Many patients benefit the most from organ-specific transplant support groups. These monthly groups allow patients in every stage of the process to air their

feelings with select members of the transplant team and to raise issues that concern them.

Conclusion Patients with end-organ failure who are approaching transplantation have few alternatives. These patients are disabled and often desperate. Prompt recognition and treatment of psychiatric illness can significantly impact the quality of life for these patients. Post-transplant patients face different but equally daunting challenges. Early recognition and treatment of psychiatric symptoms can bolster adherence with medical regimens, prevent complications, and improve the likelihood of a favorable outcome.

Suggested Readings 1. Chen F, Fuginaga T, Shoji T, et al: Outcomes and pulmonary function in living lobar lung transplant donors. Eur Soc Organ Transplantation . 2012; 25: 153–157. 2. Childress JF: How can we ethically increase the supply of trans-plantable organs? Ann Intern Med . 2006; 145(3): 224–225. 3. DiMartini A, Crone C, Fireman M, et al: Psychiatric aspects of organ transplantation in critical care. Crit Care Clin . 2008; 24 (4): 949–981. 4. Heinrich TW, Marcangelo M: Psychiatric issues in solid organ transplantation. Harv Rev Psychiatry . 2009; 17(6): 398–406. 5. Hipp DM, Ely EW: Pharmacological and non-pharmacological management of delirium in critically ill patients. Neurotherapeutics . 2012; 9: 158–175. 6. Lang G, Taghavi S, Aigner C, et al: Primary lung transplantation after bridge with extracorporeal membrane oxygenation: a plea for a shift in our paradigms for indications. Transplantation . 2012: 93(7): 729–736. 7. Maldonado JR, Sher Y, Lolak S, et al: The Stanford Integrated Psychosocial Assessment for Transplantation: A prospective study of medical and psychosocial outcomes. Psychosomatic Medicine 2015; 77: 1018–1030. 8. Parker R, Armstrong MJ, Corbett C, et al: Alcohol and substance abuse in solid-organ transplant recipients. www.transplantjournal.com ; 2013.

9. Prager LM: Organ transplantation. In: Stern TA, Freudenreich O, Smith FA, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 7th ed. Philadelphia, PA: Elsevier; 2018: (in press). 10. Rogal SS, Landsittel D, Surman O, et al: Pretransplant depression, antidepressant use, and outcomes of orthotopic liver transplantation. Liver Transplantation . 2011; 17(3): 251–260. 11. Segev DL, Muzaale AD, Caffo BS: Perioperative mortality and long-term survival live kidney donation. JAMA . 2010; 303: 959–966. 12. Surman OS, Cosimi AB, DiMartini A: Psychiatric care of patients undergoing organ transplantation. Transplantation . 2009; 87: 1753–1761. 13. Surman OS: The ethics of partial-liver donation. N Engl J Med . 2002; 346:1038. 14. UNOS https://www.unos.org/about/annual-report/ [Accessed November, 2016] 15. Wynn JJ, Alexander DE: Increasing organ donation and transplantation: the U.S. experience over the past decade. Transpl Int . 2011; 24: 324–332. 16. Zalai D, Szeifert L, Novak M: Psychological distress and depression in patients with chronic kidney disease. Semin Dial . 2012; 25(4): 428–438.

CHAPTER Chronic Mental Illness 77 ABIGAIL L. DONOVAN, MD; ALICIA D. POWELL MD; AND DAVID C. HENDERSON, MD

KEY POINTS Overview Chronic, severe mental illness, including schizophrenia, is characterized by persistent, disabling, psychiatric symptoms or by severely-impaired function. In the 1950s and 1960s, de-institutionalization led to thousands of formerlyhospitalized persons being discharged to live in the community, in many cases without sufficient resources to provide adequate care. Many of these patients are now homeless and not receiving adequate treatment for their psychiatric illness. Chronic mental illness also carries an increased risk of chronic medical conditions and increased mortality due to medication effects, substance abuse, and decreased utilization of, and access to, primary health care. Clinical Assessment Interviewing patients with chronic mental illness requires special consideration of interpersonal space and arranging the interview environment to maintain patient and clinician safety. Important aspects of the assessment also include a thorough review of the medical, substance use, and social histories. All patients must be assessed for risk of harm to self and others, as well as risk of becoming a victim of harm. Collateral information is critical to a thorough assessment. The mental status exam requires good observation skills, with attention given to subtle signs of psychosis, such as internal preoccupation or speech latency. Diagnostic Issues Social, economic, and cultural factors can complicate the diagnosis of mental

illness, and schizophrenia in particular. The differential diagnosis for psychotic symptoms is broad, and includes primary psychotic disorders, mood disorders, trauma, substance use disorders, organic illnesses, and medication effects. Pharmacology is a critical component of treatment for chronic and severe mental illness. Antipsychotics are the mainstay of treatment for schizophrenia. Non-adherence is common and side effects are numerous. Non-pharmacologic treatments are also important for patients with chronic mental illness. Assertive community treatment teams (providing intensive support, with around-the-clock availability) provide critical care for patients with chronic mental illness. Crisis units and day treatment centers can provide additional community-based treatment. Supportive therapy, cognitive-behavioral therapy, and family psycho-education are also important components of care.

Introduction Chronic , severe mental illness is characterized by persistent, disabling, psychiatric symptoms or by severely-impaired function. Frequently, this population is labeled as the severely and persistently mentally ill. One of the most disabling of all chronic mental illnesses is schizophrenia. Several events in the 1950s, including the development of antipsychotic medications and new commitment laws, led to dramatic changes (e.g., deinstitutionalization) in the treatment of the severely and persistently mentally ill. The l960s brought the Community Mental Health Center Program as an alternative to state hospitalization, as well as new federal programs (Supplementary Security Income [SSI], Social Security Disability Insurance [SSDI], Medicaid, and Medicare health benefits). Thousands of formerlyhospitalized mentally ill persons were discharged to live in the community. Between l955 and l985, the state hospital resident population decreased by 80% (from 559,000 to 110,000). Unfortunately, most communities lacked sufficient resources to provide adequate care for these patients. Several facts help to put this problem into perspective. The life-time prevalence of schizophrenia is about 1%, and the incidence of schizophrenia is about 0.4 per

1,000 per year. Approximately 3.1 million Americans are living with schizophrenia, although roughly 40% of those people are not receiving treatment for their illness. The prevalence of mental illness is higher in cities and in lower socio-economic neighborhoods. This is largely due to the drift of chronically-ill patients toward urban environments, where aftercare for formerly institutionalized patients has typically been concentrated. Approximately 25% of the homeless population has a serious mental illness, a significant portion of which is schizophrenia. The costs of chronic mental illness are enormous. Annual direct and indirect costs associated with schizophrenia in the United States are estimated at $62.7 billion (Wu, 2005), whereas the total annual costs for all serious mental illnesses are estimated at $317.6 billion (Insel, 2008). The direct costs consist of outpatient care, inpatient care, long-term care, and medications. Indirect costs make up the majority of the total costs, and include unemployment, reduced workplace productivity, premature mortality, and family burden. Chronic mental illness also carries an increased risk of chronic medical conditions, both due to medication effects, substance abuse (including nicotine), and decreased utilization of, and access to, primary health care. Adults with serious mental illness die 25 years earlier than other Americans, and patients with schizophrenia in particular have two- to three-fold higher mortality rates than those in the general population. Much of this excess mortality is due to potentially preventable and treatable medical conditions, such as cardiovascular disease, obesity, and diabetes.

Assessment of the Chronically Mentally Ill The Interview The assessment of any patient begins with the interview. Several aspects of the interview need special consideration when working with chronically mentally-ill patients. The clinician must be particularly aware of interpersonal space. Individuals with chronic mental illness, especially when paranoia is present, may require a larger interpersonal space to feel safe. Clinicians may want to turn their body perpendicular to the patient, as sitting directly face-to-face can be perceived as more threatening. It is important to ask the patient whether she or he is comfortable at the outset of the interview. Do not hesitate to rearrange the seating if you believe it will help put the patient at ease, or if it is important for safety. For all patients, it is good practice to arrange the room so that both the

clinician and the patient have equal access to the door; for settings in which this arrangement is not possible, preferential access to the door should be given to the clinician. All patients will be more at ease if they understand the nature of confidentiality in a psychiatric interview. This is especially true for patients with paranoia or for homeless patients who might feel generally disempowered. Although patients with chronic mental illness have probably been through many interviews in their lifetimes, it is good practice to remind them about confidentiality.

Special Considerations in History-Taking The chronically mentally-ill patient might have difficulty recalling the history of symptoms, making it necessary to obtain further history from additional sources. Asking the patient questions such as, “Who else would remember what you were going through before that hospitalization?” or, “Who has seen you at your most depressed?” can elicit the best outside sources. Patients with chronic mental illness frequently have a psychiatrist, case manager, or therapist who knows them well. These treaters should be contacted to provide collateral information about the patient’s history, baseline mental status, response to medications, and risk factors regarding safety. The medical history should never be neglected. A history of head injury, loss of consciousness, and seizures should always be assessed. The severely and persistently mentally ill often neglect their medical problems. Therefore, it is important to ask about the patient’s last physical examination and to obtain a review of systems. Substance use disorders frequently co-exist with severe mental illness; therefore, a complete substance use history must be taken for every patient. It is wise to begin your inquiry with questions about more socially-accepted addictive substances (e.g., nicotine and caffeine) and then work your way up to other drugs, e.g., alcohol, cannabinoids (both natural and synthetic), cocaine, opiates, stimulants, hallucinogens, barbiturates, benzodiazepines, and inhalants. Pertinent questions include: age at first use; amount, duration, and method of use; social or physical adverse effects; tolerance and withdrawal; longest sober periods; and date of last use. The social history of these patients should include information regarding where the patient sleeps at night, who else resides with the patient, what the educational level of the patient is, whether he or she has served in the armed forces, and the major source of the patient’s income. It is also important to inquire about sexual

activity, especially when interviewing a woman of child-bearing age. This is critical because many psychotropics are teratogenic. In addition, many patients underestimate the risk of sexually-transmitted diseases, including HIV infection. It is also important to ask about the patient’s history of violence, both as perpetrator and as a victim, for diagnostic as well as safety reasons.

The Mental Status Examination Observation is a critical component of the mental status exam (MSE ). During the interview, it is useful to make mental notes about the patient’s hygiene, attire, speech, attitude, and eye contact, as well as any abnormalities of movement (such as tremor, bradykinesia, or odd mannerisms). At times, you can obtain valuable information by asking patients questions about their attire; for example, “How did you chose to wear this piece of clothing today?” When asking about psychotic symptoms, it is best to use a gradual, gentle approach. Some patients are relieved to learn that their symptoms can be understood as the result of an extreme form of normal brain activity. For instance, when asking about visual hallucinations, the interviewer might compare them to the experience of “dreaming while you’re awake.” A normalizing approach may also be helpful in letting the patient know they are not alone in their illness. For example, saying, “Many patients that I know have the experience of hearing voices that no one else hears, does that happen for you?” Despite gentle questioning, many patients will be guarded about revealing their psychotic symptoms, so observation can be important. Clinicians should watch for patients responding to internal stimuli, appearing internally preoccupied, or having increased speech latency, as clues that the patient may be experiencing psychotic symptoms. Patients may also be reluctant to reveal delusions. If they do discuss delusional content, it is wise to neither validate nor invalidate the actual content, but simply to acknowledge the patient’s experience. A key concern in assessing any patient is safety. Clinicians should remember to ask the patient about current thoughts of suicide or homicide, command hallucinations, and possession of, or access to, weapons. Clinicians must also ask about a history of suicide attempts and a history of violence, as both significantly increase the risk for future suicide and violence. Roughly 5% of patients with schizophrenia will commit suicide during their lifetimes, and the highest risk period is early in the illness. Research on the risk of violence in patients with schizophrenia has been conflicted. However, it seems clear that patients with serious mental illness and co-morbid substance use are at increased

risk of violence (Elbogen, 2009) and that the risk of violence for patients with psychosis is highest prior to entering treatment or during periods of poor adherence to treatment (Nielssen, 2012). Despite this, people with schizophrenia are at even higher risk of becoming victims of violence than perpetrators of violence (Teplin, 2005).

Diagnostic Issues Numerous factors can complicate the diagnosis of mental illness, and schizophrenia in particular. For example, socioeconomic factors often complicate making a diagnosis. What might be seen as hypervigilance in some is just plain “street smarts” for homeless patients, patients living in dangerous areas, or even patients uncomfortable in particular institutions or environments. Paranoia can be complicated by social isolation, by a lack of private space due to homelessness, or by prior episodes of victimization on the streets. Believing that people are out to get you can be part of a delusional system, or it can be reality if you are part of a gang. Cultural issues might also play a role. In some cultures, it is a normal grief reaction to experience visitations from the ghost of a deceased relative. Careful consideration must be given to the social, economic, and cultural context in which symptoms occur. Negative symptoms of schizophrenia include apathy, social isolation, poverty of thought or speech, flattening of affect, and neglect of hygiene. Negative symptoms profoundly impair an individual’s ability to function and to engage in treatment; these symptoms can also alienate family members and caregivers. A substantial portion of the functional impairment of schizophrenia is actually due to negative symptoms, rather than positive symptoms. Medication side effects can also mimic, or contribute to, negative symptoms. In addition, patients with schizophrenia are also at high risk for co-morbid depression, which can be challenging to diagnose when negative symptoms are present. Longitudinal monitoring of mood, neurovegetative and negative symptoms, and response to medication can be necessary to delineate these diagnoses. Because psychotic symptoms can occur in many medical and psychiatric illnesses, clinicians should inquire about the onset of symptoms in relation to the use of new medications or substances, physical illness, depression, mania, or flashbacks of traumatic experiences. Seizures, brain tumors, infections, substance intoxication and withdrawal, metabolic derangements, and medication side effects can all cause psychotic symptoms. A medical etiology must be ruled-

out in any new onset of psychotic symptoms, when psychotic symptoms begin after the age of 50 years, or if atypical symptoms are present.

Treatment Strategies Pharmacologic Pharmacology is a critical component of treatment for chronic and severe mental illness. Antipsychotics are the mainstay of treatment for schizophrenia. First- and second-generation antipsychotics have similar efficacy (with the exception of clozapine), although their side effect profiles differ. First-generation antipsychotics carry a higher risk of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), whereas second-generation antipsychotics carry an increased risk of weight gain, dyslipidemia, and diabetes. The second-generation antipsychotic clozapine (Clozaril) has been shown to be effective in the treatment of refractory psychosis, and it decreases suicidality. Effective treatment with clozapine has enabled some patients to reach a higher level of function. Non-adherence is a major issue in the treatment of patients with chronic mental illness. Studies report that as many as 41.2% of patients with schizophrenia are non-adherent or partially non-adherent with their prescribed medications (Lacro, 2002). Reasons for non-adherence include poor insight, side effects, cost, and access to care. Several considerations to maximize compliance should be taken into account when treating patients with severe mental illness. Once-a-day dosing is the most convenient for patients, and the easiest to remember. Three or four times a day dosing is nearly impossible for most people to remember, let alone those with a chronic mental illness. The cost of medication is another important consideration. Although most patients have medication insurance coverage that requires only a small co-payment for each prescription, even this amount might be a burden for a patient, especially when multiple medications are prescribed and the patient is on a fixed income. Certain medication side effects (such as diarrhea and frequent urination) are problematic for homeless patients who have limited access to restrooms and laundry facilities; sedation can compromise a homeless patient’s need for self-protective vigilance. These side effects are difficult to tolerate and can lead to discontinuation of treatment. If the resources are available, monitored dosing (supervised dosing at the patient’s group residence, or daily dosing at the community mental health clinic) can facilitate compliance. In patients taking antipsychotics, a depot or a long-

acting injectable preparation may improve adherence. Both first-generation antipsychotics (e.g., haloperidol and fluphenazine), and second-generation antipsychotics (e.g., risperidone, paliperidone, aripiprazole, and olanzapine) have long-acting injectable formulations. Depot or long-acting injectable antipsychotics can also be used to “back up” a daily antipsychotic pill regimen.

Non-Pharmacologic The severely and persistently mentally ill person might be best cared for by an assertive community treatment team, also known as a Program for Assertive Community Treatment (PACT ), or by a Community/Continuous Treatment Team (CTT ). These programs are based upon a model that provides intensive support for a patient by a community-based team available 24-hours per day, seven-days per week. Program staff work long-term with patients, families, and agencies in the community to support patients and to help avert hospitalization. Each patient has an identified staff member who coordinates services. When a patient is hospitalized, the team remains directly involved in treatment planning and in discharge preparations. Randomized clinical trials of such programs demonstrated benefits in clinical status, social function, medication compliance, employment, and quality of life, as well as in reduced rates of hospitalizations when compared to conventional outpatient treatment. Additional community-based treatments can also benefit patients with severe and persistent mental illness. Some communities offer respite or short-term crisis management units that help divert a patient from a prolonged hospitalization, when only a brief crisis intervention is necessary. When possible, clinicians should avoid a prolonged, debilitating, and isolating hospitalization to maintain function and connections to the community. Day treatment also plays an important role in the treatment of the severely and persistently mentally ill. Day treatment centers provide structure in a safe setting, opportunities to socialize with others, psycho-educational groups, and at times can coordinate vocational training. Such daytime structure and socialization can be critical for the management of the negative symptoms that are prominent in schizophrenia. The severely and persistently mentally-ill patient being treated in the community is often involved with multiple providers, including case managers, outreach workers, residential staff, social workers, and primary care physicians. Frequent contact between providers can seem time-consuming, but diligent communication enhances treatment and helps to avoid costly and timeconsuming hospital treatment, or other emergency care.

While supportive psychotherapy alone is inadequate treatment for schizophrenia, it can be helpful when combined with medications. Emphasis should be placed on establishing and maintaining an alliance, fostering compliance with medication and other treatment, helping the patient cope with stressors, and assisting with reality-testing. Cognitive-behavioral treatments, when available, can be helpful for managing residual positive symptoms and reducing the severity of negative symptoms. Another component of comprehensive treatment is psycho-education and support for a patient’s family, which has been shown to significantly improve the course of the illness.

Conclusion Care of the severely and persistently mentally ill is one of the most difficult and costly of all health-related problems in this country. During the second half of the 20th century, the approach of long-term custodial care in state psychiatric hospitals gave way to community mental health models that improved the quality of life for many patients. The future of care for the chronically mentally ill will increasingly incorporate less costly care delivered by a variety of providers in community settings. Comprehensive care for this population includes not only pharmacotherapy, but also community-based treatments.

Suggested Readings 1. Elbogen EB, Johnson SC: The intricate link between violence and mental disorder: Results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry . 2009; 66: 152–161. 2. Fazel S, Gulati G, Linsell L, et al: Schizophrenia and violence: Systematic review and meta-analysis. PLoS Med . 2009; 6: e1000120. 3. Fazel S, Wolf A, Palm C, et al: Violent crime, suicide, and premature mortality in patients with schizophrenia and related disorders: a 38-year total population study in Sweden. Lancet Psychiatry . 2014; 44–54. 4. Freudenreich O, Stern TA: Clinical experience with the management of schizophrenia in the general hospital. Psychosomatics . 2003; 44: 12–23. 5. Goff DC, Gudeman JE: The person with chronic mental illness. In: Nicholi, Jr. AM, ed.: The Harvard Guide to Psychiatry . Cambridge, MA: Belknap Press of Harvard University press; 1999: 684–698.

6. Insel TR: Assessing the economic costs of serious mental illness. Am J Psychiatry . 2008; 165: 663–665. 7. Kane JM , Robinson DG , Schooler NR , et al: Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE Early Treatment Program . Am J Psychiatry . 2015; Oct 20: [epub]. ( http://dx.doi.org/10.1176/appi.ajp.2015.15050632 ). 8. Lacro JP, Dunn LB, Dolde CR, et al: Prevalence of and risk factors for medication non-adherence in patients with schizophrenia: a comprehensive review of the literature. J Clin Psychiatry . 2002; 63: 892–909. 9. Laursen TM, Munk-Olsen T, Vestergaard M: Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry . 2012; 25: 83–88. 10. Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med . 2005; 353: 1209–1223. 11. Manderscheid RW, Druss B, Freeman E: Data to manage the mortality crisis. Int J Ment Health . 2008; 37: 49–68. 12. Nielssen OB, Malhi GS, McGorry PD, et al: Overview of violence to self and others during the first episode of psychosis. J Clin Psychiatry . 2012; 73: e580–587. 13. Palmer BA, Pankratz VS, Bostwick JM: The lifetime risk of suicide in schizophrenia. Arch Gen Psychiatry . 2005; 62: 247–253. 14. Teplin LA, McClelland GM, Abram KM, et al: Crime victimization in adults with severe mental illness: comparison with the National Crime Victimization Survey. Arch Gen Psychiatry . 2005; 62: 911–921. 15. Termorshuizen F, Wierdsma AI, Smeets HM, et al: Cause-specific mortality among patients with psychosis: disentangling the effects of age and illness duration. Psychosomatics . 2013; 54: 536–545. 16. Viron MJ, Stern TA: The impact of serious mental illness on health and healthcare. Psychosomatics . 2010; 51(6): 458–465. 17. Wiechers IR, Freudenreich O: The role of consultation-liason psychiatrists in improving health care of patients with schizophrenia. Psychosomatics . 2013; 54: 22–27. 18. Wu EQ, Birnbaum HG, Shi L, et al: The economic burden of schizophrenia

in the United States in 2002. J Clin Psychiatry . 2005; 66: 1122–1129.

CHAPTER Intimate Partner Violence 78 (IPV) BJ BECK, MSN, MD AND NADA MILOSAVLJEVIC MD, JD

KEY POINTS Intimate partner violence is the intentional violent or controlling behavior of a current or previous intimate partner. Ten million women and men are abused by a partner each year. Women are six times more likely to be victims. Victims Young, poor, drug-using women are at higher risk of being victims; however, there is no pattern of socioeconomic, professional, or educational level for victims. Presentations commonly include behavioral or somatic complaints, low selfworth, depression, anxiety, and post-traumatic stress disorder. Shame, economic dependence, fear of future harm, and isolation are most common deterrents to leaving. Perpetrators Men with personality disorders, depression, low income, and low educational level are at greater risk for being perpetrators. Presentations frequently are socially congenial, intact, credible but immature, needy, with feelings of inadequacy and proneness to jealousy. Perpetrators often have a history of prebattering. The Cycle of Violence The pattern of violence often begins with gradual control over activities and finances, and then escalates to coercion and physical violence. Violent incidents followed by a period of extreme contrition and reconciliation, cause the victim to believe that the violence is over.

Remorse is often followed by a tension-building phase that culminates in another outburst. Evaluation and Treatment Clear and direct questions are common screening practices. Medical history can include multiple traumas and somatic complaints. Clinicians should look for signs of injury, sexual trauma, head trauma, suicidal ideation, hypervigilance, autonomic arousal, dissociation, numbness, and psychosis. It is important to detect and document violence and to talk to the patient about available resources. Ensuring that the patient leaves the perpetrator or reports the incident to police can put the patient at greater risk. Risk must be assessed for each patient. A safety plan requires assessment of the patient’s social and financial supports, coping strategies, logistical tools, and emergency outlets.

Introduction Definition Formerly called domestic violence, intimate partner violence (IPV ) is synonymous with spouse abuse, wife beating, battering, and violence in intimate relationships. It includes physical violence, sexual violence, stalking, and psychological aggression (including coercive tactics) by a current or former intimate partner. IPV is the intentionally violent or controlling behavior of a currently, or previously, intimate partner of the victim. The goal of the violence is to coerce, assert power, and maintain control over the victim. Examples of coercive or violent behaviors include, but are not limited to, any combination of the following: actual or threatened physical injury, sexual assault, psychological or emotional torment, economic control, or social isolation.

Overview Hardly a new problem, evidence of IPV spans the millennia and is seen in all cultures and segments of society. The public health implications of this endemic problem include injury, physical and mental disability, increased health-care costs, lost wages and productivity, the long-term effects on children who witness

violence, and death. Victims’ and healthcare providers’ attitudes toward violence are among the barriers to disclosure and detection—the necessary first steps for intervention. Victims who leave their batterers have a 75% greater risk (than those who stay) of being murdered by their batterer, which underscores the victim’s vulnerability, and the complex nature of successful interventions.

Epidemiology Prevalence In the United States, 10 million women and men each year are abused by a partner, or by a former partner. Overall, 1 in 5 women (22%) and nearly 1 in 7 men (14%) have experienced severe physical violence by an intimate partner at some point in their life-time (29 million women and nearly 16 million men.) IPV is repetitive, and it escalates over time. Ninety percent of abusive relationships involve men who abuse their female partners. Some women are violent toward their male partners, frequently in self-defense. Thirty percent to fifty percent of all married couples experience some episode of physical violence. Almost 10% of homicides involve a spouse killing a spouse. Women are more often assaulted, raped, or murdered by current or former partners than by strangers. Although less well studied, same-sex couples appear to have similar rates of IPV as those seen in heterosexual couples. In the medical setting, abused women account for 22% to 35% of women who present to an emergency department (ED) for any reason, up to 40% of women in the ED for non-motor-vehicle trauma, 14% to 28% of women attending general medical clinics, 16% to 23% of women in routine pre-natal care, and more than 50% of the mothers of abused children. In the psychiatric setting, abused women account for 25% of women who present for emergency psychiatric services, 33% of women who attempt suicide, 50% of women in psychiatric outpatient services, and 64% of women on psychiatric inpatient units.

Risk Factors Although no socioeconomic, educational, professional, ethnic, racial, or religious affiliation bestows immunity to IPV, certain women are at greater risk, including those who are young (i.e., between the ages of 17 and 28 years), single, separated, divorced, poor, or pregnant with a history of previous abuse. The use of drugs or alcohol (by the woman, her partner, or both) increases the woman’s risk for abuse. Women with excessively jealous or possessive partners,

and women who have recently applied for a restraining order are at increased risk of IPV. Despite the heterogeneity of abusers, certain men have a heightened risk of violence, including those with antisocial personality disorder, depression, a low income, a low educational level, as well as those who are young.

Clinical Presentation Victims of IPV encompass a broad spectrum of the population. There is no predisposing, or diagnostic, pre-violence personality structure. The one thing victims have in common is a violent partner. Over time, chronic physical and emotional abuse leads to a sense of worthlessness, shame, and incompetence. Victims who present to the health-care (or legal) setting may appear passive, dependent, unstable, and “somatic.” Social isolation, economic control, and threats (toward the victim, her children, family, or pets) may render the victim totally dependent on her abuser. This is a consequence of the abuse, not the cause of it. Victims of IPV might not look abused (i.e., they might not initially present with injuries or have physical evidence of abuse). They often present with behavioral or somatic complaints. Addiction, depression, anxiety, post-traumatic stress, and eating disorders are associated with abuse. IPV has also been associated with intractable abdominal pain, chronic headaches, pelvic pain, and musculoskeletal problems. Perpetrators of IPV come from all walks of life. However, perpetrators can have certain pre-battering cultural or developmental experiences and personality traits in common. After the violence has begun, perpetrators often share similar behavioral patterns. They have often witnessed or experienced violence in their families of origin. Violent men have often been violent in previous relationships. They are often immature, needy, dependent, non-assertive men with fragile selfesteem and intense feelings of inadequacy. “Insanely jealous” and untrusting, they cannot tolerate even the least hint of autonomy in others, and must dominate or control their partners. Many perpetrators abuse alcohol, or alcohol and drugs. Though they might attribute their violence to the influence of these substances, victims indicate that violence is not dependent upon the perpetrator’s recent substance use or intoxication. Abusers often minimize or deny the violence; they might blame the victim for provoking the violence. Excessively concerned with outward appearances, perpetrators are often socially congenial and able to successfully conceal their violence from friends and professional

contacts. Abusive men often appear more credible and intact than their victims, whom they portray as prone to exaggeration and emotional instability.

The Nature of Violent Relationships The violence does not begin at the onset of the relationship. A non-assaultive prodrome can include gradual control over the partner’s activities and finances as well as family, social, or professional contacts. Initial overtures can seem caring and exceptionally considerate (e.g., dropping the partner off at work and picking her up afterward; making multiple phone calls during the day; offering to support the partner or giving her spending money; accompanying her to health-care appointments). A pattern of control and dependence gradually develops. Often a major event in the couple’s life (e.g., marriage, pregnancy, or the birth of a child) precipitates actual violence. The couple’s response to the initial episode of violence might be shock and abhorrence, rationalization, and a firm belief that it is an isolated incident never to be repeated.

The Cycle of Violence The cycle of violence is repetitive and often predictable. Violence can involve weapons (e.g., guns, knives, clubs), shoving, punching, kicking, burning, forced sex, or the forced use of drugs or alcohol. It escalates over time, with increased frequency and severity. It can be life threatening. The presence of a firearm greatly increases the risk of violence. Because the motivation is to exert control over the victim, physical abuse is often accompanied by emotional abuse, humiliation, intimidation, threats, or coercion. Emotional abuse includes putting the victim down (especially in front of others), calling her names, playing mind games, or making her think she’s crazy (also known as “gaslighting”), and making her feel guilty or bad about herself. Humiliation can involve treating her like a servant, making her beg, forcing her to perform degrading or illegal acts. Intimidation encompasses the use of certain looks or gestures to incite fear, the violent destruction of the victim’s property, brandishing weapons, reckless driving, or abuse and torture of pets. Threats of violence, murder, suicide, abandonment, loss of children, or harm to a family member can be terrifying. Coercion is used to keep the woman in the relationship, to conceal the abuse or to drop charges. Perpetrators might threaten the victim with psychiatric commitment, deportation, welfare, or legal actions. Children might witness parental violence, or be co-opted by the abuser to relay messages. Victims can be made to feel guilty about their children or to fear losing them. Visitation might be used to further torment the victim.

Violence is often followed by a period of extreme contrition and reconciliation. The remorseful batterer might bestow gifts and affection on the victim, while vowing never to strike her again. In turn, the victim might feel sorry for her assailant, and guilty for having provoked him. They can both feel hopeful that “this is the last time.” Remorse is followed by a tension-building phase which inevitably culminates in another outburst of violence. The anticipation during the tension-building phase can be so stressful that some women seek to induce the violence to get it over with. Deterrents to leaving a violent relationship include the consequences of repeated battering, the dynamics of violent relationships, and the reality of inadequate support systems. Shame, humiliation, and feelings of worthlessness keep women in abusive relationships. They are repeatedly told, and might begin to believe, that they get what they deserve and that they cannot expect anything better. Fear of real and perceived danger to herself, her children, family, or friends restricts the victim’s ability to leave. Batterers might coerce their partners into staying with just such threats. Fear of being homeless, indigent, and unable to care for their children also keeps women from leaving. Financial dependence is calculated to keep the woman in the control of the abuser. She might have no knowledge of, nor access to, family assets. She might have been prevented from working outside the home. The abuser might even have taken control over any money the victim did have. Isolation from family, friends, community supports, healthcare and legal professionals, and educational opportunities make the abuser the victim’s single contact with the outside world. She might feel hopeless to find assistance, or even be believed if she tries to escape. Intermittent reinforcement of apologies, gifts, and affection give the victim recurrent hope that things will change. Many victims do not want to end the relationship; they want to end the abuse. Unsuccessful prior attempts are potent deterrents to future attempts. When women have been blamed, not believed, or not supported by family, police, physicians, or social agencies, they have little incentive to risk the real danger of another attempt to leave.

Evaluation Screening Screening for violence should be a routine part of every psychiatric evaluation, and every general medical assessment. However, the United States Preventive

Services Task Force (USPSTF ) cautions that there is insufficient evidence to recommend for or against screening. There are many types of screening tools available for clinicians, but so far none has been identified as having wellestablished psychometric properties. According to the USPSTF: “Instruments to screen for intimate partner violence have also been developed, and although some have demonstrated good internal consistency (e.g., the HITS instrument, the Partner Abuse Interview, and the Women’s Experience with Battering [WEB] Scale), none have been validated against measurable outcomes.” Other medical organizations offer only general guidelines. The American College of Obstetricians and Gynecologists (ACOG) recommends that physicians routinely ask women direct and specific questions about abuse. The American Medical Association encourages physicians to inquire routinely about their patients’ domestic violence histories and refer affected patients for medical and/or community-based services. Many patients will not volunteer information, but will respond to empathic, non-judgmental questioning. Male and female patients should be asked about their own violence, as well as whether anyone else is (or has been) hurting them. Simple questions (“Have you been hit, kicked, punched, or otherwise hurt by someone within the past year? If so, by whom?”) will identify more than 70% of women in violent relationships, as detected by lengthier screening tools (Feldhaus et al, 1997). Patients should also be asked about violence in previous relationships, and sexual assault. Partner rape is often part of IPV. Patients must be asked these questions alone (in private, confidential settings). Partners, family members, or friends should never be used as interpreters. Asking about abuse in the presence of a violent partner not only inhibits the patient from responding truthfully, but puts her at increased risk.

Barriers There are multiple barriers to screening and detecting IPV. Provider factors include time constraints, lack of training, inadequate supports (e.g., security, social services, interpreters), and lack of suspicion or awareness. Especially when patients are known socially, are highly educated, professional, or of high socioeconomic status, physicians might be embarrassed, or feel it insulting, to ask about abuse. They might feel helpless to “fix” the situation, or frustrated by a past experience in which the victim would not leave her batterer. They might simply be uncomfortable thinking or talking about violence.

Patient factors include the effects of chronic abuse: shame, fear, worthlessness, hopelessness, depression, anxiety, dissociation, or numbness. Women might feel that they will not be believed or that they will be blamed. They might fear not only increased violence, but destitution if the batterer leaves them, or is jailed. Certain groups (e.g., illegal aliens, those addicted to illegal drugs) are particularly disenfranchised and can fear legal retaliation. Victims from certain cultural or ethnic groups might feel they will shame not only themselves, but their entire extended families. The chronically mentally ill or cognitively-limited victim might not know how to talk about battering. Abused men can be especially ashamed to admit they are victims; they might also fear counterallegations from their partners. Gay and lesbian victims might not feel safe to divulge their sexual orientation, let alone their abuse, to the health-care system.

History The medical history may hold clues to previously unsuspected abuse. Multiple unscheduled, or ED, visits, multiple traumas, “accidents,” or unusual injuries with unlikely explanations are cause for suspicion of abuse. Multiple, unexplained, somatic complaints (headaches, abdominal, pelvic, musculoskeletal pains) should also trigger more careful, confidential questioning. Alcohol and drug addictions are common sequelae of abuse. Patients who disclose current or past abuse should be asked about the first episode, the worst episode, and the last episode. If there are children in the family, the victim should be asked whether the children have witnessed or experienced violence. Most states have mandatory reporting requirements for physicians who suspect child abuse or neglect, and patients should be advised of this.

Physical Examination A thorough physical examination should be performed, and carefully documented, by a knowledgeable and empathic general physician. The medical record can become important legal evidence. Care should be taken to document (using diagrams, sketches, or photographs) any injuries, including signs of sexual trauma. A screening neurologic examination should note any focal findings or suggestions of acute or repeated head trauma. The mental status exam should be equally thorough. Clinicians should inquire directly about thoughts of suicide or homicide . Signs and symptoms of anxiety, hypervigilance, autonomic arousal, flashbacks, depression, apathy, dissociation, numbness, and psychosis should be explored and carefully documented.

Differential Diagnosis The psychiatric differential diagnosis of victims of IPV includes adjustment disorders (early on), depression (with or without psychotic symptoms), anxiety disorders (generalized anxiety, panic, post-traumatic stress), dissociative disorders (especially in victims with histories of childhood physical or sexual abuse), eating disorders, substance-related disorders, and mental disorders due to acute or repeated head trauma. Repeatedly-traumatized patients can appear personality-disordered (e.g., paranoid, borderline, avoidant, dependent), but personality diagnoses are not appropriate, unless the clinician has prebattering knowledge of the victim’s personality structure. Preexisting or persistent psychiatric disorders (e.g., bipolar disorder, schizophrenia) are predictably exacerbated in chaotic, violent living situations. If the abuse is not detected, these patients may be assumed to be non-adherent to their medication or treatment programs. Their medications may be inappropriately adjusted.

Treatment Considerations The Physician’s Role The detection of violence is the beginning of treatment. Physicians should not gauge their success by when or whether the victim leaves the batterer. Leaving is a very high-risk proposition and needs to be carefully planned out. The patient needs to know the physician’s care is not dependent on her leaving. The victim is the best judge of when she is prepared, and when it is safe, for her to leave. It is not the physician’s sole responsibility to intervene, or “fix,” the abusive relationship. They should, however, know appropriate resources in their area (e.g., hot-lines, shelters, advocacy groups, emergency numbers) and be able to refer the patient as necessary. It is the physician’s responsibility to take the patient seriously, to document carefully, and to assert that violence is unacceptable, and criminal, the victim does not deserve to be hurt in any way, the victim did not bring this on herself, and it is not the victim’s fault; the perpetrator is unequivocally responsible for his actions.

Risk and Safety Risk assessment must rely heavily on the victim’s own appraisal of the immediate situation (e.g., how afraid she is right now, what she believes to be the immediate danger). However, patients may minimize their concerns to their doctor, or may not think clearly in a stressful situation. They should be asked

about the presence of guns, escalating frequency or severity of threats or violence, or new violence outside the relationship. Developing a safety plan includes conducting an assessment of the patient’s social and financial supports, coping strategies in the past, the outcome of any previous attempts to leave or disrupt the violent pattern, the patient’s current level of function at home or work, and the status of children in the home. Details of the plan include mobility, phone and car access, a safe destination, and timing. Other safety concerns (including prevention, detection, and/or treatment of sexually transmitted diseases or pregnancy) exist for women who are sexually assaulted in their relationships. Treatment of primary psychiatric disorders should avoid the use of benzodiazepines or sedating medications, if at all possible. Victims should not be further dulled, or impaired, in their ability to anticipate, flee, or protect themselves (or their children). Iatrogenic addiction is a real, though lesser, concern. Mandated reporting of suspected abuse of children, elders (60 years or older), or the disabled should be carefully considered, and carried out in a manner that does not put the victim at greater risk.

Conclusion IPV is common, under-reported, and life threatening. It escalates over time and is motivated by the need to exert control over the victim. Although the victims are predominantly women, IPV is a public health problem that cuts across all segments of society. Screening for violence should be part of every general medical or psychiatric evaluation. Victims might not voluntarily disclose their abuse, but will often open up to empathic questioning. The physician who detects abuse need not “solve” the problem, but should reframe the violence as unacceptable, document clearly, and make appropriate referrals. There are many deterrents to the victim leaving her batterer, including increased risk of murder. Victims of IPV need to know their physicians will respect their decisions and continue to work with them. RADAR (Table 78-1) is an acronym designed to remind physicians to screen, recognize, and treat abuse. Table 78-1: Mnemonic for the Recognition and Treatment of Partner Violence: Use Your RADAR RADARa

Remember to ask routinely about partner violence in your own practice. Ask directly about violence with such questions as “At any time, has a partner hit, kicked, or otherwise hurt or frightened you?” Interview your patient in private at all times. Document information about “suspected IPV” or “partner violence” in the patient’s chart. Assess your patient’s safety. Is it safe for her to return home? Find out if any weapons are kept in the house, if the children are in danger, and if the violence is escalating. Review options with your patient. Know about the types of referral options (e.g., shelters, support groups, legal advocates). a The acronym “RADAR” summarizes action steps physicians should take in recognizing and treating victims of partner

violence. Source: Massachusetts Medical Society Committee on Violence, Alpert EJ (chair), 1996. 6th ed., 2015.

Suggested Readings 1. American Medical Association Policy Statement on Family and Intimate Partner Violence H-515.965. Available at: http://www.amaassn.org/apps/pf_online/pf_online. Accessed November 28 , 2003. 2. Bair-Merritt MH, Blackstone M, Feudtner C: Physical health outcomes of childhood exposure to intimate partner violence: a systematic review. Pediatrics . 2006; 117: 278–290. 3. Breiding MJ, Smith SG, Basile KC, et al: Prevalence and characteristics of sexual violence, stalking, and intimate partner violence victimization in the United States—National Intimate Partner and Sexual Violence Survey, United States, 2011. MMWR . 2014; 63 (No. SS-8): 1–18. 4. Brookoff D, O’Brien KK, Cook CS, et al: Characteristics of participants in IPV. JAMA . 1997; 277: 1369–1373. 5. Catalano, S: Intimate Partner Violence: Attributes of Victimization, 1993– 2011 (NCJ 243300) U.S. Department of Justice. 6. Chuang CH, Liebschutz JM: Screening for intimate partner violence in the primary care setting: a critical review. J Clin Outcomes Mgt . 2002; 9: 565– 571. 7. Ellsberg M, Jansen HAFM, Heise L, et al: Intimate partner violence and women’s physical and mental health in the WHO multi-country study on women’s health and domestic violence: an observational study. Lancet . 2008; 371: 1165–1172. 8. Feldhaus KM, Kaziol-McLain J, Amsbury HL, et al: Accuracy of 3 brief

screening questions for detecting partner violence in the emergency department. JAMA . 1997; 227: 1357–1361. 9. Holt VL, Kernic MA, Lumley T, et al: Civil protection orders and risk of subsequent police-reported violence. JAMA . 2002; 288: 589–594. 10. Massachusetts Medical Society Committee on Violence, Alpert EJ, ed.: Herbert B, (chair): Partner Violence, How to Recognize and Treat Victims of Abuse: A Guide for Physicians and Other Health Care Professionals . 4th ed. Waltham, MA: Massachusetts Medical Society; 2004. 11. Matevia ML, Goldman W, McCulloch J, et al: Detection of intimate-partner violence among members of a managed behavioral health organization. Psychiatr Serv . 2002; 53: 555–557. 12. Nelson HD, Nygren P, McInerney Y, et al: Screening women and elderly adults for family and intimate partner violence: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med . 2004; 140: 387– 396. 13. Rabin RF, Jennings JM, Campbell JC, et al: Intimate Partner Violence Screening Tools Am J Prevent Med . 2009 May; 36(5): 439–445.e4. 14. Rodriguez MA, Quiroga SS, Bauer HM: Breaking the silence: battered women’s perspectives on medical care. Arch Fam Med . 1996; 5: 153–158. 15. Strauchler O, McCloskey K, Malloy K, et al: Humiliation, manipulation, and control: evidence of centrality in domestic violence against an intimate partner. J Fam Violence . 2004; 19: 339-354.

CHAPTER Abuse and Neglect 79 NADA MILOSAVLJEVIC MD, JD AND REBECCA WEINTRAUB BRENDEL, MD, JD

KEY POINTS Overview Both the elderly and youth are vulnerable to abuse because of their dependency on others for care. Child protection laws of the 1970s led to the development of similar laws for the elderly, including those that created mandated reporters. Physicians are in a good position to notice signs of abuse. Child Abuse and Neglect Four types of abuse of children are defined by federal statute: physical, emotional, sexual, and neglect. All forms of abuse can lead to debilitating psychological symptoms (e.g., anxiety, mood disorders, impaired attachments, sleep disturbances, somatization, substance abuse, eating disorders, suicidality). Bullying has been recognized as a common (20%–28%) source of abuse in school-aged children. Eighty percent of child fatalities from abuse occur in children under the age of 3 years; 80% of abusers are parents. The United States has one of the highest rates of child abuse among industrialized countries. Risk factors for child abuse are parental psychopathology and environmental factors such as poverty. Since the 1980s, treatment has emphasized care of both the parent and child and the inter-play of their behaviors. Physicians who suspect abuse must assess a child for emotional and physical development. Elder Abuse

Elder abuse includes the same sub-types of abuse as is found in children, with the addition of financial/material exploitation and self-neglect. Some of the factors that can limit an elderly person’s ability to report abuse are impaired cognitive function and reluctance to accuse a family member. The risk factors for elder abuse include a shared living environment, dementia, an economically-dependent family member, a history of abuse in a relationship. Elder abuse is more difficult to detect than is child abuse because of social isolation, and the presence of co-morbid illnesses in the elderly. Hospitals can be the only source of help for an abused elder.

Overview In the United States, up to three million children and four million elderly persons are reported abused or neglected each year, with about 680,000 cases of child maltreatment confirmed. Children and the elderly are particularly vulnerable to abuse and neglect because they are often dependent on others for their care and they might be physically or psychologically limited in their capacity to communicate and to seek help. Physicians are often in the best position to recognize and respond to abuse and neglect in these populations. As birth rates and the average life-expectancy continue to rise and these populations grow, physicians will increasingly be called upon to diagnose and to respond to such cases. In the 1970s, the federal Child Abuse Prevention and Treatment Act (CAPTA ) was passed to fund state-run programs aimed at preventing and treating child maltreatment. It set minimum standards for defining abuse and neglect. Recognition of elder abuse came out of this growing awareness of child abuse and the resulting federal legislation set minimum standards for defining elder abuse and neglect. Every state currently has laws governing child and elder abuse; states can define what counts as abuse and neglect as long as these definitions meet or exceed federal standards. Every state also has laws that mandate physician (as well as other caregivers such as police, clergy, social workers, and nurses) reporting of suspected child and elder abuse and neglect; failure to do so can result in legal prosecution and civil liability. Thus, it is important that physicians familiarize themselves with the specific laws and requirements in the areas in which they work.

Child Abuse and Neglect At the federal level, CAPTA defines child abuse and neglect as “...any recent act or failure to act on the part of a parent or caretaker, which results in death, serious physical or emotional harm, sexual abuse, or exploitation, or an act or failure to act which presents an imminent risk of serious harm.” This defines four sub-types of abuse: physical abuse, emotional abuse, sexual abuse, and neglect. All forms of abuse can cause a variety of debilitating psychological symptoms (including anxiety and mood disorders, impaired attachments, sleep disturbances, somatization, substance abuse, eating disorders, and suicidality). Abuse is also a risk factor for future criminal and antisocial behaviors. That said, whereas some children suffer severe symptoms as a result of maltreatment, other children manage to thrive despite abuse; studies are ongoing to characterize which factors promote resilience in children. Physical abuse comprises approximately 18% of reported cases of maltreatment and causes 47% of reported child fatalities from abuse and neglect in the United States. Physical abuse is most commonly recognized when there is a discrepancy between the child’s physical findings and the caretaker’s explanation for how the injury occurred. In cases where physical abuse is suspected, the American Medical Association (AMA) dictates that a full health assessment—including physical exam and developmental assessment—should be conducted. Emotional abuse occurs in approximately 9% of reported cases, although it is likely to be vastly under-reported because it is difficult to prove and is often overlooked. Emotional abuse can take the form of corrupting, degrading, ignoring, isolating, rejecting, or terrorizing a child. It can be daily and pervasive or it can occur only in the setting of certain triggers; overall, it is characterized by a damaging pattern of relating between a caretaker and a child. Emotional abuse impairs a child’s ability to form secure attachments, stifles a child’s development, and undermines a child’s sense of agency in the world. There are no physical findings in emotional abuse so it can be difficult to diagnose. However, signs of emotional abuse include: sudden changes in a child’s behavior; worsening school performance; withdrawal; difficulty concentrating; excessive compliance; aggressiveness; runaway behavior; or hypervigilance. Sexual abuse makes up 9% of reported maltreatment. Although rarely directly fatal, it can result in untreated sexually-transmitted disease and suicidality. Although girls are at higher risk, both boys and girls are victims. There are often

no physical findings in cases of sexual abuse; 96% of sexually abused children will have normal genital and anal exams. Children who have been sexually abused can manifest similar signs and symptoms as those who have suffered from emotional abuse. Other concerning signs are an increased or decreased interest in sexuality inappropriate for their developmental age, sudden avoidance of an adult, or the appearance of new toys, money, or gifts from an unexplained source. Neglect is the most common form of child abuse and it makes up 80% of all reported cases of maltreatment in the United States. It is also the cause of half of the child fatalities that result from maltreatment. It can include emotional neglect, physical neglect, medical neglect, educational neglect, and failure to thrive. Neglect—particularly medical and educational neglect—cannot be legally or ethically justified on religious or other grounds; even if parents have religious beliefs that cause them to forgo education or medical treatment, they cannot legally impose those beliefs upon a child. Signs of neglect include malnutrition, poor dentition, lack of immunizations, poor hygiene, untreated medical illness, chronic and unaddressed truancy, and substance abuse. Recently, awareness of bullying has increased. Not only is bullying abusive, leading to many of the aforementioned signs and symptoms, but it is also a risk factor for other types of abuse. Bullying can involve physical, sexual, and emotional abuse by peers. Studies suggest that as many as 20% to 28% of students experience bullying at some time, with younger, and thus more vulnerable, children at the highest risk. The psychological and physical impact of bullying can be profound, and, in some cases, it can result in suicide attempts or death. Furthermore, children who are bullied report high rates of physical, emotional, and sexual abuse outside of the context of bullying. For example, in one study, more than 30% of bullied children also reported co-morbid sexual abuse. Furthermore, there is evidence that both bullies and victims have high rates of exposure to physical violence and crime at home or in their community. Thus, students involved in bullying, as either victims or perpetrators, should be screened for other forms of abuse and neglect and vice versa . Bullying is a significant risk factor for suicidality, depression, anxiety, and school avoidance.

Epidemiology Approximately three million children are abused or neglected each year; although it is likely that the actual number of cases is higher, much abuse goes unrecognized and unreported. Children under the age of 1 year have the highest

rates of victimization and comprise 46% of fatalities from abuse. More than 80% of fatalities occur in children under the age of 3 years. Eighty percent of the perpetrators of abuse and neglect are the child’s parents and a vast majority of them are biological parents. Boys and girls are equally at risk for abuse, although girls are more at risk for sexual abuse and boys are more likely to suffer a fatality as a result of abuse or neglect. African-American, Native-American, and Pacific-Islander children have the highest rates of reported child abuse compared to other ethnicities. The United States has some of the highest rates of child abuse when compared to other industrialized nations. Certain unfairly stigmatized populations, such as gay and lesbian youth, are at elevated risk for all forms of abuse, including bullying and parental abandonment. Likely as a result of both elevated rates of abuse at school and home as well as high rates of parental abandonment, gay and lesbian youth comprise 20% to 40% of homeless youth despite making up approximately 4% to 10% of the general youth population. When a child becomes homeless, he or she is at greatly elevated risk for suicide, for physical and sexual violence, and for interruption of their education.

Risk Factors Child abuse and neglect is often the result of a number of factors, including but not limited to an individual caregiver’s psychopathology. Thus, risk factors can be broken down into child-associated risk factors, parental-associated risk factors, and environmental characteristics. Child-associated risk factors include child illness or disability and certain challenging developmental stages—such as infancy, toddlerhood, and adolescence—that may place emotional and physical demands on caregivers that exceed their capacities. Parental-associated risk factors include mental or physical illness, substance abuse, and social isolation, all of which limit a parent’s emotional and physical resources and can negatively affect their judgment and impulse control. Lack of maturity and a history of abuse are also significant parental-risk factors; parents who are immature or have suffered abuse themselves might have poor coping and parenting skills that limit their ability to respond appropriately to a child’s needs. Significant environmental characteristics include both poverty and exposure to violence. Twenty-two percent of children live below the poverty line and children from poor families are 25 times more likely to suffer abuse and neglect, likely due to both increased stress on families combined with decreased access to needed support and resources. The top three caregiver risk factors associated with

children who died from maltreatment are: financial problems (9%); exposure to domestic violence (15%); and receiving public assistance (26%). Furthermore, a large ongoing study by researchers from Kaiser Permanente and the Centers for Disease Control and Prevention (CDC) confirm that the number of adverse childhood experiences (ACE) for an individual child positively correlates with adult behaviors, such as alcoholism, drug use, suicidality, mental illness, death, and more.

Treatment Because child abuse and neglect is the result of a variety of forces, the most effective treatment takes a multi-dimensional approach. Since the 1980s, various theoretical models have emphasized this inter-play between child, parental, and environmental forces rather than focusing exclusively on the parent’s psychopathology. Thus, treatment can include: individual treatment for the maltreated child; parental education and training classes; individual treatment for an abusive parent’s psychopathology, including possible substance abuse or a history of abuse; an exploration of family dynamics via family therapy; and an enhancement of social and community supports. Because abuse often disrupts emotional and physical development of a child, children who have been abused are at high risk for developing a variety of behavioral, physical, emotional, and learning disorders. A thorough assessment leading to comprehensive and precise diagnoses is important when generating a treatment plan for children who have been maltreated. Along with detailed psychiatric and physical examinations, an assessment might include a developmental history, a neurological evaluation, and testing of cognitive and intellectual functioning. It is also important to understand and promote components of a child’s resilience, which can include personal characteristics and important supports in their community or school.

Elder Abuse and Neglect The National Center on Elder Abuse (NCEA ) defines elder abuse as “…any knowing, intentional, or negligent act by a caregiver or any other person that causes harm or serious risk of harm to a vulnerable adult.” The 1987 amendments to the Older Americans Act define elder abuse, neglect, and exploitation in the form of guidelines to help states create their own frameworks to identify and legislate elder abuse. Three types of elder abuse are recognized: self-neglect, domestic abuse, and institutional abuse.

Elders can suffer the same types of abuse as children; however, two important additions include the possibility of financial or material exploitation and the concept of self-neglect. Financial exploitation comprises more than 5% of substantiated reports of maltreatment. Self-neglect occurs as people age and they develop physical and cognitive limitations that prevent them from adequately caring for themselves. Approximately one-third of substantiated reports of elder abuse and neglect were cases of self-neglect. Overall, it is likely that cases of elder abuse and neglect are vastly under-reported and numerous factors likely contribute to this. Cognitive impairment might limit an elder’s ability to communicate, to remember, or to recognize various forms of abuse. An elder might fear further loss of independence and thus be reluctant to seek help. Furthermore, approximately 90% of perpetrators are family members, with nearly one-third of cases committed by an adult child; thus, shame, need, or reluctance to get an adult child in trouble can prevent an elder from reporting this abuse. Not surprisingly, corroborated reports of elder maltreatment are associated with shorter survival. The federal Older Americans Act (OAA), similar to CAPTA, provides minimum thresholds for elder abuse. Every state has laws that govern adult protective services (although criteria for these services can vary widely) and mandatory reporting laws for physicians. Furthermore, it is federally mandated that there be a Long-Term Care Ombudsman Program in every state, who can advocate for residents of long-term care facilities and serve as the contact agency for reports of abuse and neglect in these facilities.

Epidemiology and Risk Factors Three-to-four million adults older than age 65 are abused or neglected each year, and 42% of maltreated elders are older than 80. Similar to the case of child abuse, risk factors for elder abuse can include victim risk factors, perpetrator risk factors, and environmental characteristics. Victim risk factors include a shared living situation, dementia, and social isolation. There is also a correlation between an abusive marriage (emotionally or physically) and later elder abuse. An additional risk factor might also be a child or family member who is economically dependent on the elder. Perpetrator risk factors include mental illness, hostility, and substance abuse. Environmental characteristics include poverty and a history of domestic violence in the house (with the elder as either the victim or perpetrator of earlier violence). Depression and dementia are risk factors for self-neglect.

Detecting and Reporting A variety of factors make it likely that elder abuse is more difficult to detect than is child abuse. This includes increased social isolation (e.g., less contact with health professionals) and co-morbid physical illness whose etiology might remain unexamined (“they’re old, so of course they would be sick!”) or that can make it difficult to detect the signs and symptoms of abuse and neglect. For elders, hospitals might be their only potential source of help; thus, awareness of the issue and careful screening in suspected cases are important.

Suggested Readings Child Abuse 1. Bifulco A, Moran PM, Baines R, et al: Exploring psychological abuse in childhood II: Association with other abuse and adult clinical depression. Bull Menninger Clin . 2002; 66: 241–258. 2. Brown J, Cohen P, Johnson JG: A longitudinal analysis of the risk factors for child maltreatment: Findings of a seventeen-year prospective study of officially recorded and self-reported child abuse and neglect. Child Abuse Negl . 2002; 26: 697–714. 3. Children’s Bureau, US Department of Health and Human Services: Child Maltreatment 2010, Washington, DC, 2010; US Government Printing Office. Available at http://www.acf.hhs.gov/programs/cb/pubs/cm10/cm10.pdf#page=115 . 4. Dube SR, Anda RF, Felitti VJ, et al: Childhood abuse, household dysfunction, and the risk of attempted suicide throughout the life span findings from the adverse childhood experiences study. JAMA . 2001; 286(24): 3089–3096. 5. Felitti VJ, Anda RF, et al: Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The Adverse Childhood Experiences (ACE) Study. Am J Preventive Med . 1998; 14(4): 245-258. 6. Gladden RM, Vivolo-Kantor AM, Hamburger ME, et al: Bullying surveillance among youths: Uniform definitions for public health and recommended data elements, Version 1.0. Atlanta, GA: National Center for Injury Prevention and Control, Centers for Disease Control and Prevention

7. 8.

9.

10. 11.

12.

13. 14.

and US Department of Education; 2014. Glaser D: Emotional abuse and neglect (psychological maltreatment): A conceptual framework. Child Abuse Negl . 2002; 26: 697–714. Kairys SW, Johnson CF and the Committee on Child Abuse and Neglect: The psychological maltreatment of children-technical report, Pediatrics . 2002; 109 (4): e68. Kaufman J, Zigler E: Do abused children become abusive parents? Am J Orthopsychiatry . 1987; 57(2): 186–192. Martin HP, Beezley P: Behavioral observations of abused children. Developmenta Med in Child Neurology . 1977; 19(3); 373–387. Melton GB: Chronic neglect of family violence: More than a decade of reports to guide U.S. policy. Child Abuse and Neglect . 2002; 26(6-7): 569– 586. Milosavljevic N, Taylor JB, Brendel RW: Psychiatric consequences of abuse and neglect. In: Stern TA, Fava M, Wilens TE, et al, eds.: Comprehensive Clinical Psychiatry . 2nd ed. Philadelphia, PA: Mosby/Elsevier; 2016; pp. 904–911. National Center for Education Statistics and Bureau of Justice Statistic: School Crime Supplement. 2011. Simeon D, Gurainik O, Schmeidler J, et al: The role of childhood interpersonal trauma in depersonalization disorder. Am J Psychiatry . 2001; 158: 1027–1033.

15. Sourander A, Jensen P, Rönning JA, et al: What is the early adulthood outcome of boys who bully or are bullied in childhood? The Finnish “From a boy to a man” study. Pediatrics . 2007; 120 (2): 397–404. 16. U.S. Department of Health and Human Services: Administration for Children & Families. Child Maltreatment; 2013. http://www.acf.hhs.gov/programs/cb/resource/child-maltreatment-2013 17. Voelker R: Community a factor in suicide attempts by lesbian, gay, and bisexual teens. JAMA . 2011; 305(19): 1951–1951.

Elder Abuse

1. Abrams RC, Lachs M, McAvay G, et al: Predictors of selfneglect in community dwelling elders. Am J Psychiatry . 2002; 159(10): 1724–1730. 2. Committee on National Statistics (CNSTAT): Elder mistreatment: abuse, neglect, and exploitation of an aging America. National Academies Press; 2002. 3. Harrell R, Toronjo CH, McLaughlin J, et al: How geriatricians identify elder abuse elder and neglect. Am J Med Science . 2002; 323(1): 34–38. 4. Kahan FS, Paris BE: Why elder abuse continues to elude the health care system. Mt Sinai J Med . 2003; 70(1): 62–68. 5. Lachs MS, Pillemer K: Abuse and neglect of elderly persons. N Engl J Med . 1995; 332: 437–443. 6. Lachs MS, Williams CS, O’Brien S, et al: The mortality of elder mistreatment. JAMA . 1998; 280(5): 428–432. 7. Lifespan. (2011). Elder Abuse: Under the Radar. Lifespan of Greater Rochester Inc. Retrieved from http://www.lifespanroch.org/documents/ElderAbusePrevalenceStudyRelease.pdf . 8. National Center on Elder Abuse: FAQs http://www.ncea.aoa.gov/faq/index.aspx http://elderlaw.uslegal.com/types-of-elder-abuse/ . 9. National Center on Elder Abuse: The national elder abuse incidence study: Final report. Washington DC: Westat, Inc.; 1998.

CHAPTER Lesbian, Gay, Bisexual, 80 Transgender, and Queer (LGBTQ) Mental Health ALEX S. KEUROGHLIAN, MD, MSC

KEY POINTS Sexual orientation refers to a person’s emotional, physical, and romantic attraction to a person of the same gender and/or another gender. Gender identity, as opposed to sexual orientation, describes a person’s internal sense of their gender. Transgender people have a gender identity or expression that differs from their assigned sex at birth. Gender dysphoria is a concept that emphasizes the severe and persistent distress that can result from misalignment of gender identity and sex assigned at birth. Cross-sex hormone therapy and gender-affirming surgeries are deemed medically-necessary treatments for gender dysphoria by the American Medical Association. Lesbian, Gay, Bisexual, Transgender, and Queer populations are at higher risk for mood disorders, anxiety disorders, adjustment disorders, substance use disorders, and trauma- and stress-related disorders compared with those in the general population. According to the World Professional Association for Transgender Health, mental health screening and assessment are needed prior to referral for hormone therapy and surgical procedures, however, prior psychotherapy per se , although highly recommended, is not an absolute requirement.

Overview Sexual orientation refers to a person’s emotional , physical, and romantic attraction to a person of the same gender and/or another gender. Many people identify as lesbian (a woman primarily attracted to other women), gay (a person

primarily attracted to other people of the same gender), bisexual (a person attracted to more than one gender), or heterosexual/straight (a person primarily attracted to the opposite sex). There are, however, many other terms to describe a person’s sexual orientation. Increasingly, people are self-identifying as queer, a term many believe is more inclusive of the full spectrum of human sexual orientation. A person’s sexual behavior does not necessarily correspond with traditional societal assumptions about their self-identified sexual orientation. For example, people who identify as lesbian or gay can have romantic or physical intimacy with people of the opposite gender. Similarly, people who identify as heterosexual or straight can have romantic or physical intimacy with people of the same gender. Thus, it is important to distinguish how a person self-identifies from their romantic or sexual behavior. Gender identity , as opposed to sexual orientation, describes a person’s internal sense of their gender. Transgender people have a gender identity or expression that differs from their assigned sex at birth. People who experience misalignment of their gender identity with their assigned sex at birth may self-identify as a transgender woman or man , trans woman or man , or either male-tofemale/MTF or female-to-male/FTM . Many transgender people prefer to simply self-identify as a woman or man. Transgender women were assigned male sex at birth, and transgender men were assigned female sex at birth. Transgender people determined at some point during their life that their assigned sex at birth was misaligned with their gender identity. Thus, most transgender people undergo a gender transition. This is an individualized process of gender identity affirmation through some combination of changing their name, changing their appearance, and in many cases accessing gender-affirming medical care. Of note, many people experience a personal gender identity outside the gender binary paradigm of either male or female identity. Thus, they might describe their gender identity as genderqueer , a term associated with greater gender neutrality, gender fluidity, and/or gender inclusiveness. In contrast to gender identity, a person’s gender expression describes the full range of attributes and behaviors that are considered feminine or masculine based on societal norms. Some examples of a person’s gender expression can include their gait, hairstyle, or voice.

The Process of Coming Out

Coming out is a developmental process of gaining insight into one’s own lesbian, gay, bisexual, transgender, or queer/questioning identity, as well as disclosing this identity to other people. The coming out process is complex and differs substantially from one person to the next based on: cultural, ethnic, racial, and religious background; stage of life (e.g., childhood, adolescence, adulthood); familial and community attitudes regarding sexual orientation and gender identity; prior experiences of prejudice or discrimination; and, the availability of social supports. Pervasive bigotry and stigmatization against Lesbian, Gay, Bisexual, Transgender, and Queer (LGBTQ) people contributes to minority stress that further complicates the process of identity development and disclosure. Psychiatrists can provide crucial affirmation and validation of their patients’ sexual orientation and gender identity in order to facilitate the life-long challenge of adjusting to one’s LGBTQ identity and disclosing this identity to other people.

Historical Background Until recent years, psychiatry as a field has conceptualized same-sex attractions and gender non-conforming behaviors as disordered. As a result, many LGBTQ people continue to experience medical mistrust toward psychiatrists, which often becomes a barrier to accessing mental health treatment. During the 19th century in Europe, sexuality was understood mostly based on a religious belief system in which homosexuality was regarded as sinful and therefore routinely criminalized. In the early 20th century, Western views regarding homosexuality began to shift as a result of psychoanalytic theory in which Freud and other analysts conceptualized homosexuality as a developmental phenomenon rooted in early childhood experience. Throughout much of the early and mid-20th century, homosexuality was still considered a form of psychopathology. Alfred Kinsey’s work was influential in establishing awareness that same-sex behavior was far more prevalent than psychiatrists had previously understood, and that such behavior was a natural variant of the spectrum of human sexuality. In response to mounting pressure by gay activists, the American Psychiatric Association (APA) in 1973 removed homosexuality from the list of psychiatric disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM). In 2000, the APA issued a position statement opposing the long-held practice of “conversion” or “reparative” therapies focused on attempting to change a

patient’s sexual orientation, a practice that is now understood by psychiatric experts to be ineffective, harmful, and unethical. Similarly, the experience of having a gender identity different from one’s sex assigned at birth was classified as a disorder in the DSM for decades. In 1980, the DSM-III introduced a diagnosis of gender identity disorder, to which many transgender community activists objected on the grounds that it perpetuated stigma and supported barriers to accessing gender-affirming medical care. In 1994, the DSM-IV maintained a gender identity disorder diagnosis. As a result of advocacy by the transgender community and specialized mental health experts, this diagnosis was removed from the 2013 DSM-5 and replaced with a diagnosis of gender dysphoria , a concept that emphasizes the severe and persistent distress that can result from misalignment of gender identity and sex assigned at birth.

Gender Dysphoria in Adolescents and Adults The DSM-5’s diagnostic criteria rely on a persistent (more than 6 months) marked incongruence between one’s experienced/expressed gender and assigned gender, with at least two of the following: a marked incongruence between one’s experienced/expressed gender and primary and/or secondary sex characteristics; a strong desire to be rid of one’s primary and/or secondary sex characteristics because of a marked incongruence with one’s experienced/expressed gender; a strong desire for the primary and/or secondary sex characteristics of the other gender; a strong desire to be of the other gender (or some alternative gender different from one’s assigned gender); a strong desire to be treated as the other gender (or some alternative gender different from one’s assigned gender); or a strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from one’s assigned gender). According to the DSM-5 the condition is also associated with clinicallysignificant distress or impairment in social, occupational, or other important areas of functioning. Of note, gender identity is often fluid and can evolve over time. Some people live most comfortably part time in alternating masculine and feminine gender roles. This might be part of a prolonged process of gender identity exploration until becoming ready to transition full time to a single-gender expression and role. In other instances, people feel most comfortable with fluid gender expression that fluctuates long-term between masculine and feminine states, without ever needing to settle on one permanent gender expression.

In addition, gender diversity is not a binary phenomenon restricted to either masculine or feminine categorical states. Many people do not identify as either male or female; they might instead prefer to identify as “genderqueer” or “gender-fluid” and use gender-neutral pronouns, such as “they,” “them,” and “their.” In a 2013 community survey of 452 transgender adults, 40.9% of respondents endorsed a non-binary gender identity. To accommodate this full spectrum of gender diversity, DSM-5 diagnostic criteria for gender dysphoria allow for identification with “some alternative gender different from one’s assigned gender.”

Gender-Affirming Care for Transgender Patients An important role for psychiatrists in providing care to patients with gender dysphoria is to assist them in exploring and understanding their own gender identity. An appreciation among psychiatrists of the full range of human gender diversity serves in turn to provide patients with broader options for affirming their gender identity and adopting gender roles and expressions that best suit them. Psychiatrists ought to ask patients with gender dysphoria which aspects of their body, gender expression, and gender role they are dissatisfied with, and what specific gender-related changes they are contemplating. Psychological treatments designed to alter a patient’s gender identity to become more aligned with their sex assigned at birth have been ineffective and are no longer regarded as ethical. It is the psychiatrist’s duty to guide patients in exploring the possibility of a gender identity that is fluid and evolves over time as well as the possibility that the patient’s gender identity is non-binary and might better be described with gender-neutral language. Psychiatrists need to actively inquire about and use the gender pronouns that the patient prefers at any given time. Patients might feel safe enough only to state a preference for alternative gender pronouns after a psychiatrist directly asks the patient about gender pronoun preference and also presents a full range of male, female, and gender-neutral pronoun options. The patient’s pronoun preference should be documented in the medical chart and updated regularly. In addition to the psychiatrist’s function in fostering gender identity discovery, there is an ethical obligation to present patients with appropriate non-medical and medical strategies for gender affirmation. These can help the patient attain greater comfort with personal expression of gender to help enhance level of functioning to the extent possible. Psychiatrists should assist the patient in

making fully informed decisions regarding the personalized gender affirmation process, by presenting relevant options, discussing benefits and risks of these approaches, evaluating capacity for medical decision-making and informed consent, and arranging suitable referrals to care. Unfortunately, untreated co-occurring psychiatric disorders often impede the process of gender identity discovery and gender dysphoria alleviation. Every effort must therefore be made to stabilize co-occurring psychiatric disorders, including substance use disorders. As with other medically-necessary pharmacotherapies and surgeries, psychiatrists cannot ethically withhold information about gender-affirming medical care from patients, particularly if their co-occurring psychiatric disorders become reasonably well controlled. For cases in which co-occurring psychiatric disorders remain unstable despite full treatment, harm-reduction principles must also guide clinical management. Treatment of gender dysphoria among adults is individualized. Some people might achieve satisfactory integration of their gender identity through psychotherapy alone. Effective psychotherapy can involve focusing on: gender expression, identity, and role; adverse effects of gender dysphoria, minority stress, and stigma on psychological health; reduction of internalized transphobia; building peer and social supports; improving body image; enhancing resilience; and, considering a process of “coming out,” including reflection upon the physical, psychological, social, sexual, reproductive, economic, and legal challenges that may arise during gender transition. Most people with gender dysphoria require active changes in their gender expression and social role, by living part time or full time in another gender. Most transgender people do not achieve adequate relief from gender dysphoria without more permanent body modifications. Cross-sex hormone therapy and gender-affirming surgeries are deemed medically-necessary treatments for gender dysphoria by the American Medical Association. According to the World Professional Association for Transgender Health, mental health screening and assessment are needed prior to referral for hormone therapy and surgical procedures; however, prior psychotherapy per se , although highly recommended, is not an absolute requirement. Some gender-affirming medical care is partially reversible (e.g., cross-sex hormone therapy). Other genderaffirming medical interventions are irreversible (e.g., surgical modification of internal and external genitalia, also known as sex reassignment surgery ).

Co-Occurring Psychiatric Diagnoses in LGBTQ

Communities Patients with psychiatric diagnoses and an LGBTQ identity often face the dual stigma of mental illness and also being part of a sexual or gender minority group. In the context of pervasive stigma and discrimination that lead to chronic minority stress throughout the lifespan, LGBTQ populations are at higher risk for mood disorders, anxiety disorders, adjustment disorders, substance use disorders, and trauma- and stress-related disorders compared with those in the general population. Substance use disorders are a common strategy for coping with minority stress among LGBTQ people. LGBTQ populations are at elevated risk of violent victimization and hate crimes compared with the general population and as a result have a disproportionate prevalence of post-traumatic stress disorder. Intimate partner violence within LGBTQ relationships is unique in that the abusive partner might threaten to “out” the victim, who might not yet feel safe disclosing an LGBTQ identity to other people. The fear of coming out can also prevent LGBTQ victims of intimate partner violence from reaching out for help from family or friends, and from accessing services for survivors of violence.

Special Considerations for Gay Women/Lesbians Gay women’s sexual health needs are often not screened for and remain unaddressed by health-care providers, due to the false perception that gay women are not susceptible to sexually-transmitted illnesses. Gay women also experience disparities in clinical screening for cancers compared with heterosexual/straight women. Gay women are at increased risk of obesity as well as alcohol and nicotine use disorders.

Special Considerations for Gay Men Gay men often experience the challenge of sexual activity in the context of elevated concern about becoming infected with or transmitting Human immunodeficiency virus (HIV). HIV and other sexually-transmitted illnesses can further stigmatize gay men and result in shame and social avoidance. HIVinfected gay men often struggle with HIV status disclosure due to fear of social rejection and isolation. The use alcohol as well as “club drugs,” such as gammahydroxybutyrate, ketamine, and methamphetamine, can be linked to high-risk sexual activity and HIV risk among gay men. Gay men often experience disproportionate pressure to conform to physical ideals that are unattainable

compared with other men, thus, screening for body dysmorphic disorder, eating disorders, and anabolic steroid use among gay men is particularly important.

Special Considerations for Bisexual People Bisexuality transcends the widely held myth of binary sexuality, whereby people are either gay or heterosexual. Bisexual people often contend with the false stereotype that they are simply “confused” about their sexuality, or that their bisexuality is merely part of the process of coming out as lesbian or gay. Thus, bisexual people often experience difficulty being accepted by lesbian or gay communities and heterosexual communities alike. This exclusion from other communities is a source of vulnerability and can result in significant social isolation and distress for bisexual people.

Psychiatric Assessment and Treatment for LGBTQ People Psychiatrists delivering care for LGBTQ patients ought to continually examine their own attitudes, beliefs, and feelings regarding LGBTQ people. A psychiatrist’s lack of awareness about personal biases toward LGBTQ patients can adversely affect the quality of care delivered to these populations. For example, a psychiatrist whose own homophobia results in discomfort and avoidance inquiring about the sexual behavior of a gay male patient might fail to elicit and discuss clinically important information about the patient’s HIV risk during a psychiatric interview. In contrast, when a psychiatrist reflects upon and thoughtfully addresses personal biases about sexual orientation and gender identity, this enables delivery of affirming psychiatric care with a strengthened therapeutic alliance and optimal mental health outcomes for LGBTQ patients.

Suggested Readings 1. American Medical Association House of Delegates: Removing financial barriers to care for transgender patients . Chicago, IL: American Medical Association; 2008. 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Arlington, VA: American Psychiatric Publishing; 2013. 3. Bockting W, Coleman E: Developmental stages of the transgender coming out process: Toward an integrated identity. In: Ettner R, Monstrey S, Eyler A, eds.: Principles of Transgender Medicine and Surgery . New York, NY:

4. 5.

6. 7. 8.

9.

10.

11.

Haworth Press; 2007: 185–208. Bockting WO: Psychotherapy and the real-life experience: From gender dichotomy to gender diversity. Sexologies . 2008; 17(4): 211–224. Coleman E, Bockting W, Botzer M, et al: Standards of care, for the health of Transsexual, Transgender, and Gender Non-conforming People. Int J Transgenderism . 2012; 13(4): 165–232. Devor A: Witnessing and mirroring: a fourteen-stage model of transsexual identity formation. J Gay Lesbian Psychother . 2004; 8(1-2): 41–67. Fraser L: Depth psychotherapy with transgender people. Sex Relation Ther . 2009; 24(2): 126–142. Institute of Medicine: The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding . Washington, DC: Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities; 2011. Keuroghlian AS, Reisner SL, White JM, et al: Substance use and treatment of substance use disorders in a community sample of transgender adults. Drug Alcohol Depend . 2015; 152: 139–146. Lev AI: Transgender Emergence: Therapeutic Guidelines for Working with Gender-Variant People and Their Families . Binghamton, NY: Haworth Clinical Practice Press; 2004. Makadon HJ, Mayer KH, Potter J, et al, eds.: The Fenway Guide to Lesbian, Gay, Bisexual, and Transgender Health . 2nd ed. Philadelphia, PA: American College of Physicians Press; 2015.

12. Meyer IH: Prejudice as stress: Conceptual and measurement problems. Am J Public Health . 2003; 93(2): 262–265. 13. Nestle J, Wilchins R, Howell C: Genderqueer: Voices from Beyond the Sexual Library . Los Angeles, CA: Alyson; 2002. 14. Pachankis JE: A transdiagnostic minority stress treatment approach for gay and bisexual men’s syndemic health conditions. Arch Sex Behav . 2015; 44(7): 1843–1860.

CHAPTER Culture and Psychiatry 81 ANDREA MADU, BA; JUSTIN A. CHEN, MD, MPH; DAVID C. HENDERSON, MD; AND NHI-HA T. TRINH, MD, MPH

KEY POINTS Overview An individual’s cultural background can have a tremendous impact on diagnosis, treatment, and outcome. When treating a patient from a different culture, care must be taken when making observations or applying stereotypes, and clinicans must be mindful of their own feelings, biases, and stereotypes. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Cultural Formulation The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) emphasizes that a clinician must take into account an individual’s ethnic and cultural context in the evaluation of each DSM-5 disorder. The DSM-5 contains two updated tools for clinicians: the Outline for Cultural Formulation, and the Cultural Formulation Interview. Impact of Culture on Psychiatric Diagnosis Race and ethnicity have a significant impact on psychiatric diagnosis and treatment. Cultural differences in how psychiatric illnesses present exist and can lead to misdiagnosis. Establishing the cross-cultural meaning of seemingly bizarre beliefs and perceptions remains a clinical challenge. Cultural Concepts of Distress In the DSM-5, the term “culture-bound syndromes” has been replaced by three related cultural concepts: cultural syndromes, cultural idioms of distress, and

cultural explanations or perceived causes. Ethnicity and Psychopharmacology Understanding the impact of race and ethnicity on psychopharmacology and psychobiology is necessary to ensure that racial/ethnic minorities receive highquality care. Both non-biological and biological issues can affect pharmacologic practice. Recommendations for Observed Clinical Exercises Realize that patients from different cultural backgrounds might have unique needs and issues that require additional time and resources. Understand how personal biases and stereotyping can affect treatment. Assure patients about confidentiality. Be prepared to begin with lower medication dosages and increase the dose slowly. If a diagnosis is unclear, consider employing a structured diagnostic interview to reduce the possibility of misdiagnosis.

Introduction An individual’s cultural background can have a tremendous impact on diagnosis, treatment, and outcome. Although it is impossible for clinicians to understand every culture, knowledge of basic principles should be obtained and utilized to minimize culture clashes. In theory, psychiatric training prepares physicians to diagnose and empathically treat individuals from around the world. However, in practice, this is far from the reality. While treating a patient from a different culture, care must be taken when making observations or applying stereotypes. Clinicians must be mindful of their feelings, biases, and stereotypes. Inter-individual variability is common; a particular patient might not match the clinician’s cultural expectations. Clinicians must probe for cultural clues while remaining flexible enough to recognize that an individual’s patterns and behaviors may not fit the cultural mold.

The Concept of Culture Culture is the collected body of beliefs, customs, and behaviors that a group of people acquire socially and transmit from one generation to another through

symbols and shared meanings. It provides the tools by which members of a given society adapt to their physical environment, social environment, and to one another. It organizes groups of ready-made solutions to the problems and challenges that people often face. There are two levels of culture: physical and ideological. Physical culture—including art, literature, architecture, tools, machines, food, clothing, and means of transportation—can be observed directly through the five senses and/or through items collected in a museum or recorded on film. The physical level of culture yields more easily to change and to adaptation than does the ideological level. Ideological culture refers to aspects of culture that must be observed indirectly, usually through behaviors, including: beliefs and values; reasons for holding some things sacred and others ordinary; the events and characteristics of which a society is proud or ashamed; and the sentiments that underlie patriotism or chauvinism. Religion, philosophy, psychology, literature, and the meanings that people give to symbols are all part of the ideological aspect of culture. Without some understanding of the ideological aspect of culture, it is difficult to understand the meaning of a group purely at the physical level.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and Culture The Culture workgroup of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, proposed a number of significant changes to the way culture is conceived and utilized by mental health clinicians and others interested in psychiatric diagnosis. The DSM-5 explicitly states that “all forms of distress are locally shaped, including the DSM disorders.” As such, the discussion of each disorder contains a discussion of multi-cultural explanations for similar symptoms for direct use by clinicians as a cross-reference. For example, panic disorder contains a discussion of ataque de nervios . Section III of the DSM-5 contains two important updated tools for clinicians: the Outline for Cultural Formulation and the Cultural Formulation Interview (CFI).

Outline for Cultural Formulation The DSM-5 emphasizes that a clinician must take into account an individual’s ethnic and cultural context in the evaluation of each DSM-5 disorder. This

process, called cultural formulation , includes five distinct components. Cultural identity of the individual: It is important to consider racial, ethnic, and cultural references, as well as the degree to which an individual is involved with his or her culture of origin (versus the culture in which he or she lives). It is crucial to listen for clues and to ask specific questions concerning a patient’s cultural identity. For instance, an Asian-American individual who grew up in the southern United States might exhibit patterns, behaviors, and views of the world more consistent with a Caucasian-American southerner. Language abilities, preference, and pattern of use must also be considered to address difficulties accessing care and identify the need for an interpreter. In addition, attention to religious affiliation, socioeconomic background, country of origin, migrant status, and sexual orientation can be considered important aspects of cultural identity. Cultural conceptualizations of distress: How an individual understands and experiences his or her symptoms is often communicated through cultural syndromes and idioms of distress (e.g., “nerves,” possession by spirits, somatic complaints, misfortune). Thus, the meaning and severity of the illness in relation to one’s culture, family, and community should be determined. This “explanatory model” can be helpful when developing an interpretation, diagnosis, and treatment plan. Psychosocial stressors and cultural features of vulnerability and resilience: It is important to identify psychosocial stressors and supports within a patient’s environment (e.g., religion, family, social circle). Cultural interpretations of social stress and support, and the individual’s level of disability and function, must also be addressed. It is the physician’s responsibility to determine a patient’s level of functioning, resilience, and disability in the context of his or her cultural reference groups. Cultural features of the relationship between the individual and the clinician: Cultural aspects of the relationship between the individual and the clinician, as well as of treatment, should be considered. Common barriers for clinicians include difficulties with language, establishing rapport, and eliciting symptoms or understanding their cultural significance. Overall cultural assessment for diagnosis and care: The formulation concludes with a summary of the implications of each component outlined above for psychiatric diagnosis, treatment, and other clinically relevant issues. This step directly acknowledges the fact that each society establishes its own

criteria regarding which forms of behavior are acceptable or abnormal and which behaviors represent a medical problem—all of which bears on the way mental health care is conceived of and delivered.

Cultural Formulation Interview The DSM-5 also includes the Cultural Formation Interview, a semi-structured interview composed of 16 questions that physicians can use to assess the influence of culture on a patient’s clinical presentation and care. The CFI focuses on four domains of assessment: 1) cultural definition of the problem; 2) cultural perceptions of the cause, context, and support of the problem; 3) cultural factors affecting self-coping and past help-seeking; and, 4) cultural factors affecting current help-seeking. The interview aims to avoid stereotyping in so much as it centers on the individual and incorporates the cultural knowledge of the patient as well as the social context of his or her illness experience. The CFI can be utilized when physicians experience difficulties in diagnostic assessment due to cultural differences, difficulties in determining illness severity or impairment, disagreements with patients regarding course of treatment, or difficulties engaging patients in treatment.

Impact of Culture on Psychiatric Diagnosis In the United States, race and ethnicity have a significant impact on psychiatric diagnosis and treatment. People of color are frequently misdiagnosed as having schizophrenia when instead they have bipolar disorder or psychotic depression. Several studies have confirmed the misdiagnosis of schizophrenia in blacks, Hispanics, and the Amish in the United States. Moreover, treatment approaches and responses often differ depending on the diagnosis. Biases in psychiatric treatment persist and must be acknowledged. African-American patients are more likely to receive higher doses of antipsychotic agents, have higher rates of involuntary psychiatric hospitalizations, have a shorter length of stay despite a higher symptom severity, and to be placed in seclusion or restraints while in psychiatric hospitals more than are Caucasian inpatients. Cultural differences in how psychiatric illnesses present also exist. As a result, primary-care physicians can misdiagnose depression in minority populations. For instance, a Cambodian woman might present with complaints of fatigue and back pain, and might downplay other neurovegetative symptoms, such as dysphoria. In addition, in many non-Western societies, particularly those

possessing traditional beliefs, spirits of the deceased are regarded as being capable of interacting with, and possessing, those who are still alive. Thus, a non-psychotic patient might admit to hearing voices of his or her ancestors; this might be culturally appropriate in certain contexts. Establishing the crosscultural meaning of seemingly bizarre beliefs and perceptions remains a clinical challenge. It can be difficult to determine whether symptoms are “bizarre enough” to qualify for a diagnosis of schizophrenia without an adequate understanding of a patient’s sociocultural and religious background. On the other hand, caution must be taken not to assume that bizarre symptoms are culturally appropriate, when they in fact reflect an underlying psychotic process.

Acculturation and Immigration Recent immigrants or refugees often arrive in the United States facing a host of difficulties and psychosocial problems. Physicians should ask about, and make an effort to understand, the circumstances surrounding immigration (e.g., an individual might have been a political prisoner, a victim of trauma and torture, or have been lost or separated from family members). Under these circumstances, the level of depression and post-traumatic stress disorder (PTSD) experienced can be high. The impact of acculturation can also lead to symptoms of depression, “culture shock,” and even PTSD-like symptoms.

Cultural Concepts of Distress Cultural concepts of distress refer to “ways that cultural groups experience, understand, and communicate suffering, behavioral problems, or troubling thoughts or emotions.” The DSM-5 outlines three types of cultural concepts: 1) cultural syndromes; 2) cultural idioms of distress; and, 3) cultural explanations or perceived causes. These three concepts (described in greater detail in the section that follows) have been deemed more clinically relevant then “culturebound syndromes” and have replaced the term in the DSM-5. Specifically, the term culture-bound syndrome does not take into account that some “syndromes” are actually variations in ways people experience distress rather than distinct collections of symptoms (e.g., nervios ), whereas others are casual explanations for a range of symptoms (e.g., dhat syndrome ). The term “culture-bound syndrome” also over-emphasizes the localized nature and limited distribution of cultural concepts of distress. Cultural syndromes are clusters of symptoms that occur among individuals in specific cultural groups or communities. Cultural idioms of distress are shared ways of experiencing, communicating, and expressing personal or social

concerns. Cultural explanations or perceived causes are labels, attributions, or features that indicate causation of symptoms, illness, or distress. As an example, depression fulfills the criteria for all three concepts. Western clinicians understand major depressive disorder as a “syndrome,” or a cluster of symptoms that often appear together. Depression is also the cultural idiom of distress, which is commonly used to talk about a certain type of emotional distress. Finally, as a cultural explanation of distress or perceived cause, the term “depression” helps imbue a set of behaviors with meaning and associated etiology.

Specific Cultural Concepts of Distress Although the term “culture-bound syndrome” has been eliminated, the creators of the DSM-5 continue to acknowledge the usefulness of certain well-studied examples of cultural syndromes, explanations, and idioms of distress. Table 81-1 details nine such concepts that were retained in the DSM-5, in the “Glossary of Cultural Concepts of Distress.” These concepts might aid physicians in identifying how individuals from different cultures and communities exhibit and explain psychological issues. Table 81-1: Cultural Concepts of Distress Meaning Description

Countries/Regions

Ataque de nervios

Attack of the A cultural syndrome that involves symptoms of distress that Caribbean, Latin America, nerves include uncontrollable shouting, attacks of crying, trembling, a Latin Mediterranean sense of heat in the chest that migrates to the head, as well as verbal and physical aggression. It frequently occurs as a result of a direct event, often related to the family. The fact that ataques are associated with a specific event, and that there is often an absence of acute fear, allows it to be distinguished from panic disorder. Many times, affected individuals experience amnesia and then rapidly return to their usual functioning.

Dhat syndrome

Semen loss

Khyâl cap

Wind attacks A cultural syndrome with symptoms (such as dizziness, Cambodia palpitations, dyspnea, cold extremities, and neck soreness) similar to those of panic attacks. Khyâl attacks involve a catastrophic fear that khyâl (a wind-like substance) might rise in the body, along with blood, and cause a range of serious effects, such as shortness of breath, asphyxia, blurry vision, tinnitus, and a fatal syncope.

A cultural explanation for patients with diverse symptoms, Southeast Asia including: anxiety, fatigue, weakness, weight loss, impotence, depressed mood, and somatic complaints. Characterized by anxiety and stress about loss of dhat (white discharge noted upon defecation or urination) in absence of any identifiable physiologic dysfunction.

Kufungisisa Thinking too A cultural explanation and idiom of distress among the Shona of much Zimbabwe. As a cultural explanation, “thinking too much” is considered damaging to mind and body, causing depression, anxiety, and symptoms such as headaches and dizziness. As an idiom of distress, it reflects interpersonal and social difficulties causing emotional and somatic symptoms (e.g., “my heart is painful because I think too much”).

Zimbabwe

Maladi moun

Humanlycaused illness

A cultural explanation for a range of medical and psychiatric Haiti disorders. Involves beliefs that inter-personal envy and ill will cause people to harm their enemies by sending illnesses (e.g., psychosis, depression), social or academic failure, and inability to perform activities of daily living. Can be provoked by economic success (new job, expensive purchase) or being attractive, intelligent, or wealthy.

Nervios

Nerves

An idiom of distress which refers to a state of vulnerability to Latin America stressful life experiences and circumstances. Encompasses a wide range of symptoms, such as headaches, “brain aches,” irritability, GI discomfort, insomnia, nervousness, tearfulness, difficulty concentrating, trembling, paresthesias, and mareos (dizziness). Ranges in severity from individuals free from mental disorder to those with presentations similar to anxiety, depressive, dissociative, or psychotic disorders.

Shenjing shuairuo

Weakness of A cultural syndrome characterized by physical and mental fatigue, China the nervous dizziness, headaches, pains, poor concentration, sleep difficulties, system and memory loss. Individuals may also experience nausea, vomiting, diarrhea, sexual dysfunction, irritability, and agitation.

Susto

Fright

Taijin kyofusho

Interpersonal A cultural syndrome that refers to an individual’s intense fear that Japan fear disorder one’s body parts/function (e.g., appearance, odor, movement, facial expressions) displease, embarrass, or are offensive to others.

A cultural syndrome attributed to a frightening event causing the Latin America, Mexico, soul to leave the body. Symptoms include headache, pain, Central and South America diarrhea, changes in appetite and sleep, sadness, and a lack of interest or motivation. Symptoms might appear from days to years after the event has occurred.

Ethnicity and Psychopharmacology Understanding the impact of race and ethnicity on psychopharmacology and psychobiology is necessary to ensure that high-quality care is provided for ethnic minorities. Both non-biological and biological issues can affect pharmacologic practice.

Non-Biological Issues That Affect Psychopharmacology Culturally-shaped beliefs play a major role in determining whether an explanation and treatment plan will make sense to, and be accepted by, an

individual patient. For example, some Hispanics or Asians often expect rapid relief with treatment, and are wary of potential side effects (including addiction) induced by Western medicine. Since Asians from traditional backgrounds might be familiar with the prescription of multiple herbal substances to treat a variety of conditions, some might believe that polypharmacy is required. Traditional and/or alternative methods are often utilized by minority populations. For example, Asians, Hispanics, and blacks frequently use herbal medicines. Some herbal medicines interact with psychotropic medications. For instance, the Japanese herbs Swertia japonica and Kamikihi-To , and the Cuban Datura candida , have anticholinergic properties that can interact with tricyclic antidepressants (TCAs) or with low-potency neuroleptics. South American holly, Ilex guayusa , has a high caffeine content. The Nigerian root extract of Schumanniophyton problematicum (which is used to treat psychosis) is sedating and can interact with neuroleptics and benzodiazepines. The Chinese herbs Fructose schizandrae , Corydalis bungeana , Kopsia officinalis , Clausena lansium , muscone , ginseng, and glycyrrhiza , increase the clearance of many psychotropic medications by inducing cytochrome P450 (CYP) enzymes. Oleanolic acid in Swertia mileensis and Ligustrum lucidum also inhibit CYP enzymes. An herbal weight-loss supplement containing Ephedra sinica (MaHuang) , which is the main plant source of ephedrine, can induce mania and psychosis. Patient adherence can be affected by incorrect dosing, by medication side effects, and by polypharmacy. Other factors include a poor therapeutic alliance, a lack of community support, money, or transportation, as well as substance abuse or concerns about a medication’s addictive potential. Beliefs held by a patient regarding illness and treatment should be explored. Often, clinicians do not take the time to explain the reason for the use of medications and their anticipated side effects. Communication difficulties and divergence between a patient’s and his or her treater’s “explanatory model” can play an important role in why a person from an ethnic minority is significantly more likely to be non-adherent to prescribed medications or to drop out of treatment entirely. The way a family interacts and functions has a significant impact on psychiatric treatment. Hispanics and Asians typically have a “closed network” that consists of multiple family members, kin, and intimate friends. Many Hispanics rely on interactions with relatives for social support, and some become more demoralized when such interactions do not increase with treatment.

The use of well-trained interpreters who possess knowledge of a patient’s understanding of treatment recommendations can significantly impact adherence. Finally, other factors to consider regarding drug response and adherence include: misdiagnosis of a psychiatric condition, a placebo response, mistrust of the health care system, attention-seeking at a later stage of illness, and cultural beliefs and expectations.

Biological Aspects of Psychopharmacology Pharmacokinetics depends on absorption, distribution, metabolism, and excretion. The activity of liver enzymes is controlled genetically, although environmental factors can also alter activity. Pharmacokinetics may be influenced by genetics, age, gender, total body weight, environment, diet, toxins, drugs, alcohol, and disease states. Environmental factors include medications, drugs, herbal medicines, steroids, sex hormones, caffeine, alcohol, constituents of tobacco, and dietary factors. Understanding how pharmacokinetics and environmental factors relate to different populations will help to predict side effects, blood levels, and potential drug-drug interactions. The CYP 2D6 isoenzyme metabolizes many antidepressants, including the tricyclic and heterocyclic antidepressants, and the selective serotonin re-uptake inhibitors (SSRIs). CYP 2D6 also plays a role in metabolizing antipsychotics, including clozapine, haloperidol, perphenazine, risperidone, thioridazine, and sertindole. The incidence of poor metabolizers at the CYP 2D6 ranges from 3% to 10% in Caucasians, 1.9% to 7.3% in African-Americans, 2.2% to 6.6% in Hispanics, and approximately 0% to 4.8% in Asians. Another genetic variation of the metabolizer gene leads to “intermediate metabolizers,” or individuals who exhibit CYP 2D6 activity that is between that of poor (little or no CYP 2D6 function) and extensive metabolizers (normal CYP 2D6 function). Approximately 18% of Mexican Americans and 33% of Asian-Americans and African-Americans have this gene variation. This might explain ethnic differences in the pharmacokinetics of neuroleptics and antidepressants. The CYP 2C9 isoenzyme is involved in the metabolism of ibuprofen, naproxen, phenytoin, warfarin, and tolbutamide. Approximately 18% to 22% of Asian-Americans and African-Americans are poor metabolizers of these drugs. The CYP 2C19 isoenzyme is involved in the metabolism of diazepam, clomipramine, imipramine, and propranolol; it is inhibited by fluoxetine and sertraline. The rates of poor metabolizers of this enzyme are approximately 3%

to 6% in Caucasians, 4% to 18% in African-Americans, and 18% to 23% in Asian-Americans. With the preceding in mind, some observations have been made concerning the use of psychotropics in different ethnic groups. Clinicians should keep in mind that significant inter-individual variations are common. Asians tend to require lower doses of TCAs, whereas African-Americans can respond faster to TCAs and at lower doses, but with a greater risk of neurotoxicity. Hispanics can respond to lower doses of TCAs and experience greater side effects. Asians experience extrapyramidal symptoms (EPS) at a greater rate than AfricanAmericans, Hispanics, and Caucasians. Asians appear to respond better to clozapine as well as to have greater side effects at lower doses. Asians also appear to be more sensitive to benzodiazepines, compared with Caucasians. Asians respond to lower levels of lithium (with literature suggesting they can be successfully maintained at serum levels of 0.4–0.8 mEq/L), whereas AfricanAmericans appear to have a greater risk of neurotoxicity, likely related to a slower lithium-sodium pathway and a higher propensity for hypertension.

Recommendations for Observed Clinical Exercises Realize that patients from different cultural backgrounds might have unique needs and issues that require additional time and resources. The clinical relationship will be more complex, and it will likely take longer to develop trust and alliance. Be respectful to all patients and address them formally (e.g., Mr., Ms., Mrs.). Understand how personal biases and stereotyping can affect treatment. Racial and ethnic groups are highly heterogeneous and can include a diverse mix of individuals with different cultures, over-lapping identities, languages, practices, and experiences. Be careful not to make assumptions about a patient’s values or behavior based on race, ethnicity, or culture, as such generalizations can be misleading and have harmful effects on a patient. Assure patients about confidentiality. It may be more important than usual due to shame, fear, or paranoia related to prior traumatic experiences. Pay attention to communication (e.g., non-verbal communication, expressive styles, the meaning of words). Anticipate that the patient may have mistrust or fear of treatment due to prior poor experiences with

healthcare systems. Be prepared to start with lower medication dosages, and increase the dose slowly (as tolerated and as clinically indicated). When encountering a patient of color, one should avoid assuming that every patient of color will tolerate the same doses of medications. In addition, be sure to ask about the use of herbal medicines, as use of these agents has increased dramatically in the United States in the past few years. Remember that drug-herbal medicine interactions exist and should be carefully considered. If a diagnosis is unclear or might be impacted by ethnicity or culture, consider employing a structured diagnostic interview tool (such as the Cultural Formulation Interview) to reduce the possibility of misdiagnosis. Consider interviewing patients with a bilingual, bicultural interpreter, who can facilitate the education of patients and families to reduce stigma surrounding mental illness.

Suggested Readings 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013 2. Bhugra D, Bhui K, eds.: Textbook of Cultural Psychiatry . New York: Cambridge University Press; 2011. 3. Eack SM, Newhill CE: Racial disparities in mental health outcomes after psychiatric hospital discharge among individuals with severe mental illness. Soc Work Res . 2012; 36(1): 41–52. doi: 10.1093/swr/svs014. 4. Hays P: Addressing Cultural Complexities in Practice: Assessment, Diagnosis, and Therapy . Washington DC: American Psychological Association; 2007. 5. Henderson DC, Nguyen DD, Wills MM, et al: Culture and psychiatry. In: Stern TA, Fricchione GL, Cassem NH, et al, eds.: Massachusetts General Hospital Handbook of General Hospital Psychiatry . 6th ed. Philadelphia, PA: Saunders Elsevier; 2010: pp. 629–637. 6. Henderson DC, Yeung A, Fan X, et al: Culture and psychiatry. In: Stern TA,

Rosenbaum JF, Fava M, et al, eds.: Massachusetts General Hospital Comprehensive Clinical Psychiatry . Philadelphia, PA: Mosby Elsevier; 2008: pp. 907–916. 7. Lim R, ed.: Clinical Manual of Cultural Psychiatry . Washington DC: American Psychiatric Press; 2006. 8. Lewis-Fernandez R, Aggarwal NK, Baarnhielm S, et al: Culture and psychiatric evaluation: operationalizing cultural formulation for DSM-5. Psychiatry . 2014; 77(2): 130–154. doi: 10.1521/psyc.2014.77.2.130. 9. Snowden LR: H ealth and mental health policies’ role in better understanding and closing African American–White American disparities in treatment access and quality of care. Am Psychol . 2012; 67(7): 524–531. doi: 10.1037/a0030054.

CHAPTER Approaches to Collaborative 82 Care Psychiatry and Primary Care BJ BECK, MSN, MD AND JUDITH PUCKETT, MD

KEY POINTS Overview Background Health-care costs and limited resources have moved the locus of psychiatric consultation to outpatient clinics. The high cost of poorly managed psychiatric morbidity is increasingly recognized. The move from patient- to population-based care has highlighted the systems’ financial benefits of treating psychiatric disorders. Collaborative care is a systematic approach to management of psychiatric illness in outpatient medical settings. Epidemiology Depression and anxiety are the most frequent disorders in primary-care populations. Only a minority of patients with mental health disorders are seen by mental health specialists, whereas those with severe mental illness have reduced access to medical care. Collaborative care is a model based on measurement of care with targeted goals and a stepped-up approach. Barriers to Treatment Primary-care physicians (PCPs) infrequently ask about psychiatric symptoms secondary to a lack of training, a lack of time to fully address possible issues, personal defenses, and a lack of knowledge on how to treat or refer. Patients frequently do not tell their physician about their symptoms secondary

to stigma against mental health problems and their focus on physical complaints. Systems factors favor carve-outs that reduce reimbursement of PCPs for treatment of mental health and have restrictive formularies. The Improvement Goals of Collaboration Access Mental health care in primary-care setting is less stigmatizing. PCPs are more likely to identify mental disorders when have easy access to a consultant. Improved screening and diagnosis improves access. Treatment Collaboration can lead to improved PCP choice, dose, and management of psychotropic medications. Outcomes Outcomes are better with PCP-psychiatrist collaboration. Collaborative care decreases total health care spending. Collaborative care leads to better patient engagement in self-care and improved satisfaction with care. Improved Communication The PCP is responsible for the patient’s overall care and the role of the consultant as well as what information is shared must be clearly defined. Collaborative Models There is a systematic way of identifying patients with mental illness. There is team-based delivery of mental health care. There are trackable patient outcomes. A Variety of Models Exist Multiple models are described. The choice of model is discussed.

Overview Changes in the health-care system have increased the need for new and better approaches to the psychiatric care of patients in the general medical setting. These changes have been driven by the need to contain health-care costs and better manage limited resources, and, to a lesser extent, by advances in medications and technology. The transition from inpatient to outpatient care, with shorter medical/surgical hospitalizations and more outpatient procedures (e.g., same-day surgery) has moved the locus of psychiatric consultation to the outpatient medical clinic. Shorter psychiatric hospitalizations have also moved the care of more seriously ill psychiatric patients to the community. Changes in reimbursement from fee-for-service, to pre-paid (e.g., provider-risk health maintenance organization [HMO]), managed, and capitated health-care plans have forced a new awareness of the high cost of untreated (or poorly managed) psychiatric morbidity among high utilizers of medical care. The primary-care provider (PCP) gate-keeper system has evolved to manage the expense of specialty care. This is both a deterrent to the PCP’s recognition of psychiatric disorders as well as an incentive for the PCP to initiate treatment for the more common psychiatric problems in the primary care setting. Managed care entities (MCEs) commonly “carve-out” management of mental health and substance use (i.e., behavioral health) services to managed behavioral health organizations (MBHOs). This can increase the PCP’s difficulty in referring patients when the limited MBHO network does not include the PCP’s psychiatric colleagues. The move from patient- to population-based care, necessitated by the need to allocate limited resources, is among the most painful changes, given our individualistic culture. However, this focus on public, rather than individual health has highlighted the economic burden of psychiatric co-morbidity and disability, and the potential cost-offset of adequate, timely treatment. The presence of a psychiatric disorder correlates with greater (medical) health-care utilization, subjective disability, number of missed work days, unemployment, and mortality. Collaborative care is a systematic approach to the management of psychiatric disorders in medical settings. It provides patients with specialty-level care in the setting of primary medical treatment through the use of teams; recognizing that treating mental disorders requires a long-term approach and continuity of care. Collaborative programs have been shown to improve mental and physical health outcomes, quality of life, and functioning in a variety of clinical populations.

Models are designed to provide decision support to primary providers while engaging patients in self-managed care by increasing connections to community resources. Numerous trials have demonstrated that these programs are cost effective or lead to cost reduction and can improve outcomes for a range of mental health conditions. Despite this, lack of adequate reimbursement for this care model has limited the utility and expansion of its implementation.

Epidemiology Psychiatric problems in the general population are prevalent in the National Co-morbidity Survey (NCS) of the early 1990s. Adults in the United States had a life-time prevalence of at least one psychiatric disorder of 50%, with the 1-year prevalence being 30%. The most prevalent disorders were alcohol dependence and depression. In the early 2000s, the rigorous replication of this survey (NCSR) found for the first time that more than half (55.1%) of depressed community respondents seeking care were seen in the mental health sector, and, of those who received treatment in any medical setting, 90% received medication. Despite this perceived improvement in community-based depression treatment, only 21.6% received care consistent with recent, evidence-based guidelines (64.3% treated by mental health providers, and 41.3% of those treated by general medical providers), taking into account that almost half (42.7%) still received no treatment. Recognition of psychiatric problems in primary care can be difficult, but more recent studies in primary-care patients suggest that PCPs recognize the more severely depressed or anxious patients. However, a third or more of these patients present with sub-syndromal symptoms (i.e., symptoms that do not reach full Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM5] criteria for a diagnosable mental disorder). Primary-care patients can present earlier in the course of psychiatric illness, and then they present primarily with physical complaints, which further complicates the clinical detection of psychiatric problems. However, the clinical significance of PCPs’ failure to diagnose has not been clearly established. Outcomes are generally good in less depressed primary-care patients, despite shorter courses of less substantial doses of antidepressant medication. Although research in psychiatric specialty clinics supports the more prolonged use of medication at relatively higher doses, some primary-care patients respond to less intensive treatment, and improve without use of medications. This might be because some of the depressive symptoms result from adjustment disorders that clear over a relatively brief time, either

with the resolution of the initiating event, or the expressed concern from their PCP, and the placebo effect of a few days of medication. Only 20% of adult patients with mental health disorders are seen by mental health specialists, and many prefer to maintain treatment in a primary-care setting. Individuals with chronic and severe mental illnesses are more likely to be seen by mental health providers, but they have reduced access to medical care, which has been associated with higher mortality rates. This data highlights the systemic need for better communication among mental health and primarycare providers. In terms of the clinical approach, collaborative care programs follow the three basic principles. First, collaborative care is based on measurement-based care in efforts to replicate a model used by PCPs for chronic medical conditions (e.g., hemoglobin A1c for type II diabetes or lipid panel tracking). Patient progress is monitored using validated clinical rating scales (e.g., PHQ-9 for depression). Second, treatment is designed with a targeted goal, for example, specific improvement on PHQ-9 scores. Third, treatment is adjusted when patients do not improve. This is referred to as a stepped-up approach .

Barriers to Treatment Even when patients are screened and PCPs are informed of the results, treatment might not be initiated. PCP, patient, and systems factors collude to inhibit the necessary discussion to promote treatment (“Don’t ask/Don’t tell”). Physician factors (“Don’t ask”) include the failure to take a social history or do a mental status examination (MSE). This has been attributed to deficits in medical school and residency curricula, time and productivity pressures, and personal defenses (e.g., identification, denial, isolation of affect). PCPs are more comfortable dealing with their patients’ physical complaints and might fear patients will leave their practice if asked about mental health issues. Like many of their patients, the PCP might not believe treatment will help. Insecurity about what to do (e.g., how, and whether, to treat or refer) is a major deterrent to identifying the problem within the context of a 15-minute, primary-care visit. Patient factors (“Don’t tell”) include the widespread stigma against mental health problems. Patients are often ashamed or embarrassed to bring up what they see as a personal weakness. They may not know they have a diagnosable, or treatable, mental disorder. In the primary-care setting, patients more frequently present with physical complaints, which increases the diagnostic complexity:

medical disorders can simulate psychiatric disorders; psychiatric disorders can lead to physical symptoms; psychiatric and medical disorders can co-exist. Beyond the financial imperatives to contain cost and increase efficiency, systems factors are increasingly ruled by the changeable health-care finance and reimbursement climate. With managed care, carve-outs, provider-risk, capitation, fee-for-service, free care, coding nuances, differential formularies, and prior authorization, the systemic instability, confusion, and administrative time-creep significantly overpower any urge to actively treat a possibly self-limited condition. Mental health carve-outs have either eliminated or greatly complicated the possibility of reimbursing PCPs for the treatment of mental disorders. Pre-paid plans (e.g., HMOs) decrease incentives to offer anything “extra.” The necessity to increase productivity (and documentation) has excessively shortened the “routine visit,” now often less than 15 minutes. Despite the improved standardization of electronic medical records (EMRs), they have introduced their own time-consuming processes. The enhancement of new, safer, more tolerable psychotropic medications is being negated by soaring pharmacy costs and the advent of more restrictive (possibly shortsighted) formularies. Primary care has reached a crisis point: few PCPs can sustain fulltime clinical practice with these overwhelming pressures.

The Improvement Goals of Collaboration Considerable research demonstrates that these models address and meet the “triple aim” goals of health reform: improving the patient experience of care, improving the health of populations, and lowering health-care costs.

Access Patients prefer the primary-care setting; they feel more comfortable there than in the less familiar mental health clinic or psychiatric office. Receiving mental health care in the primary-care setting is less stigmatizing; even creating a mental health floor or wing in the primary-care setting can decrease patient acceptance. Without the onus of referral, PCPs more readily identify mental disorders, and they are more likely to initiate appropriate treatment when there is easy access to a known and trusted consultant. Additional goals of the collaborative-care model include improvement in screening and diagnosis. There is little formal data reported though some studies have shown an improvement in this area when compared to typical care. This is likely secondary to the introduction of systematic screening and the fact that

PCPs are more likely to participate in screening given increased support in managing those who screen positively.

Treatment Without ready consultation, PCPs often prescribe insufficient doses of older medications (e.g., amitriptyline 25 mg for major depressive disorder [MDD]); they have historically also prescribed benzodiazepines more frequently than any other class of psychotropic medication, even for MDD. Moreover, PCPs are increasingly comfortable with selective serotonin re-uptake inhibitors (SSRIs) (and many SSRIs are now generic). This comfort, however, has fostered new concerns; patients with poorly-defined distress might be started prematurely on SSRIs, when watchful waiting might be more appropriate and effective. Conversely, patients who might meet criteria for SSRI-responsive disorders are started on a low dose, without further monitoring for adequate response. Collaboration with the psychiatrist can improve the choice, dose, and management of psychotropic medications.

Outcomes More seriously depressed primary-care patients have been shown to have better outcomes with PCP-psychiatrist collaboration. Cost-offset is difficult to demonstrate because of the many hidden costs of psychiatric disability. However, some studies have shown a decrease in total health-care spending when mental health problems are adequately addressed. Care for the patient’s psychiatric problem (e.g., depression) can be more cost effective than the same amount of money spent addressing the often non-responsive somatic complaints of high-utilizing medical patients. Also, untreated psychiatric disorders can interfere with the patient’s ability to adequately manage their medical conditions (e.g., diabetes). Integration of a care manager within a collaboration model is also likely to increase patient adherence and self-care through increased support and more frequent check-ins outside of doctor visits. Data supports increased satisfaction with care among patients and general practitioners as well as improved quality of life. However, data regarding superiority to care-as-usual is variable.

Communication Collaboration implies communication—an end to the “black box” of psychiatry. Patients must be made aware of the collaboration and shared communication between the PCP and the psychiatrist. Communication should be

written and, whenever possible, verbal. And, it must be two-way: PCPs provide pertinent information and state the clinical question; psychiatrists relate findings, diagnoses, and recommendations.

Collaborative Roles, Relationships, and Expectations The PCP is responsible for the patient’s overall care, and must broker and oversee any specialty services. The psychiatrist is a consultant to the PCP, and sometimes a co-treater. The patient should understand what to expect from the visit with the psychiatrist when the referral is made by the PCP. Likewise, the consultant should clearly state the parameters of the contact at the beginning of the visit (e.g., a one-time consultation, possibility of medication follow-up, possibility of referral for therapy). If the psychiatrist sees the patient more than once, the relationship between the PCP and the psychiatrist might need to be restated. This avoids a sense of abandonment by the PCP (when the patient is referred to the psychiatrist) or by the psychiatrist (when the patient is returned to the PCP for ongoing psychiatric management). Collaboration does not breach patient confidentiality, because the PCP and psychiatrist are now within the circle of care, and the patient is informed of this relationship. If patients ask that particular details not be placed in their general medical record, and these details do not directly alter their medical care (e.g., history of childhood incest), it is reasonable to respect this wish. The pertinent information (e.g., patient experienced a childhood trauma) can be expressed in more general terms. However, information that affects medical treatment (e.g., current or past drug addiction) or safety (e.g., suicidal or homicidal intent), cannot be withheld from the PCP, and the patient should be so informed. Placing psychiatric or mental health notes in the general medical record greatly enhances communication but also raises issues of confidentiality and privacy, especially in the era of HIPAA (Health Insurance Portability and Accountability Act of 1996) regulations. Most states require a specific release for mental health or substance use (or human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS]) treatment records. Psychiatric or mental health notes in the general medical record should be color-coded or otherwise flagged so that they can be removed when records are copied for general medical release of information. In practices with an electronic medical record (EMR) system, there should be an algorithm in place to avoid the inadvertent release of this information.

Collaborative Models Collaborative models vary along a number of dimensions (e.g., where the patient is seen; whether there is a combined medical record; what the mode of provider communication will be; and whether the psychiatrist recommends, initiates, or provides ongoing treatment). Whether the PCP and psychiatrist are members of the same medical staff and the psychiatrist’s availability (physically, electronically, or telephonically) to the PCP also differentiate between the models. Despite the variety of models, collaborative programs have three essential components: (1) a systematic way of identifying patients with psychiatric disorders; (2) team-based delivery of mental health interventions; and (3) implementing trackable patient outcomes. Teams are often composed of a PCP, specialty physicians as indicated, as well as care managers. The care manager often plays the lead role in patient follow-up, performing check-ins, patient education, as well as tracking adherence and progress, and promoting and arranging change in treatment plans for those who do not improve. Types of case managers might include registered nurses, master’s-level mental health workers, and social workers. Data supports the notion that those with more clinical experience facilitate more effective outcomes.

Outpatient Consultation Models Consultation implies collaboration because the patient is referred or presented to the psychiatrist by the PCP for expert advice or recommendations. Depending on the setting or the system, there might be one shared medical record, or providers might maintain separate records and share pertinent information; patients might be seen in either the psychiatric or primary-care setting. This is different than private psychiatrists who have established referral sources in the primary-care sector, in that private psychiatrists generally do not develop truly collaborative relationships, with ongoing communication or shared records.

Specialty Psychiatric Clinics Specialty psychiatric clinics (e.g., an eating disorders clinic) generally maintain separate records, require the patient to be seen in the psychiatric clinic, and must develop some means of ongoing, clinically-relevant communication with the PCP. Such clinics are most often located in teaching hospitals or tertiary-care centers. Patients generally need to have well-defined and recognized problems to be referred; stigma can interfere with patient adherence to such a referral. A

major advantage of such clinics is the expert, multi-disciplinary approach they provide for patients with complex psychiatric and medical problems.

Consultation Psychiatrists Consultation psychiatrists might render a one-visit opinion, most often in the primary-care clinic. This model is similar to the consultation model used in the inpatient medical setting. This consultation should be written and placed in the primary-care record; immediate verbal communication, in person or by phone or voice mail, greatly enhances the utility of such consultations. Treatment is usually not initiated by the consultant, but practical recommendations are made. The role of the PCP and occurrence in the primary care setting enhance patient participation and decrease stigma. This model also promotes opportunities for ongoing informal education between the PCP and consultant.

Psychiatric Teleconsultation Psychiatric teleconsultation is a service with full-time, experienced, consultation psychiatrists available for immediate telephone consultation to PCPs. This service, which is not accessible to patients, can provide general psychiatric information, consultation about pharmacologic or behavioral management, or triage and referral functions. Computer technology is used to maintain a database, promote timely referrals, and generate follow-up letters to the PCPs. There is currently no direct third-party reimbursement for the full-time teleconsultants’ services. Increased capitation, which never materialized, was expected to provide a funding source as the cost offset of this timely service was realized. This lack of sustainable funding has been the demise of some of these services.

Telepsychiatry With technologic advancements and improvements, a newer form of telepsychiatry is emerging. This service provides a video-conferencing platform to unite patient with the geographically-remote psychiatrist for evaluation and possibly ongoing treatment. As one vendor claims: “Telepsychiatry is just psychiatry with the use of a computer.” In rural and remote areas of the country, this type of service is addressing the need for otherwise inaccessible psychiatric services. Although telepsychiatry is not in and of itself a model of care, when it takes place in a primary-care setting, it has the potential to be most comparable to either the consultation psychiatry model (discussed earlier), or any one of the models in which the psychiatrist is a member of the primary-care clinic medical

staff. (This assumes the same psychiatrist is regularly available to the same clinic, PCPs, and patients, and meets the same, on-site tenets of collaboration). This is different from the preceding description of teleconsultation, which, again, is a service accessed telephonically by the PCP, and is not a service directly available to the patient.

Three-Component Model A formalized system of consultative care supported by the MacArthur Initiative on Depression in Primary Care , Three-Component Model (TCM ) promotes depression (and now also anxiety) treatment in primary care, as a chronic disease. Regular adherence measures and outcome tools (e.g., the PHQ-9) guide medication and other treatment adjustments according to evidence-based protocols. There are well-developed educational modules for PCPs, consultant psychiatrists, phone-based care managers, and patients. The multiple symptom and adherence measures are recorded on a standard form that facilitates consultation, communication, organized treatment review, planning, and adjustment. Not only addressing the care needs of the large population of depressed or anxious primary-care patients, dissemination of the model, with materials, manuals, and educational modules also provides data to inform policy (and payment) decisions. Other evidence-based endeavors include the Health Disparities Collaboratives (the combined effort of the Department of Health and Human Services, Health Resources and Services Administration, and the Bureau of Primary Health Care) and the IMPACT Model (initially funded by the John A Hartford, California HealthCare, Hogg, and Robert Wood Johnson Foundations).

Psychiatrist on the Primary-Care Clinic Medical Staff Being medical staff colleagues enhances the potential for psychiatrist and PCP collaboration and for shared care. The psychiatrist can (1) consult as a member of the medical team, (2) evaluate and treat patients in parallel with the PCP, (3) alternate visits with the PCP while treatment is initiated, or (4) evaluate, stabilize, facilitate referrals to outside mental health providers, and/or return the patient’s care to the PCP with recommendations for continued care. This proximity between PCP and consultant promotes communication, formal and informal education, and immediate access to curbside consultation. This arrangement can also provide an excellent training opportunity for both psychiatric and primary care residents. Patients appreciate being seen in the more familiar primary-care setting, and feel less stigmatized.

Staff Consultant Consultations, as those just described, are written in the regular medical record. The permanency of the psychiatrist allows for a more finely-tuned consultant– PCP relationship. For instance, with previously established agreement, the consultant might initiate the recommended treatment. The psychiatric consultant might offer clinically-relevant suggestions during case conferences or discussions of more complex patients. The psychiatrist might also see the patient with the PCP during the primary-care visit, capitalizing on the PCP’s extensive knowledge of, and long-term relationship with the patient to provide more timely treatment recommendations.

Parallel Care If the psychiatrist assumes the ongoing psychiatric care of patients, in parallel with the PCP, some clinics have separate mental health charts. This requires some overt means of communication to keep all providers informed. Clinics with an EMR will have the advantage of a unified, up-to-date medication list, and possibly an integrated record. Some primary-care clinics incorporate a mental health unit, or clinic; to the extent that this is an identifiable, special area within the clinic, it is fraught with the same problems of stigma that occur when the clinics are truly separate. The psychiatric capacity of primary-care clinics that offer these services is often inadequate to meet the needs of the total patient population. This can be problematic and delay access because most patients would like to be treated in this setting. Uniform criteria facilitate the triage of patients for in-house treatment or outside referral, and include such considerations as diagnosis, available community resources, language requirements, or payment source. Insurances with mental health carve-outs might not cover psychiatric care in the same setting in which they cover medical services. Capitation will favor treating the patient in-house, whereas patients with indemnity plans might have more options for outside referrals.

Collaborative Management In collaborative management, the patient alternates visits between the psychiatrist and the PCP, in the primary-care setting, during initiation of treatment (the first 4–6 weeks). The PCP assumes responsibility for patients’ continued psychopharmacologic treatment. This model was developed as a research protocol for the treatment of depressed, primary-care patients, but has

now been expanded to also treat patients with anxiety or post-traumatic stress disorder (PTSD). Patients are referred by the PCP, usually after an initial (and ineffective) trial of medication. The collaborative management model has several underlying assumptions. The model assumes that PCPs can initiate appropriate treatment for depression, manage the care of patients stabilized on antidepressant medications, and provide better care for more seriously depressed patients with the collaboration of in-house psychiatric consultation. The model also recognizes that successful collaboration begins with PCP education. For this reason, PCPs receive prior training, and participate in regular teaching conferences. Also integral to the treatment is a psychoeducational module for patients. This intensive program of care has been cost effective for more severely depressed, primary-care patients.

Primary-Care-Driven Model The primary-care-driven model evolved from the practical necessity to assist PCPs in the provision of quality psychiatric care for their own primary care patients, with limited psychiatric resources. This model incorporates elements of consultation, teleconsultation, and collaborative management with the goal of maximizing the treatment of appropriate primary-care patients, in the primary care setting. Established criteria are used for triage; the appropriateness of PCP management is the first consideration. All psychiatric notes and evaluations are provided (electronically or photocopied) to the referring PCP and placed in the regular (EMR) medical record. The clinic provides psychiatric training for both psychiatric and primary-care residents. This model also has several implicit assumptions, including, but not limited to, those of collaborative management, as appropriate to its broader diagnostic range. Additional assumptions of the primary-care-driven model include that collaboration begins with education of PCPs and psychiatrists that patients’ psychiatric needs should be met in the primary-care setting when consistent with good care, and that responsibility for total care requires communication between the PCP and any other involved care provider or consultant. Not specific to a diagnosis, the model also assumes that PCPs can manage the care of patients stabilized on psychiatric medications, and that PCPs can initiate appropriate treatment for some psychiatric disorders. However, a major assumption is that not all patients or all disorders are appropriate for primary-care management. Patients with inherently unstable conditions (e.g., psychotic disorders, bipolar disorder), primary substance use or addiction, suicidal thoughts (especially with

intent or plan), severe personality disorders, or complicated medical regimens are better served by ongoing specialty care. It is the psychiatrist’s role to help the PCP recognize those patients not recommended for primary care management and to assist with appropriate referrals. Requests for consultation or referral come from the PCP, in writing (or electronically). The request includes the clinical question or problem to be addressed and any medication trials initiated by the PCP. PCPs are also encouraged to call or stop by the psychiatrist’s office, located within the primary-care clinical area, for more general information about diagnoses, medications, and psychiatric or behavioral management. A broad range of available psychiatric services include formal evaluation, stabilization over several visits then return of the patient to the PCP’s care with recommendations (e.g., how to follow, how long to continue, when to re-refer); informal consultation without the patient present (i.e., “curbside”); brief consultation with the patient and the PCP during the patient’s appointment with the PCP; or behavioral treatment planning for difficult-to-manage patients. Reevaluation of patients previously seen when there is a change (e.g., recurrence of symptoms, new problem, medication side effects, change in medical condition or medications that affects psychiatric symptoms or medications) is also readily available. Masters-level clinicians, located within the primary-care clinical areas they serve, provide focused, short-term, goal-oriented, individual or group, therapy, Collaborative-care management is a service that assists the PCP when patients with complex medical, psychiatric, and addictions problems are referred out and require treatment that spans several community agencies. After a comprehensive diagnostic and functional assessment, necessary releases are signed so that the care manager serves as a liaison between the PCP and all other care providers. The care manager involves the patient and all treaters in the development of a comprehensive treatment plan, within a network of services, and tracks the patient from site to site throughout this plan. As a member of the discharge planning team, the care manager ensures that the patient returns to the appropriate network of services after care in a hospital, detoxification program, or other residential/institutional setting. Similar to teleconsultation, the lack of sustainable funding for care management in the primary care setting has led to the demise of some of these programs.

The Choice of Model

The choice of model for a given clinical setting depends on a number of factors, including the patient population, payor mix, range of available community resources, and the location, type, and size of the practice. Patients with a higher educational or socioeconomic status might feel less stigmatized and be more able and willing to seek, and pay for, outside psychiatric services. Some patients feel more comfortable in private practice settings that allow the greatest possible privacy. Mental health problems are less acceptable, or even shameful, in some cultures, which favor a more integrated, “invisible,” system of care in the primary-care setting. Capitation, all-inclusive and provider-risk programs will most clearly demonstrate the cost-offset and cost-effectiveness of in-house, collaborative models, telepsychiatry (in remote areas), and teleconsultation. The primary-care-driven model requires adequate community resources to which patients not appropriate for primary-care management can be referred. Suburban or rural areas that lack these resources are better served by parallel, or shared-care models, or possibly telepsychiatry. Small groups or solo practitioners might favor consultation models, either with a very part-time, but regularly scheduled consultant, or with access to an outside consultant, or teleconsultant, as needed. Large practices, and especially training facilities, will benefit most from the full range of in-house consultative and collaborative services, including formal education, case conferences, curbside consultation, and collaborative-care management.

Summary The merits of collaboration between psychiatrists and PCPs go beyond the mandates of the changing health-care system. These models increase access and improve mental health treatment for patients who would be unable, or unlikely, to receive care outside of the primary-care setting. Patient, practice, community, and payor factors help determine the best-fit model for a given setting. The continued evolution of the health-care system, treatment methods, and new technologies will require ongoing flexibility, on the part of psychiatrists and PCPs, to incorporate the adaptive changes required to keep models of care viable and cost effective. Medical, psychiatric, and patient education will need to reflect these changes in caregiver roles and expectations.

Suggested Readings

1. Beach SR, Walker J, Celano CM, et al: Implementing collaborative care programs for psychiatric disorders in medical settings: a practical guide. Gen Hosp Psychiatry . 2015 Dec 31; 37(6): 522–527. 2. Coleman SM, Blashill AJ, Gandhi RT, et al: Impact of integrated and measurement-based depression care: clinical experience in an HIV clinic. Psychosomatics . 2012; 53: 51–57. 3. Committee on Quality Health Care in America, Institute of Medicine: Crossing the Quality Chasm: A New Health System for the 21st Century . Washington, DC: National Academy Press; 2001. 4. Druss BG, Rohrbaugh RM, Levinson CM, et al: Integrated medical care for patients with serious psychiatric illness. Arch Gen Psychiatry . 2001; 58: 861–868. 5. Goodrich DE, Kilbourne AM, Nord KM, et al: Mental health collaborative care and its role in primary care settings. Current Psychiatry Reports . 2013 Aug 1; 15(8): 1–2. 6. Huffman JC, Niazi SK, Rundell JR, et al: Essential articles on collaborative care models for the treatment of psychiatric disorders in medical settings: a publication by the Academy of Psychosomatic Medicine Research and Evidence-Based Practice Committee. Psychosomatics . 2014 Apr 30; 55(2): 109–122. 7. Katon WJ, Roy-Byrne P, Russo J, et al: Cost-effectiveness and cost offset of a collaborative care intervention for primary care patients with panic disorder. Arch Gen Psychiatry . 2002; 59: 1098–1104. 8. Katon WJ, Schoenbaum M, Fan M-Y, et al: Cost-effectiveness of improving primary care treatment of late-life depression. Arch Gen Psychiatry . 2005; 62: 1313–1320. 9. Katzelnick DJ, Williams MD: Large-scale dissemination of collaborative care and implications for psychiatry. Psychiatric Serv . 2015 Jun 1; 66 (9): 904–906. 10. Kessler RC, Berglund P, Demler O, et al: The epidemiology of major depressive disorder, results from the National Co-morbidity Survey Replication (NCS-R). JAMA . 2003; 289: 3095–3105. 11. O’Reilly R, Bishop J, Maddox K, et al: Is telepsychiatry equivalent to faceto-face psychiatry? Results from a randomized controlled equivalence trial. Psychiatr Serv . 2007; 58: 836–843.

12. Oxman T, Dietrich AJ, Williams JW, et al: A three-component model for reengineering systems for the treatment of depression in primary care. Psychosomatics . 2002; 43: 441–450. 13. Pirl WF, Beck BJ, Safren SA, et al: A descriptive study of psychiatric consultations in a community primary care center. Primary Care Companion J Clin Psychiatry . 2001; 3: 190–194. 14. Robertson SM, Stanley MA, Cully JA, et al: Positive emotional health and diabetes care: concepts, measurement, and clinical implications. Psychosomatics . 2012; 53: 1–12. 15. Roy-Byrne P: Collaborative care at the crossroads. Br J Psychiatry . 2013 Aug 1; 203(2): 86–87. 16. Ruskin PE, Silver-Aylaian M, Kling MA, et al: Treatment outcomes in depression: comparison of remote treatment through telepsychiatry to inperson treatment. Am J Psychiatry . 2004; 161: 1471–1476. 17. Simon GE, Khandker RK, Ichikawa L, et al: Recovery from depression predicts lower health service costs. J Clin Psychiatry . 2006; 67: 1226– 1231. 18. Stewart WF, Ricci JA, Chee E, et al: Cost of lost productive work time among US workers with depression. JAMA . 2003; 289: 3135–3144. 19. Thota AB, Sipe TA, Byard GJ, et al: Collaborative care to improve the management of depressive disorders: a community guide systematic review and meta-analysis. Am J Prev Med . 2012 May 31;42(5): 525–538. 20. Unützer J, Harbin H, Druss MD: The collaborative care model: An approach for integrating physical and mental health care in Medicaid health homes. Center for Health Care Strategies and Mathematica Policy Research. May. 2013 May 30. 21. Unutzer J, Katon W, Callahan CM, et al: Collaborative care management of late-life depression in the primary care setting, a randomized controlled trial. JAMA . 2002; 288: 2836–2845. 22. Van Orden M, Hoffman T, Haffmans J, et al: Collaborative mental health care versus care as usual in a primary care setting: a randomized controlled trial. Psychiatric Serv . 2015 Jan 13.60 (1): 74–79. 23. Worth JL, Stern TA: Benefits of an outpatient psychiatric teleconsultation

unit: results of a 1-year pilot. Primary Care Companion J Clin Psychiatry . 2003; 5: 80–84.

CHAPTER 83

Community Psychiatry BJ BECK, MSN, MD AND DAVID L. BECKMANN, MD, MPH

KEY POINTS Overview Community psychiatry, “the third psychiatric revolution,” has an undulant history of reform and neglect. The scope of community psychiatry has progressively narrowed to the publically- funded care and management of the community-based population with serious mental illness, focusing primarily on inpatient and outpatient services. Thus, community psychiatry is distinct from (but depends on) community mental health with the mandate to address the needs of all community members with a broader array of services (e.g. case management, residential treatment, crisis stabilization. The four underlying principles of community mental health are population responsibility, prevention, community-based care with citizen involvement, and continuity of care. In public health models, there are three levels of prevention: primary (decreasing the incidence of disease onset by preventing new cases), secondary (decreasing incidence via early detection and intervention), and tertiary (minimizing severity and disability of existing disease). Case (or care) managers are often necessary to coordinate services and help patients navigate this complex and uncoordinated system.

Overview Community psychiatry is a discipline, or sociopolitical system of care, best understood within its historical context, as the “third psychiatric revolution” (with moral treatment and psychoanalysis being the first and second revolutions,

respectively). With an undulant, developmental course, community psychiatry has, at times, been synonymous with public or population-based psychiatry; at other times it has been more disparate. It has embraced the tenets of public health, prevention, and, at times, social activism, rather than more patientfocused, psychodynamic treatments. The history of community psychiatry in the United States is the history of shifting sources and decreased amounts of financial support; the history of public outrage and reform which has alternated with denial and neglect. Likely no other branch of medicine has had to be as continually creative to fulfill its mandate with such ever-shrinking resources.

Terms and Definitions An understanding of community psychiatry requires familiarity with multiple inter-related disciplines and their (often imprecise) terminology. Social psychiatry is a theoretical field of research that emphasizes the sociocultural features of mental disorder and treatment, and the use of psychiatry and psychological variables to predict, explain, and intervene in social problems. Community psychiatry is a clinically-applied field of social psychiatry whose various definitions reflect the lack of consensus over its boundaries, appropriate emphasis, general principles, and core services. At the very least, community psychiatry involves work with individuals, groups, and systems, and the development of an optimal system of care, for a defined population, with limited resources. The definitions that follow reflect the ebb and flow of the scope of community psychiatry, in terms of purpose, population, and inclusive services: “…focusing on the detection, prevention, early treatment, and rehabilitation of emotional disorders and social deviance as they develop in the community rather than as they are encountered at large, centralized psychiatric facilities” (Stedman, 1982). “…subspecialty area in which psychiatrists deliver mental health services to populations defined by a common workplace, activity, or geographical area of residence” (Borus, 1988). “…responsible for the comprehensive treatment of the severely mentally ill in the community at large. All aspects of care—from hospitalization, case management, and crisis intervention, to day treatment, and supportive living arrangements—are included…” (Kaplan et al, 1994). Community mental health (CMH ) (per the vision of the Community Mental Health Center [CMHC] Acts of 1963 and 1965 ) is a multi-disciplinary system

of publicly funded, community-based mental health services, for all in need of such services, and residing in a geographically-defined area, regardless of ability to pay. Public psychiatry, on the other hand, is the government-funded system of inpatient and outpatient mental health services for those unable to access private sector (e.g., fee-for-service, or third-party insurance) services. Initially conceived to meet the needs of all citizens, the domain of public psychiatry has been progressively narrowed to the needs of the population with serious mental illness (SMI). Privatization is the request for, and acceptance of, private sector bids to provide public sector services, with governmental oversight. The move toward privatization might alter the definition of “public” psychiatry. Population-based psychiatry is a system of care responsible for the mental health needs of all members of a given group, as defined by such attributes as geography, workplace, or payor/care system (e.g., health maintenance organization [HMO]). Population-based responsibility extends to the defined population, as well as to the individual being treated. A catchment area is a geographic, CMH service area with a population of 75,000–200,000 (taken from sanitation engineering, the term refers to the large cistern into which all the sewage of a given geographic area is dumped).

Public Health and Social Terms Models of public health include three levels of prevention. Primary prevention measures are those taken to decrease the incidence (new onset) of a disease or disorder. Application of the principles of primary prevention (elimination of causative agents, reduction of risk factors, enhancement of host resistance, and disruption of disease transmission) has successfully eradicated certain infectious diseases, deficiency states, and toxic exposures, and has contributed to the decrease in heart disease and lung disease. In psychiatry, the effects of primary prevention can be more difficult to prove because that involves an assumption about what would have happened without an intervention. Examples include: anticipatory guidance (e.g., for parents with young children); enrichment, resilience, and competence-building programs (e.g., Head Start or Outward Bound); social support or self-help programs for at-risk individuals (e.g., bereavement or cancer support groups); and early- or crisis-intervention after a traumatic event or experience (e.g., on-site counseling for students after the suicide of a classmate).

Secondary prevention refers to measures taken to decrease the prevalence (number of existing cases in a population at a given point in time) of a disease or disorder through early recognition (case finding) and prompt treatment. The goals of secondary prevention are to shorten the course and minimize or prevent residual disability. An example in psychiatry would be community education and screening for post-partum depression. Tertiary prevention is rehabilitative efforts to minimize the prevalence and severity of residual defect and disability from a disease or disorder. Ongoing, community-based psychiatric treatment (e.g., medication management, socialization and skills groups, individual and group therapies) largely falls into the tertiary prevention category. De-institutionalization refers to the sociopolitical (and economic) policy to discharge long-term psychiatric inpatients from public hospitals, to live and receive services in the community. This term is widely recognized and used, despite the cogent argument that it should have been called de-hospitalization or trans- institutionalization, as patients were generally maintained in other (i.e., non-hospital) institutional settings. Case, or care, management is a service, usually provided by a social worker or other mental health clinician, to assure continuity of care, communication between providers, and the patient’s successful negotiation of a complex and fragmented system of agencies, care, and services. The more numerous and complex the patient’s needs, the more intensive the care management needs to be. Care managers use outreach, support, and advocacy to engage the patient in appropriate treatment. As a member of the treatment-planning team, the care manager follows the patient through all levels (e.g., inpatient, aftercare, residential) and types (e.g., mental health, substance use, physical health) of care and services/agencies (e.g., housing, welfare, public entitlements). There is an inverse relationship between the intensity of care management provided and the allowable size of the care manager’s caseload.

Managed Care Terms Managed care (as opposed to care management) refers to organized attempts to control a population’s health-care costs, and possibly quality, through management and monitoring of allocated services to individuals within that population. Managed-care organizations (MCOs) contract to provide this management function for public or private insurers of a given population, sometimes with financial incentives to contain costs within a fixed budget, and/or financial penalties when the service budget is exceeded. Common cost-

containment strategies include pre-treatment authorization, primary-care referral for specialty services, and concurrent review of treatment (utilization management) to determine ongoing need and effectiveness of treatment. Even though cost of care is not a new concern for patients or health-care providers, the advent of managed care has intruded the payor’s interests into the doctor–patient relationship in a way that critics feel impinges on the therapeutic process. Proponents, however, feel this has led to greater standardization and transparency as well as more evidence-based care, and possibly the tremendous increase in pay-for-performance initiatives. Now that even public-sector care has been managed for more than two decades, more progressive MCOs are adopting more self-management incentive strategies with network providers (e.g., for select inpatient psychiatric units, replacing prior authorization and utilization reviews with quarterly monitoring of such metrics as average length of stay, aftercare appointments made and kept, and re-admission rates). Carve-out is a process to separate the benefit management of mental health and substance-use services from the management of other (physical) health-care benefits. Managed behavioral health organizations (MBHOs) manage the carveout, mental health, and substance-use treatment benefits for public and private insurers. The National Committee for Quality Assurance (NCQA ) is the largest single accrediting body for MCOs, and includes standards for MBHOs (or for the behavioral health portion of non-carve-out MCOs). NCQA standards attempt to address the critical concerns that managed care is too focused on financial constraints, and not on quality of care. These standards cover such issues as accessibility and availability of appropriate, culturally-sensitive services coordination between behavioral and physical health-care services, and communication between all care providers. MCOs and MBHOs (sometimes collectively referred to as managed care entities [MCEs]) are required to manage both over- and under-utilization of services to assure that patients receive the care they need and are not denied or discouraged from accessing care. NCQA also requires a clear grievance process for patients to appeal the MCE’s decisions about their care. Cost-shifting refers to the practice of shifting the locus of care either for, or with the effect of, offloading the cost of the care to another system or payment source, without necessarily affecting the quality or overall cost of the care. Moving patients from state hospitals to community settings (where they become eligible for federal subsidies and entitlements) decreases the financial burden on

the individual state, and is, therefore, an example of state-to-federal costshifting. Privatization, which transfers the risk of escalating mental health costs from states to MCEs, is an example of public to private cost-shift. Mental health to physical health cost-shift occurs when patients do not access the mental health system, but seek general health services (either for their mental health problems directly or for somatic complaints), increasing the cost of general and emergency medical care. Mental health to corrections cost-shift occurs when substance users, persons with severe mental illness (SMI), dually diagnosed, and other disenfranchised individuals do not access appropriate CMH services, but receive their only consistent treatment when they are incarcerated for legal transgressions. Capitation is a method of contracting for health-care provision, for a given population, based on the up-front payment of a set monetary amount (i.e., cap), per member, per month. Capitation plans have tended to carve out mental health and substance use services, which set the stage for cost-shifting between mental and physical health capitation pools. Possibly in response to such cost-shifting, single, or global, cap programs are now encouraging the development of collaborative and coordinated systems of cost-effective care to provide for the total health of patients and populations.

Historical Background The history of Western community psychiatry is an epic of roiling reform and neglect set within a sociocultural, political, and economic context.

The Age of Enlightenment (Reform ) In the late 18th century, Phillipe Pinel, a French alienist (psychiatrist), removed the shackles of “mental patients” and promoted the notion that fresh air and work would restore mental health. This was the advent of “moral treatment,” considered the “first psychiatric revolution.” In the late 17th century, the first laws in the American Colonies were passed to jail persons with mental illness who were felt to be a risk to society (i.e., criminalizing mental illness). By the early 19th century, it is estimated that 20% of persons in jails or prisons had SMI, resulting in Rev. Louis Dwight’s putting pressure on government agencies to reform these establishments and separate care of persons with mental illness. The United States government funded institutions for persons with mental illness and behavioral deviance, and Dorothea Dix advocated for the building of state institutions and village-type asylums in which the insane could escape the

stresses of everyday life. These interventions were in some respects effective; the proportion of inmates with SMI dropped from 20% to less than 1% (Torey et al, 2010). By the late 19th century, however, crowding and serious deterioration of asylums and state institutions made “moral treatment” an impossible challenge, and gave way to the Industrial Revolution, which championed productivity and organization over fresh air and “asylum.” By the end of the century, burgeoning state hospital populations led to regimented, custodial care (neglect ), and “scientific” somatic therapies, most of which, with two notable exceptions, were unproven and not beneficial. One exception was the use of high malarial fevers to cure tertiary neurosyphilis, allowing many patients with general paresis to be discharged. The other useful therapy, promoted by Freud and his followers, found psychological understanding of patients useful in the treatment of conversion and possibly other disorders.

Early 20th Century Awareness (Reform ) Adolph Meyer wrote about prevention and the social context in which mental illness occurred. This “mental hygiene” movement was parallel to the preventive, public health movement of the time, fueled by industrialization, urbanization, and the need for sanitation and infection control. In 1905, Clifford Beers published his first-person report of life and conditions inside the mental institution (A Mind that Found Itself ). Beers, along with Meyer and William James, formed the National Association for Mental Health in 1909. The movement promoted smaller hospitals, community-based outpatient evaluation, inter-disciplinary training, greater affiliation with medical schools and mainstream medicine, and application of psychodynamic principles. Demonstration outpatient mental health clinics, developed to focus on evaluation, prevention, and differentiation between chronic and acute disorders, were less stigmatizing than state institutions. A continuation of the mental hygiene movement, the child guidance movement applied psychoanalytic theory in childhood, with the expectation that it would result in a decreased incidence of adult mental disorders. The vague goals and unsubstantiated assumptions led to disappointment and apathy; the theory remained unmeasurable and unproven. The Great Depression brought shrinking resources, professional infighting, long wait-lists, and rigid acceptance criteria, which led to disillusionment and abandonment of these programs (neglect ).

Mid-20th Century Military, Legislative, Pharmacologic, and

Epidemiologic Influences (Reform ) In World War II, when rejected recruits and psychiatric casualties and evacuees outnumbered the available new armed services recruits, military psychiatrists were prompted to lower screening thresholds for acceptance and to move the locus of treatment to the field. From this experience, and the post-war optimism, came three central tenets of community psychiatry: immediacy (i.e., treatment should not be delayed), proximity (i.e., treatment should occur “on-site,” or close to the patient’s usual environment to avoid secondary gain or the development of avoidance), and expectancy (i.e., the system of care should foster the expectation that the patient will improve and return to baseline function). The National Mental Health Act of 1946 provided federal funds for research and mental health training, and the establishment of the National Institute of Mental Health (NIMH), in 1949. Chlorpromazine was first used in the United States in 1954. The resultant decrease in psychotic symptoms and behavioral problems in state hospitals exposed the detrimental effects of long-term, institutional living (e.g., apathy, poor social and self-care skills). Patients treated at home with chlorpromazine were found to have better symptomatic, cognitive, and functional outcomes. At the height of inpatient custodial care (neglect ), with 550,000 patients in state hospitals, public outrage (reform ) was again kindled by a number of expository works on the overcrowded and dehumanizing conditions. The 1955 Mental Health Study Act created the Joint Commission on Mental Illness and Health, and funded its nation-wide assessment of available treatment services for persons with mental illness. By the late 1950s, de-institutionalization had begun, and eventually decreased the number of state hospital beds to about 100,000. Inadequate community services, limited family supports, and patients’ poor self-advocacy, social, and coping skills, led to a revolving-door policy, with 80% of patients re-hospitalized within 2 years. Epidemiologic studies indicated that psychiatric symptoms and mental health functional impairment were exceedingly common in the general, rural, and urban, populations (Stirling County, 1959 [Leighton, 1959]; Midtown Manhattan, 1962 [Strole et al, 1962]). The New Haven study confirmed that mental health services were the least available to the population (social class) most in need (Hollingshead and Redlich, 1958). In 1961, the report of the Joint Commission’s nationwide assessment recommended improvement of the public hospitals, decrease in their size, increase of their resources, and focused funding

on the improvement of treatment for patients with psychosis and major mental illness.

Birth of the American CMH Movement (Reform ) In 1963, President Kennedy delivered the first presidential message concerning mental illness and retardation to Congress. Kennedy invited a “bold new approach,” to successfully treat the majority of persons with mental illness in their communities, where they might resume productive roles. Kennedy opposed enhancement of the existent institutional system of care, and called for a “new type of health facility,” the CMHC. Weeks before his assassination, Kennedy signed the CMHC Act that provided funds in 1963 to build the CMHCs, and funds in 1965 to staff the CMHCs. The Act specified five essential services: inpatient care, partial hospitalization, outpatient services, 24-hour emergency care, and consultation/education. By the late 1960s, state and federal funds began to decrease (neglect ). Fewer than projected CMHCs were built (800 versus 2,000). Staff funding was often diminished even as a center was under construction. The public was critical and conflicted about the appropriate role of community psychiatrists (e.g., social activism versus treatment). The Congressional Act of 1975 was passed to partially refund and revitalize the CMHCs, prioritize the care of those who most disturbed the community, and increase the mandated essential services to include specialized programs for children and elderly, direct mental health screening services for the courts, follow-up care and transitional housing for the deinstitutionalized, and specialized drug and alcohol programs. As the first grant cycle for staff funds was ending in the late 1970s, it was clear that the insurance system was not supporting CMH services. At the same time, the decreased state hospital capacity was flooding communities with persons with SMI. President Carter established the President’s Commission on Mental Health, in 1977, to assess the state of the nation’s mental health services. The National Alliance for the Mentally Ill (NAMI), started by mothers of children with mental illness in 1979, began the rise of the self-help movement in CMH. Recommendations in the 1980 Mental Health Systems Act (reform ) included the funding of improved care for the underserved (i.e., the old, the young, persons with SMI, and minorities), to build new CMHCs, to improve the coordination of total health care (through linkages between mental and physical health-care providers), and the funding of essential, non-revenue-producing services (e.g., consultation, education, coordination of care, CMHC administration).

Late 20th Century However, in 1981, the Reagan Administration repealed the 1980 Mental Health Systems Act before it was ever implemented (neglect ). Thus ended 18 years of categorical federal funding for CMH. Block grants left the individual states to determine how to spend the inadequate funds for substance use and mental health services. In the early 1980s, privatization, and exemption from the Diagnosis-Related Groups (DRG) legislation, promoted the growth of for-profit, private psychiatric and substance use hospitals. In 1984, the Epidemiologic Catchment Area (ECA) study demonstrated the prevalence of symptoms and mental disorders in the general population. The majority of symptomatic community residents never accessed the mental health system but sought care in the general medical system: the de facto mental health system (Regier et al, 1993). By the beginning of the 21st century, the other notable piece of the de facto mental health system was, once again, jails and prisons. Although the rise of state hospitals decreased the estimated proportion of inmates with SMI from 20% (in the 1840s) to 1% (at the end of the 19th century), “trans-institutionalization” has completely reversed these gains. At present the proportion of detained and incarcerated persons with SMI is once again about 20% (Torey et al, 2010). Escalating health-care costs, the growth of the private psychiatric hospitals, the lack of treatment guidelines, standards, or criteria for level or type of care made mental health an easy target for managed care, which was on the rise in private and public sectors. Carve-out financing and management of public and private mental health services promoted cost-shifting strategies. This “pass the buck” avoidance increased the difficulty of vulnerable populations to access needed services, and in particular increased the disenfranchisement of persons who were poor, homeless, non-English-speaking, uninsured, and de-institutionalized.

Underlying Principles of CMH Population The CMHC was conceived to be responsible for all the mental health needs of all the individuals, and the entire catchmented population (75,000–200,000 residents) it served, regardless of ability to pay. No member of the population can be denied service. Responsibility requires planning for the allocation of limited resources in the development of the best possible system of care to meet the population’s needs. Services must match the patient’s needs (e.g., groups

should be offered when clinically and culturally appropriate, not as a less costly form of treatment).

Prevention Although community psychiatry modeled the public health movement’s focus on prevention to decrease the incidence, prevalence, and disability of mental illness or disorders, most of the limited treatment resources are now utilized for tertiary prevention (i.e., rehabilitative efforts to limit disability in persons with SMI).

Community-Based Care Services are provided in the patient’s community (proximity) to maintain family and social supports, avoid geographic isolation, and promote the patient’s functional roles in that community. Patients with persistent mental illness also retain better social and self-care skills when treated in their own communities. An array of services has evolved to treat and to maintain patients safely in the community, rather than in long-term custodial settings. Citizen involvement dates to the lay-professional partnership of Beers and Meyer when they formed the National Association for Mental Health (1909). Citizens are invited to be involved in their community’s mental health service system. Community boards work with mental health professionals to set relevant priorities and formulate general policies. Involved community members are also powerful political advocates for the needed resources to keep the system vital.

Continuity of Care CMHCs were to be “closed systems,” encompassing all aspects and levels of treatment, and to be responsible for both direct service and coordination of all required services. Because this “circle of care” extended across inpatient, residential, and outpatient settings, the flow of relevant information was to follow the patient and to facilitate clinical communication between involved providers in the various settings. This total responsibility for the patient’s care, regardless of setting, would also prevent cost-shifting strategies which have plagued the present, discontinuous system.

Components and Services of CMH Systems Inpatient Care

Not to be confused with the custodial care of the past, hospitalization is still a needed resource reserved for more seriously and acutely ill patients. More beds now exist in less stigmatizing, general medical and private psychiatric hospitals for brief, intense evaluation and treatment, and safe containment. Many inpatient units are “locked,” and require the patient to meet commitment standards (e.g., suicidal, homicidal, or unable to care for self on the basis of mental illness), even to be voluntarily admitted. The development of less restrictive measures, financial constraints, and legal mandates to protect the civil liberties of persons with mental illness, have made long-term inpatient care all but non-existent. For many persons with SMI, multiple, brief admissions (the revolving door) have replaced extended hospital stays.

Partial Hospitalization Less expensive and restrictive than inpatient hospitalization, “partials” provide structure and hospital-based treatment programs to patients who transition back to their homes in the community at the end of each day. This gradual resumption of community living, with the extra support of the hospital treatment program, is one attempt to avoid, or decrease the length of, inpatient hospitalization, provide less restrictive care, and combat the revolving door, for patients with stable living arrangements.

Outpatient Services A broad range of services and service modalities permits the effective treatment of patients with more SMI in the outpatient setting. The array of services includes medication management, individual, group, and family therapies, psycho-education, skills training, self-help groups, day-treatment programs, transitional housing, half-way houses, and supervised boarding rooms. There are also specialized services for children and for the elderly, as well as alcohol and drug-use treatment programs.

24-Hour Emergency Services Crisis teams, or crisis clinicians in emergency rooms, provide pre-hospital screening, crisis intervention, and immediate access to care.

Community Consultation/Education As federal oversight diminished along with funding, these non-revenueproducing activities have also greatly diminished. However, with the advent of the primary-care “gatekeeper” system, community-based psychiatrists are being

called upon to consult with primary-care providers (PCPs). Many primary-care patients present with somatic complaints, mood, anxiety, or addiction problems. As managed care and global capitation encourage PCPs to treat lesscomplicated/more-common mental disorders, they increasingly look to community psychiatrists to assist them with appropriate diagnosis, treatment, or referral.

Case Management The less-inclusive nature of CMHCs has made case (or care) management essential to track the patient’s progress through a potentially-fragmented system of services. Care managers remain the liaison between treaters, though appropriate releases are now required to permit this important communication.

Homeless Outreach The increasing population of homeless persons with mental illness does not access needed mental health services, either because of poor insight, fear, undocumented immigration status, or previous negative experiences. Flexible outreach workers in non-traditional settings (e.g., public parks, shelters) establish credibility to bring services to members of this disenfranchised population.

Disaster or Trauma Response The lessons from military psychiatry have prompted some agencies to develop immediate response teams for on-site assessment and treatment of disaster victims, to mitigate post-traumatic syndromes and residual disability. Controversy exists as to the role of such response teams, as the “debriefing” of victims of trauma has been shown to increase the likelihood of post-traumatic stress disorder (PTSD) in a sub-set of persons who do not desire such an intervention. Cognitive-behavioral therapy (CBT) shortly after trauma exposure, for persons who do not seem to be coping well, has the best evidence for preventing PTSD. Several medications given directly after trauma exposure have been studied; propanolol in particular has shown some promise. However, a 2014 Cochrane meta-analysis suggested that there is insufficient evidence for any pharmacological interventions in the prevention of PTSD (Amos et al, 2014).

Evaluation and Research

Federal mandates notwithstanding, the real impetus toward program evaluation, or “outcomes research,” has been the need to contain cost and to identify cost effectiveness. True cost-effectiveness research must span the multiple departments, agencies, and services of the population to determine possible cost offset from one program to another (e.g., improved [and appropriate] but more costly mental health services decrease the overall cost by relatively larger decreases in the expense of [sometimes inappropriate] general medical care, or increased pharmacy or crisis team expense results in greatly decreased inpatient expense). Just as carve-out management of mental health has been accused of cost-shifting, global capitation will require total systems research to identify cost-offset.

Trends Disenfranchisement Although the pendulum has swung toward maintaining the persons with SMI in the community, and prioritizing the CMH dollar for their care, that dollar and the services it buys continue to shrink, whereas barriers to access increase. This vulnerable population is increasingly over-represented in homeless and correctional populations as well as in persons with substance-use disorders.

Managed Care: The “Fourth Psychiatric Revolution?” Initially charged with cost-shifting (“dumping”) and fragmentation of services, the incentives in the more progressive MCEs have shifted from purely financial to issues of quality and cost effectiveness. When most of the initial savings came from decreased inpatient hospitalization, it was clear that earlier discharge was not sufficient to maintain persons with SMI in the community. What was found to be cost effective, was to develop a network of closely affiliated services that spanned the levels of progressively less-intensive and restrictive care, with intensive clinical managers to assist patients through these timely transitions and to assure communication between (serial and parallel) treaters. These networks bear a conceptual similarity to the vision of the CMHCs of the 1960s and have been developed under some of the same mandates and constraints: to provide coordinated continuity of quality care, for a given population, with finite resources. Also like CMHCs, progressive MCEs invite input and feedback from members of their lay and provider populations to insure relevant, culturallyappropriate programs and user-friendly service.

MCEs have pushed the public and private sectors to develop alternative levels of care that were not previously available (or no longer available). The MCEs have gone further. Using data to inform policy, they have set standards for treatment planning, monitoring, and recording; for timely access to care; for coordination of care; for communication with PCPs; and for relating symptoms and level of function to level of care.

Primary Care The de facto system is now, in fact , the system encouraged by gatekeeper and global capitation systems, to care for many of the sub-syndromal mental health problems in the community population. As provider groups assume financial risk for total care of populations, there will be a growing need for innovative programs to integrate and coordinate physical and mental health services.

Creative Solutions Community Treatment Teams (CTT ), or Assertive Community Treatment (ACT ), are innovative attempts to engage persons with SMI in community treatment by working with them where they live. Members of these multidisciplinary teams meet patients in their homes, boarding rooms, or shelters to organize a flexible array of services, which may include medication management, activities of daily living, and social skills training. By incorporating the patient’s usual setting, family or social supports, into the treatment, patients are monitored more closely, and can be offered more intense services when needed. ACT has kept persons with SMI from falling between the cracks, as evidenced by greatly decreased rates of hospitalization. (Conversely, discontinuation of ACT has resulted in sharply increased rates of admission.) A criticism of ACT, and other non-traditional programs, is that they do not fit the usual reimbursement structures. Flexible community-based programs and clinicians will need the support of flexible administrators to straddle systems and agencies, and maintain a vision of the big picture.

Trauma-Informed Care, Patient-Centered Care, and the Recovery Model As these ideas continue to be implemented, studied, and refined, specific ideas and interventions are becoming more commonplace in community psychiatry, each with the goal of providing patients with a greater sense of agency. TraumaInformed Care seeks to recognize the importance of trauma in the pathogenesis

of mental illness, and to avoid or minimize the retraumatizing of patients (e.g., through coercive practices, physical restraints). Patient-Centered Care (PCC ) seeks to shift the focus of psychiatric care from accomplishing the practitioner’s goals (e.g., the reduction of symptoms of psychosis) to the goals of the patient (e.g., increasing functionality so as to be able to maintain a job or a romantic relationship). Related to these ideas is the Recovery Model approach to mental illness, which focuses on hope, personal goals, social inclusion, and supportive relationships. Substance Abuse and Mental Health Services Administration (SAMHSA) defines recovery as “a process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential” (2016). These ideas are not new (the Recovery Model has existed since the 1970s), but a new and growing body of evidence supports the importance of these concepts. One application of these principals in the treatment of persons with SMI is the Finnish practice of Open Dialogue . This comprehensive system of care includes the involvement of people from aspects of the patient’s life, and puts the patient at the center of this dialogue at all times; the patient is not discussed in his or her absence. Although the American system of mental health care described here has made application of Open Dialogue in this country challenging, facets have been adopted successfully. A small example is the way that mental illness is talked about; using patient-centered language seeks to remove stigma and recognize that patients are not defined by their diagnoses. Attempts to address this have included shifts in language; examples include the change from calling a patient “a schizophrenic” to “a schizophrenic person” to “a person with schizophrenia,” and referring to utlizers of mental health resources as “consumers” rather than “patients” when they are not actively in the patient role. The goals of all of these interventions are to decrease the stigma of mental illness, make those with mental health needs more likely to access and remain in care, and live more fulfilling lives in accordance with their own values.

Political Changes to Mental Health Care in the 21st Century The most significant change in mental health legislation of this century has been the passage of the Affordable Care Act (ACA ) in 2010. Although this is too recent to know the full extent on the American mental health-care system,

several of the law’s provisions have increased access for persons with mental illness. The ACA defines mental health and substance-use services as essential, and requires that plans presented on health-care exchanges provide parity for these services. Access is further increased by childrens’ ability to remain on their parents’ insurance plans until the age of 26. Perhaps most important for patients seeking treatment in the public sector, states were given the ability to dramatically increase their Medicaid services, potentially reaching a significant number of disenfranchised persons. Indeed, Ali et al (2016) estimated that 5.9 million Americans would gain access to mental health care through the ACA: 2.8 million through Medicaid expansions and 3.1 million through health insurance exchanges. By the time the ACA is fully implemented by 2019, an estimated 3.7 million more persons with SMI will access care [Garfield, 2011]. Even though this represents an important increase in access for persons with serious illness, there are significant concerns about the current mental health infrastructure’s ability to accommodate this increased demand. The long-term clinical, societal, and financial implications of increasing access—and utilization—of behavioral health care by up to 40% remains to be seen.

Conclusion Historical accounts of community psychiatry refer to three “revolutions”: moral treatment, psychoanalysis, and CMH. The implied definition of revolution is the over-throw of tradition: radical change. However, closer scrutiny reveals a complex machine with multiple revolutions of neglect and reform (defined as cycles or rotations: coming full circle), and two swinging pendulums of public opinion: one between focus on the “worried well” versus persons with SMI, the other between institutional containment versus community-based treatment. History suggests we are currently in the midst of such repetition, and provides an opportunity to recognize our gains, hold onto lessons learned, and try not to repeat mistakes. This will not be the last revolution; systems of care will not only need to be dynamic and responsive, but influential, to meet the needs of their populations.

Suggested Readings 1. Ali MM, Teich J, Woodward A, et al: The implications of the affordable

2.

3.

4.

5.

6.

7. 8.

9.

10. 11.

12. 13.

care act for behavioral health services utilization. Administration and Policy in Mental Health and Mental Health Services Research. 2016; 43(1): 11– 22. Amos T, Stein DJ, Ipser JC: Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev . 2014 Jan 1;7. Appelbaum PS: Response to the presidential address – the systematic defunding of psychiatric care: a crisis at our doorstep. Am J Psychiatry. 2002; 159: 1638–1640. Beck BJ: Community psychiatry. In: Stern TA, Fava M, Wilens TE, et al, eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry, 2nd ed. Philadelphia, PA: Elsevier; 2016: pp. 726–732. Bernstein R, Koyanagi C: Disintegrating Systems: The State of States’ Public Mental Health Systems. Washington, DC: The David L. Bazelon Center for Mental Health Law; 2001. Borus JF: Community Psychiatry. In: Nicholi AM, ed.: The New Harvard Guide to Psychiatry . Cambridge, MA: Harvard University Press; 1988: pp. 780–796. Christensen RC: The ethics of cost shifting in community psychiatry. Psychiatr Serv. 2002; 53: 921. Duckworth K, Borus JF: Population-based psychiatry in the public sector and managed care. In: Nicholi AM, ed.: The Harvard Guide to Psychiatry, 3rd ed. Cambridge, MA: Harvard University Press; 1999: pp. 778–797. Garfield RL, Zuvekas SH, Lave JR, et al: The impact of national health care reform on adults with severe mental disorders. Am J Psychiatry. 2011: 168:486–94. Hollingshead AB, Redlich FC: Social Class and Mental Illness . New York: John Wiley; 1958. Kaplan HI, Sadock BJ, Grebb JA, editors: Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry, 7th ed. Baltimore: Williams & Wilkins; 1994, 201–206. Leighton A: My Name is Legion. New York: Basic Books; 1959. Mowbray CT, Grazier KL, Holter M: Managed behavioral health care in the public sector: will it become the third shame of the states? Psychiatr Serv.

2002; 53: 157–170. 14. Regier DA, Narrow WE, Rae DS, et al: The de facto U.S. mental and addictive disorders system. Arch Gen Psychiatry. 1993; 50: 85–94. 15. Rubin B: Community psychiatry: an evolutionary change in medical psychiatry in the United States. Arch Gen Psychiatry. 1969; 20: 497–507. 16. Seikkula J, Olson ME: The open dialogue approach to acute psychosis: Its poetics and micropolitics. Family Process. 2003; 42(3): 403–418. 17. Stedman’s Medical Dictionary, 24th ed . Baltimore: Williams & Wilkins; 1982: p. 1163. 18. Strole L, Langner TS, Michael ST, et al: Mental Health in the Metropolis: The Midtown Manhattan Study. In, Rennie TAC, editor. Series in Social Psychiatry . Vol. 1. New York: McGraw-Hill; 1962. 19. Substance Abuse and Mental Health Services Administration: Recovery and Recovery Support. http://www.samhsa.gov/recovery . 2015. Accessed March 31, 2016. 20. Substance Abuse and Mental Health Services Administration: TraumaInformed Approach and Trauma-Specific Interventions. http://www.samhsa.gov/nctic/trauma-interventions . 2015. Accessed March 29, 2016. 21. Talbott JA: Has academic psychiatry abandoned the community? Acad Psychiatry. 1991; 15: 106–114. 22. Thompson KS: Re-inventing progressive community psychiatry: the use of history. Commun Mental Health J. 1993; 29: 495–508. 23. Torey EF, Kennard AD, Eslinger S, et al: More mentally ill persons are in jails and prisons than hospitals: A survey of the states. Arlington, VA: Treatment Advocacy Center; 2010. 24. Waldemar AK, Arnfred SM, Petersen L, Korsbek L: Recovery-Oriented Practice in Mental Health Inpatient Settings: A Literature Review. Psychiatric Services . 2016 Feb 29. 25. Zeldon S, Larson R, Camino L, et al: Intergenerational relationships and partnerships in community programs: purpose, practice, and directions for research. J Community Psychology. 2005; 33: 1–10.

CHAPTER Psychiatric Care of Military 84 Personnel and Returning Veterans MARY C. VANCE, MD; MARIA D. RUBIO, MD, PHD; NAOMI M. SIMON, MD, MSC; AND MIREYA NADAL, MD, PHD

KEY POINTS Overview Military personnel who have served in the Iraq and Afghanistan conflicts are exposed multiple stressors that place them at risk for developing mental disorders. These conditions can affect them and their families for years to come. Service members, veterans, and their families represent a small percentage of the United States population, and an understanding of the differences between military and civilian culture is paramount to providing optimal clinical care. Military personnel face a number of barriers to care, and the Veterans Administration/Department of Defense (VA/DoD) is embarking on large-scale efforts to overcome these barriers. Post-traumatic Stress Disorder Exposure to potentially traumatic events is common during military service, and an estimated 14% to 16% of deployed personnel suffer from posttraumatic stress disorder (PTSD). Evidence-based treatments for PTSD include cognitive-behavioral therapy, which includes primarily exposure-based and cognitive techniques. Pharmacotherapy also plays a first-line role in the treatment of PTSD. Traumatic Brain Injury The majority of combat-related traumatic brain injury (TBI) is a result of blast injuries. Mild TBI, also known as mTBI or concussion, is the most common

form of TBI, and it is manifest by a host of physical, cognitive, and neuropsychiatric symptoms. Treatment of mTBI often involves inter-disciplinary and rehabilitative care. Co-morbid Conditions Major depressive disorder and substance-use disorders often affect service members and veterans. The suicide rate in the military has climbed steadily since the Iraq and Afghanistan conflicts and now exceeds the demographically-matched civilian suicide rate, making it a major public health concern. Building Resilience Multiple service branches have developed and implemented resilience training programs in an effort to promote mental health and mission-readiness in their troops.

Overview Since the beginning of operations in Iraq and Afghanistan, more than 2.5 million United States military personnel have been deployed to combat zones. Service members are exposed to a multitude of stressors that place them at risk of developing physical and mental health sequelae that can affect them and their families for years to come, particularly when left untreated. Although service members as a group are highly resilient despite exposure to substantial stressors, the need for mental health services is growing as this generation of service members and veterans re-integrates into civilian society. This chapter provides an overview of the psychiatric needs of military service members and returning veterans, outlines the basics of military service and culture as they relate to military mental health, and provides clinical guidelines for common mental health concerns experienced by this population. Emphasis is placed on the most recent research data available, which has been gathered since the Iraq and Afghanistan conflicts. The importance of family-focused care in the treatment of service members and veterans is also highlighted.

General Considerations Military Service and Culture

Broadly speaking, military personnel are divided into an active component and a reserve component. Active duty personnel belong to one of the five military branches (Army, Navy, Marine Corps, Air Force, and Coast Guard), are full-time military employees, and can be deployed at any time. The reserve component includes the Reserve and the National Guard. All branches of the military have a Reserve component under their command, whereas the National Guard comprises the Army National Guard and the Air Force’s Air National Guard. Members of the reserve component are not full-time military personnel and serve as trained units that can be called into active duty when a need arises, such as during times of war or in a national emergency. The Reserve is fully a federal entity, while the National Guard is federally-funded but controlled by the state except in times of war. In this chapter, the terms “military personnel” and “service member” are used to describe active duty and reserve military (including National Guard), and the term “veteran” is used to describe separated or retired former military. To care optimally for military service members, veterans, and their families, it is important to understand the demographic and cultural context from which they come. According to the 2014 American Community Survey data, there are 19.3 million veterans living in the United States and Puerto Rico, of which 1.6 million were women. The Army has the largest number of veterans (more than 10 million), followed by the Navy, Air Force, and Marine Corps. Comparing male with female veterans, the median age was 64 years for male veterans and 49 years for female veterans. Compared to non-veterans, male veterans were more likely to be white, non-Hispanic, and married. They were also more likely to hold management and professional occupations, more likely to have a combination of public and private health care, and less likely to live below the poverty line. Similar to male veterans, female veterans were more likely to be non-white, non-Hispanic, and widowed. They were also more likely to be working in management and professional occupations and more likely to have a combination of public and private health insurance coverage than their non-veteran counterparts. A higher percentage of female veterans than male veterans had completed some college (45.3% versus 36.4%), received a bachelor’s degree (20.1% versus 15.7%), or an advanced degree (14.0% versus 10.6%). Because a small percentage of the United States population serves in the military, they are often misunderstood by civilian mental health providers. In addition, emerging trends in the nature of military service (e.g., the use of an all-

volunteer force, a high operational tempo, more frequent and longer deployments, shorter dwell times between deployments) have placed additional strain on service members and their families. These facts underscore the need to provide more robust mental health support for this population as well as to educate civilian providers in the “culturally competent” care of service members, veterans, and their families who might or might not seek care through militaryinformed services, such as the Veterans Health Administration. The behavioral health cultural paradigm differs from the military cultural paradigm in several notable ways. Military culture values stoicism in the face of adversity, as would be necessary for survival and mission completion in wartime scenarios; however, this can contrast with the idea of seeking and receiving care for mental health problems. The pathology-based model of mental health can also seem foreign to military personnel, whose culture is more strength-based; this might in part account for the emphasis on resilience training programs in several branches of the military. The individualistic culture often found in the civilian population and in behavioral health settings is supplanted in the military by a collectivistic culture that values unit cohesion and esprit de corps . The internal locus of control emphasized by many psychotherapies, including the directive toward self-reflection and intrapsychic change, conflicts with the external locus of control (in which a clear hierarchy and chain of command is necessary for operational success) with which service members might be more familiar. Recognizing the military focus on service for others can help with engagement in care. Finally, unlike the civilian mental health culture, which typically focuses on the individual, it is increasingly recognized in the military that the mental health of the family as well as that of the service member is crucial for ensuring mission readiness. Civilian clinicians who recognize and understand these differences have a higher chance of engaging successfully with patients having a military background.

Barriers to Care The Department of Defense (DoD) and the Department of Veterans Affairs (VA) are the two entities of the federal government that provide health care benefits for active duty service members and veterans, respectively. Although commonly confused with each other, the DoD’s Military Health System and the VA’s Veterans Health Administration are two separate systems, and the transition from DoD to VA care when service members change status has historically been difficult, which introduces a significant barrier to continuous care. The two

systems have been integrating over the past 10 to 15 years to improve care, but a recent Institute of Medicine assessment determined that timeliness and adequacy in the care delivery continues to be problematic. According to the report of the United States Government Accountability Office (GAO), the key barriers for transitioning health care from the DoD to the VA system have included a lack of a unified electronic medical record, difficulties in managing medication prescriptions during the transition, and insufficient integration of case management and care coordination for the seriously wounded during the transition. According to the Mental Health Advisory Team 9 (MHAT-9) Operation Enduring Freedom (OEF) 2013 Afghanistan report, 10% of the study population met criteria for acute stress, depression, and anxiety. A VA mental health GAO report on veterans who accessed VA mental health care from fiscal year 2006 to fiscal year 2010 concluded that 2.1 million veterans were actively receiving mental health care at the VA, but only 12% were veterans of the OEF/ Operation Iraqi Freedom (OIF) conflicts. This percentage increased from 4% in 2006, and has been attributed to the increased number and intensity of OEF/OIF deployments. The main barriers to treatment that have been identified include mental health stigma and misconceptions, poor understanding of mental health care (thinking it is only for extremely ill individuals, thinking their condition is not related to mental health problems or that they do not need mental health care), mistrust of VA mental health services (negative perceptions about the VA, perceiving VA care as low quality, perceiving VA care as variable among locations), and difficulties with VA logistics (thinking VA care applies to other ranks or to older veterans, lack of registration for services, inefficient scheduling of appointments, dealing with distance from care and transportation issues), family problems (challenges arranging for daycare, lack of integration of care for military families). Many of these difficulties are shared by the general population and have been the target of political concern. In 2012, President Obama released 19 executive orders on the mental health of service members, veterans, and families. These were focused on improving the transition from the DoD to the VA and civilian health care, improving the access to and quality of mental health care in the VA/DoD, re-asserting the government’s commitment to improve treatment of mental health conditions such as post-traumatic stress disorder (PTSD), raising mental health awareness, improving patient safety, preventing suicide, and strengthening the resources available in the community for service members, veterans, and families.

Clinical Care Guidelines Psychiatric disorders are among the leading causes of morbidity in the military, with health-care visits and days out of work for mental illnesses being especially high. The following sections outline the epidemiology, diagnosis, and treatment of the most common and best-studied mental health problems associated with military service, including the so-called “signature injuries” of war, PTSD and traumatic brain injury (TBI). Although special attention is given to the treatments best supported by the current evidence, sound clinical judgment should take precedence in the treatment of an individual service member, veteran, or family member.

Psychological Trauma and PTSD Psychological trauma : In addition to the range of traumatic and stressful life events to which all individuals might be exposed, military service members often face severe stressors not typically seen in the civilian population (e.g., combat and its attendant risk of sustaining, witnessing and/or carrying out operations resulting in physical injury or death; harsh working conditions; and a front-line duty to maintain the safety of themselves and others in potentially hostile environments). Minority military populations can also encounter discrimination and, especially in the case of but not limited to female service members, an elevated likelihood of sustaining sexual assault. Additionally, the life-altering and sometimes sudden transitions between locations and contexts frequently experienced by service members (e.g., between duty assignments, between deployments, from active military status to civilian status upon separation or retirement) has the potential to disrupt established routines, environments, and supports in such a way as to make natural recovery from traumas and stressors more difficult. The adverse psychological impact of service-related traumas has been increasingly recognized over the past several decades. Research efforts have delineated post-traumatic stress reactions along a continuum based on the time elapsed since a traumatic event. Acute stress reactions typically occur immediately after a trauma and subside within minutes, hours, or days. When a stress reaction lasts between three days and one month, it is termed acute stress disorder (ASD); when the stress reaction persists for more than a month, PTSD can be diagnosed.

PTSD: PTSD , as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as a psychiatric disorder that has its etiological roots in exposure to a traumatic event by directly experiencing it, witnessing it first-hand, learning of its occurrence in a loved one, or being repeatedly exposed to it in the line of work. The syndrome is characterized by four inter-related symptom clusters: intrusive memories of the traumatic event (such as nightmares or flashbacks); avoidance of stimuli associated with the trauma; negative cognitions and emotional numbing in relation to the trauma; and alterations in arousal responses (e.g., hyperviligance and sleep disturbances) following the trauma. PTSD is associated with poor outcomes in multiple domains, including physical health problems, marital and family conflict, work-related difficulties, and legal problems. Although there is some variability across studies involving different military sub-populations, it is estimated to affect approximately 14% to 16% of deployed United States military personnel, as compared to 7% to 8% of the United States population, making it among the most prevalent of mental health concerns. There has been a notable increase in the prevalence of PTSD since the start of the current United States operations in Iraq and Afghanistan; demand for PTSD services in the VA and the DoD health-care systems is at an all-time high and continues to grow. To assist researchers and clinicians in practice, a range of symptomscreening, tracking, and diagnostic tools are available on-line from the National Center for PTSD, including the self-rated PTSD Check List for DSM-5 (PCL-5) and the longer “gold standard” Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Evidence-based treatments for PTSD: Treatments for PTSD can be divided broadly into psychotherapeutic and psychopharmacologic approaches. Multiple workgroups, including the VA/DoD, have released recommended treatment guidelines summarizing the strength of the research evidence for the currently available therapies and medications. An abbreviated list of these is presented in Table 84-1. Table 84-1: Treatments for PTSD and the Strength of Their Evidence Base According to VA/DoD Guidelines Treatment Type

Evidence Base (VA/DoD)

Psychotherapy Exposure therapies

A

Prolonged exposure Cognitive therapies

A

Cognitive processing Eye movement desensitization and reprocessing

A

Stress inoculation training

A

Group therapy

C

Image rehearsal therapy

C

Psychodynamic psychotherapy

C

Psychopharmacology Antidepressants SSRIs

A

SNRIs

A

Tricyclics and MAOIs

B

Mirtazapine

B

Trazodone (adjunctive)

I

Antipsychotics Atypical

B (adjunctive); I (monotherapy) – except risperidone

Risperidone

D

Typical

I

Benzodiazepines

D

Non-benzodiazepine hypnotics

I

Anti-adrenergic agents Prazosin

B (for sleep/nightmares); C (for global PTSD)

Guanfacine

D

Clonidine

I

Buspirone

I

Bupropion

I

Gabapentin

I

Propranolol

I

Adapted from IOM 2013, “Returning home from Iraq and Afghanistan”; and VA/DoD 2010, “VA/DoD clinical practice guidelines for management of post-traumatic stress.” Legend: A = good evidence that intervention improves health outcomes B = fair evidence that intervention improves health outcomes, benefits outweigh risks

C = fair evidence that intervention improves health outcomes, benefits do not outweigh risks D = fair evidence that intervention is ineffective, risks outweigh benefits I = insufficient evidence to make a recommendation

The vast majority of randomized controlled trials (RCTs) on psychotherapies for PTSD have been performed on cognitive-behavioral therapy (CBT) modalities, which can be further sub-divided into exposure-based and predominantly cognitive techniques. These include prolonged exposure, cognitive processing therapy, stress inoculation training, and Eye Movement Desensitization and Reprocessing (EMDR). The current evidence from RCTs points towards the efficacy of these interventions in reducing PTSD symptoms and improving mood and functioning. Although other approaches that target interpersonal relationships or emotion regulation have also shown promise, based on the weight of available evidence, the VA/DoD has engaged in sustained efforts to promote prolonged exposure and cognitive processing therapy as firstline psychotherapy interventions for PTSD. Psychopharmacology also has a first-line role in the treatment of PTSD, according to the VA/DoD practice guidelines. The strongest evidence base exists for use of selective serotonin re-uptake inhibitors (SSRIs), particularly fluoxetine, paroxetine, and sertraline, and serotonin norepinephrine re-uptake inhibitors (SNRIs), particularly venlafaxine. Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and mirtazapine are also recommended as antidepressants. Atypical antipsychotics (except risperidone) and prazosin, an α 1 adrenergic blocker, are recommended as adjunctive treatments, but there is insufficient evidence to support their use as PTSD monotherapy. The VA/DoD recommends against the use of risperidone, benzodiazepines, guanfacine, and certain anticonvulsants (tiagabine, topiramate, and valproate) for PTSD, citing evidence that these agents demonstrate a potential for harm that outweighs benefits.

Traumatic Brain Injury Traumatic brain injury (TBI ) is a common cause of injury and death, with an estimated 1.5 million Americans sustaining a TBI each year, and one-third of yearly injury-related deaths attributable to TBI. Since the commencement of operations in Iraq and Afghanistan, the incidence and awareness of TBI has risen significantly. The majority of recent combat-related TBI is a result of blast injury (exposure to an explosion), although TBIs are frequently sustained in other contexts.

TBI is defined as a traumatically-induced brain insult that causes cerebral dysfunction. Clinical signs of TBI include a loss or alteration of consciousness, amnesia for events occurring immediately before or after the injury, and neurological deficits. Evidence for TBI is also assessed by brain imaging abnormalities. Symptoms are highly variable and may overlap with those from other medical and psychiatric conditions, making diagnosis difficult. Manifestations can be classified as physical, cognitive, and neuropsychiatric, with headache being reported most commonly; other symptoms include tinnitus, dizziness, memory impairment, inattention, anxiety, depression, impulsivity, and aggression. TBI ranges from mild to severe, with the majority of injuries being mild, also known as mild TBI (mTBI) or concussion. Because mTBI is both common and often under-recognized, the VA/DoD has issued clinical practice guidelines for this injury. The diagnosis of mTBI is made on the basis of the clinical interview and on the physical exam, including a thorough neurological evaluation. Imaging is commonly inconclusive and rarely needed in the assessment of mTBI. A multimodal treatment approach is emphasized by most guidelines, given the complex nature of TBI. Emphasis is placed on early education about the injury, early interventions, gradual resumption of work duties, and the development of supportive strategies to cope with the impact of TBI on activities of daily living. Although the evidence to support pharmacologic treatments for mTBI is limited, guidelines generally recommend symptom-based management, including the use of non-narcotic analgesics (e.g., acetaminophen and non-steroidal antiinflammatory agents) for headache; non-benzodiazepine sedative-hypnotics (e.g., trazodone and mirtazapine) for sleep disruption; and SSRIs for anxiety, irritability, and depression. The course of mTBI is usually time limited, with most patients recovering without long-term sequelae. However, a more variable course can be seen in certain populations, including those who have sustained prior TBI. For those who have a variety of persistent symptoms that requires intervention, care by an inter-disciplinary team (that might include physiatry, neurology, psychiatry, physical therapy, occupational therapy, speech and language therapy, audiology, and optometry) is recommended. Awareness and concurrent treatment of co-morbid conditions (such as depression, PTSD, and pain syndromes) is essential for optimal care. In addition, thinking broadly in terms of a differential diagnosis is important, as many symptoms of mTBI (e.g., cognitive impairment) can also be hallmarks of other conditions such as PTSD and depression.

Other Disorders Although PTSD and TBI have received widespread publicity and research attention as the “signature injuries” of the operations in Iraq and Afghanistan, other stress-related mental health problems are common in service members, and veterans and should be assessed and treated. Chief among these are major depressive disorder (MDD), substance-use disorders (SUDs), and anxiety-related conditions.

MDD In the general population, the most common adverse psychiatric outcome following trauma is depression, not PTSD. Although recent studies of MDD in the military are more limited than those on PTSD, one longitudinal assessment of mental health outcomes three to six months post-deployment to Iraq found that 10%-13% of service members screened positive for depression. Rates of comorbidity between depression and PTSD are high, and adequate treatment for depression as well as screening for associated suicidal ideation and behaviors helps to reduce morbidity and mortality.

SUDs Rates of substance misuse in the military have been found to be higher than those in the civilian population, with spikes in use after return from deployment and amongst veterans. Tobacco and alcohol use are most prevalent, likely owing to their legality, availability, and social sanction, but illicit substances and prescription medications, including pain medications, also have high rates of misuse. SUDs are associated with an increased risk of impulsive and high-risk behaviors in both civilian and military populations. Notably, there are prohibitions against substance misuse in the military, and referrals for treatment trigger automatic involvement of the chain of command. Such policies can lead to under-reporting and under-referral due to fear of repercussions, and clinicians should strive to maintain engagement with at-risk service members and veterans. Evidence-based treatment for SUDs encompass both psychotherapeutic (e.g., motivational interviewing, CBT) and psychopharmacologic (e.g., naltrexone, buprenorphine) modalities; depending on the severity and type of addiction, higher levels of care for achieving initial abstinence might be indicated. Alcoholics Anonymous is another resource for helping to support sobriety.

Suicide

Suicide has long been recognized as an outcome of concern in service members and veterans. Until the conflicts in Iraq and Afghanistan, the suicide rate in the military was lower than in civilians. The military suicide rate has climbed steadily and now exceeds the demographically-matched civilian suicide rate through all DoD service branches (e.g., rising from 9.0 per 100,000 in 2001 to 21.7 per 100,000 in 2009 within the United States Army). This has resulted in widespread concern about suicide as a public health problem in the military and in veterans, as well as the development of large-scale, ongoing research and prevention programs to mitigate its occurrence. The approach currently utilized in the assessment and management of suicidal ideation and behavior is similar for military and civilian populations. Because untreated mental illness is known to be a major risk factor for suicide in both populations, a large component of managing suicide risk involves the treatment of underlying psychiatric disorders. A history of suicide attempts is a robust predictor of suicide, but a completed suicide may occur without a history of attempts. Substance use and problematic interpersonal relationships also increase risk. For these reasons, treatment plans that specifically target suicidality as a syndrome above and beyond mental illness diagnoses are necessary. The development of a safety plan, a prioritized list of strategies and resources to cope with periods of increased vulnerability, has been protocolized by the VA for the management of suicidal ideation and behaviors. Although the VA and DoD have implemented an array of suicide prevention programs, such efforts have yet to be standardized and coordinated across the military programs. Moreover, there is no validated and widely accepted suicide screening tool for use in the military or civilian populations. Although the VA has implemented mandatory suicide screening assessments, independent workgroups have raised concerns that such practices, which go beyond the evidence base, may be time-consuming and stigmatizing. The design of effective suicide prevention efforts, therefore, continues to be a work in progress. There is compelling evidence that restricting access to lethal means is one of the few policies, along with educating physicians about the recognition and treatment of depression, with demonstrable effectiveness in suicide prevention. This finding is especially relevant for the military and veteran populations, in which access to and possession of firearms is not only common but is often required for duty. Among service members and veterans, firearms are the leading lethal means of suicide, and a recent DoD report showed that more suicides occur using non-military-issue firearms than using military-issue firearms. This

data supports the benefit of temporarily restricting access to lethal weapons in the acutely suicidal service member or veteran, with attention to both militaryowned and privately owned firearms.

Building Resilience The lengthy conflicts in Iraq and Afghanistan have tested the resilience (defined as the capacity to adapt to risk and adversity) of military service members and their families. In an effort to aid the DoD in the understanding and enhancement of resilience in the military, the Research and Development Corporation (RAND) conducted an extensive literature review in 2011 that summarized the resilience mechanisms used in various resilience training programs (including the Army Center for Enhanced Performance [ACEP], Operational Stress Control and Readiness [OSCAR ], the Marine Resiliency Study [MRS ], the Penn Resilience Program [PRP ], and the Warrior Resiliency Program [WRP ], among others). In this review, they identified several factors that were suggested to promote resilience at the individual, family, unit, and community levels. At the individual level, positive coping (teaching military members and their families skills to deal with the stress of deployment and returning home), positive affect (mainly by utilizing CBT techniques to challenge negative thoughts), realism (focused on mind–body self-regulation of stress), behavioral control skills (based on emotion regulation and self-discovery), physical fitness (including sleep, nutrition, and health), and altruism (through spiritual training and self-awareness) were identified as resilience-promoting factors. Family-level factors included emotional ties (family education about deployment, group support and emphasis on family support during deployment), family communication (encouraging sharing of feelings among family members and promoting communication as a tool for resilience), family support (including peer support and volunteer programs), family closeness (promoting family activity and building trust, love, and intimacy in families), family nurturing (providing parental skills in a positive environment), and family adaptability (encouraging flexibility and teaching families to function despite deployment). At the unit level, beneficial factors included positive command climate (teaching leaders to be more open to feedback from their unit members and to be more aware of their own feelings and the feelings of those around them), teamwork (enhancing the presence of mental health providers and other members of the resilience team among the troops for early detection and

prevention of mental health problems), and unit cohesion (promoting sharing of feelings among soldiers, thus preparing them for deployment and the rigors of combat). Community-level factors included community cohesion (by bringing programs to military families and their communities to aid during predeployment and deployment), community connectedness (enhancing the quality and number of connections between veterans and their communities), and collective efficacy (based on the principle that individual well-being impacts overall performance). The success of resilience programs remains controversial. The Institute of Medicine has found no generally accepted, comprehensive set of measures to assess structure, process, and outcomes in resilience, prevention, and reintegration programming, which increases the difficulty of conducting a rigorous, replicable study. The DoD is currently working toward the development of a unified definition of resilience and the creation of standardized measurement tools to improve the quality of future studies.

References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. Bui E, Kredlow MA, Charney MD, et al: Acute and chronic reactions to trauma. In: Fogel B, Greenberg DB eds.: Psychiatric Care of the Medical Patient , 3rd ed. New York: Oxford University Press; 2015. 3. Cozza SJ, Goldenberg MN, Ursano RJ, eds.: Care of Military Service Members, Veterans, and their Families . Washington, DC: American Psychiatric Publishing; 2014. 4. Department of Veterans Affairs and Department of Defense. VA/DoD Clinical Practice Guideline for Management of Concussion/Mild Traumatic Brain Injury (mTBI). 2009. 5. Department of Veterans Affairs and Department of Defense. VA/DoD Clinical Practice Guideline for Management of Post-traumatic Stress . 2010. 6. Hughes JH, Cameron F, Eldridge R, et al: Going to war does not have to hurt: preliminary findings from the British deployment to Iraq. Br J

Psychiatry. 2005; 186: 536–537. 7. Institute of Medicine. Returning home from Iraq and Afghanistan: assessment of readjustment needs of veterans, service members, and their families. Washington, DC: The National Academies Press . 2013. 8. Institute of Medicine. Treatment for Post-traumatic Stress Disorder in Military and Veteran Populations: Initial Assessment . Washington, DC: The National Academies Press. 2012. 9. MacDonald C, Chamberlain K, Long N, et al: Mental health, physical health, and stressors reported by New Zealand Defence Force peacekeepers: a longitudinal study. Mil Med . 1998; 163(7): 477–481. 10. Michel P-O, Lundin T, Larsson G: Stress reactions among Swedish peacekeeping soldiers serving in Bosnia: a longitudinal study. J Trauma Stress . 2003; 16(6): 589–593. 11. Milliken CS, Auchterlonie JL, Hoge CW: Longitudinal assessment of mental health problems among active and reserve component soldiers returning from the Iraq war. JAMA . 2007; 298(18): 2141–2148. 12. Nock MK, Deming CA, Fullerton CS, et al: Suicide among soldiers: a review of psychosocial risk and protective factors. Psychiatry . 2013; 76(2):97–125. 13. Prorokovic A, Cavka M, Cubela Adoric V: Psychosomatic and depressive symptoms in civilians, refugees, and soldiers: 1993-2004 longitudinal study in Croatia. Croat Med J . 2005; 46(2): 275–281. 14. Tanielian T, Jaycox LH, Adamson DM, et al: Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery . Santa Monica, CA: RAND Corporation; 2008. http://www.rand.org/pubs/monographs/MG720.html .

CHAPTER 85 Sports Psychiatry NICOLE DANFORTH, MD AND PETER NEWBERRY, MD

KEY POINTS Overview Sport psychiatry is an emerging and evolving field that aims to optimize the delivery of psychiatric services to athletes at all levels. There is no “athletic personality,” per se , but competitive athletes can be more apt to demonstrate traits of extraversion, narcissism, and perfectionism. The most prevalent disorders in competitive athletes at the college and elite level are eating disorders and substance use disorders. The Female Athlete Triad involves low energy availability, menstrual dysfunction/amenorrhea, and low bone mineral density. Anxiety and depressive disorders in athletes must be distinguished from other factors that might mimic these symptoms, such as “state anxiety trait” and “over-training syndrome” or “burnout.” Use of performance-enhancing drugs or “doping” can result in psychiatric side effects. Therapeutic use exemptions may be required for commonly-prescribed psychiatric medications when treating college-level and higher athletes. Side effects must be carefully considered to avoid having an unexpected effect on athletic performance or safety. There might be barriers to accessing talk therapy but these can be minimized by offering targeted, problem-based interventions. The sport psychiatrist might need to consider the priorities of the coach, team, and other players in addition the athlete patient; moreover, they can create a potential source of conflict of interest. Ongoing characterization of the prevalence of psychiatric conditions in athletes and associated evidence-based interventions will improve the delivery of care to this unique population.

Introduction

Sports psychiatry is an emerging and still evolving sub-specialty of general psychiatry. It can be defined as the assessment, diagnosis, and treatment of psychiatric symptoms and illnesses in patients who identify themselves primarily as athletes (including professional, Olympic, collegiate, and even school-aged athletes). Even though sports psychology and sports psychiatry share a common goal of performance enhancement, they differ in their approach; the sports psychologist typically focuses on thought processes and psychological skills (such as goalsetting, meditation, and visualization to attain peak performance), whereas the sports psychiatrist is aware of mental health issues unique to athletes and the assessment, diagnosis, and treatment of behavioral health symptoms is performed within the context of their sport.

Psychology of the Athlete No single personality profile distinguishes the athlete from the non-athlete. However, research supports the theory that there are characteristics that discriminate competitive athletes from non-athletes. The most common personality traits in athletes are extraversion, perfectionism, and narcissism. Research shows that professional athletes rate themselves higher in measures of self-esteem, sensation-seeking, and mental health than do amateur athletes, who in turn rate themselves higher in these categories than non-athletes. It is important for the sports psychiatrist to recognize the impact of past performances, outside pressures, and typical personality traits that can be a part of the athlete’s presentation because these will provide a context for diagnosis and treatment. For example, at an early age, elite athletes might develop a narrow focus on achievement and performance that can interfere with typical maturity and development; consequently, excellence in sports might not translate into interpersonal and psychological ability. The risk of early sports specialization, as with other similar restrictions of interests and experiences, include over-use injuries, “burnout” at a young age, and a lack of personal pleasure gained from the pursued activity. The elite athlete is often seen as famous or special, and can be at risk for receiving sub-optimal psychiatric care because of his or her VIP status. The risks associated with treating such VIPs for the sports psychiatrist include a distortion of professional boundaries as well as potential ethical breaches of confidentiality. In addition, the famous athlete can present as entitled, demanding, and unreasonable and can be challenging to treat. A sports psychiatrist functions

most effectively as part of a multi-disciplinary team of providers; such an approach can minimize complications.

Mental Illness in Athletes Elite athletes and even those who participate informally in sports are generally perceived as a resilient, fit, and healthy. Despite this association with health and achievement, it is evident that athletes are at a similar risk of developing mental health issues as those in the general population. Several studies have looked at the prevalence of psychiatric disorders in athletes; eating disorders and substance use disorders appear to be the best studied, and eating disorder not otherwise specified has the highest incidence. However, relatively common illnesses (such as depression, bipolar disorder, anxiety disorders, and attention deficit hyperactivity disorder [ADHD]) occur in athletes, with a frequency similar to that seen in the general population. In a sample of French high-level athletes, the prevalence of mental disorders was similar to the prevalence rates observed in the general population. In this study, 17% of the athletes met criteria for at least one current or recent (i.e., within the last 6 months) mental disorder, and the life-time prevalence rate was 25%. Women were 1.3 times more likely to have at least one mental disorder, and twice as likely to have two or more disorders. Another study of elite Australian athletes found that prevalence rates in the athletes were similar to those in community populations: 46% of 224 athletes had at least one disorder, with symptoms of depression being most commonly reported (27%). Of note, athletes who were dealing with injuries were more likely to have symptoms of depression and generalized anxiety disorder than non-injured athletes. Prevalence studies with athletes can be complicated by minimization of behavioral health symptoms, by a lack of awareness of coaches or trainers who spend significant time with athletes, and by a “be mentally tough” mind-set in this population. Similar to the general population, stigma around mental health issues can confound recognition of illness and delay treatment in athletes.

Mood Disorders Despite the well-established understanding that exercise has beneficial effects on physical and mental health, mood disorders affect athletes. It can be challenging to elicit symptoms that are not primarily physical from an athlete. When an elite athlete is injured or physically ill, their recovery can be closely

monitored and be openly discussed among fans and the media. In contrast, the emotional state of an athlete is often overlooked, and this makes identifying emotional or psychiatric illness more difficult. Like those in the general population who suffer from psychiatric symptoms, athletes are sensitive to being perceived as “weak” or vulnerable. Most research on prevalence that has investigated depression in athletes has been done with collegiate athletes. In a recent survey of 465 Division 1 athletes, nearly one in four college athletes reported “clinically relevant” levels of depressive symptoms, with nearly 30% of female athletes and 18% of male athletes reporting mood symptoms. Another cohort study, based on a pre-season team meetings survey of 257 NCAA athletes found that athletes who were female, freshman, or had self-reported pain had significantly increased odds of experiencing depressive symptoms. Athletes can have different risk factors for depression (such as increased stress about performance, injury, burnout or over-training, “choking” or competitive failure, or retirement); however, a mood disorder in an athlete might be wholly unrelated to their athletic involvement. Similar to the general population, athletes with a personal or family history of depression, female gender, substance use disorders, or a recent significant psychosocial stressor are at an elevated risk of developing a depressive disorder. Depression in an athlete can present in atypical ways. The typical depressive symptom of poor concentration can manifest as a “slump” in the depressed athlete, or, might present as a decreased interest in training or practice. An athlete suffering from depression might not present with classic symptoms, but instead can present with increased irritability, poor performance in practice and in competition, lack of enjoyment from competing, excessive self-criticism, or drug or alcohol use. Such symptoms can be mistaken as purely performancerelated issues. Thus, a sports psychiatrist must be alert to an athlete’s specific signs and symptoms of a mood disorder. Few studies of bipolar disorder in athletes exist, but they should be considered especially in the college-aged athlete who presents with an expansive mood and a grandiose sense of ability or performance. More severe bipolar illness can affect the training and competitive capacity of an athlete to the extent that he or she might be unable to sustain an elite level of performance.

Anxiety Disorders

Anxiety disorders have been minimally studied in athletes. Many athletes report “state anxiety,” which is a normal level of anticipation prior to a performance that does not generalize to having a negative impact on non-athletic pursuits. In a study that compared elite intercollegiate athletes to a sample of non-athlete peers, female athletes reported greater mean scores on measures of social anxiety and depressive symptoms than did male athletes and male and female non-athletes. In an American College Health Association study of 195,000 college students—including student athletes—nearly half of the female student-athlete respondents and 32% of male athletes reported experiencing “overwhelming anxiety” in the previous 12 months. Specific phobias and panic disorder have been minimally studied in athletes. The relationship between performance and anxiety is examined thoroughly in sports psychology studies, and it is likely that an athlete would be more open to discuss any “performance anxiety” than a generalized or social anxiety symptoms. Anxiety about performance is a common chief complaint for an athlete seeing a sports psychiatrist. The assessment should include whether this is a pervasive clinical symptom that is having a negative impact on the athlete’s overall functioning, or is a response to the pressures of performing at a high level. Anxiety can also be a complication of an injury as an athlete returns to competition, and managing distress symptoms can enable an athlete to make a smooth return to their pre-injury level of performance. An athlete might have a self-concept that depends upon skill and prowess, and as such can be at risk of increased anxiety and psychological distress when their athletic participation is impaired. Similarly, an injured athlete might experience anxiety related to uncertainty regarding their injury treatment, recovery, and worry about the possibility of losing a position on the team.

ADHD Attention deficit hyperactivity disorder (ADHD ) is a common neurodevelopmental disorder, with a prevalence of 3% to 6%. As a result, ADHD is common among college and professional athletes, and some anecdotal reports suggest that it might be even more prevalent in athletes than non-athletes. This might be because the athletes with ADHD might be drawn to playing sports as a means of coping with their disorder, and that they find success with physical activity more so than with sedentary pursuits.

The athlete with ADHD might find certain aspects of training and competing more challenging than the non-ADHD afflicted athlete. For example, athletes with ADHD might be less able to follow game rules or to abide by strict practice guidelines, or a young athlete might be characterized by a coach as disruptive and a behavioral problem. Stimulants, the most widely accepted treatment for ADHD, can be a problematic intervention for the athlete. Stimulants are considered performanceenhancing drugs (PEDs) and their use at the professional, Olympic, and NCAA level is allowed only via a therapeutic use exemption (TUE). There is some concern that such extra steps needed to obtain appropriate treatment for a condition can serve as a barrier to seeking adequate treatment and also contribute to the stigma surrounding mental health issues.

Eating Disorders Eating disorders (including anorexia nervosa [AN], bulimia nervosa [BN], binge-eating disorder and eating disorder not otherwise specified [ED NOS]) are the most studied psychiatric illnesses in athletes. Athletes are at a greater risk of developing these illnesses than are those in the general population, and this is true for both men and women. It is especially true for athletes who participate in sports that emphasize leanness or where low body weight confers a competitive advantage. It might be that certain traits (such as intense drive, perfectionism, and an obsessional focus), which help an elite athlete attain excellence, are also frequently seen in patients with eating disorders; or perhaps possessing these pre-morbid traits predispose an individual to seek a more socially-sanctioned activity, such as sport. It is more common to see unhealthy attitudes toward body image, weight control, and nutrition, than to see athletes who meet full diagnostic criteria for an eating disorder. The most prevalent eating disorder among both athletes and nonathletes is ED NOS, and it can present in myriad ways, such as the athlete who becomes psychologically dependent on excessive training or the athlete who is rigidly obsessed with physiologic parameters (such as body fat percentage, caloric intake, and expenditure) at the expense of general health. At the college level, 32% of female varsity athletes responding to an anonymous survey reported engaging in weight-controlling behaviors (such as purging or laxative abuse) on a daily basis for at least one month. At the elite level, a study of Australian women athletes involved in different sports showed that AN or BN was present in 15% of those in leanness sports (gymnastics,

running, and figure skating) and 2% of non-lean sports, compared to 1% of controls. In a larger study that included 1,620 athletes and 1,696 controls who completed a questionnaire, interview, and clinical exam, 20% of female athletes met criteria for an eating disorder, compared to 9% of controls. A well-identified and serious consequence of drastic caloric restriction and/or over-training is the “Female Athlete Triad.” This constellation of symptoms includes low energy availability (caloric intake unable to keep up with demand), menstrual dysfunction or amenorrhea, and osteoporosis or low bone mineral density. Individual components of the triad are seen more often than all three. These athletes are prone to developing stress fractures, and can be at risk of developing cardiac problems, fertility issues, or irreversible bone loss. It is most often diagnosed in athletes who play sports that emphasize appearance or leanness. Eating behaviors in an athlete that shift from disciplined to pathologic can be a diagnostic challenge for providers. Careful assessment of personal and family history can be useful identifying those at risk of developing an eating disorder versus those with highly rigid eating habits. Those athletes at risk for developing an eating disorder include a family or personal history of disordered eating and chronic dieting, female gender, or a history of a mood or anxiety disorder. It is, however, important to note that both male and female athletes are at risk.

Substance Use Disorders According to the 2004 National Institute on Drug Abuse data, college-level athletes have similar trends of substance use to those in the general population. Alcohol is the most commonly-used substance among athletes with similar rates of use reported, ranging from 75% to 93% for men and 71% to 93% for women. Additionally, this survey noted higher alcohol use in the sports of swimming/diving, soccer, baseball, and softball in comparison to basketball, volleyball, and track. Student-athletes are at higher risk of binge drinking than their non-athlete peers, with one study reporting episodic heavy drinking rates of 25% to 50% for athletes, compared with 16% to 43% for non-athletes. A 2001 survey of nearly 14,000 NCAA athletes noted that use in the previous year of alcohol, cannabis, and smokeless tobacco was 85%, 28%, and 23%, respectively. Negative health and adverse athletic performances are problems for the substance-using athlete. College athletes report that alcohol is the agent that most negatively affects performance and health, and its harmful effects are cited two to three times more often than those for cigarettes, smokeless tobacco, or

marijuana. In addition, alcohol and other substances can affect performance by impairing sleep, increasing aggression, altering nutrition, and increasing highrisk or disinhibited behaviors (such as drinking and driving, gambling, or use of illicit drugs). The sports psychiatrist should be familiar with screening tools, such as the CRAFFT screen, and can amend the questions to bring the context of performance to the athlete. For example, the screening question “Have you ever gotten into trouble while you are using alcohol or drugs?” could be asked as, “Have you ever had trouble meeting performance or competitive goals while you are using alcohol or drugs?” Other valid screens for substance use include the BSTAD and S2B1.

Doping/Use of Performance Enhancing Drugs Professional and other elite athletes use some substances, in particular those that have real or perceived positive effects on performance, at higher rates than non-athletes. PEDs include anabolic steroids, amphetamines, human growth hormone, and erythropoietin. Doping refers to the use of banned or illegal substances to improve athletic performance and it occurs at all levels of sport from Olympic to high school athletics. Doping is intended to gain a competitive advantage by increasing strength, speed, or endurance, or to hide (mask) the use of other PEDs. Athletes are randomly drug tested at varying intervals depending on the level of sport and the league or organization rules. Drug testing protocols test for both performance-enhancing substances as well as illegal drugs and prescription medications; the most common include anabolic agents or steroids, stimulants, beta-blockers, narcotic analgesics, street drugs (such as cannabis, cocaine, phencyclidine [PCP], club drugs, and opiates) and β 2-agonists. Specific sport associations and governing bodies maintain lists of banned substances for specific sports to guide clinical care. Consequences of PED use can include psychiatric symptoms. For example, hostility and aggression are well-established behavioral side effects of anabolic steroid use, and a 1994 study of 160 athletes concluded that 23% of anabolic steroid-users reported symptoms of mania, hypomania, or depression. An athlete might misuse a stimulant to gain focus, drive, and energy, but place himself or herself at risk for experiencing increased irritability, poor sleep, decreased appetite (and thus lower energy levels), and mood flattening. Banned substances frequently include medications that are prescribed by psychiatrists, such as stimulants and beta-blockers. If a prescription for one of

these medications is appropriate, a physician can obtain a therapeutic use exemption (TUE). A TUE is documentation of the athlete’s condition, including testing where appropriate, that the athlete’s condition merits treatment with the otherwise banned drug. Most professional and Olympic governing bodies, as well as the NCAA, allow for an athlete to obtain a TUE. There are some concerns that the antidepressant, bupropion, might be performance enhancing, and this agent is on the World Anti-Doping Agency’s Monitoring List; however, but at this time bupropion does not require a TUE. A provider should review the list of banned substances for the league or organization in which the athlete competes in (such as the NCAA) prior to prescribing any medication.

Injury and Recovery Issues Injury is part of playing sports, and a sports psychiatrist might be enlisted to manage recovery from a significant injury. Injured athletes can experience a psychological response to their injury that parallels symptoms of post-traumatic stress disorder (PTSD), especially when the injury poses a significant level of threat to the athlete’s identity and security. Such symptoms include avoidance (such as disconnecting from teammates or trying to stay away from the spot where the injury occurred); intrusive thoughts (such as re-experiencing or preoccupation with the injury); and hyper-arousal symptoms (including nightmares and anxiety). Effective management of injury recovery includes reclaiming identity in a manner not unlike a trauma survivor, in which the focus is on safety (predictable outcomes), adjustment (managing any associated limitations), and re-connection (restoration of self).

Treatment Issues: Pharmacotherapy The psychiatrist must be mindful that routine side effects can be significantly more disruptive to an athlete than a non-athlete. Sedation, tremor, and physiologic effects of psychotropic medications can have a significant effect on performance for those performing at an elite level. A slight tremor that generates no distress in one individual could create significant distress to a Division 1 basketball player shooting free throws. Lithium, effective for treatment of bipolar mood disorder and augmentation of antidepressant treatment, can cause fine tremor and can be a poor choice for athletes who are especially dependent on fine-motor control (such as golf, shooting sports, and archery). Additionally, adequate hydration for athletes on lithium is essential, especially in warm

climates or during warm months, to maintain therapeutic drug levels and to minimize the risk of lithium toxicity. Stimulants, a mainstay of ADHD treatment, have both pharmacologic and administrative concerns. The routine side effects of appetite suppression, rebound fatigue, sleep disturbance, and modest increase in heart rate and blood pressure are well known and can be easily monitored. The greatest complexity surrounding the use of stimulants is related to their performance-enhancing effects. An athlete treated with a stimulant will need a TUE. Typical toxicology screens for drugs of abuse will test positive for substances (such as amphetamine salts for ADHD or benzodiazepines for panic disorder) that otherwise have a sound basis for therapeutic use. Real or perceived concern about medication side effects can be barriers to providing adequate treatment for an athlete. The impact of the risk/benefit profile of a medication therapy can vary significantly by sport and participant. A comprehensive understanding of any proposed pharmacologic intervention and a candid, empathic dialog with the athlete/patient should allow for an effective collaboration.

Treatment Issues: Therapy Various treatment models of therapy are available to athletes, and it is important to note that while talk therapy is not traditional “sports psychology” the goal is to enhance an athlete’s level of functioning that may in turn improve performance. The sports psychiatrist should be familiar with terms associated with performance work, such as goal-setting, arousal-regulation, self-talk, and imagery; comfort using these terms can help build an alliance with the athlete in therapy and be useful tools within the therapy. Issues of confidentiality are common when doing therapy with athletes. Athletes might be reticent to disclose symptoms or issues due to concern regarding perceived or actual allegiances of the psychiatrist to the team, and clear boundaries and full transparency and reassurance about a patient’s confidentiality will lead to the most effective treatment. The goal in doing therapy with the athlete is to restore function promptly and effectively. Cognitive-behavioral therapy (CBT) is often appealing to athletes, because is it time-limited, manual-based, and focuses on specific goals. The goal of increasing awareness of possible barriers to success with brief supportive therapy has also been helpful to the athlete. Longer-term psychodynamic, individual or family therapy can be a challenge for active athletes because the

treatment can disturb beliefs or coping strategies and thus elicit vulnerability or a decrease in confidence that many athletes try to avoid.

Conclusion/Future Direction Sports psychiatry merges the standard clinical model of contemporary psychiatry with the unique considerations of the athlete-patient. Effective treatment of the athlete at all types and levels of sport demands specialized knowledge to deliver excellent care. As this relatively new specialty evolves, further characterization of illness prevalence and evidence-based models of treatment in the athletic community will be essential.

References 1. Gulliver A. Griffiths KM, Mackinnon A, et al: The mental health of Australian elite athletes. J Science and Med in Sport . 2015; 18(3): 255–261. 2. Hughes L, Leavey G: Setting the bar: athletes and vulnerability to mental illness. Br J Psychiatry . 2012; 200: 95–96. 3. Johnson L, et al: Monitoring the future National Survey Results on Drug Use, 1975–2004. Vol II. College Students and Adults Ages 19–45. 2005. 4. Joy E, Kussman A, Nattiv A: 2016 update on eating disorders in athletes: a comprehensive narrative review with a focus on clinical assessment and management. Br J Sports Med . 2016; 50: 154–162. 5. Kamm RL: Interviewing principles for the psychiatrically aware sports medicine physician. Clin in Sports Med . 2005; 24(4): 745–769. 6. McDuff D, Baron D: Substance use in athletics: a sports psychiatry perspective. Clin in Sports Med . 2005; 24(4): 885–897. 7. Meeusen R, Duclos M, Foster C, et al: Prevention, diagnosis, and treatment of the overtraining syndrome: joint consensus statement of the European College of Sport Science and the American College of Sports Medicine. Medicine and Science in Sports and Exercise . 2013; 45(1): 186–205. 8. O’Connell S, Manschreck TC: Playing through the pain: Psychiatric risks among athletes. Curr Psychiatry . 2012; 11(7): 16–20. 9. Reardon CL, Factor RM: Sport psychiatry. Sports Med . 2010: 40(11): 961–

980. 10. Roy-Byrne P, Craske MG, Sullivan G, et al: Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. JAMA . 2010; 303(19): 1921–1928. 11. Wolanin A, Gross M, Hong E: Depression in athletes: prevalence and risk factors. Current Sports Medicine Reports . 2015; 14(1): 56–60.

CHAPTER Global Mental Health: 86 Concepts and Personnel KAVITHA KOLAPPA, MD, MPH; SONALI SHARMA, MD, MSC; MELVYN FREEMAN, MA; GIUSEPPE RAVIOLA, MD, MPH; CARMEN MARTÍNEZ-VICIANA, MSC

KEY POINTS Overview Building capacity of local mental health-care providers is a critical aspect of strengthening mental-health care and closing the treatment gap globally. Training, sustained supervision, and service delivery are most successful when working within existing health infra-structure and with involvement from health leadership. Prior to the start of a training, conducting an informal needs assessment helps to understand the needs of trainees, and this knowledge should inform the training agenda. A variety of non-didactic techniques can be utilized to engage trainees effectively. Mental-health legislation must be rooted in a human rights framework, and the United Nations and World Health Organization have established key guidelines for policy-makers. Policy implementation relies on a range of stakeholders; obtaining buy-in from all stakeholders at the inception of a program facilitates its execution. Reduction of the use of restrictive hospital care settings, decentralization to community-based care networks as well as integration of mental health into primary-care services comprise key aims in the provision of mental-health programs around the globe. Non-governmental organizations that provide community-based mental-health services linked to existing primary-care systems can serve as effective partners for governments seeking to decentralize mental health care. Constraints faced in providing mental health-services in humanitarian crises include insecurity, migration of persons requiring services, remote management of programs, as well as difficulty finding specialized staff.

Psychoeducation groups in the community can raise awareness about the normal range of reactions expected after trauma and facilitate discussions about positive coping mechanisms and signs that warrant further care.

Introduction According to the 2013 Global Burden of Disease study , mental disorders causes an estimated 7% of all disability-adjusted life years (DALYs) and 21% of years lived with disability (YLDs) globally. Major depressive disorder has been found to be the single largest cause of YLDs in more than 50 countries and the second largest cause globally. Unfortunately, in spite of the well-documented burden of mental disorders, mental-health care remains under-resourced in developing areas. Financial resources allocated to, and human resources available for, mentalhealth services are inadequate globally. According to the 2014 Mental Health Atlas, government expenditures for mental-health services are relegated to less than $2 per capita in low- and middle-income countries, compared with close to $59 dollars per capita in high-income countries. Moreover, the vast majority of these resources are used for inpatient treatment and not for community-based services. Roughly 90% of public expenditures in lower-middle-income and 60% of public expenditures in upper-middle-income countries are used for mental hospitals, other inpatient or daycare, leaving only 10% and 40% of public funds for outpatient and primary care in lower-middle-income and upper-middleincome countries, respectively. Although there are on average more than 50 mental-health workers per 100,000 persons in high-income countries, there were less than 1 per 100,000 persons in the lowest income countries, slightly more than 3 per 100,000 persons in the lower-middle-income countries, and close to 16 per 100,000 persons in the upper-middle-income countries. When analysed by training level, this translates to 6.6 psychiatrists per 100,000 persons in high-income countries versus 0.1 in low income, 0.4 in lower-middle, and 1.2 in upper-middle-income countries. Furthermore, the availability of essential psychotropic medications in lowincome countries remains poor. According to the 2009 WHO Assessment Instrument for Mental Health Systems (AIMS ) report of 42 low- and middleincome countries, essential psychiatric medications were available in all primary health clinics in only 40% of upper-middle-income countries and 15% of lowincome countries surveyed.

A recently-released economic analysis by the World Health Organization (WHO) found that treatment of mental disorders, specifically depression and anxiety, would have a four-fold cost–benefit for every dollar invested in treatment. The chasm between those who need treatment and those who actually receive it must be addressed in multiple spheres (e.g., policy, programmatic, and clinical settings) and be rooted in a framework that guarantees human rights. In each of these spheres, decision-making based on best available evidence is critical, as well as an appreciation of the nuances in culture, language, and practices. In this chapter, we introduce key concepts and personnel in global mental health. First, we discuss training priorities in capacity-building efforts in low and middle-income countries. We also discuss the importance of mental-health legislation and policies, with a spotlight on South Africa. We then discuss the importance of decentralization of mental-health services and an innovative care model developed by Partners In Health. Lastly, we highlight the mental-health needs of populations affected by humanitarian crises from the perspective of Médecins Sans Frontières .

Capacity-Building in Global Mental Health: Training Priorities A critical aspect of strengthening mental-health care and closing the treatment gap around the world is building the capacity of mental-health providers in under-served areas. Educational efforts to convert knowledge into meaningful practices must be adaptable to the local context. Each training experience brings its own set of characteristics, needs, and challenges, which should inform and shape the nature of the training. Mental-health programs require participation of both medical and non-medical providers at multiple levels (i.e., community, primary, secondary, and tertiary levels). Therefore, trainings must be adapted across disciplines, across various levels of the health care system, and often across sectors. Communicating in a way that is fluid and understandable to all is key, especially with regard to all types of cultures and ethnic backgrounds. When planning trainings, the use of existing, validated training materials that have been tested across various contexts is highly recommend. The WHO has developed a set of training tools for the integration of mental health in primary care and non-specialist settings via the mhGAP (mental health Gap Action

Programme ). The mhGAP Intervention Guide, which has been translated into six languages, was designed to train non-specialists in mental health, neurological problems, and substance-use care. Other useful training materials have been developed by non-governmental organizations, such as Médecins Sans Frontières , Basic Needs, and International Federation of Red Cross and Red Crescent Societies. Another popular manual aimed for non-specialists, published via the Royal College of Psychiatrists, is “Where There is No Psychiatrist .” Sustainability should be taken into account when planning trainings. Trainings are most successful when they are embedded into a larger, comprehensive public mental-health approach, working within an existing health infra-structure, and with involvement from health leadership. Each training experience differs with respect to the local context, and as such flexibility and adaptability are key. Working in partnership with local health leaders and providers cannot be underestimated, as for trainings to be relevant, they must be conducted with an understanding of local context, health system, and cultural beliefs. Prior to the start of a training, an informal needs assessment should be conducted to understand the needs of trainees; this knowledge can inform the training agenda. A pre-test is recommended to determine the baseline level of knowledge, with post-test assessments of the training to measure effectiveness. Further, it is important to check-in with your team each day to ensure that the needs of the trainees are being met. If not, the program should be modified to the extent possible. Clinicians should ensure that the training is culturally relevant. Various training methods can be utilized to engage trainees effectively. Nondidactic techniques (e.g., brainstorming, group exercises, small group discussions, case-based learning, individual presentations and role-plays) can be more effective in engaging and empowering participants and solidifying knowledge than traditional lectures. Utilizing multiple teaching techniques will enhance the integration of knowledge into clinical practice. At the end of a training session, group participation in a collaborative process is recommended to develop a training action plan to ensure that learning extends beyond the initial training. Also critical are refresher training sessions, on-site clinical supervision, as well as other resources and supports (including distance supervision if possible, as well as access to journals and on-line supports) to ensure maximum impact of training sessions.

Mental Health Policies and Legislation: Spotlight on

South Africa Mental-health legislation must be rooted in a human-rights framework, and the United Nations (UN) and the WHO have established guidelines toward this end. In 1991, the UN General Assembly adopted the Principles for the Protection of Persons with Mental Illness and the Improvement of Mental Health Care. The subsequent WHO Resource Book on Mental Health and its Checklist on Mental Health Legislation, published in 2005, serve as a guide for policy makers by outlining practical components of, and standards for, responsible mental health legislation, as well as safeguards to prevent abuses. Further, the UN General Assembly adopted the UN Convention on the Rights of Persons with Disabilities in 2006, which brought the human rights of all persons with disabilities (including psychosocial disabilities) to the fore. A core tenet of responsible mental-health policy and legislation is inclusivity and accountability. Policy implementation relies on having a range of stakeholders; having buy-in from all stakeholders from the outset facilitates its execution. Negotiations in all-inclusive policy processes include two key aspects. First, differences of opinion or interests between stakeholders must be reconciled. For example, this might involve considering varying perspectives on the appropriateness of involuntary treatment and under which circumstances. This is a crucial debate to have, considering the large number of human rights abuses that are faced by persons with mental illness (often at the hands of the health system). Secondly, the aspirational objectives of stakeholders should be tempered by the very real financial and human resource constraints faced in many low- and middle-income countries. Here, we focus on the experience of South Africa. Inclusive and accountable policy/legislation development is a goal to which South Africa aspires. In 2012, the Minister of Health of South Africa, Dr. Aaron Motsoaledi, called for a consultative process that would receive inputs for a new mental health policy. To this end, consultative conferences were held in all nine provinces of South Africa, culminating in a National Mental Health Summit. Meetings at both the provincial and national level were attended by representatives from a broad range of stakeholders, including mental-health users, clinicians, researchers, academics, professional associations, statutory health institutions, the private sector, as well as members of the Department of Health in South Africa and the WHO.

In the interest of ensuring that the new policy would be based on reliable information, research was conducted on the prevalence of mental disorders and the existence of baseline services, which provided information on the social determinants of mental health in the country. This research was presented at the National Mental Health Summit. In addition, key talks were presented, including those by the South African Human Rights Commission, to ensure that the policy would safeguard the human rights of persons with mental disabilities. This process yielded eight “catalytic” objectives that would need to be achieved and were subsequently captured in the National Mental Health Policy Framework and Strategic Plan (2013–2020). The objectives were as follows: Develop district mental health teams as part of primary health-care reengineering Build institutional capacity at different levels of the health system Improve surveillance, research, and innovation Improve infrastructure and capacity of facilities Ensure mental-health technology, equipment, and medicines Ensure inter-sectoral collaboration Increase human resource capacity for mental health Increase advocacy, mental-health promotion, and the prevention of mental illness In the service of these objectives, the Strategic Plan established timelines and assigned responsible organizations and personnel. In the process of delineating the Strategic Plan, various stakeholders were united in working toward agreedupon targets. Although much progress has been made to implement this policy in recent years, significantly more efforts are still needed to meet the 2020 targets. In implementing mental-health legislation, it is important to evaluate progress, assess existing legislation, and adjust/update the plans as needed. Following the Summit, the Minister of Health formed a Ministerial Advisory Committee comprising a range of stakeholders to inform the Department of Health about the progress made toward the realization of the Policy Framework, as well as the difficulties experienced in achieving the objectives.

Integration of Mental Health into Primary Care:

Spotlight on Partners In Health Reduction of the use of restrictive hospital care settings, decentralization of community-based care networks linked to government-run district hospitals, as well as integration of mental-health into primary-care services, comprise key aims in the provision of mental health programs globally. Non-governmental organizations that provide community-based mental-health services linked to existing primary-care systems can serve as effective partners for governments seeking to decentralize mental-health care. In this section, we consider the innovative work of Partners In Health (PIH ) in the provision of mental-health care in low- and middle-income nations. PIH is an international health-care delivery organization working in 10 countries around the globe. Since 2010, PIH has increasingly supported the development of community-based models of mental-health care. A cross-site mental-health program supports local teams, which develop safe, effective, and culturally-relevant mental-health services that are focused on the alignment of service delivery, training, and implementation-focused research. Services provided seek to combine contemporary biopsychosocial approaches as well as strong traditional perceptions and beliefs. Considering limited resources and well-known co-morbidities between mental illness and other diseases (e.g., HIV infection, tuberculosis, as well as non-communicable diseases) as well as poverty and exposure to violence more broadly, PIH programs seek to integrate mental-health services as a central part of primary-care packages across sites and systems. In Haiti, for example, in the aftermath of the 2010 earthquake, PIH mobilized an initial emergency response. Following that response, a qualitative assessment of local beliefs provided valuable information concerning the local acceptability of formal mental-health services, which led to the decision to prioritize depression as a condition around which a formal community-based model of mental-health care could be created. This model built upon a pre-existing community-based health-delivery system that was focused on care for people living with HIV infection and tuberculosis. By 2012, PIH had developed a locally derived and validated depression screening tool, which was used in both initial screening and to track treatment progress. Over the next several years, PIH piloted a depression care system that included services delivered by nonspecialists. Informed in part by the WHO’s aforementioned mhGAP Intervention Guide, context-specific training materials were further developed and adapted

for use by various levels of the health-care system—physicians, nurses, community health workers, and a small cadre of psychologists. A collaborative, stepped-care delivery model evolved that included triage pathways for mildly or moderately ill persons to receive home-based support from community health workers and for severely-ill persons to receive medications from trained physicians, and psychotherapeutic support from psychologists trained in a locally-adapted curriculum of interpersonal therapy (IPT). Care pathways were subsequently added for psychotic disorders, epilepsy, and child and adolescent mental-health problems. Through more formal research, school-based care pathways that engaged teachers were also developed. Systems for sustained clinical supervision, ongoing monitoring and evaluation of clinical and functioning outcomes as well as qualitative data collection to understand service user and caregiver experience were established and iteratively improved. Between 2013 and 2015, PIH recorded more than 10,000 patient visits in primary-care settings in rural Haiti. Ongoing efforts have included improvements to training curricula and supervisory systems, efforts to ensure a consistent supply chain of medications, integration of electronic medical record (EMR) systems, as well as utilization of mobile-health technologies. PIH is also working with the Ministry of Health and the Pan-American Health Organization toward national mental-health planning efforts to continue to make the best use of funds and resources following the 2010 earthquake.

Mental Health in Humanitarian Emergencies: Spotlight on Médecins Sans Frontières Mental health needs are often neglected during humanitarian crises, as funding and services are initially focused on the stabilization of the community in terms of safety, security, and tending to physical injuries. In the aftermath of humanitarian crises, however, the complex psychosocial needs of the affected population must be addressed. Here we will consider the ground-breaking work of Médecins Sans Frontières (MSF ). MSF is an international medical humanitarian organization that provides care to populations in distress, victims of natural and human-caused disasters, and victims of armed conflict (regardless of race, religion, or political beliefs). MSF has been providing medical humanitarian care for more than 40 years and it currently runs nearly 400 projects in 65 countries around the world.

MSF considers interventions for mental-health problems and disorders as a primary objective in many contexts. Mental health and psychosocial support (MHPSS) is necessary during acute and chronic crises, as an integrated component of medical care. Although efforts have been made to take mental health into consideration more broadly in the field of humanitarian work, it can still be challenging to address mental health needs from the beginning of a crisis. Constraints faced in the field include insecurity, migration of persons requiring services, remote management of programs, difficulty finding psychiatrists, psychologists, and other specialized staff, as well as limitations in evidencebased practices in humanitarian contexts. During acute emergencies, basic mental-health services can be implemented while a more extensive exploratory phase is begun. Although MSF already has much experience studying the mental-health impacts of multiple crises, a needs assessment is of paramount importance to better analyze the local context, the consequences of the particular emergency, and to adapt the overall strategy accordingly. Moreover, understanding the population’s mental-health cultural beliefs and health-seeking behaviors, including traditional healing practices and community support/coping structures, is necessary for development of a relevant MHPSS program. In this regard, it is crucial to work with members of the community to understand the results of any assessments. According to the local context and results of the needs assessment, MSF then decides how extensive a program to implement. Medical staff are trained in skills to provide mental-health care within primary health care consultations, including psychological First Aid, basic counseling, and the use of psychotropic medications. This requires regular training and supervision for medical staff, which can be difficult to do during emergencies. MSF focuses on enhancing the capacity of general health staff to identify signs and symptoms of mental distress. Unfortunately, a large proportion of the people affected by humanitarian crises who experience psychosocial difficulties do not obtain medical consultation. Community-based activities are therefore a key strategy in raising awareness about the importance of mental health, distress, and disorders. MSF works within the community to identify formal and informal leaders, to increase access to the general population, as well as to identify groups that may be especially vulnerable. Psychoeducation groups in the community can raise awareness about the normal range of reactions likely to arise after traumatizing events, as well as discuss positive coping mechanisms and signs that warrant further care.

Additionally, MSF seeks to train community health workers from within the community, as this avoids cultural distance and language barriers. Community health workers are trained to provide psychological First Aid and counseling. For persons who suffer from more severe illness, there is a referral system to receive specialized care (from psychiatrists and psychologists). A reality of working with a population that may be in transit (or displaced), as well as with people who live in remote areas, is that follow-up sessions might not be possible. For this reason, MSF has developed a strategy of psychological “single sessions” to reduce the risk of harmful practices and in an attempt to provide the best possible alternative when regular care is not practical. MSF programs employ a holistic approach of clinical care and community-based activities, with triaged services to meet a population’s needs as much as possible in the face of constraints imposed by humanitarian crises.

Suggested References

1. Barbui C, Chattherjee S: Improving access to medicines for mental disorders in low-resource settings: some achievements but still a long road ahead. Epidemiol Psychiatr Sci . 2016 Feb; 25(1): 1–3. 2. Chisholm D, Sweeny K, Sheehan P, et al: Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet . 2016 April E-pub; 3(5): 415–424. 3. Freeman M, Pathare S: WHO Resource Book on Mental Health, Human Rights and Legislation. Geneva: World Health Organization; 2005. 4. Hansen P, Ager W, et al: Psychosocial Interventions: a Handbook. International Federation of Red Cross and Red Crescent Societies Reference Center for Psychosocial Support. Available from: http://psp.drk.dk/graphics/2003referencecenter/Docman/Documents/docs/Psychosocial%20interventions%20A%20handbook%20LowRes.pd . 5. Lee P, Kolappa K, Raviola G: Global health and behavioral medicine . Behavioral Medicine. ed. Feldman MD, Christensen JF, Satterfield JM. McGraw-Hill Education, 2014; Print. 6. Mental Health Atlas 2014. Geneva: World Health Organization, 2015. Available from:

7.

8.

9.

10.

11. 12.

13.

http://apps.who.int/iris/bitstream/10665/178879/1/9789241565011_eng.pdf? ua=1&ua=1 . Mental health systems in selected low- and middle-income countries: a WHO-AIMS cross-national analysis. Geneva: World Health Organization, 2009. Available from: http://www.who.int/mental_health/evidence/who_aims_report_final.pdf . mhGAP intervention guide for mental, neurological and substance use disorders in non-specialized health settings: Mental Health Gap Action Programme (mhGAP). Geneva: World Health Organization, 2010. Available from: http://apps.who.int/iris/bitstream/10665/44406/1/9789241548069_eng.pdf . Murray C, et al: GBD 2013 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015 Nov 28; 38(10009): 2145–2191. Patel V, Chisholm D, Dua T, et al, eds.: 2015. Mental, Neurological, and Substance Use Disorders. Disease Control Priorities . 3rd ed. Volume 4. Washington, DC: World Bank; 2015. doi: 10.1596/978-1-4648-0426-7. Patel V: Where there is no psychiatrist: A mental health care manual . London: Royal College of Psychiatrists; 2003. Raja S, Magnusdottir E: Mental Health Care: An Introductory Manual for Training General Health Personnel. Basic Needs; 2012. Available from: http://www.basicneeds.org/download/_impact_in_the_field,_transferability_of_the_basic up/PUB%20-%20MentalHealthCareAnIntroductoryManualForTrainingGeneralHealthPersonnel.pdf . Vos T, et al: Global Burden of Disease Study Collaborators. Global, regional, and national incidence, prevalence , and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systemic analysis for the Global Burden of Disease Study 2013. Lancet . 2015 Aug 22; 386(9995): 743–800.

CHAPTER Quality Assurance and 87 Quality Improvement NICOLE M. BENSON, MD AND JOHN B. TAYLOR, MD, MBA

KEY POINTS Overview Quality improvement (QI) in medicine is a system for modifying a process or system to improve patient outcomes. QI is typically accomplished by reviewing a system, pro-actively designing a process improvement, and measuring whether outcomes change with implementation. Quality assurance (QA) in medicine is a system for monitoring quality of care to ensure that a set of standards is being met. QA is typically accomplished with retrospective review of processes, procedures, and patient outcomes. QA can be perceived as punitive and can elicit fear or resentment from health-care providers, whereas QI is designed to focus on process improvement without placing blame on any one person. Donabedian Triad Classification System Physician and researcher Avedis Donabedian developed a classification system containing three categories: structure of the health-care facility (including equipment and human resources, and organization structure); process of care (from diagnosis to treatment); and outcome of care (for the patient and population health). Institute of Medicine Report: To Err is Human, 1999 This landmark report revealed that 44,000 people in the United States were dying every year from preventable medical errors in hospitals. Institute of Medicine Report Crossing the Quality Chasm, 2001 This report insisted that large-scale change was needed across the board to diminish medical errors. The report stressed that changes should involve health-care professionals, policy makers, regulators, purchasers of care, and patients.

The Institute of Medicine outlined six aims for improvement: health care must be safe, effective, patient-centered, timely, efficient, and equitable. National Efforts in QA/QI Over the past two decades, patient safety organizations, such as the Institute for Healthcare Improvement, the National Patient Safety Foundation, and the Leapfrog Group, have been formed to develop patient safety programs and advocate for patient safety. The Institute for Healthcare Improvement coined the term Triple Aim , an approach intended to decrease variability in care and to develop practice guidelines, preferably with automated implementation. Bohmer identified four key characteristics prevalent in high-value health-care organizations: – Specification and planning: Criteria are used to establish standards of practice and decision-support tools are used to assist with the implementation of these standards – Infrastructure design: Specialized facilities and staff are matched with appropriate sub-populations of patients – Measurement and oversight: Outcomes are assessed, often by external entities, including payers – Self-study: Clinical care is examined to determine how closely the standards are followed Identifying a QI Goal The first step in improving quality is selecting a deficiency. The problem can be identified in a variety of ways, including after a particular incident, in response to personnel concerns, or when new guidelines and protocols are introduced. SMART Aim Statement The SMART Aim statement outlines a process to address a particular quality change, by specifying relevant criteria to be considered before a QI plan is implemented. The key components are that it is specific, measurable, achievable, relevant, and timely. Using Root Cause Analysis to Investigate an Adverse Event The primary objective is to identify deficits in the systems that might have led to the outcome of interest and to find possible solutions to prevent such events

from occurring again. Using Fishbone Diagrams to Outline Components of Care The fishbone diagram (also known as Ishikawa diagram or herringbone diagram ) visually depicts the key components that can contribute to an unwanted outcome in a diagram that looks like a fish skeleton. The key components often include some or all of the following: equipment or supply; process; personnel; materials; environment; and, rules, policies, and procedures. Quality Measures Process measures assess the extent to which health-care providers adhere to evidence-based guidelines and practices. Outcome measures assesses the clinical status of a patient following a particular intervention or encounter with the health-care system by attempting to assess whether a particular intervention or aspect of the care provided affected the outcome. The Plan-Do-Study-Act Cycle Plan-Do-Study-Act (PDSA) is a method used to structure QI initiatives that is similar to a scientific investigation, except that these processes continue to evolve and change during the course of QI attempts. The first step is to develop a plan and consider the likely outcome (hypothesis). The next step, do , is to carry out the plan and collect data. The study step of the project follows, which involves analysis of the data and summary of the findings (results). The last phase is act , which utilizes the results to identify those changes that were successful and to point to other changes that can be implemented in the next PDSA cycle for further QI.

Introduction Quality improvement (QI ) in medicine is a system for modifying a process or system to improve patient outcomes. QI is typically accomplished by reviewing a system, pro-actively designing a process improvement, and measuring whether outcomes change with implementation. Quality assurance (QA) in medicine is a system for monitoring quality of care to ensure that a set of standards is being met. QA is typically accomplished with retrospective review of processes,

procedures, and patient outcomes. QA can be perceived as punitive and can elicit fear or resentment from health-care providers, whereas QI is designed to focus on process improvement without placing blame on any one person. This chapter explores the history of QI and QA in medicine and their roles in medical practice today.

Background Efforts toward QI in medicine can be observed as early as the 19th century when Ignaz Semmelweiss fought for the implementation of hand washing prior to obstetrical procedures to reduce maternal mortality. Adoption by peers was slow and other QI initiatives in medicine were developed infrequently over the course of the following century. Since the Industrial Revolution, near the turn of the 19th century, QA and QI have played an important role in manufacturing, such as in the automobile industry to streamline the production of automobile parts without defects, in the mining industry for the safety of workers, and in the aviation industry to prevent accidents. In systems engineering, an extremely successful process known as Six Sigma was developed for manufacturing in the 1980s to identify and address causes of defects with the ultimate goals of eliminating all defects and minimizing variability. The system is now used by many large corporations and has been credited with improving safety, product quality, and efficiency, while saving companies large sums of money. As the value of QI and QA was recognized in many industries, attempts were made to apply the principles and techniques to the medical industry. Beginning in the 1960s, with passage of legislation in the United States Congress establishing Medicaid and Medicare, participating health-care facilities were required to meet certain standards of practice for those patients receiving care. Over the ensuing 10 years, as part of their participation, facilities were required to form Utilization Review committees to ensure that appropriate services were being provided. In parallel with Congress’s efforts, the Joint Commission for the Accreditation of Hospitals was established and, as part of the accreditation process, defined minimum quality standards for health-care facilities, which required demonstration through periodic inspections. As the focus on assessing quality of care grew, a mechanism for measuring quality was needed. To address this need, physician and researcher Avedis Donabedian developed a classification system containing three categories: structure of the health-care facility, including equipment and human resources,

and organization structure; process of care from diagnosis to treatment; and outcome of care on the patient and population health. He advocated that quality be assessed in each of these three categories rather than isolated to a single process. As part of his triad, he stressed that patient satisfaction should be an indispensable part of assessing quality of care, foreshadowing the current emphasis on patient-centered medicine. Despite an increasing focus on quality of care, results did not follow. The Institute of Medicine (IOM) published the landmark report To Err Is Human in 1999, which revealed that in the United States, 44,000 people were dying every year from preventable medical errors in hospitals. Two years later, The IOM published a follow-up report, Crossing the Quality Chasm , which insisted that large-scale change was needed across the board to diminish medical errors. The report stressed that changes should involve health-care professionals, policy makers, regulators, purchasers of care, and patients. The IOM outlined six aims for improvement: health care must be safe , effective , patient-centered , timely , efficient , and equitable . With these new focuses, the expected results would be a safer health-care system, which would prevent injury to patients from care that was intended to help them. Care would be evidence-based and beneficial and would be respectful and responsive to patient needs. In the process, improvements would reduce waste, avoid lengthy wait times for patients, and promote consistent care regardless of patient characteristics, geographic location, or socioeconomic status. Since this report, attempts have been made to improve the quality of health care but the results continue to be disappointing in the United States. Despite spending a larger percentage of its annual gross domestic product on health care (17% now, projected to be 20% in 2020) than other developed nations, the United States continues to have worse outcomes in life expectancy, infant mortality, and maternal mortality. Across the country, health care has been shown to be variable and inconsistent, such that, in one report in 2003, McGlynn and colleagues found that only half of patients surveyed had received the recommended treatment for their basic health conditions. Improvements have been made, however, through QI and QA programs across the country. Some areas where this has been most successful in Medicine are targeted interventions to reduce catheter-related blood stream infections in intensive care units and the incorporation of check-lists in the operating room to reduce morbidity and mortality.

National Efforts in QI/QA Over the last two decades, patient safety organizations, such as the Institute for Healthcare Improvement, the National Patient Safety Foundation, and the Leapfrog Group, have been formed to develop patient safety programs and advocate for patient safety. These groups aim to reduce cost while improving population health care and improving the patient experience. The Institute for Healthcare Improvement has coined this approach the Triple Aim . The goals of these patient safety organizations are to decrease variability in care and to develop practice guidelines, preferably with automated implementation. Others have attempted to describe systems that are effective for improving quality so that these characteristics can be replicated more broadly. Bohmer identified four key characteristics prevalent in high-value health-care organizations: Specification and planning: Criteria are used to establish standards of practice and decision-support tools are used to assist with the implementation of these standards. Infrastructure design: Specialized facilities and staff are matched with appropriate sub-populations of patients. Measurement and oversight: Outcomes are assessed, often by external entities, including payers. Self-study: Clinical care is examined to determine how closely the standards are followed. Regardless of an organization’s resources, structure, and function, these four principles were strongly evident in those organizations with high-value health care.

Overview of Improving Quality When deciding how to improve quality, the first step is to determine where there is a need to improve quality of care. The next step is to determine what changes should be made to improve the process. After a potential change has been identified, careful planning is necessary to implement the new practice. Following implementation, results must be assessed using process or outcome measures. Finally, processes should be modified if necessary, and then implemented broadly if the changes achieved the desired outcome.

Identifying a QI Goal The first step in improving quality is selecting a deficiency. The problem can be identified in a variety of ways, including after a particular incident, in response to personnel concerns, or when new guidelines and protocols are introduced. The quality issue at hand will dictate the proposed changes. Building on the IOM’s six aims for health-care improvement, a system was developed for outlining a process to address a particular quality change, termed the SMART Aim Statement . This statement outlines in detail how to implement quality improvement by specifying relevant criteria to be considered before a QI plan is implemented. The key components of the SMART Aim Statement are that it is: Specific: Aims should be clear and well defined, including identifying staff and personnel who will need to be involved in the process. Measureable: Goals should be quantifiable, with a specified target and with available resources to collect and analyze data. Achievable: The target must be attainable, including having the resources to make the change. Relevant: Aims should be pertinent to the institution and personnel. Timely: The target or aim should be built around a time-frame that is reasonable for the particular project selected. These principles are critical to a successful QI initiative because they provide a framework for stakeholders and institutions. By explicitly identifying the aim of a project with goals that are measurable and achievable, the success or failure of a project can be determined during a specified period. An example of an aim statement might be one that attempts to reduce medical errors that result from signout and might read, “By January 2020, 50% of signouts or handoffs at Massachusetts General Hospital will be conducted using I-PASS.”

Planning Change for QI There are a variety of tools that can be employed for QI projects. One such tool is process mapping. A process map provides a visual outline of the steps that are taken, and the personnel who take them, to reach a particular outcome. Process maps were originally used in engineering but have been adapted in the medical

industry to identify areas of inefficiency or possible sources for errors. QI is accomplished by addressing specific areas along the process map. Root cause analysis is a process used to investigate and analyze what occurred leading up to a serious adverse event. The adverse event is sometimes called a sentinel event. The analysis is typically comprehensive and exhaustive, identifying any possible relevant details that might have contributed to the event. The primary objective is to identify deficits in the systems that might have led to the outcome of interest and to find possible solutions to prevent such events from recurring. Several important elements are key to the success of a root cause analysis: it should be conducted with an inter-disciplinary team, including as many personnel involved in the incident as possible, and focus primarily on the process rather than the final summary. Those who perform root cause analyses have pointed to the Swiss Cheese Model of James Reason, which was developed based on studies of accident investigations in several fields including nuclear power and aviation. The model shows that errors can occur with devastating results even when there are several layers of protection because the layers might be incomplete or have holes in them, like Swiss cheese, allowing mistakes to slip through. The focus of the model for medical errors is to have multiple layers each with smaller holes to decrease the chance that an error will slip through all of the layers at one time. The root cause analysis of this type of model looks at each layer to understand where the deficit might have occurred. One of the tools for gathering the data regarding the root cause of an event is the fishbone diagram (also known as Ishikawa diagram or herringbone diagram ). This tool visually depicts in a diagram that looks like a fish skeleton the key components that can contribute to an unwanted outcome. The key components often include some or all of the following: equipment or supply; process; personnel; materials; environment; and, rules, policies, and procedures. By looking at each of these components, factors that could have contributed to the adverse event can be isolated. During a root cause analysis, a fishbone diagram might be used to investigate possible factors in each category that could potentially have contributed to the adverse event. Such tools keep the analysis directed toward systems and processes and away from placing blame in specific places or on specific people. Root cause analyses take the data collected and analyze it to identify the likely cause of the adverse event. From there, recommendations are developed to

address the deficit and are then implemented. Quality measures are used to determine the success of the change.

Quality Measures Quality measures can be categorized as process measures or outcome measures . Process measures assess the extent to which health-care providers adhere to evidence-based guidelines and practices. QI can be achieved when changes are made to clinical guidelines and subsequently adopted into practice. However, when procedures are changed with the goal of improving quality and process measures show excellent adherence to these changes, the assessment might not show whether quality of care has improved. An example of a process change was published by Thompson and associates from western Melbourne. This group instituted an initiative to improve compliance with metabolic screening prior to beginning antipsychotics for patients at a first episode psychosis clinic. The intervention included education for health-care providers, purchasing of monitoring equipment, a check-list with prompts, and reminders from clinician leaders. Eighteen months after implementation, the rate of metabolic screening was significantly increased from less than 25% to greater than 80%. An outcome measure assesses the clinical status of a patient following a particular intervention or encounter with the health-care system by attempting to assess whether a particular intervention or aspect of the care provided affected the outcome. While outcome measures are key for assessing the quality of care, these types of measurements can be difficult to study. Factors inhibiting the collection and assessment of good outcome data include difficulty accounting for confounding medical conditions, a time lag in determining the outcome from the time of the intervention, and a change in the outcome depending on when the outcome is measured (e.g., one month versus 5 years after surgery). QI can be achieved by assessing outcomes from specific interventions to attempt to identify areas for improvement. For example, outcome measures were used to show that decreasing the time from entering the Emergency Department to a percutaneous coronary intervention in patients with acute myocardial infarctions decreased in-hospital mortality. This led to attempts to streamline the process, and involved systems and personnel from emergency services to cardiology to expedite patient care.

Implementing Change for QI

A variety of methods have been developed for implementing change in engineering and manufacturing that have been successfully adopted in health care, such as Six Sigma and Plan-Do-Study-Act (PDSA ). PDSA is a method used to structure QI initiatives that is similar to a scientific investigation, except that these processes continue to evolve and change during the course of QI attempts. The first step is to develop a plan and consider the likely outcome (hypothesis). The next step, do , is to carry out the plan and collect data, similar to the methods in a scientific study. Then, the study step of the project follows, which involves analysis of the data and summary of the findings (results). The last phase of this cycle is act , which utilizes the results to identify those changes that were successful and to point to other changes that can be implemented in the next PDSA cycle for further QI.

Maintaining Change To create lasting change, it is important to consider the culture of the institution and the stakeholders involved. The most successful initiatives are those in which the stakeholders are involved in the development and implementation of the changes. Unfortunately, it is often not practical to include all personnel involved. In addition, processes can evolve over time before the specifics of the steps for improvement are established, and during that time personnel might change. Lastly, many of those who have been in health care for a long time have developed resistance to change, providing yet another barrier to QI initiatives. Implementing change begins with disseminating the results of investigations that have identified deficiencies or inefficiencies, such as QI projects or root cause analyses, so that personnel understand the importance of the changes that need to be introduced. If at all possible, the changes should involve automation or computerized models to facilitate the adoption and continued use of the new procedures or practices and to reduce variability in application of the new processes. The next step in implementation is education and training of all personnel who might be involved in these changes. Lastly, the new practices need to be adopted widely across the institution through changes to policies and procedures. Several approaches help to promote permanent improvements to processes and overcome barriers to change. These fall into two categories: (1) rewards for QI and (2) negative consequences for failing to implement QI. A system of rewards that promotes QI might be one such as Meaningful Use. This federal program provides financial incentives for hospitals and health-care providers to

computerize their medical records and systems. It is based on the principle that computerized health records will decrease medical errors and improve patient care. Another example is Pay for Performance Programs, which pay financial bonuses to hospitals, institutions, or health-care providers based on a variety of performance and quality measures. Negative consequences can also be applied as a method to promote QI. The most striking example of this is the Re-admission Penalties applied to Medicare payments to those hospitals that have high re-admission rates. This type of penalty incentivizes hospitals to seek ways to reduce re-admissions. Another example of penalty-based incentives includes Value-based Purchasing, where reimbursements to hospitals are withheld and institutions are given the opportunity to earn them back based on outcome measures and patient satisfaction. Although some Pay-for-Performance Programs reward improvement, as mentioned above, others impose negative financial repercussions for failing to adhere to standards or for poor outcomes, such as withholding payments for treatment of patients with some hospital-acquired infections.

QI versus Research QI is designed to improve processes and procedures to advance the quality of health care. Research, on the other hand, is intended to contribute to the general knowledge of a field of health care. QI is typically promoted by the institution to improve operations and clinical practices. Research is usually independently performed and will not benefit the institution as a whole. In addition, research requires the approval of an Institutional Review Board to ensure the protection of human subjects. The results of a QI project are typically disseminated within the institution and might never be published, whereas research is published and shared with the scientific community.

Suggested Readings 1. Bohmer RM: The four habits of high-value health care organizations. N Engl J Med . 2011; 365: 2045–2047. 2. Donebedian A: The quality of care how can it be assessed? JAMA . 1998; 260: 1743–1748. 3. Institute of Medicine: Crossing the quality chasm: a new health system for

the 21st Century. Committee on Quality of Health Care in America, ed. Washington, DC: N.A. Press; 2001. 4. McGlynn E, Asch S, Adams J, et al: The quality o f health care delivered to adults in the United States. N Engl J Med . 2003; 26: 2635–2645. 5. Thompson A, Hetrick SE, Alvarez-Jimenez M, et al: Targeted intervention to improve monitoring of antipsychotic-induced weight gain and metabolic disturbance in first episode psychosis. Australian and New Zealand J Psychiatry . 2011; 45: 740–748. 6. Wachter RM: Understanding Patient Safety . 2nd ed. Columbus, OH: The McGraw-Hill Companies, Inc.; 2012.

CHAPTER Ethical Considerations in 88 Psychiatry Throughout the Life-span MARTA D. HERSCHKOPF MD, MST AND M. CORNELIA CREMENS, MD, MPH

KEY POINTS Introduction The four principles model understands bioethical issues as conflicts within or amongst the following principles: respect for autonomy; beneficence; nonmaleficence; and justice. Other bioethical models contrast Kantian ethics (acting on universal principles), and Utilitarian ethics (acting to maximize good outcomes). Many professional organizations publish guidelines on ethical physician behavior to guide research and clinical practice. Ethical Aspects of Forensic Considerations With regard to forensic issues of informed consent, competency/capacity, boundary violations, and malpractice, the ethical issues at stake include the tensions of respecting autonomy when psychiatric illness compromise that autonomy, and the importance of protecting the patient’s interests when a psychiatrist is tempted to act in ways counter to those interests. Perinatal Period Ethical issues arise in reproductive psychiatry in trying to balance the wellbeing of a gestating or nursing mother with the well-being of a fetus or infant. Psychiatrists have an obligation to inform patients of the risks and limitations of various forms of genetic testing, and to consider the legal and psychological ramifications of such testing for clinical and research purposes. Childhood/Adolescence

The problem of multiple agentry refers to serving multiple interested parties who may be pursuing conflicting agendas, such as a child patient, parents, and organizations, such as child protective services. While minor patients are legally denied many rights involving agency in their own care, ethically these rights are constantly assessed within the framework of the patient’s maturational development, according to what is in the patient’s best interest. Boundary issues often arise in working with children/adolescents and their families; psychiatrists should base their behavior on the therapeutic needs and developmental maturity of their patients. Geriatrics With the patient’s consent, involving family members in an elderly patient’s care early on can help older patients remain active participants in their care as long as possible while they have their mental faculties. Abused or neglected elders may present to psychiatrists with symptoms of depression/anxiety, or may be brought in by family members pressuring a psychiatrist to declare a elder “incompetent.” End-of-Life Physician-assisted suicide is considered ethical in the context of a terminal illness and full patient decision-making capacity. The rule of double effect is a principle by which an action that has a likelihood of causing both good and harm is permissible in the context of being intended for its good effect, when that good effect outweighs the harm. Managed Care, Insurance, and Pharmaceutical Company Interactions Psychiatrists have a duty to disclose potential financial conflicts of interest to their patients, and to consider whether those conflicts of interest impact treatment recommendations. Research Ethics The principles of research ethics include voluntary informed consent, conducting research in a manner that minimizes potential harm to subjects, and minimizing research in vulnerable groups unless that research is likely to be beneficial to that group.

Introduction The topics of ethics and professionalism are drawing increasing attention in medical education generally, and psychiatry in particular. Several models for considering bio-ethical issues are frequently cited in the literature.

Four Principles The Four Principles of Beauchamp and Childress , first published in 1979, comprise the following: Respect for Autonomy: Understood as respecting the right of an individual patient to make their own decisions, to act rationally and freely in accordance with their values. Beneficence: Understood as acting in the best interests of the patient, or of society. Non-maleficence: Understood as not acting in a way that might bring harm to a patient or society, either in taking a harmful action or in failing to take a helpful action. Another formulation of Hippocrates’s dictum primum non nocere , “First do no harm.” Justice: Understood as emphasizing fairness across society and treating all individuals equally. Ethical issues often arise when one or more of these principles are in conflict. For example, when a patient is making a decision that does not appear to be in their best interests, the principles of respect for autonomy and beneficence/nonmaleficence can be in conflict. Ethical issues also arise when it is not clear how to act in accordance with a given principle. For example, when a physician can offer a patient a treatment that might be in the patient’s best interests but not in the best interests of society, it is not clear how to act consistently with the principles of beneficence/non-maleficence.

Kantian versus Utilitarian Ethics Another model is contrasting Kantian and Utilitarian ethics . Kantian ethics are based on the work of German philosopher Immanuel Kant (1724–1804), and particularly on a moral formulation known as the Categorial Imperative. Kantian ethics emphasize acting on universal principles that apply in all situations, rather than considering likely outcomes, and on treating all persons as ends rather than “mere means.” For example, taking a dying patient off an extracorporeal

membrane oxygenation (ECMO) machine to give that machine to a patient more likely to live would run counter to Kantian ethics, as the first patient is being treated as a means, rather than being recognized to have intrinsic value. Furthermore, a Kantian ethicist would argue that it violates a universal principle against hastening a person’s death. Utilitarian ethics, a form of consequentialism, are based on the work of British philosopher John Stuart Mill (1806–1873) and emphasize acting in a way to maximize utility, or well-being. The use of quality-adjusted life years to guide clinical decision-making is based in utilitarian ethics. A Utilitarian ethicist would argue that in the aforementioned ECMO example, the physician has a duty to give the machine to the patient who is more likely to live, to maximize the chances of total well-being.

Professional Association Guidelines Several professional psychiatric organizations have published guidelines on ethical physician behavior, both in clinical practice and in research, interactions with colleagues, and involvement with other organizations. The American Psychiatric Association (APA) first published ethical guidelines in 1973, based on a statement of principles of medical ethics published by the American Medical Association (AMA). The most recent revisions of this document include The Principles of Medical Ethics with Annotations Especially Applicable to Psychiatry and the APA Commentary on Ethics in Practice , both available on the APA website. The statements provide guidelines for aspects of clinical and research ethics, which generally emphasize having the patient’s best interests, broadly defined, be the guide to ethical behavior. Similarly, the World Psychiatric Association first approved the Declaration of Hawaii in 1977, delineating ethical guidelines for psychiatric practice, subsequently codified as the Declaration of Madrid and updated in various councils, most recently in Argentina in 2011. Many other psychiatric organizations have published ethical guidelines of particular interest to various psychiatric subspecialties.

Cultural Relativism Cultural relativism is a principle stating that an individual’s morality should be judged according to their own cultural context, rather than by the standards of an outside culture. The challenge of this stance is that it draws into question whether an absolute morality exists. Many contemporary scholars note that bioethical principles are frequently framed with a particular Western, secular

humanist bias, and might not be applicable to many members of a pluralistic society.

Ethical Aspects of Forensic Considerations The distinction between ethical and forensic considerations can be subtle, and there is significant overlap between this chapter and chapters dedicated to forensic issues, including informed consent, competency/capacity, treatment refusal, civil commitment, boundary violations, confidentiality, and malpractice. The ethical issues at stake in many of these cases include tensions between the principle of respecting patient autonomy (informed consent, competency/capacity) versus beneficence/non-maleficence (treatment refusal, civil commitment), with the understanding that many forms of psychiatric illness can compromise a patient’s ability to act autonomously. Another theme is the importance of protecting a patient’s interests when a psychiatrist is tempted to act in ways that run counter to those interests, either because of dual loyalties (such as a psychiatrist employed by the forensic system forcibly administering antipsychotic medication to render an inmate competent to be executed), or because the psychiatrist’s own interests might favor another course (such as in the case of sexual boundary violations). Ethical issues that arise around these topics at various points of the life cycle are reviewed in this chapter. The full ethical implications of psychiatrists’ involvement with the legal system is beyond the scope of this volume.

Peri-Natal Period Reproductive Psychiatry Common ethical issues that arise in reproductive psychiatry involve balancing the well-being of a gestating or nursing mother with the well-being of a fetus or nursing infant. Many psychiatric medications cross the placenta and/or are secreted in breastmilk, and families are understandably concerned that a medication that is helpful to the mother could potentially harm her child. It is important to note, however, that untreated symptoms of mental illness can similarly harm fetuses and infants. Ethical practice in this realm includes an emphasis on informed consent in the realm of uncertainty, educating patients and families of the relevant research on effects of medications as well as of untreated mental illness, and helping families formulate a plan of medication, monitoring, and nursing that is consistent with their values.

Genetic Testing Research on the genetic bases of mental disorders is a developing field. Currently there does not exist technology to test embryos or patients for gene patterns of specific psychiatric illnesses beyond the psychiatric co-morbidities of other conditions such as chromosomal abnormalities and some rare forms of late-onset Alzheimer’s Disease. However, this technology could become a reality in the future. Genome scans purporting to predict a person’s risk of developing various medical conditions, including psychiatric disorders, are already being marketed to the general public, and psychiatrists have an obligation to inform patients of the limitations of such testing. The use of embryonic genetic testing for mental illness to guide family planning is not currently technologically feasible, but has the potential to become a significant ethical concern in the future. Any genetic testing has implications not just for a patient, but also for family members and particularly children. Part of informed consent for any testing is discussing with a patient the ways that disclosure of results could be harmful to the patient or their family, by such means as stigma, insurance coverage, or psychological distress due to uncertainty about the future. Genetic testing for research purposes, therefore, should be strongly protected against un-authorized access. Genetic testing to quantify enzymatic activity regarding medication metabolism is a growing but not fully developed technology, and psychiatrists have a duty to fully inform patients of the limitations of such tests and avoid expensive testing if it will be of minimal benefit to the patient.

Childhood/Adolescence Child and adolescent psychiatry involves several ethical issues related to working with dependent minors.

Multiple Agentry Psychiatrists have dual loyalties to the patient’s parents or guardians as well as to the patient, and to a variety of organizations that might have a stake in the patient’s welfare, including the school system, foster care, or child protective services. Trying to serve multiple interested parties who might be pursuing conflicting agendas is called the problem of multiple agentry ; ethical practice emphasizes that psychiatrists should act as the agent of the patient themselves to the greatest degree possible. However, psychiatrists are legally obligated to report suspected child abuse or neglect, whether their patient is the child, the

suspected perpetrator, or a witness, even when such reporting can have potential adverse consequences for the child or patient. Finally, sometimes a child might be the identified patient in a dysfunctional family system, and serving the child can actually mean addressing issues within the larger family unit.

Assent, Consent, and Confidentiality Minor patients, by virtue of their cognitive and emotional immaturity , are legally denied many rights involving agency in their own care, including the ability to make their own treatment decisions and the right to confidentiality. One ethical principle of child and adolescent psychiatry is that these rights are constantly assessed within the framework of the patient’s maturational development, according to what is in the patient’s best interest. A major ethical concern in child and adolescent psychiatry is to what degree minors are able to act autonomously. Legally, a minor patient cannot provide informed consent to most medical procedures, although different jurisdictions might allow adolescents this capacity, particularly with regard to sexually-related concerns. Informed consent is provided by a patient’s legal guardians. Psychiatrists should encourage a minor patient to be informed about their treatment and assent to the care plan formulated. Similarly, a psychiatrist should respect a minor patient’s confidentiality as much as possible; it is important to discuss the nature and limits of confidentiality with the patient and guardians together at the outset of treatment. Ethical issues arise when a patient and their guardians disagree about treatment, or if two guardians disagree amongst themselves. In emergency situations, care can and should be administered over a minor patient’s objections. In other situations, the psychiatrist must balance the medically-indicated treatment (beneficence) with the potential psychological ramifications of treating a patient against their will (non-maleficence).

Boundaries Child and adolescent patients are a particularly vulnerable population, but the maintenance of the strict boundaries that are typical in adult psychiatry can be complicated. Whereas adult patients would understand a psychiatrist’s reticence to hug or engage in physical contact, a child could see this as a hurtful rejection. Limits should be formulated as part of compassionate care in a developmentallyappropriate manner. Furthermore, psychiatrists, especially those working in smaller communities, might have personal or professional relationships with members of a patient’s family. Such relationships should be minimized where

possible, and the psychiatrist should remain aware of how these relationships can affect their care of the patient.

Geriatrics Geriatric psychiatry involves ethical issues related to working with older adults as their physical and mental capacities begin to decline.

Assent, Consent, and Confidentiality Unlike minors, older adults generally begin with full legal rights regarding agency in their own care that might be withdrawn as clinically appropriate. Ethically, these rights should be assessed within the framework of the patient’s cognitive and functional status, according to what is in the patient’s best interest. Although it can be considered paternalistic to involve family members in an elderly patient’s care early on, this approach (with the patient’s consent) can help older adults remain active participants in their health-care decisions for as long as possible, respecting their autonomy by facilitating collaborative decisionmaking according to their stated wishes and value. Furthermore, discussing patients’ wishes regarding end-of-life care should be addressed early and revisited often to help clarify their wishes while they maintain the capacity to make some decisions. The use of health-care proxies, advanced directives, durable power of attorney, and other legal documents can pre-emptively address issues that might become problematic in later years. Respecting a patient’s wishes must be balanced with what support can reasonably be expected of family members, who themselves might suffer from caregiver fatigue. A psychiatrist should respect the patient’s confidentiality as much as possible, and clarify with the patient their preferences regarding information-sharing with family members. It should be noted that many cultures value not sharing distressing information with elderly family members, particularly in the context of terminal illness diagnoses.

Capacity and Exploitation Older adults are vulnerable to exploitation as they lose their physical and mental capacities. All 50 states have laws encouraging or mandating professionals to report suspected elder abuse or neglect. Abused or neglected elders might present to psychiatrists with symptoms of depression or anxiety, and it is incumbent upon psychiatrists to screen for and report suspected abuse. However, psychiatrists can also be pressured by family members or other

interested parties to declare an elderly patient incompetent, giving others control over a patient’s medical and financial affairs. The psychiatrist cannot know whether these interested parties are necessarily motivated by what is in a patient’s best interest. Furthermore, elderly patients are vulnerable to various forms of coercion by family members or caregivers, who might threaten to withhold care or resources if the patient does not agree to various financial demands. Many adults with early dementia might retain the capacity to make financial and other decisions, whereas others may lack insight into their limitations and put themselves and others at risk, for example, by living in an unsafe home environment or continuing to drive. The role of the psychiatrist is to conduct an assessment as warranted and potentially to reach out to elder services or other authorities if there are concerns for exploitation. As with any capacity assessment, capacity evaluations in the elderly should be for a particular decision, and should be based on a comprehensive evaluation, not simply a diagnosis of dementia.

End-of-Life Psychiatrists can play an important role in facilitating end-of-life discussions while patients are in full possession of their faculties and can make their wishes known. Unfortunately, not every clinical situation can be anticipated. Ethical dilemmas can arise when there is disagreement among family members regarding end-of-life decision-making or when a family member wants to act contrary to an advanced directive or similar document. Other ethical issues arise around treatments offered at the end of life. Some ethicists argue that continuing to treat patients in intensive care units at the behest of their families even when the chance of recovery is negligible violates the principle of justice, citing concerns for cost and access for those who could benefit more from such care.

Capacity for Physician-Assisted Suicide Physician-assisted suicide is currently legal in a handful of states, and psychiatrists will become increasingly involved in assessing a person’s capacity to access this option. Physician-assisted suicide is generally considered ethical in the context of terminal illness and full patient capacity. In other situations, when an illness might not be terminal or when a patient’s capacity might be impaired by the presence of cognitive limitations or concomitant depression, the ethical ramifications of physician-assisted suicide are increasingly problematic. This area will receive increasing clinical and ethical attention in coming years.

Rule of Double Effect The principle of double effect is an ethical principle by which an action that has a likelihood of causing both good and harm is permissible in the context of being intended for its good effect, when that good effect outweighs the harm. The classic example is giving pain medication to a terminally ill patient despite the risk of respiratory compromise and death. A similar argument can justify the use of antipsychotic or sedating medication in terminally ill patients with agitated delirium.

Managed Care, Insurance, and Pharmaceutical Company Interactions Psychiatrists are increasingly working within complex systems of care, both as employees of hospitals and other care-delivery organizations, and also with their income based on what insurance and managed-care companies are willing to reimburse. A major goal of such organizations is cost containment, both as a way to maximize profits for shareholders of private companies, but also as a way to maintain the ability to serve many subscribers, consistent with the principle of justice. Unfortunately for the individual patient, this results in barriers to various forms of care, including prior authorizations for expensive treatments, limits on numbers of visits, and a maximum allowed number of hospital or rehabilitation days. This often creates a conflict between what might be in a patient’s best interest and what is in the best interest of the organization. Psychiatrists have an ethical duty to advocate what is in a patient’s best interest while also being mindful of financial realities and guiding patients accordingly, informing them of treatment restrictions and identifying alternatives outside of a given system if possible. Many psychiatrists collaborate with pharmaceutical companies in helping to develop, test, and market innovative treatments. Psychiatrists have a duty to disclose these potential conflicts of interests to their patients and to audiences when making presentations. Furthermore, psychiatrists should continually consider whether recommending a given treatment is truly in the best interests of the patient or guided by industrial interests, seeking supervision or counsel from a colleague if necessary.

Research Ethics

Physicians and psychiatrists have historically been involved in exploitative and unethical experimentation on human subjects, prompting a number of ethical research codes including the Declaration of Helsinki , last updated in 2013. The principles of research ethics include voluntary informed consent of subjects (autonomy), conducting research in a manner that minimizes potential harm to subjects (non-maleficence), and minimizing research in vulnerable groups unless such research is likely to be beneficial to that group and cannot be carried out in a non-vulnerable group (justice). Human subjects with severe mental illness are a particularly vulnerable population, and researchers must remain aware of potential exploitation of this group. Some ethicists argue that certain mental illnesses render a patient incapable of informed consent for research, and that family members must be involved in consenting such patients for studies.

Suggested References

1. American Academy of Child and Adolescent Psychiatry: Code of Ethics. AACAP; 2009. https://www.aacap.org/App_Themes/AACAP/docs/about_us/transparency_portal/aacap_ . 2. American Psychiatric Association: APA Commentary on Ethics in Practice. American Psychiatric Association; 2015. http://www.psychiatry.org/psychiatrists/practice/ethics . 3. American Psychiatric Association: The Principles of Medical Ethics with Annotations Especially Applicable to Psychiatry. 2013 ed. American Psychiatric Association; 2013. http://www.psychiatry.org/psychiatrists/practice/ethics . 4. Beauchamp TL, Childress JF: Principles of Biomedical Ethics , 7th ed. New York: Oxford University Press; 2013. 5. Rabins PV, Black BS: Ethical issues in geriatric psychiatry. Int Rev Psychiatry . 2010; 22: 267–273. 6. Sadler JA, Fulford KWM, van Staden CW, eds.: Oxford Handbook of Psychiatric Ethics . New York: Oxford University Press; 2015. 7. Turner L: Bioethics in a multi-cultural world: medicine and morality in pluralistic settings. Health Care Anal . 2003; 11: 99–117. 8. World Medical Association: World Medical Association Declaration of

Helsinki: ethical principles for medical research involving human subjects. JAMA . 2013; 310: 2191–2194. 9. World Psychiatric Association: Madrid Declaration on Ethical Standards for Psychiatric Practice. World Psychiatric Association . 2011. http://wpanet.org/detail.php?section_id=5&content_id=48 .

Questions and Answers

S E C T I O N S I X

Review Questions

CHAPTER 1: Test-Taking Strategies and Combating Test Anxiety 1-1. Which of the following preparation strategies most improves test performance for most candidates? A. Avoid telling others about your study plans for the exam B. Copy or rewrite the chapters or material you are studying C. Plan to study intensively for at least 3 hours per day, approximately 2 weeks before the exam D. Study consistently for 3 or more months before the exam E. Take practice exams one section per day the week of the exam 1-2. Which of the following practices have been associated with higher exam scores? A. Changing one’s answers when reviewing items where one felt uncertain. B. Going more quickly through the exam. C. Maintaining a mental frame that the items will have “tricky” phrases to recognize. D. Studying densely (the night before or morning of the exam). E. Using alcohol or sleep medications to optimize sleep the night before the exam. CHAPTER 2: The Psychiatric Interview

2-1. Which of the following elements of the Clinical Skills Verification (CSV) would be considered a critical area of inquiry to pass the examination? A. Fund of knowledge B. Marital history C. College academic performance D. Trauma history E. Medication trials

2-2. Which of the following components of the psychiatric interview is unique to the Annual Oral Examination (AOE)? A. Substance-use history B. Mood C. Prognosis D. Case presentation E. Mental status examination CHAPTER 3: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 3-1. Which of the following best describes the rationale behind DSM-5’s move toward a more dimensional rather than categorical approach to diagnosis? A. Dimensional diagnoses could reduce clinicians’ reliance on “Not Otherwise Specified” diagnoses. B. Categorical diagnoses were considered too broad to be clinically useful. C. Dimensional diagnoses reflect psychiatry’s agnosticism regarding the pathophysiologic underpinnings of psychiatric disorders. D. The categorical diagnoses of DSM-IV-TR were difficult to match to the World Health Organization’s (WHO’s) International Statistical Classification of Diseases and Health Related Problems (ICD) . 3-2. Which of the following is not a major conceptual change in DSM-5? A. Expanded emphasis on the role of culture in psychiatry. B. Elimination of the multi-axial diagnostic system introduced in DSM-III. C. Move toward a more phenomenological organizational scheme. D. Increased emphasis on the organization and grouping of disorders, with conceptually-related disorders located adjacent to one another. CHAPTER 4: Child and Adolescent Development

4-1. A 5-year-old child is worried that her brother tripped in the playground because she was mad at him. This is an example of: A. Deductive reasoning B. Magical thinking C. The “strange situation” D. Object constancy 4-2. Risky behavior in adolescence is best explained by which of the following? A. Synaptic pruning B. Synaptogenesis C. Delayed maturation of prefrontal cortex compared to the limbic system D. Loss of hippocampal mass

CHAPTER 5: Child and Adolescent Disorders 5-1. Symptoms of ADHD must present before which of the following ages? A. 6 B. 7 C. 12 D. 18 5-2. A 4-year-old girl, adopted at the age of 6 months, presents to clinic due to concerns of interacting with unfamiliar adults in an overly trusting way and never checking back with her mom after venturing away. She most likely has which of the following? A. Reactive Attachment Disorder B. PTSD C. Disinhibited Social Engagement Disorder D. Normal behavior CHAPTER 6: Tics and Tourette Disorder 6-1. A 10-year-old boy comes into clinic with his mother. He has a diagnosis of Tourette disorder and ADHD. His tics are mild and do not bother him. However, the boy and his mother both feel as though his hyperactivity and inattention are “out of control,” and he is failing fourth grade. He tried Tenex in the past with little effect. Which medication should be started? A. Methylphenidate B. Atomoxetine C. Risperidone D. Haloperidol 6-2. You are seeing an 8-year-old boy for the first time. His father reports that he first noticed the child eye-blinking at age 5, which then stopped without treatment. The child recently had a cold, and his dad brings

him in today because he noticed that his son has continued to cough and sniffle despite not having other cold symptoms. The father reports that his mother has a psychiatric disorder, but he can’t remember its name. What diagnosis might the mother have that would be consistent with this child having Tourette disorder? A. Psychotic disorder B. Alcohol use disorder C. Major depressive disorder D. OCD CHAPTER 7: Autism Spectrum Disorders 7-1. Which one of the following conditions or symptoms would be least likely to be co-morbid in a 10-year-old boy with autism spectrum disorder (ASD)? A. Intellectual disability B. Seizure disorder C. Attention deficit hyperactivity disorder (ADHD) D. Social communication disorder (SCD) E. Constipation 7-2. You are evaluating a 9-year-old boy with ASD in your outpatient clinic. He presents as being hostile and confrontational toward his parents, and they note that he has a long history of being physically aggressive at home toward his siblings. A medical assessment has ruled-out a physical cause, and behavioral interventions have not been successful. They note that his sleep and appetite have not changed. Which of the following medications would be most appropriate in this case? A. Divalproex sodium B. Fluoxetine C. Quetiapine D. Lorazepam E. Aripiprazole

CHAPTER 8: Delirium 8-1. You are consulted on a 45-year-old man in the intensive care unit who was injured in a car accident during the preceding night. His admission labs showed a significantly elevated ethanol level and MCV, and an AST:ALT ratio of 3:1. He is currently intubated and sedated but the surgical team has noted an increasing tachycardia despite euvolemia on exam. Which of the following would you recommend as they plan to wean his sedation? A. Arranging for a cardiology consultation B. Administration of an atypical antipsychotic C. Administration of a benzodiazepine D. Administration of IV fluids 8-2. Which of the following is the hallmark symptom of delirium? A. Confabulation B. Somnolence C. Impaired attention D. Hallucinations CHAPTER 9: Dementia 9-1. A patient diagnosed with Alzheimer disease (AD) is demonstrating signs of impaired reasoning. You suspect an alteration in which area of the brain? A. Frontal lobes B. Amygdala C. Temporal lobes D. Ventricles E. All of the above 9-2. You are assessing an elderly patient who is disoriented to time and place. Which additional finding would support a diagnosis of dementia? A. Rambling and incoherent speech

B. Attention is impaired C. Slow and progressive course D. Acute onset of symptoms E. A, B, and C 9-3. During a patient examination, you note that the patient is aphasic. Which behavior supports this finding? A. Difficultly with motor function B. Inability to speak C. Inability to recognize objects D. Difficulty swallowing E. B and C 9-4. During the administration of the MoCA exam, you ask the patient to copy a simple geometric shape. This part of the exam tests which of the following mental functions? A. Hearing and language skills B. Attention and calculation abilities C. Orientation and short-term memory D. Visual comprehension and praxis E. All of the above 9-5. A patient is admitted to the hospital with a diagnosis of vascular dementia. Which of the following describes the brain alteration involved in this disorder? A. Hypoxic damage to brain tissue B. Enlargement of the ventricles C. Formation of amyloid-β plaque D. Decreased choline acetyltransferase E. Increased BDNF 9-6. A patient with a history of depression experiences memory lapses and word-finding difficulty. Which of these represents a characteristic of his cognitive issues?

A. Psychosis is a prominent feature B. Cognitive impairments are reversible C. Lewy bodies form within the brain tissue D. Eventually evolves into AD E. None of the above 9-7. When planning care for a patient diagnosed with AD, which of these interventions is most therapeutic? A. Giving the patient several directions at a time to improve memory B. Involving family and caregivers C. Encouraging both verbal and non-verbal communication D. Speaking in a loud, clear voice when talking to the patient E. B and D 9-8. Which of the following is the most common form of dementia in middleaged and older adults? A. Lew-Body Dementia (DLB) B. Frontotemporal dementia (FTD) C. AD D. Vascular dementia (VaD) E. Chronic traumatic encephalopathy 9-9. Which of the following is an environmental risk factor for cognitive decline? A. High educational level B. Head injury C. Low body weight D. Increased physical activity E. All of the above 9-10. Which of the following contributes to genetic susceptibility to lateonset AD? A. Presenilin gene mutations B. Apolipoprotein E4 genotype

C. Amyloid precursor protein mutations D. Angiotension-converting enzyme gene mutations E. A and C

9-11. Which of the following statements is false ? A. Diabetes increases the risk of AD B. Inflammation is linked to post-stroke depression C. Aphasia involves speech and reading deficits but spares writing D. Executive functions deficits are traced to the frontal lobe E. The right hemisphere is responsible for speech prosody 9-12. Which of the following drugs or drug combinations have been shown some promising results for halting mild cognitive impairment (MCI) conversion to dementia? A. Gingko 120 mg twice daily B. Donepezil 10 mg daily plus memantine 10 mg twice daily C. Memantine 10 mg twice daily D. Omega-3 fatty acids E. Rivastigmine 3 mg twice daily 9-13. AD is caused by which of the following? A. Amyloid plaques in the brain B. Neurofibrillary tangles in the brain C. Inflammatory processes in the brain D. Oxidative stress E. The cause of AD is unknown 9-14. The concept of caregiving burden and burnout is best characterized by which of the following? A. Occurs only under certain circumstances B. Leads to high level of depression C. Exemplifies social suffering in system diseases D. B and C E. None of the above CHAPTER 10: Intellectual Disability

10-1. What is the most common genetic cause of intellectual disability? A. Fragile X syndrome B. Phenylketonuria C. Down syndrome D. Prader-Willi syndrome 10-2. Which of the following is the most common co-morbidity in fragile X syndrome? A. Anxiety B. Attention-deficit/hyperactivity disorder (ADHD) C. Autism D. Depression CHAPTER 11: Mental Disorders Due to Another Medical Condition 11-1. Which of the following conditions often presents with delirium and bizarre visual hallucinations? A. Hypothyroidism B. Chronic renal insufficiency C. Acute renal insufficiency D. Acute intermittent porphyria E. Fungal infection 11-2. “Pseudobulbar palsy” from lacunar infarcts is characterized by which of the following symptoms? A. Affective incontinence B. Dysarthria C. Dysphagia D. Bifacial weakness E. All of the above CHAPTER 12: Alcoholism and Alcohol Use Disorders

12-1. A 45-year-old male presents to the emergency room with an unsteady gait, confusion, disorientation, and dysconjugate gaze when testing the cranial nerves. The police officer that brought the patient to the hospital reports he vomited multiple times en route to the hospital. His breath smells strongly of alcohol, and by breathalyzer blood alcohol content is estimated to be 0.28 g/dL. Which of the following would be the most appropriate next step in the treatment of this patient? A. Contact his primary-care physician to obtain collateral information B. Re-hydrate via IV normal saline with 5% dextrose C. Give a low dose of antipsychotic medication D. Give IV thiamine E. Administer the CAGE questionnaire 12-2. A 60-year-old female is admitted to the hospital after presenting to the ED with bloody emesis and requiring emergency surgery for a ruptured esophageal varicosity. 72 hours after admission, she becomes increasingly tremulous, is tachycardic and hypertensive, and becomes confused and disoriented, believing she is being held captive in a foreign prison. She points out rodents crawling on her hospital bed and hears children repeatedly calling her name from the hallways. Her treatment team correctly identifies her condition as alcohol withdrawal delirium. Which of the following most clearly distinguishes her condition from alcoholic hallucinosis? A. Tremors B. Hypertension C. Disorientation D. Auditory hallucinations E. Visual hallucinations CHAPTER 13: Substance-Related Disorders: Cocaine and Opioids 13-1. All the following statements are true about cocaine except : A. Cocaine inhibits the pre-synaptic uptake transporters for dopamine, norepinephrine, and serotonin.

B. Cocaine use increases the risk of fetal hypoxia and placental abruption due to its vasoconstriction properties. C. Cocaine is metabolized in the liver to benzoylecgonie, which can be detected in the urine for up to 36 hours with acute use, to more than a week with heavy daily use. D. Episodic smoking of cocaine is less likely to progress to chronic use than episodic intranasal use. E. Recent studies have failed to show benefits of dopamine agonists for cocaine withdrawal. 13-2. Most drugs of abuse have their acute reinforcing effects through the: A. GABA system B. Mesocortical dopamine system C. Mesolimbic dopamine system D. Nigrostriatal dopamine system E. Reticular activating system 13-3. All of the following are true about opioids except : A. Methadone has a slow onset of subjective effects and long half-life, both properties of which make it an ideal agent for opioid substitution. B. Opioids can be measured in blood, saliva, and hair. C. Most short-acting opioids are detected in the urine 12 to 36 hours after administration. D. Methadone is safer than buprenorphine for the neonate during pregnancy. E. SSRI antidepressants inhibit the metabolism if methadone, via CYP 450 3A/4 enzyme system, with the potential of raising methadone to toxic levels in the blood. 13-4. Which of the following statements is false ? A. Buprenorphine is a partial mu receptor agonist and a kappa receptor antagonist. B. Methadone has a half-life of 24 to 36 hours. C. According to the CDC, about 50% of IV drug users in the United States are infected by hepatitis C.

D. For methadone maintenance, studies have shown that doses averaging 70 to 80 mg/d are needed to block opioid cravings and drug use. E. Buprenorphine induction should not be initiated without the presence of withdrawal symptoms and without a delay of more than 12 hours after the last dose for short-acting opioids and more than 24 hours after the last dose of methadone. CHAPTER 14: Psychosis and Schizophrenia 14-1. All of the following criteria are required for a diagnosis of schizophrenia except : A. Hallucinations, delusions, or disorganized speech B. Negative symptoms C. Symptoms are not due to the physiologic effect of a substance or an underlying medical condition D. Continuous signs of illness for at least 6 months 14-2. Which of the following factors does not predict a poor overall outcome in schizophrenia? A. Longer duration of untreated psychosis B. Younger age of onset of symptoms C. Prominent negative symptoms D. Female gender E. Initial poor response to antipsychotic medication CHAPTER 15: Depressive Disorders 15-1. All of the following statements are true about the course of major depressive disorder (MDD) except : A. The probability of relapse of depression is 50% after three episodes of depression. B. The time to recurrence of depression shortens with increasing number of episodes.

C. Eighty percent of MDD episodes occur in the context of a significant stressor in the previous 6-month period. D. Anxiety and panic attacks are prodromal symptoms for MDD episodes. E. The average life-time number of MDD episodes is four. 15-2. All of the following statements about the treatment of MDD are true except : A. Patients who achieved remission rather than response were less likely to relapse at 12-month naturalistic follow-up. B. In the STAR*D study, the cumulative QIDS-SR remission rates for Levels 1 to 4 were 37%, 56%, 62%, and 67%, respectively, suggesting that aggressive treatment of MDD can lead to high rates of remission. C. It has been shown that suicidal thoughts or behaviors are decreased in adults over the age of 50. D. Longitudinal studies demonstrate that a history of three or more episodes of depression conveys a greater than 80% risk for recurrence. E. Depressed patients who are treatment resistant to antidepressants are also treatment resistant to ECT. CHAPTER 16: Bipolar Disorder 16-1. A 71-year-old man with a long history of depression and multiple suicide attempts is treated with high dose corticosteroids for a COPD exacerbation. Several days after treatment is initiated, he is brought into the ED by police after disrobing in public and assaulting several people on the street. His wife reports that he has not slept in 5 days. Physical exam is benign aside from hyperechoic lungs and sinus tachycardia; history from the patient is limited by psychomotor agitation and distraction. His only other medications include inhalers and sertraline 100 mg, which he has taken for years. Which of the following is the most appropriate treatment? A. Discontinue corticosteroids B. Discontinue selective serotonin re-uptake inhibitors (SSRI) and continue corticosteroids C. Discontinue corticosteroids and the SSRI

D. Continue the current medication regimen and start an antipsychotic agent until mania resolves E. Discontinue corticosteroids, continue the SSRI, and start an antipsychotic agent until mania resolves 16-2. A 22-year-old woman with bipolar disorder, type I has been hospitalized several times in the past year for both manic as well as depressive episodes. She has failed lithium monotherapy as well as several other mood stabilizers, developed akathisia from lurasidone and is currently taking Symbyax (olanzapine/fluoxetine combination capsule) but remains moderately depressed. She asks about lamotrigine, to which you respond: A. Lamotrigine is contraindicated in patients taking olanzapine/fluoxetine due to cytochrome inhibition. B. Lamotrigine needs to be rapidly titrated due to auto-induction of the P450 enxyme system. C. Lamotrigine is one of the FDA-approved treatments specifically for bipolar depression. D. Lamotrigine has been shown to have a modest effect size in meta-analyses examining its efficacy in treating bipolar depression. E. The risk of rash and Stevens-Johnson syndrome is increased when prescribing lamotrigine and olanzapine together. CHAPTER 17: Anxiety Disorders 17-1. What is the life-time prevalence of anxiety disorders in the United States? A. 5% B. 15% C. 25% D. 40% 17-2. Which of the following anxiety disorders requires that symptoms last for at least 1 month to meet the diagnostic criteria? A. Panic disorder

B. Social anxiety disorder C. Specific phobia D. Generalized anxiety disorder CHAPTER 18: Obsessive-Compulsive and Related Disorders 18-1. Which of the following would be considered a first-line pharmacologic treatment for a 25-year-old female with moderately severe body dysmorphic disorder (BDD)? A. Fluoxetine B. Risperidone C. N -acetylcysteine D. Lorazepam 18-2. Your case load includes four patients: a 57-year-old with hoarding disorder, a 29-year-old with trichotillomania (TTM), a 19-year-old with BDD, and a 34-year-old with obsessive-compulsive disorder (OCD). Which of the four patients is likely to have the highest suicide risk? A. The 57-year-old with hoarding disorder B. The 29-year-old with TTM C. The 19-year-old with BDD D. The 34-year-old with OCD CHAPTER 19: Trauma and Post-Traumatic Stress Disorder 19-1. A 22-year-old presents to the emergency department 2 weeks after being involved in a motor vehicle accident in which his girlfriend died. He complains of recurrent nightmares, flashbacks of the accident, and feeling like, “I’m in a daze.” His DSM diagnosis is most likely to be which of the following? A. Acute stress disorder (ASD) B. Adjustment disorder C. Complicated grief

D. Post-traumatic stress disorder (PTSD) 19-2. Which anti-adrenergic medication has been found to be helpful in treatment of nightmares associated with PTSD? A. Clonidine B. Guanfacine C. Prazocin D. Propranolol 19-3. Which class of medication has a relative contraindication for the treatment of PTSD? A. Atypical antipsychotics B. Benzodiazepines C. Selective serotonin re-uptake inhibitors D. Tricyclic antidepressants CHAPTER 20: Somatic Symptom and Related Disorders 20-1. A 32-year-old woman is referred to you by her primary-care physician due to “anxiety.” She does not feel that she needs a psychiatrist, but rather needs to move away from her condominium, which she feels is too close to power lines, and which she moved to a year ago because her previous building’s management company used “harsh chemicals” for routine cleaning of the hallways. She is wearing a visibly thick amount of sunscreen, and is angry that her doctor will not order her a “full body scan” for non-specific cancer surveillance. The most likely diagnosis of this patient is which of the following: A. Somatic symptom disorder B. Illness anxiety disorder C. Delusional disorder, somatic type D. Factitious disorder E. Generalized anxiety disorder 20-2. Which of the following statements concerning the distinction between factitious disorder and conversion disorder is always false?

A. Factitious and conversion disorders can both be means of pursuing “primary gain.” B. Conversion disorder always presents with signs, whereas factitious disorder can present with symptoms or signs. C. Factitious and conversion disorder are both attempts to consciously deceive health care providers. D. Video monitoring can be useful in the inpatient evaluation of both conversion and factitious disorder. E. Evidence of “secondary gain” is believed to suggest malingering as opposed to both factitious and conversion disorders. CHAPTER 21: Deception Syndromes: Factitious Disorder and Malingering 21-1. Which of the following is not an example of secondary gain? A. Shelter B. Avoidance of responsibility C. Assuming the sick role D. Freedom from legal issues 21-2. Which of the following is not recommended in terms of the approach to a patient suspected of engaging in deceptive behavior? A. Contact collateral sources of information B. Confront the patient early to avoid further deception C. Conduct a thorough medical work-up as indicated D. Consider neuropsychological testing CHAPTER 22: Dissociative Disorders 22-1. Which of the following is true about dissociative identity disorder? A. This syndrome has been called multiple personality disorder because it is best categorized as a personality disorder. B. Patients must not be aware of their alters. C. Co-consciousness refers to the appreciation by the patient of the existence

and feelings of an alter. D. Dissociative identity disorder (DID) is rare, affecting less than 0.5% of the population. 22-2. What is the best treatment approach for depersonalization/derealization disorder? A. Electroconvulsive therapy (ECT) is the most effective and least invasive treatment. B. Antipsychotic medications remain a mainstay of treatment. C. Convincing patients that they are different from the person whom they incorrectly think that they are. D. Treating co-morbid conditions and using directed psychotherapy with an emphasis on therapy for trauma. CHAPTER 23: Sexual Disorders and Sexual Dysfunction 23-1. Which of the following diagnoses is included in the Diagnostic and Statistical Manual of Mental Disorders, Fi fth Edition (DSM-5)? A. Hypoactive sexual desire disorder B. Male orgasmic disorder C. Sexual aversion disorder D. Female orgasmic disorder E. Vaginismus 23-2. Which of the following is a medication approved by the United States Food and Drug Administration (FDA) for the treatment of female sexual dysfunction? A. Avanafil B. Flibanserin C. Tibolone D. Yohimbine E. EROS-CTD

CHAPTER 24: Eating Disorders 24-1. Which of the following pharmacologic treatments has FDA-approval for the treatment of an eating disorder? A. Fluoxetine and topiramate B. Olanzapine and lisdexamfetamine dimesylate C. Bupropion and fluoxetine D. Topiramate and olanzapine E. Lisdexamfetamine dimesylate and fluoxetine 24-2. A college sophomore presents with a metatarsal stress fracture. Her history reveals a weight gain of 10 pounds during her freshman year. She reports unsuccessful attempts to diet, and the emergence of bingeeating episodes during the second semester of freshman year. Over the past four months, she reports binge-eating once or twice weekly. She tried over-the-counter weight loss pills, but found they did not work. She denies any vomiting or laxative use. In the fall of her sophomore year, she joined an intramural soccer team, which she found helped her manage her weight. She began to extend her workouts well beyond what her teammates were doing. After the season ended, she began a rigid regimen of 1 hour of weight lifting followed by running four to five miles daily, no matter what the weather was or what social or academic obligations she had. She also admitted that she continued to run even when her foot pain began 3 weeks earlier, feeling driven to do so. During her sophomore year, she lost 15 pounds and now weighs 125 pounds at 5’4”. She cannot shake her strong preoccupation that she would look and feel better if she could lose five more pounds and berates herself about her weight. What is the most likely diagnosis? A. Major depression B. AN C. BED D. BN CHAPTER 25: Sleep Disorders

25-1. Which of the following sleep stages is associated with relatively lowvoltage, mixed-frequency waves on the electroencephalogram? A. NREM 1 B. NREM 2 C. NREM 3 D. REM 25-2. Which of the following age groups is most closely associated with having REM sleep occupying 50% of time asleep? A. Birth to age 2 years B. Teenage years C. Age 25 to 45 years D. Age > 65 years CHAPTER 26: Disruptive, Impulse-Control, and Conduct Disorders 26-1. A 16-year-old girl is brought to the clinic by her mother for evaluation of self-injurious behaviors. The girl has repeatedly cut her arms and thighs over the past 14 months. She says she is upset by the fact that she cuts, and feels that she has lost control over the problem. She describes her mood as “bad,” but denies symptoms of anhedonia or low energy. She denies any history of suicide attempts or gestures. What is the most appropriate diagnosis? A. Borderline personality disorder B. Major depressive disorder C. Impulse-control disorder NOS D. Obsessive-compulsive disorder E. Unspecified Anxiety disorder 26-2. A 17-year-old boy with a history of attention deficient disorder comes to the clinic for routine follow-up. During the appointment, he discloses that he burned down a building while playing with a lighter. He expresses minimal remorse about the fire. He has a history of

shoplifting, school truancy, and breaking curfew. What is the most appropriate diagnosis? A. Pyromania B. Impulse-control disorder C. Antisocial personality disorder D. Oppositional defiant disorder E. Conduct disorder CHAPTER 27: Adjustment Disorders, Grief, and Bereavement 27-1. Which of the following best describes the rituals and actions a person goes through after the death of a loved one? A. Bereavement B. Complicated grief C. Grief D. Mourning 27-2. A 62-year-old woman is referred to you by her primary care physician one month after her husband died. She reports feelings of guilt and wanting to die as a means of being with him. She reports hearing his voice on occasion, but denies neurovegetative symptoms of depression. Which of the following is her most likely diagnosis? A. Adjustment disorder B. Complicated grief C. Major depressive disorder with psychotic features D. Normal grief CHAPTER 28: Personality Disorders 28-1. Which cluster A personality disorder is considered more etiologically and phenomenologically related to schizophrenia than to other cluster A disorders? A. Schizoid personality disorder

B. Schizotypal personality disorder C. Avoidant personality disorder D. Paranoid personality disorder 28-2. Approximately what percentage of patients with borderline personality disorder attempt suicide during their lifetime? A. 33% B. 50% C. 75% D. 90% CHAPTER 29: Psychiatric Disorders Associated with the Female Reproductive Cycle 29-1. A 25-year-old woman presents with of irritability, increased anxiety, and tearfulness, which occur for 2 to 3 days prior to her period. During the remainder of the month, her mood is euthymic and she has minimal anxiety. All of the following treatments could be recommended except : A. Lifestyle changes: improved sleep hygiene, aerobic exercise, avoidance of alcohol B. Fluoxetine dosed during the luteal/pre-menstrual phase of the cycle C. Venlafaxine D. Bupropion E. Alprazolam 29-2. A 35-year-old woman with bipolar disorder, with the most recent episode involving depression, comes to the clinic for consultation regarding her plans for pregnancy. She has done well on a regimen consisting of lamotrigine 200 mg, lithium 300 mg, and aripiprazole 10 mg. A. Because all of the medications she is taking are teratogens, she should taper these medications prior to her attempts to conceive. B. None of the medications she is taking carries any risk during pregnancy, so she should continue all of them.

C. The use of lithium during pregnancy has been associated with increased risk for neural tube defects and therefore should be avoided. D. She should switch from lithium to another mood stabilizer such as valproic acid. E. For some women with bipolar disorder, certain atypical antipsychotics can be used safely and, while the data is limited, these agents have not been associated with teratogenic risk. CHAPTER 30: HIV Infection and A IDS 30-1. Which statement about HIV screening is correct? A. The CDC recommends cohort screening for HIV infection. B. Most patients with HIV infection are unaware of their HIV status. C. Psychiatrists should consider screening patients with new-onset mania for HIV infection. D. In most jurisdictions, HIV testing requires written consent and post-testing counseling. 30-2. Which of the following statements best concludes the sentence ? Preexposure prophylaxis (PrEP) with emtricitabine/tenofivir (brand name Truvada)... A. …is indicated for almost all patients with HIV infection and should be strongly recommended. B. …has been shown to be essentially ineffective. C. …is harmful because PrEP requires the use of at least three antiretroviral agents. D. …is FDA-approved for HIV prevention. CHAPTER 31: Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome 31-1. Which of the following is a common finding in a patient with serotonin syndrome (SS)? A. Hyperactive bowel sounds

B. Hyporeflexia C. Miosis D. Dry skin 31-2. Which of the following is the treatment of choice for catatonia? A. Intravenous haloperidol B. Intramuscular lorazepam C. Intravenous lorazepam D. Oral diazepam CHAPTER 32: Neuroimaging in Psychiatry 32-1. A 58-year-old man was brought by ambulance to the emergency department. He was accompanied by his wife, who said that 20 minutes earlier he fell to the ground, was unable to move his right leg and arm, and was making sounds but could not speak coherently. On exam, you identify right-sided hemiparesis and expressive aphasia. Which of the following imaging tests would you order first to rule-out a suspected ischemic stroke, and what would you expect to see? A. Magnetic resonance imaging (MRI): diffusion-weighted imaging (DWI) hyperintensity and apparent diffusion coefficient (ADC) hypointensity in the left middle cerebral artery (MCA) territory B. MRI: DWI hyperintensity and ADC hyperintensity in the left MCA territory C. Computed tomography (CT): Normal exam D. MRI: DWI hyperintensity, normal ADC and T2 hyperintensity in the left MCA territory E. CT: Hyperdense cortical signal in the left MCA territory 32-2. A 72-year-old woman presents to your clinic complaining of memory problems, insomnia, and anhedonia. Her Montreal Cognitive Assessment (MoCA) score is 21/30. Her neurological exam is normal except for decreased vibratory sensation bilaterally below the ankles. You suspect Alzheimer’s pathology and order an MRI scan, which shows bilateral hippocampal atrophy and periventricular T2 hyper-

intensities. Which of the following additional imaging tests could you order and what would you expect to see to confirm your hypothesis of a neurodegenerative etiology? A. Magnetic resonance spectroscopy (MRS): decreased GABA and increased Tau in the hippocampi B. 15 O-H2 O positron emission tomography (PET): Decreased perfusion in the frontal lobes C. Diffusion tensor imaging (DTI): Reduced fractional anisotropy (FA) in the fimbria and cingulate bundle D. FDG-PET: Reduced uptake in the mid-temporal lobe, posterior cingulate, and parietal cortex E. SPECT: Increase beta-amyloid depositions in the hippocampi and fimbria CHAPTER 33: Diagnostic Rating Scales and Psychiatric Instruments 33-1. The SCID-5 differs from the SCID-IV in the following ways except : A. The bereavement exclusion for a major depressive episode has been eliminated. B. Obsessive-compulsive disorder is now categorized separately from Anxiety Disorders. C. It includes a category called Externalizing Disorders. D. The SCID-CT version for clinical trials is re-designed as a comprehensive diagnostic assessment. E. Substance abuse and dependence are now categorized under Substance Use Disorders. 33-2. Which of the following statements about diagnostic instruments is/are false ? A. The MINI has been validated against the SCID and is increasingly used in clinical trials. B. The SCID-II Personality Questionnaire is often used as an adjunct to the full SCID-II but may lengthen the time needed to assess the patient. C. Some versions of the HAM-D have been adapted to cover shorter symptom periods of 1-3 days for clinical trials of potentially rapidly-

acting therapies such as ketamine. D. The 15-item MADRS can be helpful if a study is assessing atypical depression symptoms. E. The SDQ covers both depressive and anxious symptoms. CHAPTER 34: Psychological Assessment 34-1. True or False. The reliability of a measure refers to the repeatability, stability, and consistency of a given instrument in measuring a given construct. 34-2. True or False. Although the objective test provides a view of the patient’s “conscious” or explicit self-presentation, the performancebased tests provide insight into the patient’s typical style of perceiving, organizing, and responding to ambiguous external and internal stimuli. CHAPTER 35: Neuropsychological Assessment 35-1. What are the primary goals of a neuropsychological assessment? A. To relate a patient’s test performance to both the status of their central nervous system (CNS) and their real-world functional capacity B. To determine the best pharmacological approach C. To establish the personality style D. To determine whether a patient has the capacity to accept or refuse a medical procedure 35-2. Which of the following is a core domain typically assessed in a neuropsychological evaluation? A. Overall intellectual functioning (IQ) B. Predominant psychological defensive style C. Presence of major depressive disorder D. Prognosis of neuropsychiatric impairment CHAPTER 36: Laboratory Tests and Diagnostic Procedures

36-1. A 72-year-old woman presents reporting depressed mood over the past 3 months. Symptoms initially began after her husband passed away unexpectedly, but have been progressively worsening since then. She notes that the most difficult time is evening as her husband had always been the one who cooked all the meals in the house. In addition to depressed mood, she complains of poor energy, and lately has had difficulty concentrating and feels “off balance.” Physical examination reveals mild conjunctival pallor and reduced proprioception in the lower extremities. CBC reveals hemoglobin of 10.9 g/dL (N = 12–15 g/dL) with MCV of 94 fL/RBC (N = 80–96 fL/RBC). At her last visit 9 months prior, these values were within the normal range. Routine labs, TSH, and iron studies reveal mild iron deficiency; serum folate is normal and B12 is borderline low-normal. Which of the following additional test results would confirm the likely diagnosis? A. Low free T4 B. High serum methylmalonic acid C. Low serum methylmalonic acid D. Low red blood cell folate level E. High serum GGT 36-2. A 63-year-old, right-handed man with hypertension presents for evaluation of several months of falls, progressive cognitive impairment, and occasional visual hallucinations. Family history is positive for a diagnosis of Alzheimer’s disease in the patient’s mother at age 59. Cognitive examination supports a diagnosis of major neurocognitive disorder (dementia). Which of the following tests would provide supporting evidence for the suspected diagnosis? A. Polysomnography B. MRI C. CT D. PET E. fMRI CHAPTER 37: Functional Neuroanatomy

37-1. A 35-year-old truck driver sustains a traumatic brain injury in a motor vehicle accident. He makes an excellent motor/sensory recovery but is more susceptible to “road rage” since the accident, and his wife notices that he is occasionally sexually inappropriate and prone to “make scenes” in public. Which frontal sub-cortical circuit is he most likely to have damaged in the accident? A. Dorsolateral prefrontal cortex B. Orbitofrontal cortex C. Anterior cingulate gyrus D. Frontal eye fields E. Supplementary motor area 37-2. Which structure is not thought to be part of the attention/executive network? A. Hippocampus B. Cerebellum C. Parietal lobe D. Dorsolateral prefrontal cortex E. Basal ganglia CHAPTER 38: The Neurologic Examination 38-1. What is the most likely location of a lesion leading to a working memory deficit? A. Dentate gyrus B. Subiculum C. Medial temporal gyrus D. Posterior cingulate E. Dorsolateral prefrontal cortex 38-2. A 52-year-old woman presents with a 4-month history of new behavioral changes, including impulsivity and interpersonal conflicts leading to termination from work due to repeated disrespectful

comments to her manager. Her husband does not understand how this can have happened, because she always had a very strong work ethic and tremendous respect for her managers; he states that he does not recognize his wife at times. On exam, you observe a flirtatious attitude with lack of social graces, and identify bitemporal visual field deficits. What additional findings could you expect in this patient? A. Left up-going toe B. Positive Romberg C. Anosmia D. Poor phonemic and semantic fluency E. Rightward bias in line bisection CHAPTER 39: Neuropsychiatric Dysfunction 39-1. Which of the following syndromes and disorders is NOT accompanied by fluctuation of consciousness and cognition? A. Delirium B. Dementia of the Lewy body type C. Schizophrenia D. Catatonia secondary to primary psychopathology E. Catatonia secondary to a general medical condition 39-2. Tools for assessing executive functioning include all of the following EXCEPT : A. Ramparts B. Luria (hand) maneuvers C. Clock draw D. Trails-B task E. Forward digit span CHAPTER 40: Clinical Neurophysiology and Electroencephalography 40-1. Which of the following statements about the scalp EEG is correct?

A. The EEG provides high specificity but low sensitivity. B. The EEG can be used to diagnose epilepsy even if a patient has never had a seizure. C. The EEG provides equal coverage of both superficial and deep cortical regions. D. The EEG is higher yield if stage II sleep is captured. E. The EEG does not vary with age. 40-2. Which of the following EEG abnormalities is most likely to be seen with epilepsy? A. Generalized delta slowing B. A reactive alpha posterior dominant rhythm C. Left temporal theta slowing D. Right frontal spike and slow wave discharges E. Excessive beta activity 40-3. A routine EEG is ordered on a patient on the inpatient psychiatry service. Which of the following psychotropic medications from the patient’s medication list is associated with the presence of epileptiform abnormalities on the EEG? A. Fluoxetine B. Clozapine C. Clonazepam D. Valproic acid E. Lamotrigine CHAPTER 41: Seizure Disorders 41-1. A previously healthy 24-year-old right-handed woman is brought to the emergency department by her friends after her first generalized tonic–clonic seizure. She feels she is back to baseline and her vital signs are stable. Which of the following is not a necessary component of her initial work-up? A. A complete metabolic panel

B. Neuroimaging (CT or MRI) C. An EEG D. Lumbar puncture E. Urine toxicology 41-2. Which of the following medications should be avoided in a patient with generalized anxiety disorder and focal epilepsy, due to the possibility of seizure exacerbation? A. Clonazepam B. Bupropion C. Buspirone D. Sertraline E. Pregabalin 41-3. You are asked to see a 40-year-old man with a poorly controlled major depressive disorder, currently maintained on escitalopram and aripirazole. He experiences recurrent focal dyscognitive seizures over a 1-week period. Which of the following anti-seizure medications should you avoid? A. Valproic acid B. Carbamazepine C. Oxcarbazepine D. Lamotrigine E. Levetiracetam 41-4. A 25-year-old man with a history of post-traumatic stress disorder presents for a second opinion regarding spells of altered awareness. You are shown a video of a typical event characterized by eye closure, sideto-side head-shaking, and erratic movements of the extremities. His current medication regimen includes: sertraline, lamotrigine, alprazolam, and levetiracetam. A prior work-up has included a normal MRI scan of the brain. Which of the following is the most appropriate next step? A. Discontinue the levetiracetam B. Optimize sertraline and alprazolam dosing

C. Add a beta-blocker D. Refer for video EEG monitoring E. Repeat the brain MRI 41-5. Which of the following anti-seizure medications is not a hepatic enzyme inhibitor or inducer? A. Lamotrigine B. Carbamazepine C. Valproic acid D. Oxcabazepine E. Phenobarbital CHAPTER 42: Headache 42-1. Which of the following is true regarding patients with cluster headaches? A. They are more likely to be female B. They are likely to lie in a quiet, dark room with an ice pack over the affected temple during an attack C. They are usually non-smokers and non-drinkers D. They are known to attempt suicide secondary to their pain 42-2. An 18-year-old girl has intermittent bitemporal and occipital headaches that are worse when she is at school. She has undergone counseling at school for depression and anxiety. Which of the following is the most likely diagnosis? A. Cluster headache B. Malingering C. Migraine headache D. Temporal arteritis E. Tension-type headache CHAPTER 43: Pain

43-1. Referral to a multi-disciplinary pain center is usually most appropriate when patients demonstrate evidence of which of the following? A. Purely psychiatric mechanisms B. Purely neuropathic mechanisms C. Both psychological tension and physical muscle tension D. Both somatic and psychological factors 43-2. Which of the following tricyclic antidepressants is most appropriate for treatment of pain in an 80-year-old male with post-herpetic neuralgia and urinary retention? A. Amitriptyline B. Doxepin C. Desipramine D. Imipramine CHAPTER 44: Stroke 44-1. A 67-year-old, right-handed man with a history of hypertension, hyperlipidemia, obesity, and smoking, but no prior psychiatric or neurologic history, is brought by family to the emergency department for an evaluation of depression. Per his family, he was in his usual state of health until five days earlier when he began speaking “gibberish” and then tripped and sustained a fall without a head-strike. Since this incident, he has been withdrawn, quiet, and lacking of motivation to tend to his activities of daily living (ADLs). His family notes that he has been adamantly denying any problems, despite not being able to find the bathroom in his home. Mental status exam is notable for abnormal speech with flattened prosody, increased latency, and slurring of his words. Which stroke syndrome is he most likely to have and what would you look for on the neurologic exam? A. Anterior cerebral artery; Ataxia, nystagmus, and cranial nerve deficits B. Middle cerebral artery; Left facial droop, left-sided pronator drift C. Posterior cerebral artery; Contralateral hemianopia with macular sparing

D. Cerebellar stroke; Motor weakness on left upper and lower extremity 44-2. A 72-year-old woman is recovering in a rehabilitation facility 1 week after sustaining a large, left-sided anterior cerebral artery stroke. Although she was initially motivated to participate in physical, occupational, and speech therapy, she is now disengaged from her treatment and requesting to be discharged early. On interview, she notes a lack of interest and motivation, feelings of hopelessness, feeling like a burden on her family, insomnia, difficulty with energy, motivation, and appetite. What treatment has been shown to improve motor functioning in addition to depressive symptoms in the post-stroke period? A. Methylphenidate 5 mg twice daily (BID) B. Fluoxetine 20 mg daily C. Mirtazapine 15 mg nightly D. Valproid acid 500 mg BID CHAPTER 45: Movement Disorders 45-1. A 61-year-old man with no prior psychiatric history presents for evaluation of hallucinations and memory impairment that have progressed over the past eight months. His wife reports that for the previous several years he has exhibited thrashing and yelling during sleep; she adds that at times he will not respond to her at all and seems “lost in space.” He endorses visual hallucinations of small animals and people, but is usually aware of their unreality. Exam shows rigidity in both upper extremities; however, the medical workup, including head imaging, is otherwise unremarkable. Which of the following would be the most appropriate treatment of his psychiatric symptoms? A. Pimavanserin B. Clozapine C. Levodopa D. Deep brain stimulation (DBS) of the globus pallidus E. Risperidone

45-2. A 17-year-old is brought to the clinic by his mother for reported disruptive behaviors at school. She notes that 3 years earlier, he was diagnosed with attention deficit hyperactivity disorder (ADHD) for which he takes methylphenidate. He recently began to bark, blink, and grimace (both in class and at home); these behaviors occur sporadically and are non-repetitive. His mother noted that he experienced similar symptoms for about 2 years when he was younger, but they resolved on their own. Which is the least important feature in determining that these behaviors are complex tics and not stereotypies? A The patient reports that prior to these movements, he feels a sudden “urge” that the movement relieves. B. The behaviors include verbal as well as motoric elements. C. The movements and vocalizations occur sporadically and are not continuously expressed. D. The behaviors disappeared for many years prior to their return. E. The patient has a previous diagnosis of ADHD. CHAPTER 46: Basic Psychopharmacology 46-1. The tolerance that develops with prolonged exposure to an anxiolytic is thought to be the result of: A. Desensitization of γ -amino butyric acid (GABA) receptors B. Changes in levels of ionotropic receptor gene expression via secondary messenger signaling cascades C. Up-regulation of G-protein-coupled receptors (GPCRs) D. The immediate effects of the influx of ions 46-2. Which of the following synaptic connections would not allow for a neural signal? A. Axo-dendritic B. Axo-somatic C. Axo-axonal D. Dendritic-dendritic

CHAPTER 47: Treatment of Anxiety Disorders 47-1. Which of the following benzodiazepines has the longest half-life? A. Alprazolam B. Diazepam C. Oxazepam D. Lorazepam 47-2. Which of the following s elective serotonin re-uptake inhibitors (SSRIs)/serotonin norepinephrine re-uptake inhibitors (SNRIs) is FDAapproved for all major anxiety disorders (panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder)? A. Venlafaxine B. Sertraline C. Fluoxetine D. Paroxetine CHAPTER 48: Antipsychotic Drugs 48-1. Rank the risk of tardive dyskinesia (TD) for the following antipsychotics in descending order (highest risk to lowest): A. Aripiprazole > haloperidol > clozapine B. Paliperidone > fluphenazine > haloperidol C. Haloperidol > risperidone > clozapine D. Brexpiprazole > aripiprazole > lurasidone 48-2. Which combination of medications should be avoided due to adverse interactions? A. Risperidone and lamomtrigene B. Clozapine and carbamazepine C. Lurasidone and ibuprofen D. Haloperidol and benztropine

CHAPTER 49: Antidepressants and Somatic Therapies 49-1. The most common side effects of SSRIs are thought to be mediated by serotonin receptors in different parts of the brain and body. Which one of the following pairings is incorrect? A. Nausea–hypothalamus and brainstem serotonin receptors B. Insomnia–mesocortical serotonin receptors C. Bowel motility, cramps and diarrhea–gastrointestinal system serotonin receptors D. Sexual dysfunction–mesocortical and spinal cord serotonin receptors 49-2. Which antidepressant is an inhibitor of 2D6? A. Venlafaxine B. Citalopram C. Duloxetine D. Sertraline CHAPTER 50: Electroconvulsive Therapy 50-1. Which one of the following is not an expected physiological change during routine electroconvulsive therapy (ECT) administration? A. Parasympathetic discharge leading to bradycardia and even asystole following initial electrical stimulation B. Decrease in cerebral oxygen consumption by 50% C. Hypertension and tachycardia during seizure associated with raise in the sympathetic flow and circulating cathecolamines D. Rise in cerebral blood flow and intracranial pressure E. Increase in blood–brain barrier permeability 50-2. Which is the following has been associated with fewer cognitive side effects during ECT? A. Bilateral electrode placement B. Pre-treatment hypoventilation

C. 0.3 ms pulse width D. Advanced age E. Pre-existing neurological conditions CHAPTER 51: Neurotherapeutics 51-1. A 45-year-old woman with a history of treatment-resistant depression asks you about neural stimulation treatments for depression. Which neurostimulatory treatment is least invasive? A. Vagal nerve stimulation B. Transcranial magnetic stimulation C. Deep brain stimulation D. All of the above are equally invasive 51-2. A 34-year-old man with major depressive disorder has failed 4 adequate anti-depressant trials and is seeing you for a TMS treatment consultation. He wants to know about the potential adverse effects of TMS treatment. Which of the following are possible adverse effects of TMS? A. Headache B. Syncope C. Seizure D. All of the above CHAPTER 52: Lithium 52-1. Which of the following classes of medications is most likely to decrease serum levels of lithium? A. ACE inhibitors B. Calcium channel blockers C. Non-steroidal anti-inflammatory drugs (NSAIDs) D. Thiazide diuretics E. Xanthines

52-2. Which of the following adverse effects is least likely to be seen in cases of lithium toxicity? A. Aphasia B. Ataxia C. Diarrhea D. Tremor E. Vomiting CHAPTER 53: Anti-Epileptic Drugs and Psychiatric Illness 53-1. Routine monitoring of the white blood cell count is particularly important when prescribing which of these anti-epileptic drugs? A. Lamotrigine B. Topiramate C. Gabapentin D. Carbamazepine 53-2. A 24-year-old woman presents with at least two weeks of “moodiness,” characterized by a irritability, anger, and passive suicidal ideation (when her boyfriend leaves the apartment for work in the morning). She has had a single episode of hypomania and several past episodes of depression. She is not currently psychotic, and has a completely unremarkable past medical history and physical exam. Of note, her recent mood episodes tend to remit when her boyfriend returns home from work or her friends take her to dinner. She also has trigeminal neuralgia. You should consider prescribing: A. Pregablin B. Valproate C. Lamotrigine D. Lithium E. Carbamazepine CHAPTER 54: Stimulants, Atomoxetine, Beta-Adrenergic Blocking Agents,

and Alpha-Adrenergic Blocking Agents 54-1. Which of the following first-line treatments for attention deficit hyperactivity disorder (ADHD) is associated with the greatest risk of sedation? A. Amphetamine B. Atomoxetine C. Clonidine D. Guanfacine E. Methylphenidate 54-2. Compared to stimulants, a notable complication of atomoxetine treatment for ADHD is which of the following? A. Increase in depression symptoms among adults with ADHD B. Requirement of regular dosing to sustain therapeutic blood levels C. Substance abuse in patients reporting nicotine use D. Weight gain in patients older than 35 E. Contraindication to use with other ADHD medications CHAPTER 55: Drug–Drug Interactions in Psychopharmacology 55-1. Which of the following drug–drug interactions involves a pharmacodynamic rather than pharmacokinetic mechanism: A. Lithium toxicity following initiation of hydrochlorothiazide B. Reduction in the efficacy of pramipexole due to co-prescription of risperidone C. Inhibited conversion of tamoxifen into its active form due to concurrent paroxetine D. Elevated clozapine levels following smoking cessation 55-2. Compared with individuals who are normal (“extensive”) metabolizers with respect to a given cytochrome enzyme, an individual who is a “poor metabolizer” by virtue of a genetic polymorphism will exhibit

which of the following when administered a substrate whose metabolism relies on that enzyme: A. Lower likelihood of side effects when administered that substrate B. Higher concentrations of that substrate’s metabolite C. Increased sensitivity to an inhibitor of that enzyme D. Higher concentrations of the substrate CHAPTER 56: Cardiovascular and Other Side Effects of Psychiatric Medications 56-1. Which atypical antipsychotic medication has been associated with the greatest degree of QTc prolongation? A. Aripiprazole B. Olanzapine C. Ziprasidone D. Lurasidone 56-2. Which atypical antipsychotic medication carries the highest risk for tardive dyskinesia? A. Olanzapine B. Risperidone C. Clozapine D. Ziprasidone CHAPTER 57: Natural Medications in Psychiatry 57-1. Which of the following statements about 5-methyl tetrahydrofolate (Deplin) is false ? A. It has been shown to be effective augmentation therapy for selective serotonin re-uptake inhibitor non-responders. B. It is FDA-approved for treatment or prevention of vitamin deficiencies. C. It is available by prescription only.

D. It has preparations that contain additional nutrients (vitamins B2 , B6 , B12 , and n-acetyl cysteine) that are approved to treat dementia. E. It crosses the blood-brain barrier directly. 57-2. Which of the following statements is true ? A. S-adenosyl methionine was recently shown to be more effective in women than in men. B. The main active ingredients of St. John’s wort (hypericum) include hypericin, hyperforin, and kavapyrones. C. Omega-3 fatty acids may prevent depression in patients who are taking interferon therapy for hepatitis. D. Inositol should be avoided in pediatric populations. E. Ginkgo has recently been shown to be more effective than cholinesterase inhibitors in dementia. CHAPTER 58: Suicide 58-1. Which of the following is the best predictor of suicide? A. Presence of a mood disorder B. Prior suicide attempt C. History of divorce D. Access to firearms 58-2. Which of the following is the most common means of completed suicide in the United States? A. Use of a firearm B. Suffocation C. Overdose D. Drowning CHAPTER 59: Psychiatry and the Law I: Informed Consent, Competency, Treatment Refusal, and Civil Commitment

59-1. Criteria for civil commitment can include: 1. Dangerousness to self as evidenced by threats or attempts to cause selfharm 2. Dangerousness to others as evidenced by threats or attempts to cause harm 3. Dangerousness to self as evidenced by inability to provide for oneself 4. Inability to make informed decisions regarding treatment of one’s mental illness A. 1 and 2 B. 2 and 4 C. 1, 2, and 3 D. All of the above 59-2. Exceptions to informed consent include: 1. Emergency 2. Incompetence 3. Waiver 4. Patient would be dissuaded from making the right decision A. 1 and 2 B. 2 and 4 C. 1, 2, and 3 D. All of the above CHAPTER 60: Psychiatry and the Law II: Criminal Issues and the Role of Psychiatrists in the Legal System 60-1. The reasons for requiring that the defendant be competent to stand trial during criminal proceedings include: 1. It makes the trial go faster. 2. It preserves the integrity of the legal system 3. It makes the defense attorney’s job easier. 4. It helps to ensure a fair trial. A. 1 and 3

B. 2 and 4 C. 1, 2, and 3 D. All of the above 60-2. True statements about the psychotherapist-patient privilege include: 1. Unlike confidentiality, the patient must raise the privilege to keep the physician from testifying. 2. A treating clinician may be required to testify concerning otherwiseconfidential information about his patient if the patient asks him to (express waiver). 3. A treating clinician may be required to testify concerning otherwiseconfidential information about his patient if the patient has put his mental state in issue as part of the legal proceedings (implied waiver). 4. He believes it is in the patient’s best interests. A. 1 and 2 B. 2 and 4 C. 1, 2, and 3 D. All of the above CHAPTER 61: Patient Adherence 61-1. Which of the following statements is true? A. Optimal adherence increases the likelihood that patients will experience treatment response or remission, thereby reducing the burden of illness for patients, families and health-care systems. B. There is weak evidence to support the notion that non-adherence is common across all branches of clinical medicine. C. Adherence is closely correlated with income levels of patients and families. D. Paranoid patients are more likely to be adherent with treatment given that they are vigilant about what they take into their body. 61-2. Which of the following statements is most accurate? A. Challenges to adherence are multi-level, including patient factors (e.g.,

cognitive impairment), clinician factors (e.g., approach to patient care), structural issues (e.g., healthcare fragmentation), and social concerns (e.g., stigma of illness). B. Treatment decisions should not be influenced by a patient’s perception about their health. C. Collaborative decision-making has little impact on a patient’s feelings of empowerment. D. Daily prompts have little impact on adherence with medication-taking. CHAPTER 62: An Overview of the Psychotherapies 62-1. A patient has a difficult session with his therapist and then is late for the next three appointments. He notes that traffic is always bad but that he somehow can’t seem to leave early enough to be on time for his appointments. From a psychotherapeutic standpoint, which of the following unconscious processes is most likely active? A. A negative cognition B. Resistance C. Overt hostility D. Poor executive function 62-2. A man is worried that he will faint in the subway station. His therapist teaches him to relax and then eventually takes him into a subway station. This is an example of: A. Cognitive-behavioral therapy (CBT) B. Psychodynamic therapy C. Group therapy D. Behavioral therapy CHAPTER 63: Brief Psychotherapy 63-1. Which of the following individuals is most closely associated with brief psychodynamic psychotherapy? A. Beck

B. Budman C. Klerman D. Sifneos 63-2. Which of the following is typically considered to be an exclusion criterion for patient selection for brief therapy? A. A desire for relief B. An ability to commit to treatment C. A history of positive relationships D. A significant risk of self-harm 63-3. Which of the following is not typically considered as a treatment focus for brief therapy? A. Developmental desynchronizes B. Executive dysfunction C. Interpersonal conflicts D. Losses (past, present, or pending) CHAPTER 64: Couples Therapy 64-1. According to John Gottman’s research on couple’s fighting, which of the following is a true statement? A. Couples should learn to paraphrase what their partners say to show that they have heard each other. B. The presence of fighting in newlyweds is predictive of divorce. C. The presence of defensiveness, criticism, stonewalling, and contempt during a fight is predictive of divorce. D. Teaching couples how to “fight fairly” is important in decreasing conflict. 64-2. Which of the following is not part of doing a couples evaluation? A. Creating a relational description of the presenting problem B. Talking to the individual therapists to find out any secrets about the couple’s relationship C. Finding out about stresses and changes in the last year

D. Asking about the couple’s sexual relationship CHAPTER 65: Family Therapy 65-1. Whenever his parents engage in a verbal argument, one child predictably engages in a physical altercation with his younger sibling. The typical result is that the parents become distracted from their original argument to address the aggression between the siblings. A behavioral family therapist would most likely attribute this pattern of behavior in the older sibling to which of the following: A. Anticipation B. Positive reinforcement C. Negative reinforcement D. Extinction 65-2. A family therapist poses the question “What are some of the things depression does to Sally in order to block her family from helping her beat it?” This is an example of: A. Re-framing B. Externalization C. Paradoxical intervention D. Circular questioning CHAPTER 66: Group Psychotherapy 66-1. What is the least important factor in determining the success of any type of group psychotherapy? A. The ability of the therapist to provide a safe container and meaning for the group B. The ability of the therapist to attend to breaches of the contract so as to convey the importance of the contract and to understanding the meaning of breaches C. The ability of the leader to create a feeling of cohesion in the group and thereby giving it value

D. The ability of the leader to be reimbursed in a timely fashion by group members E. The ability of the leader to spend time in preparing each group member for the group so that he or she comes into the group understanding the goals and role expectations for the members and the leader 66-2. Which of the following is not an ingredient of a typical group agreement? A. Regular attendance B. Meeting financial obligations to the group leader C. Maintaining confidentiality of the group D. Regular use of psychotropics CHAPTER 67: Cognitive-Behavioral Therapy 67-1. Which of the following is not a cognitive technique? A. Problem solving B. Guided discovery C. Reattribution D. Modification of core beliefs E. Advantages and disadvantages analysis 67-2. Which of the following is not a principle of cognitive-behavioral therapy (CBT)? A. CBT focuses on subjective experience and the centrality of self. B. CBT is time-limited for both Axis I and Axis II disorders. C. CBT focuses on the present initially. D. Axis I disorders differ from Axis II disorders with regards to access to adaptive core beliefs. E. According to the CBT model, in order to achieve lasting behavioral change, core beliefs need to be modified. CHAPTER 68: Mind–Body Medicine

68-1. Which of the following is not a demonstrated effect of mind–body techniques? A. Epigenetic changes that alter expression of genes involved in inflammation and metabolism B. Decreased heart rate, vascular tone, respiratory rate, and oxygen consumption C. Decreased oxidative stress D. Increased activity of the innate immune system 68-2. Which of the following conditions requires caution when recommending use of mindfulness techniques? A. Depression B. Psychosis C. Musculoskeletal pain D. Seizure disorder CHAPTER 69: Geriatric Psychiatry 69-1. Which of the following statements about suicide in the elderly is most accurate? A. Roughly 1 in 18–20 suicide attempts in the elderly result in death. B. Suicide is uncommon in the elderly. C. The risk of death after a suicide attempt in those > 65 years old is double that of those in the United States population. D. While older adults comprise 12% of the United States population, they accounted for 22% of the deaths by suicide. 69-2. Which of the following activities is considered to be an instrumental activity of daily living? A. Cooking B. Dressing oneself C. Maintaining hygiene D. Using the bathroom

69-3. Which of the following statements about depression in the elderly is most accurate? A. Approximately 50% of those with dementia have co-morbid major depressive disorder. B. Depression lowers the life expectancy of the elderly. C. Depression leads to psychiatric hospitalization in approximately 10% of those afficted. D. Nearly 30% of depressed patients have co-morbid anxiety. 69-4. Which of the following conditions is most common? A. Alzheimer’s disease B. Frontal lobe dementia C. Lewy body disease D. Vascular dementia CHAPTER 70: Psychiatric Epidemiology 70-1. Which is the most prevalent psychiatric disorder recognized in the National Co-morbidity Survey-Replication Study (NCS-R)? A. Panic disorder B. Nicotine dependence C. Major depression D. Phobia E. Alcohol abuse/dependence 70-2. Alcohol abuse is related to all of the following except : A. Low educational level B. Male gender C. Older age D. Divorced status E. Low income

CHAPTER 71: Statistics in Psychiat ric Research 71-1. Which of the following scales is most likely to be nominal? A. Age in years B. Race C. Body mass index D. Medication dose in mg 71-2. You have identified four methodologically-equivalent randomized double-blind placebo-controlled trials for which the patient in front of you would have met inclusion criteria. All used the same outcome score and treatment intervals. All four report a Cohen’s d (a measure of effect size) and a p- value for the t-test on the difference of means. Based on the following d’s and p’s alone which study drug would you prescribe? A. d = 3.4, p = 0.4 B. d = 0.1, p = 0.00001 C. d = 2.5, p = 0.002 D. d = 0.3, p = 0.65 CHAPTER 72: Psychiatric Research Metho dology 72-1. Which of the following study designs allows for causal conclusions? A. Randomized controlled trial B. Cohort study C. Case control study D. Cross sectional study 72-2. If two psychiatrists perform a structured clinical interview on a research participant and come to different conclusions, this would reflect poorly on which of the following? A. Test-retest reliability B. Face-validity C. Inter-rater reliability

D. Construct validity CHAPTER 73: Genetics and Psych iatry 73-1. Which of the following is not a genetic mutation in DNA associated with causing psychiatric illness? A. Copy number variant B. Translation C. Deletion D. Single nucleotide polymorphism E. De novo mutation 73-2. A 32-year-old married woman and her 34-year-old husband are hoping to conceive a baby in the coming year. The woman has a family history of bipolar disorder and panic disorder in two different seconddegree relatives. Her husband was raised by a father with alcohol use disorder and he and his brother both suffer from unipolar depression. The couple is interested to learn about the genetic heritability of these disorders prior to conceiving a baby. Which of the following disorders has the highest rate of genetic heritability? A. Panic disorder B. Unipolar depression C. Alcohol use disorder D. Bipolar disorder E. Both bipolar disorder and unipolar depression have similarly high heritabilities 73-3. A psychiatric researcher is studying a large cohort of individuals to assess genes that may be implicated in anorexia nervosa. She has designed a genome wide association study (GWAS) to ascertain which mutations might be implicated in this disorder. Which of the following is true of GWAS study design? A. Hundreds or thousands of samples might be required to obtain sufficient statistical power B. A high logarithm of the odds (LOD) score means that an identified

mutation is likely due to random chance and is not associated with the disease C. Prior knowledge of target genes of interest is required for study design D. Fluorescent probes are used to bind to complementary strands of DNA E. Only the genomes of related individuals can be compared to one another 73-4. Which of the following is not associated with Down syndrome/trisomy 21? A. Congenital heart defects B. Early-onset Alzheimer disease C. Duodenal atresia D. Hypothyroidisim E. Obesity related to chronic hunger CHAPTER 74: Psychiatry and the Law III : Malpractice and Boundary Violations 74-1. Which of the following are elements of a malpractice claim? A. Departure from the standard of care B. Existence of a duty of care C. Direct or proximate causation D. Damages E. A and C F. B and D G. A, B, and C H. All of the above 74-2. Sexual relations with a patient can result in which of the following? A. Suspension or loss of the psychiatrist’s medical license B. Ethical censure C. A malpractice claim D. Criminal conviction

E. A and C F. B and D G. A, B, and C H. All of the above CHAPTER 75: Psychiatric Consultation to Me dical and Surgical Patients 75-1. Which of the following is not among the most common reasons for psychiatric consultation in a general hospital setting? A. Delirium B. Depression C. Delusional disorder D. Decision-making capacity 75-2. Which of the following statements is most accurate with regard to psychotherapeutic interventions in medically ill hospitalized patients? A. It is intended to explore long-standing intrapsychic conflicts. B. It focuses on the here-and-now and attempts to bolster adaptive reactions to stress. C. It is modality-specific and targets specific psychiatric disorders. D. It is utilized only when interpersonal conflicts arise between patients and the medical–surgical team. CHAPTER 76: Organ Transplantation 76-1. Which of the following organizations in the United States regulates the allocation and distribution of donor organs? A. AMA B. AACAP C. UNOS D. APM E. OPTN

76-2. True or False? There are no universally accepted guidelines for the psychiatric evaluation of potential candidates for organ transplantation. A. True B. False CHAPTER 77: Chronic Mental Illness 77-1. Patients with schizophrenia are at highest risk for which of the following? A. Being a victim of violence B. Perpetrating violence C. They aren’t at increased risk for interpersonal violence, only suicide D. They aren’t at increased risk for interpersonal violence or suicide 77-2. On average, adults with serious mental illness die ____ compared to those in the general population? A. 5 years earlier B. 5 years later C. 25 years earlier D. At the same time CHAPTER 78: Intimate Partner Violence (IPV) 78-1. Which factor may prevent a clinician from considering intimate partner violence (IPV) in a patient who presents with a suspected broken arm injury? A. Physician is embarrassed to ask about abuse B. Patient has a high socio-economic status C. Physician does not have access to referral agencies or supports such as shelters or interpreters D. Lack of training and awareness of IPV on behalf of the physician E. All of the above

78-2. Which item of medical history is not consistent with possible IPV? A. Somatic complaints B. Multiple visits to the ED C. Fibromyalgia D. Unusual injuries with unlikely explanations E. A history of accidents CHAPTER 79: Abuse and Neglect 79-1. The daughter of an 85-year-old woman brought her mother to the mother’s physician and reported that her mother, who lives alone, has been inconsistently taking her medications and not eating or drinking regularly. She’s also been hoarding newspapers, food boxes, coupons, and mail. She hasn’t been bathing regularly or washing her clothes. What is the best characterization of the patient’s condition? A. Dementia B. Alzheimer’s disease C. Self-neglect D. Depression E. Dehydration 79-2. Which of the following is not a sign of neglect of a child? A. Malnutrition B. Poor dentition C. Lack of immunization D. Poor hygiene E. Untreated medical illness F. Chronic and unaddressed truancy G. Depression H. Substance abuse 79-3. Which of the following are reasons that make it difficult to detect abuse in the elderly?

A. The elderly are often too frail to advocate for themselves. B. The perpetrator is most likely a family member and the victim doesn’t want to implicate them. C. Signs of abuse may be mistaken for signs of illness. D. Dementia, if present, can interfere with a victim’s ability to assess her own situation. E. Financial exploitation is not typically presented in a clinical exam. F. All of the above. CHAPTER 80: Lesbian, Gay, Bisexual, Transgender, and Queer (LGBTQ) Mental Health 80-1. Which of the following is the minimum duration of gender dysphoria needed to meet DSM-5 diagnostic criteria? A. 3 months B. 6 months C. 9 months D. 12 months 80-2. Which of the following constitutes appropriate psychiatric management for an adult patient assigned male sex at birth, with active alcohol use disorder (severe) and schizophrenia with delusions, who has consistently reported being a woman to you and requested feminizing cross-sex hormone therapy for the past 3 years? A. Treat the patient’s alcohol use disorder and schizophrenia; the patient’s gender dysphoria is part of a delusional belief system and will hopefully resolve with sobriety and antipsychotics. B. Treat the patient’s alcohol use disorder and schizophrenia; the patient’s gender dysphoria might persist, but cross-sex hormone therapy is contraindicated for patients with schizophrenia. C. Treat the patient’s alcohol use disorder and schizophrenia; the patient lacks medical decision-making capacity for cross-sex hormone therapy. D. Treat the patient’s alcohol use disorder and schizophrenia; as these disorders become reasonably well controlled, gender-affirming cross-sex

hormone therapy is indicated if the patient has capacity to make medical decisions. CHAPTER 81: Culture and Psychiatry 81-1. Which of the following concepts has been eliminated from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)? A. Cultural syndrome B. Culture-bound syndrome C. Cultural idiom of distress D. Cultural explanation 81-2. Which class of medications is most likely to be affected by racial/ethnic genetic variations in psychotropic drug metabolism? A. Anticonvulsants B. Benzodiazepines C. Selective serotonin re-uptake inhibitors D. Stimulants CHAPTER 82 : Approaches to Collaborative Care Psychiatry and Primary Care 82-1. You have been asked to see a 68-year-old woman with a history of chronic depression as the specialty physician on a collaborative-care team. What type of care manager will contribute most to the best patient care outcomes? A. A master’s-level mental health specialist who started work as a care manager 6 months ago. B. A registered nurse who transferred from the inpatient care after 10 years of practice. C. A social worker with L.C.S.W. who completed an internship focused on collaborative care earlier this year. D. An office manager with no clinical training.

82-2. A 19-year-old patient presented to his primary-care physician’s office with his mother. She noted that his personality had changed with reduced sleep and talkativeness; in addition, he spent all of his savings from his summer job on new clothes, which was unusual for him. If this patient were to be followed in a collaborative care model, what would be the model’s essential components? A. Having a systematic way of identifying patients with mental illness, where identified patients are followed by a team, who works together to deliver interventions and track his progress through specified monitoring. B. Having a primary-care physician work in the same office as a psychiatrist and having them meet regularly to discuss the patient’s case and progress. C. Having a team of nurses who follow the patient and check in with him weekly, updating both the primary-care doctor and the mental health physicians as indicated. D. Having a systematic referral system, in which he would be seen by a psychiatrist immediately and then be followed by a care team who encourages the patient to engage in community resources. CHAPTER 83: Community Psychiatry 83-1. Which of the following terms best defines a method of contracting for health-care provision, for a given population, based upon up-front payment of a set monetary amount, per member, per month? A. Capitation B. Carve-out C. Cost-shifting D. Managed care 83-2. Who among the following is most closely associated with the advent of “moral treatment”? A. Clifford Beers B. John Kennedy C. Adolf Meyer

D. Phillipe Pinel CHAPTER 84: Psychiatric Care of Military Personnel and Returning Veterans 84-1. Which of the following psychotherapy treatments for post-traumatic stress disorder (PTSD) has the most robust evidence base for efficacy? A. Psychodynamic psychotherapy B. Stress inoculation training C. Prolonged exposure D. Image rehearsal therapy 84-2. Most military service members and veterans who complete suicide do so by which of the following means? A. Drug overdose B. Firearms C. Hanging D. Automobile CHAPTER 85: Sports Psychiatry 85-1. Which of the following disorders is more prevalent in athletes than in the general population? A. Eating disorder not otherwise specified (ED NOS) B. Anxiety disorders C. ADHD D. Substance use disorders E. Mood disorders 85-2. Which of the following medications will likely require a TUE (Therapeutic Use Exemption) for an athlete playing at college or professional level? A. Fluoxetine

B. Lithium C. Methylphenidate D. Amitriptyline E. Aripiprazole CHAPTER 86: Global Mental Health: Concepts and Personnel 86-1. According to the World Health Organization, which illness is the second leading cause of disability? A. Cancer B. Depression C. Bipolar disorder D. Renal disease 86-2. According to the World Health Organization, what is the projected cost–benefit for each dollar invested in the treatment of depression and anxiety? A. $1 B. $2 C. $4 D. $10 86-3. While working in international mental health, which of the following ethical practices is/are crucial: A. Collaboration with local community leaders in establishing programs B. Understanding culturally-relevant conceptions of and terminologies for mental illness C. Focusing on local capacity building and task-shifting wherever possible D. All of the above CHAPTER 87: Quality Assurance and Quality Improvement

87-1. The SMART Aim statement was designed to do which of the following? A. Assist with the investigation into adverse events B. Assist with the design of a quality improvement project C. Characterize high-value health-care organizations D. Measure clinical outcomes of a quality improvement project 87-2. The fishbone diagram (also known as Ishikawa diagram or herringbone diagram) is a tool sometimes used for which of the following? A. For implementing quality improvement measures in health care B. To incentivize hospitals and health-care providers to adopt computerized medical records C. To investigate sentinel events D. To determine adherence to clinical standards CHAPTER 88: Ethical Considerations in Psychiatry Throughout the Lifespan 88-1. A psychiatrist is consulted to evaluate the capacity of a patient with extensive blood loss from a gastric ulcer who is refusing blood transfusion. The patient explains that he is a Jehovah’s Witness and that he would rather risk death than violate his community’s religious doctrine against receiving blood products. The psychiatrist concludes that the patient has the capacity to refuse the transfusion. The medical team does not give the patient any blood products, and the patient subsequently dies. What ethical principle justifies the medical team’s actions? A. Respect for autonomy B. Beneficence C. Non-maleficence D. Justice E. Virtue

88-2. A patient with terminal lung cancer is placed in hospice care. The patient is grimacing in pain, and the nurse continues to administer small doses of morphine even though the patient’s breathing is noticeably slowing. What ethical principle justifies this action? A. Informed consent B. Multiple agentry C. Double effect D. Therapeutic privilege E. Cultural relativism

Review Answers

CHAPTER 1: Test-Taking Strategies and Combating Test Anxiety 1-1. ANSWER: D . Study consistently for 3 or more months before the exam Studying for longer intervals, using material from the past 5 years, has been associated with better performance. Practice exams are most helpful if taken to simulate the actual exam (all on one day over the same time interval), and contracting with oneself and others to improve adherence to a study schedule. 1-2. ANSWER: A. Changing one’s answers when reviewing items where one felt uncertain. Changing answers when one is uncertain is helpful, whereas those who finish early do not score higher, and using medications or alcohol impairs memory more than improves sleep the night before the exam. Looking for “tricks” distracts from focusing on the pertinence of an item and can attune one to the wrong components of an item. CHAPTER 2: The Psychiatric Interview 2-1. Answer: D. Trauma history. 2-2. Answer: C. Prognosis. CHAPTER 3: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

3-1. Answer: A. Dimensional diagnoses could reduce clinicians’ reliance on “Not Otherwise Specified” diagnoses. The DSM-5 cites the preponderance of “Not Otherwise Specified” (NOS) diagnoses under earlier editions of the manual to argue that traditionally too much emphasis has been placed on excluding false-positive diagnoses, resulting in categories that were overly narrow and not clinically useful— especially in the areas of eating disorders, personality disorders, and autism spectrum disorders. Dimensional diagnostic groupings were created with the intention of facilitating future genetic, neurobiological, and epidemiologic research geared toward gaining a better understanding of pathophysiology and commonalities between disorders, and not as a reflection of agnosticism regarding pathophysiology. 3-2. Answer: C. Move toward a more phenomenological organizational scheme. The DSM-5 represents an attempt to move away from a purely phenomenological organizational scheme, and toward a more neurobiologically-coherent framework, in line with recent calls from the National Institute of Mental Health Research Domain Criteria (RDoC) project. For example, based on their distinct neurocircuitry pathways, new chapters were created for Obsessive-Compulsive and Related Disorders, Depressive Disorders, and Bipolar and Related Disorders, which previously had been subsumed under the less specific categories of Anxiety Disorders and Mood Disorders. CHAPTER 4: Child and Adolescent Development 4-1. Answer: B. Magical thinking. 4-2. Answer: C. Delayed maturation of prefrontal cortex compared to the limbic system. CHAPTER 5: Child and Adolescent Disorders 5-1. Answer: C. 12. According to DSM-5, the symptoms of ADHD must be present before the age of 12. Many children are diagnosed after this age, but the symptoms

often have been present for years prior. Impairment must cross situations and must be noted in at least two settings (e.g., school and home). The symptoms must not be exclusively present when another disorder, such as depression, is present. 5-2. Answer: C. Disinhibited Social Engagement Disorder. In Disinhibited Social Engagement Disorder, the child actively approaches and interacts with unfamiliar adults in an overly familiar way. Like with reactive attachment disorder, the child has a disturbed and developmentally inappropriate ability to relate socially because of social neglect or situations that limit appropriate social interaction and formation of selective attachments. In Reactive Attachment Disorder, there is a consistent pattern of inhibited, emotionally withdrawn behavior toward adult caregivers. CHAPTER 6: Tics and Tourette Disorder 6-1. Answer: A. Methylphenidate. Methylphenidate. Methylphenidate should be the next medication started because it is the gold-standard treatment for ADHD. Although stimulants had been contraindicated in children with tics in the past, a recent metaanalysis by Cohen et al (2015) did not support an association between psychostimulant use and new onset or worsening of tics. Atomoxetine is a non-stimulant ADHD medication typically used in individuals who cannot tolerate stimulants. Risperidone and haloperidol are medications used to treat tics, but not ADHD. 6-2. Answer: D. OCD. Tourette disorder and OCD are highly co-morbid with each other. Studies have shown that individuals with Tourette disorder are more likely to have first-degree relatives with OCD, and individuals with OCD are more likely to have first-degree family members with Tourette disorder. Although there does seem to be increased prevalence of mood disorders in those with Tourette disorder, there is no evidence of a genetic link at this time. There are no known genetic associations between alcohol use or psychotic disorders and Tourette disorder (Hirschtritt et al, 2015). CHAPTER 7: Autism Spectrum Disorders

7-1. Answer: D. Social communication disorder (SCD). A diagnosis of autism spectrum disorder (ASD) supersedes a diagnosis of social communication disorder (SCD), and therefore they cannot be comorbid. A diagnosis of SCD precludes the presence of restricted and repetitive behaviors that are found in ASD. Intellectual disability, seizure disorders, ADHD, and constipation are all commonly seen in children and adolescents with ASD. They would be independently investigated and treated. A medical work-up would be needed for gastrointestinal symptoms and seizures. 7-2. Answer: E. Aripiprazole. Aripiprazole an atypical antipsychotic, is the only medication in this list that is FDA-approved for the treatment of irritability for children with ASD. Although quetiapine is also an atypical antipsychotic, it is not approved for the treatment of the symptoms of irritability related to ASD. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI) that is FDA-approved for the treatment of major depressive disorder (MDD) and OCD in children and adolescents. In this case, the diagnosis of MDD and OCD is less likely than is irritability associated with ASD. Divalproex sodium is a mood sta bilizer and antiepileptic that has not been FDA-approved for use in symptoms associated with ASD. CHAPTER 8: Delirium 8-1. Answer: C. Administration of a benzodiazepine. These history and lab findings are suggestive of chronic alcohol use and benzodiazepines can be used for prophylaxis (and treatment) in the setting of acute discontinuation of alcohol. 8-2. Answer: C. Impaired attention. Impaired attention is the hallmark of delirium. CHAPTER 9: Dementia 9-1. Answer: A. Frontal lobes.

9-2. Answer: E. A, B, and C. 9-3. Answer: E. B and C. 9-4. Answer: D. Visual comprehension and praxis. 9-5. Answer: A. Hypoxic damage to brain tissue. 9-6. Answer: B. Cognitive impairments are reversible. 9-7. Answer: E. B and D. 9-8. Answer: C. AD. 9-9. Answer: B. Head injury. 9-10. Answer: B. Apolipoprotein E4 genotype. 9-11. Answer: C. Aphasia involves speech and reading deficits but spares writing. 9-12. Answer: D. Omega-3 fatty acids. 9-13. Answer: E. The cause of AD is unknown. 9-14. Answer: D. B and C. CHAPTER 10: Intellectual Disability 10-1. Answer: C. Down syndrome. 10-2. Answer: B. Attention-deficit/hyperactivity syndrome. CHAPTER 11: Mental Disorders Due to Another Medical Condition 11-1. Answer: C. Acute renal insufficiency. 11-2. Answer: E. All of the above. CHAPTER 12: Alcoholism and Alcohol Use Disorders 12-1. Answer: D. Give IV thiamine.

This patient presents with the classic triad of ataxia, confusion, and ophthalmoplegia indicative of Wernicke’s encephalopathy. This is caused by a deficiency in thiamine. Without treatment, there is a risk of progression to Korsakoff syndrome, the irreversible condition characterized by anterograde amnesia and confabulation. Initial treatment is with intravenous (IV) thiamine for three days followed by oral supplementation. IV normal saline with dextrose would be contraindicated in this patient as a first step because thiamine is required for cellular ATP generation, and providing sugar could lead to further increase in lactic acid and worsening of the damage associated with thiamine deficiency. An antipsychotic medication would not correct the confusion and disorientation associated with Wernicke’s encephalopathy. Assessing the patient’s alcohol use history with a screening tool would be an acceptable part of treatment but not advisable in the acute stage of this patient’s presentation. Collateral information is useful but this is also not a first step in treatment for this patient and he is not in a state to give consent for his primary care physician to release protected health information. 12-2. Answer: C. Disorientation. A clouded sensorium is the primary distinguishing feature of alcohol withdrawal delirium (AWD) when compared to alcoholic hallucinosis. Visual hallucinations are more common in AWD but can occur in both conditions, as can auditory hallucinations, vital sign instability and tremulousness. The onset of alcohol withdrawal delirium is most common 2 to 4 days after the last drink but can occur as late as a week after the last drink. It is important to screen for regular alcohol use in patients admitted to the hospital where they will not have access to it. CHAPTER 13: Substance-Related Disorders: Cocaine and Opioids 13-1. Answer: D. Episodic smoking of cocaine is less likely to progress to chronic use than episodic intranasal use. Smoking cocaine is more likely to progress to chronic use compared to episodic intranasal use. 13-2. Answer: C. Mesolimbic dopamine system. Mesolimbic dopamine system, involving dopamine projections from the

ventral tegmental area to the nucleus accumbens. 13-3. Answer: D. Methadone is safer than buprenorphine for the neonate during pregnancy. Buprenorphine has been shown to produce significantly less intense withdrawal symptoms, significantly shorter duration of neonatal abstinence syndrome, and shorter lengths of stay post-delivery than methadone. 13-4. Answer: C. According to the CDC, about 50% of IV drug users in the United States are infected by hepatitis C. According to the CDC, about 80% of IV drug users in the United States are infected by hepatitis C. CHAPTER 14: Psychosis and Schizophrenia 14-1. Answer: B. Negative symptoms. To meet the criteria for schizophrenia, an individual must experience active symptoms for at least one month, function below the expected level, and the duration of illness must be for at least 6 months. Active symptoms must include at least two of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms. At least one of the symptoms must include delusions, hallucinations, or disorganized speech. An underlying medical etiology must be ruled out. 14-2. Answer: D. Female gender. Risk factors for a poor functional outcome include prolonged duration of untreated psychosis, younger age at onset of symptoms, prominent negative symptoms, and an initial poor response to antipsychotic medication. Females in general have an overall better prognosis than males. CHAPTER 15: Depressive Disorders 15-1. Answer: A. The probability of relapse of depression is 50% after three episodes of depression. The probability of relapse is 80%. 15-2. Answer: C. It has been shown that suicidal thoughts or behaviors are

decreased in adults over the age of 50. Suicidal thoughts or behaviors are increased in adults older than age 65 years of age. CHAPTER 16: Bipolar Disorder 16-1. Answer: E. Discontinue corticosteroids, continue the SSRI, and start an antipsychotic agent until mania resolves. The patient is most likely presenting with a secondary (corticosteroidinduced) mania and likely psychosis (evidenced by disorganized and violent behavior). When treating secondary mania, the first intervention should be to discontinue the offending agent(s), in this case the steroid. In addition, treatment of the mania and psychosis with an antipsychotic medication is critical, particularly in this patient’s case due to grossly impaired judgment and risk for further violent behavior. While antidepressants are often discontinued in the setting of acute mania, this patient’s history of severe depression and absence of prior evidence of bipolar disorder suggest that the most appropriate treatment would be to continue with antidepressant therapy while concurrently managing the acute mania, which should resolve over a course of days once the steroids are discontinued. 16-2. Answer: D. Lamotrigine has been shown to have a modest effect size in meta-analyses examining its efficacy in treating bipolar depression. Lamotrigine is an anti-epileptic drug (AED) that in meta-analyses has been shown to have a modest treatment effect for bipolar depression. Unlike many other AEDs, lamotrigine does not induce its own metabolism (B ), and it has less drug-drug interactions (and is safe with either olanzapine or fluoxetine, (A ). Lamotrigine is infamous for causing dermatologic reactions, both benign rashes as well as Stevens-Johnson syndrome; the risk may be largely mitigated by always starting at low doses and increasing the dose slowly and cautiously; the risk of rash is increased when prescribing lamotrigine and valproate together, not olanzapine (E ). Only quetiapine, lurasidone, and Symbyax (olanzapine/fluoxetine) are FDA-approved specifically for bipolar depression (C ). Note: there is no evidence that lamotrigine is an effective anti-manic agent, and thus it is not appropriate for long term anti-manic prophylaxis in type I bipolar patients.

CHAPTER 17: Anxiety Disorders 17-1. Answer: C. 25%. 17-2. Answer: A. Panic disorder. Social anxiety disorder, specific phobia, and generalized anxiety disorder all require that symptoms last for 6 months or more to meet the diagnostic criteria. CHAPTER 18: Obsessive-Compulsive and Related Disorders 18-1. Answer: A. Fluoxetine. Of the options listed, only option A (fluoxetine) is a selective serotonin reuptake inhibitor (SSRI). Research has demonstrated that SSRIs are an efficacious first-line treatment for adults with BDD. For option B, research has not yet demonstrated that atypical antipsychotics, such as risperidone, are effective augmenting agents. For option C, NAC has demonstrated efficacy for trichotillomania but not for BDD. Lastly, for option D, this is a short-acting benzodiazepine that is not considered a first-line intervention for BDD. 18-2. Answer: C. The 19-year-old with BDD. Research demonstrates that individuals with BDD have significantly higher rates of suicidal ideation and attempts than those with other obsessivecompulsive and related disorders. CHAPTER 19: Trauma and Post-Traumatic Stress Disorder 19-1. Answer: A. Acute stress disorder. ASD involves symptoms from the same three clusters as PTSD (intrusion/re-experiencing, avoidance/numbing, and hyperarousal), although fewer are required. ASD adds and emphasizes dissociation. In ASD the disturbance lasts from 2 days to 4 weeks of the traumatic event. 19-2. Answer: C. Prazocin. Prazocin in a dosage of 10 mg daily or higher has been found effective in

the treatment of nightmares. The use of propranolol, guanfacine, and clonidine is experimental. 19-3. Answer: B. Benzodiazepines. Benzodiazepines should be used with caution in PTSD because they can exacerbate dissociative symptoms or promote behavioral disinhibition. Tolerance and dependence are common problems, so use of these medications in patients with a history of alcohol or substance abuse is contraindicated. Nevertheless, in selected, non-addiction-prone patients with PTSD, their anxiolytic effect can be beneficial, thus they are relatively contraindicated. CHAPTER 20: Somatic Symptom and Related Disorders 20-1. Answer: B. Illness anxiety disorder. 20-2. Answer: C. Factitious and conversion disorder are both attempts to consciously deceive health care providers. CHAPTER 21: Deception Syndromes: Factitious Disorder and Malingering 21-1. Answer: C. Assuming the sick role. Assuming the sick role is known as primary gain, and is seen in factitious disorders. Secondary gain involves a tangible reward, such as shelter, freedom from legal issues, or avoidance of responsibility, and is seen in malingering. 21-2. Answer: B. Confront the patient early to avoid further deception. The approach to the patient suspected of deceptive behavior should include a thorough work-up to exonerate medical or psychiatric etiologies, contacting collateral sources to verify the patient’s report, and consideration of neuropsychological testing as a way of identifying common patterns of deception. Early confrontation should be avoided because it can provoke evasion, defensiveness, or flight from the hospital. CHAPTER 22: Dissociative Disorders

22-1. Answer: C. Co-consciousness refers to the appreciation by the patient of the existence and feelings of an alter. Co-consciousness refers to the ability of patients with DID to be aware of the feelings and experiences of their alters. Although older conceptualizations of DID required patients to not be aware of their alters, that has changed as the definition of the syndrome has broadened. DID is in fact relatively common, affecting between 1% and 3% of the population. Multiple personality disorder is an old and often lay term for DID, but DID has never been categorized as a personality disorder. 22-2. Answer: D. Treating co-morbid conditions and using directed psychotherapy with an emphasis on therapy for trauma. Most patients with depersonalization/derealization disorders also have comorbid psychiatric conditions, such as depression or anxiety. Treating these conditions, along with appropriate psychotherapies, is the best approach. ECT is rare unless there is co-morbid severe depression. Depersonalization refers to feeling outside of one’s sense of self. It is not related to a patient thinking that he or she is somebody different. Antipsychotics have not been found to be mainstay treatments for these conditions. CHAPTER 23: Sexual Disorders and Sexual Dysfunction 23-1. Answer: D. Female orgasmic disorder. Of the above diagnoses, only female orgasmic disorder appears in the DSM5. The remaining diagnoses were included in DSM-IV but have not been retained in the DSM-5. There is now only a “male” hypoactive sexual desire disorder. Male orgasmic disorder is most analogous to the DSM-5 diagnosis “delayed ejaculation.” Sexual aversion disorder has been eliminated but may be coded as an “other specified sexual dysfunction.” Vaginismus has also been discontinued in DSM-5 but encompassed under the new umbrella term, “genito-pelvic pain/penetration disorder.” 23-2. Answer: B. Flibanserin. Among the choices listed above, flibanserin is the only medication approved by the FDA for the treatment of female sexual dysfunction. Specifically, it may be prescribed for pre-menopausal women who meet criteria for the DSM-IV diagnosis, “hypoactive sexual desire disorder” (a diagnosis that in

fact does not exist in DSM-5). Avanafil is the newest FDA-approved phosphodiesterase type 5 (PDE-5) inhibitor for the treatment of erectile disorder. Tibolone is a novel steroid that has been investigated for the treatment of female sexual dysfunction but was rejected by the FDA. Yohimbine is approved only for erectile disorder. EROS-CTD is FDAapproved for female sexual dysfunction, but it is not a medication; rather, it is a clitoral therapy suction device. CHAPTER 24: Eating Disorders 24-1. Answer: E. Lisdexamfetamine dimesylate and fluoxetine. There are only two pharmacologic agents with an FDA indication for the treatment of one of the eating disorders: fluoxetine has an indication for the treatment of bulimia nervosa and lisdexamfetamine dimesylate has an indication for the treatment of binge-eating disorder (BED). Other agents have been shown effective in RCTs, including topiramate in treating bulimia nervosa (BN) and BED, but their use should be considered off-label. Moreover, bupropion was found to be associated with a greater-thanexpected occurrence of seizures when evaluated in patients with BN and is thus contraindicated in BN. Because the mechanism underlying the seizure risk is unknown, bupropion should be avoided when treating individuals with a current or past eating disorder. A meta-analysis evaluating the use of olanzapine in patients with anorexia nervosa (AN) has not found it to be effective in treating the primary symptoms of AN or in promoting weight gain. 24-2. Answer: D. BN. BN is characterized by recurrent binge eating and compensatory behaviors to avoid associated weight gain, at least once weekly. This individual is engaging in binge eating at least once weekly. Although she is neither vomiting nor using laxatives—two of the most common compensatory behaviors associated with BN—recurrent and excessive exercise can also fulfill the criterion for inappropriate compensatory behavior (BN criterion B). In this case, it is very likely that her driven exercise is being used as an inappropriate behavior to compensate for the caloric intake associated with her binge eating and in order to avoid associated weight gain. It would not be uncommon for an individual with BN to report that the motivation for

exercise is to stay healthy or fit, and it is sometimes clinically challenging to ascertain whether an exercise regimen is excessive. In this case, this individual’s rigid adherence to her regimen, even while injured and apparently interfering with her social functioning, and exercise which is also well in excess of what her peers are doing, are consistent with a recurrent compensatory behavior of BN. There is also evidence of self-disparagement related to her weight, which is consistent with a diagnosis of BN. Bingeeating and excessive exercise can also occur in individuals with AN, but this young woman’s weight is within normal range and thus excludes a diagnosis of AN. Binge eating is a hallmark of BED, but the presence o f recurrent in appropriate compensatory behaviors exclude BED as a diagnosis. There are no clinical signs of depression described in this vignette. Therefore, the most likely diagnosis is BN, non-purging type. CHAPTER 25: Sleep Disorders 25-1. Answer: D. REM. Wakefulness typically reveals alpha waves (4–7 Hz). NREM 1 typically reveals theta waves (4–7 Hz). NREM 2 typically shows theta waves, sleep spindles (12–14 Hz > 0.5 sec), and K-complexes (triphasic). While NREM 3 is comprised by delta waves (0.5–2 Hz) present > 50% of the time. REM sleep reveals with relatively low-voltage, mixed-frequency waves on the electroencephalogram. 25-2. Answer. A. Birth to age 2 years. Approximately 20% of a person’s time asleep is REM sleep after he or she reaches the age of 2 years; however, soon after birth, roughly 50% of sleep is spent in REM sleep. CHAPTER 26: Disruptive, Impulse-Control, and Conduct Disorders 26-1. Answer: C. Impulse-control disorder NOS. The patient denies anhedonia or depressed mood required for a diagnosis of major depressive disorder. She does not presently meet age criteria for borderline personality disorder and describes only one symptom of it. She does not endorse obsessions around the cutting or ideas that the cutting will

in some way alleviate an obsessional concern, as is characteristic with obsessive-compulsive disorder. This leaves other specified impulse-control disorder as the best option. 26-2. Answer: E. Conduct disorder. The patient endorses symptoms including destruction of property, theft, and serious violation of rules. He meets criteria for a conduct disorder. He does not meet the age criteria for antisocial personality disorder. Full symptoms of oppositional defiant disorder are not described in the vignette. Reports of multiple occasions of fire setting are required for the diagnosis of pyromania. CHAPTER 27: Adjustment Disorders, Grief, and Bereavement 27-1. Answer: D. Mourning. The adjustment process that a person goes through after a loss is called grief. Grieving is normal and universal, and it should be expected after a significant loss. Bereavement is defined as the emotional and cognitive process a person goes through when someone close to that person dies. Mourning is the outward expression of loss and grief after a death which involves rituals and other actions that are specific to each person’s culture, personality, and religion. Bereavement and mourning are both part of the grieving process. 27-2. Answer: D. Normal grief. The presentation of normal grief (bereavement) often resembles a brief depressive episode, with sadness, insomnia, diminished appetite, and loss of interests. Feelings of guilt are common, as are wishes to die as a means of joining the deceased. Suicidal ideation or desire is not normal and warrants additional investigation and management. CHAPTER 28: Personality Disorders 28-1. Answer: B. Schizotypal personality disorder. Some patients with schizotypal personality disorder can experience periods of brief reactive psychosis or schizophrenic decompensation. Genetic

studies have supported a link to schizophrenia, as well. Paranoid personality disorder and schizoid personality disorder also have an increased incidence of psychosis including schizophrenia in family members, but the association is less robust. Avoidant personality disorder is a cluster C personality disorder most phenomenologically related to social anxiety disorder, and many clinicians assert the two disorders are indistinct. People with avoidant personality disorder often lead interpersonally deprived lives, much like the cluster A personality disorders, but a key difference is that they crave human relationships. 28-2. Answer: C. 75%. About 75% of patients with borderline personality disorder will attempt suicide during their lifetime, and up to 10% will have completed suicide by the age of 30 years. Borderline personality disorder is the most prevalent disorder in all clinical settings and is associated with high levels of comorbid mood disorders as well as eating disorders, substance abuse, and post-traumatic stress disorder. Dialectical behavioral therapy and mentalization-based therapies have been shown to be the most effective at reducing symptom severity in borderline personality disorder. CHAPTER 29: Psychiatric Disorders Associated with the Female Reproductive Cycle 29-1. Answer: D. Bupropion. The patient described here most likely suffers from pre-menstrual dysphoric disorder or PMDD where there are mood symptoms only during the luteal phase of the menstrual cycle. First line pharmacologic treatment for PMDD are the serotonin re-uptake inhibitors. There is also data to support the use of certain lifestyle modifications and alprazolam. 29-2. Answer: E. For some women with bipolar disorder, certain atypical antipsychotics can be used safely and, while the data is limited, these agents have not been associated with teratogenic risk. Because the risk of relapse of bipolar illness is high during pregnancy in the setting of medication discontinuation, many women may benefit from maintenance treatment with a mood stabilizer. While the data are limited regarding the reproductive safety of atypical antipsychotics, these agents

have not been associated with teratogenic risk. Lithium has been associated with an increased risk of cardiovascular malformations. Some, but not all, data suggest that lamotrigine may be associated with an increased risk of cleft lip and palate. Valproic acid carries a high risk of congenital malformations, including neural tube defects, and therefore is rarely used during pregnancy. CHAPTER 30: HIV Infection and A IDS 30-1. Answer: C. Psychiatrists should consider screening patients with newonset mania for HIV infection. 30-2. Answer: D. …is FDA-approved for HIV prevention. CHAPTER 31: Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome 31-1. Answer: A. Hyperactive bowel sounds. Hyperactive bowel sounds are common in SS due to serotonin excess. Other common symptoms include hyperreflexia, mydriasis, and diaphoresis. 31-2. Answer: C. Intravenous lorazepam. Intravenous lorazepam is preferred over other benzodiazepines, given its ease of administration, relatively quick onset of action, long effective length of action and high affinity for GABAA receptors. Intramuscular benzodiazepines are not recommended, because they can worsen the fear that accompanies catatonia and can increase the risk for progression to malignant catatonia. Neuroleptic agents such as haloperidol can also worsen the risk for malignant catatonia or NMS. CHAPTER 32: Neuroimaging in Psychiatry 32-1. Answer: C. Computed tomography (CT): Normal exam. Although in the context of an acute stroke you might observe DWI hyperintensity and ADC hypointensity, the first test to order in an emergency setting is a CT to rule-out a hemorrhagic stroke and then to start

tissue plasminogen activator (tPA) promptly. A hyper-acute stroke (minutes from the beginning of symptoms) will often show as a normal non-contrast head CT, though later in time (1–3 hours), clinicians might observe cortical hypo-density and effacement of the gray-white matter border, signaling edema. 32-2. Answer: D. FDG-PET: Reduced uptake in the mid-temporal lobe, posterior cingulate, and parietal cortex. In the context of a suggestive history for Alzheimer’s pathology and an equivocal MRI, FDG-PET can identify abnormalities in metabolism before neurodegeneration (i.e., focal patterns of volume loss) is clear on the MRI. A typical FDG-PET pattern of Alzheimer pathology will show decreased metabolic activity (i.e., reduced FDG uptake) in temporal, posterior cingulate, and parietal regions. CHAPTER 33: Diagnostic Rating Scales and Psychiatric Instruments 33-1. Answer: D. The SCID-CT version for clinical trials is re-designed as a comprehensive diagnostic assessment. All of the above are true except that the SCID-CT version is specifically tailored and streamlined to specific clinical trials and is not considered a comprehensive clinical assessment. 33-2. Answer: B. The SCID-II Personality Questionnaire is often used as an adjunct to the full SCID-II but may lengthen the time needed to assess the patient. All of the above are true except that the SCID-II Personality Questionnaire actually expedites administration of the SCID-II by allowing the clinician to eliminate SCID-II items that a patient did not endorse in the selfadministered Personality Questionnaire. CHAPTER 34: Psychological Assessment 34-1. Answer: True. The reliability of a measure refers to the repeatability, stability, and consistency of a given instrument in measuring a given construct. It can be

evaluated by comparing test administrations at different points in time (testretest reliability) as well as by assessing the comparability of two raters’ scores (inter-rater reliability). On the other hand, validity refers to whether an instrument truly measures its intended construct. Although an instrument with poor validity can still be considered reliable, validity is often very difficult to achieve when reliability is weak. 34-2. Answer: True. Performance-based measures are typically less structured and require more effort on the part of the patient to make sense of, and to respond to, the test stimuli. As a result, the patient is provided with a great degree of freedom to demonstrate his or her own unique personality characteristics and psychological organizing processes. Whereas the objective test provides a view of the patient’s “conscious” or explicit self-presentation, the performance-based tests provide insight into the patient’s typical style of perceiving, organizing, and responding to ambiguous external and internal stimuli. When combined together, data from objective and projective tests can provide a fairly complete picture or description of a patient’s range of functioning. CHAPTER 35: Neuropsychological Assessment 35-1. Answer: A. To relate a patient’s test performance to both the status of their central nervous system (CNS) and their real-world functional capacity. The main goal of a neuropsychological evaluation is to relate a patient’s test performance to both the status of their central nervous system (CNS) and their real world functional capacity. The specific goals of a neuropsychological assessment include diagnosis (e.g., depression versus dementia), prognosis, patient care, and planning for the future. 35-2. Answer: A. Overall intellectual functioning (IQ). Although specific test batteries might vary, most neuropsychological assessments cover the following core domains: 1) overall intellectual functioning (IQ); 2) attention and concentration; 3) language (expressive and receptive), 4) memory (immediate and delayed), 5) visualspatial/constructional, 6) executive functioning and abstract thinking, and

sensorimotor and motor functions. Neuropsychological evaluations cover similar areas to those assessed in the mental status examination (MSE) used in neurology and psychiatry. However, these evaluations differ in that a neuropsychological evaluation is far more comprehensive, and based on the use of precise normative data, allowing for a more refined and quantified assessment of the major cognitive functions. CHAPTER 36: Laboratory Tests and Diagnostic Procedures 36-1. Answer: B. High serum methylmalonic acid. The patient is experiencing depressed mood and fatigue in the setting of a new anemia. Normocytic anemia can occur in the setting of a macrocytic anemia (due to B12 or folate deficiency) superimposed on a microcytic anemia due to iron deficiency. Furthermore, she is exhibiting neuropsychiatric symptoms of B12 deficiency (poor memory, loss of balance, reduced proprioception). In many cases of B12 deficiency, B12 levels can be low-normal or borderline. The anemia can be mild or non-existent, whereas MCV might be within normal limits if masked by a co-occurring disorder. This patient’s nutritional intake has likely suffered both as a consequence of bereavement and possible depression as well as absence of her husband who we are told formerly prepared all meals. In cases of suspected B12 deficiency where serum B12 levels are in the borderline range, an elevated level of methylmalonic acid (MMA), a metabolic intermediate, will confirm the diagnosis. 36-2. Answer: D. PET. The patient is presenting with symptoms of dementia with Lewy bodies (DLB), a neurodegenerative disease characterized by fluctuating levels of consciousness, sleep disturbance, cognitive decline, visual hallucinations (often detailed and complex), and parkinsonism. Autonomic instability might be present, and falls, due to either orthostatic hypotension or parkinsonism, are common. Diagnosis is usually made based on history and exam, but for cases in which the diagnosis is unclear, PET can help differentiate DLB from other forms of dementia such as Alzheimer’s disease (AD—for which the patient in this case is at risk, given family history of early onset disease). Specific findings on PET include occipital hypo-

metabolism and low dopamine transporter uptake in the basal ganglia. SPECT can also be used. CHAPTER 37: Functional Neuroanatomy 37-1. Answer: B. Orbitofrontal cortex. 37-2. Answer: A. Hippocampus. CHAPTER 38: The Neurologic Examination 38-1. Answer: E. Dorsolateral prefrontal cortex. Working memory is a sub-component of executive functions localized to the frontal cortico-striato-pallidal-thalamo-cortical loops that originate from the dorsolateral prefrontal cortex, or DLPFC. 38-2. Answer: C. Anosmia. Changes in impulsivity and social behavior in the context of bitemporal visual deficits (hemianopsia) are suggestive of a mid-line process affecting the orbitofrontal cortex and optic chiasm. This lesion could affect the olfactory nerve leading to anosmia (unilateral or bilateral). CHAPTER 39: Neuropsychiatric Dysfunction 39-1. Answer: C. Schizophrenia. 39-2. Answer: E. Forward digit span. CHAPTER 40: Clinical Neurophysiology and Electroencephalography 40-1. Answer: D. The EEG is higher yield if stage II sleep is captured. 40-2. Answer: D. Right frontal spike and slow wave discharges. 40-3. Answer: B. Clozapine. CHAPTER 41: Seizure Disorders

41-1. Answer: D. Lumbar puncture. 41-2. Answer: B. Bupropion. 41-3. Answer: E. Levetiracetam. 41-4. Answer: D. Refer for video EEG monitoring. 41-5. Answer: A. Lamotrigine. CHAPTER 42: Headache 42-1. Answer: D. They are known to attempt suicide secondary to their pain. 42-2. Answer: E. Tension-type headache. CHAPTER 43: Pain 43-1: Answer: D. Both somatic and psychological factors. 43-2: Answer: C. Desipramine. CHAPTER 44: Stroke 44-1. Answer: B. Middle cerebral artery; Left facial droop, left-sided pronator drift. The patient’s speech is notable for flattened prosody and slurring of words, which are related to a stroke in the non-dominant middle cerebral artery (MCA). The slurring of words is likely attributed to a facial droop. Other symptoms of MCA strokes include: contralateral upper extremity weakness; left-sided neglect; difficulty with visuospatial system; possible aphasia (much more common when dominant side affected); and anosagnosia. 44-2. Answer: B. Fluoxetine 20 mg daily. The patient’s presentation is consistent with post-stroke depression following a stroke affecting the left frontal lobe. The patient’s difficulties engaging in physical therapy during the post-stroke recovery period are

concerning for post-stroke depression and warrant immediate intervention. Fluoxetine has been shown to improve motor recovery in addition to having antidepressant effects when used in the post-stroke period. CHAPTER 45: Movement Disorders 45-1. Answer: B. Clozapine. The patient has classic dementia with Lewy bodies (DLB): vivid visual hallucinations, fluctuating levels of consciousness, parkinsonism (rigidity), and cognitive impairment, as well as what likely is a REM sleep behavioral disturbance that might have preceded other symptoms by several years. Patients with DLB are exquisitely sensitive to dopaminergic blockage, rendering most antipsychotics unsuitable (E ). Although dopamine replacement therapy can improve rigidity, it might also worsen psychosis (C ). DBS (D ) is used to treat Parkinson’s disease but is not a first-line choice for treatment of psychiatric symptoms of DLB. Pimavanserin (A ) is currently being studied for treatment of psychosis in idiopathic Parkinson’s disease, which, unlike in DLB, usually occurs only in later stages of the disease. 45-2. Answer: B. The behaviors include verbal as well as motoric elements. Verbal elements can be seen in both complex tics and stereotypies. The patient is exhibiting complex motor and vocal tics and meets criteria for Tourette’s syndrome (onset before age 18, tics for at least one year’s duration). Tics can spontaneously remit for even years at a time (D ), in contrast to stereotypies, which are longer lasting and more continuously expressed than tics (C ). In addition, tics are often associated with a premonitory “urge” that is relieved by the expression of the tic (A ). Tourette’s syndrome is highly co-morbid with both ADHD and obsessivecompulsive disorder (E ), whereas stereotypies and stereotypic movement disorder are associated with intellectual impairment and autism spectrum disorders. CHAPTER 46: Basic Psychopharmacology 46-1. Answer: B. Changes in levels of ionotropic receptor gene expression

via secondary messenger signaling cascades. Many anxiolytics and hypnotics act directly on ionotropic receptors, and the immediate effects of the influx of ions (which decrease excitability) are thought to help explain the immediate effects of some anxiolytics and hypnotics. In contrast, the tolerance that develops with prolonged exposure to an anxiolytic is thought to be the result of the change in levels of ionotropic receptor gene expression via secondary messenger signaling cascades. 46-2. Answer: D. Dendritic-dendritic. Axons are essential to neural transmission because they are the output station of the neuron, so all synaptic connections involve at least one axon. CHAPTER 47: Treatment of Anxiety Disorders 47-1. Answer: B. Diazepam. The half-life of diazepam is 20 to 100 hours, whereas the half-lives of alprazolam, oxazepam, lorazepam are no more than 20 hours. 47-2. Answer: D. Paroxetine. Paroxetine is the only SSRI/SNRI that is FDA-approved for all major anxiety disorders; however, older medications, including benzodiazepines (e.g., diazepam, lorazepam) have a non-specific FDA-approval for “anxiety disorders.” CHAPTER 48: Antipsychotic Drugs 48-1. Answer: C. Haloperidol > risperidone > clozapine. First-generation antipsychotics (FGAs), such as haloperidol, have the highest risk of tardive dyskinesia (TD) because they are high-affinity D2 receptor antagonists. In contrast, second-generation antipsychotics (SGAs) have a lower risk of TD, given their lower D2 receptor affinity. Clozapine appears to have the lowest risk of TD of all antipsychotics, and may in fact improve symptoms of TD. 48-2. Answer: B. Clozapine and carbamazepine.

Clozapine can cause agranulocytosis and carbamazepine can cause bone marrow suppression. The combination of the two should be avoided due to increased risk of serious blood cell abnormalities. None of the other combinations have adverse interactions. CHAPTER 49: Antidepressants and Somatic Therapies 49-1. Answer: B. Insomnia–mesocortical serotonin receptors. Insomnia is due to the effects of serotonin on serotonin receptors in brainstem sleep areas. Given that selective serotonin re-uptake inhibitors (SSRIs) are the most widely prescribed antidepressants, knowledge of the most common side effects of the SSRIs and what gives rise to them are essential: nausea (mediated by serotonin receptors in the hypothalamus and brainstem); mental agitation/anxiety (mediated by stimulation of serotonin receptors in the amygdala and limbic cortex); motor symptoms including restlessness, akathisia, and psychomotor retardation (mediated by serotonin receptors in the basal ganglia); insomnia (mediated by serotonin receptors in brainstem sleep areas); sexual dysfunction including decreased libido, impotence and anorgasmia (mediated by mesocortical and spinal cord serotonin receptors); gastrointestinal (GI) distress including bowel motility, cramps, and diarrhea (mediated by serotonin receptors in the GI tract). 49-2. Answer: C. Duloxetine. Duloxetine is an inhibitor of 2D6. Medications that affect the cytochrome P450 enzymes can cause clinically-significant pharmacokinetic drug–drug interactions, via changes in drug levels. Therefore, knowledge of which medications on the P450 system, especially isoenzymes 2D6 and 3A4, is critical. CHAPTER 50: Electroconvulsive Therapy 50-1. Answer: B. Decrease in cerebral oxygen consumption by 50%. Autonomic hyperactivity associated with ECT leads to significant cardiovascular effects. Parasympathetic discharge predominates initially, and can cause bradycardia, premature ventricular contractions, or even several seconds of asystole. Subsequently, sympathetic outflow from the

diencephalon, through the spinal sympathetic tract, to the heart, further prolonged by a rise in the circulating catecholamines leads to hypertension and tachycardia. After the seizures end, parasympathetic tone remains strong, often causing transient bradycardia, with return to baseline function after 5 to 10 minutes. Cerebral oxygen consumption doubles, cerebral blood flow rises up to 400%, and, as a result, increases in intracranial pressure and blood–brain barrier permeability are seen. 50-2. ANSWER: C. 0.3 ms pulse width. Ultra-brief pulse (0.3 ms) has been associated with fewer cognitive difficulties following ECT when compared to brief pulse (0.5–1 ms). Bilateral electrode placement, high stimulus intensity, inadequate oxygenation and prolonged seizure activity are known risk factors; older patients and those with neurological diseases are at particularly higher risk. CHAPTER 51: Neurotherapeutics 51-1. Answer: B. Transcranial magnetic stimulation. Transcranial magnetic stimulation is the least invasive neurostimulatory treatment as it does not require surgical placement of a stimulation device. 51-2. Answer: D. All of the above. Headache is the most common adverse effect. Syncope and seizure are much less common adverse effects (since FDA approval in 2008 there have been 7 seizures reported). CHAPTER 52: Lithium 52-1. Answer: E. Xanthines. Several classes of medications (e.g., carbonic anhydrase inhibitors, osmotic diuretics, xanthine diuretics) decrease serum lithium levels, whereas others (e.g., ACE inhibitors, antibiotics, calcium channel blockers, COX-2 inhibitors, thiazide diuretics, and NSAIDs) increase serum levels of lithium. 52-2. Answer: A. Aphasia. As lithium levels increase and toxicity becomes more readily apparent, symptoms often include nausea, cognitive dulling, tremor, ataxia, vomiting,

and seizures. Although aphasia has been reported to occur with lithium toxicity, it is an uncommon manifestation of lithium toxicity. CHAPTER 53: Anti-Epileptic Drugs and Psychiatric Illness 53-1. Answer: D. Carbamazepine. Both valproate and carbamazepine can lead to hematological toxicity, such as rare aplastic anemia, persistent leukopenia, and isolated thrombocytopenia. Clinical trials have shown that approximately 10% of patients taking carbamazepine develop transient leukopenia, usually during the first month of treatment. This resolves despite continuation of the medication. 53-2. Answer: C. Lamotrigine. This case describes a young woman with affective instability and a pain syndrome that would both benefit from the stabilizing properties of lamotrigine. There is no history of mania or psychosis, and her mood disorder is characterized by depression and mood reactivity, making lamotrigine the best choice. CHAPTER 54: Stimulants, Atomoxetine, Beta-Adrenergic Blocking Agents, and Alpha-Adrenergic Blocking Agents 54-1. Answer: C. Clonidine. Of the first-line treatments listed, clonidine is most commonly associated with sedation. Amphetamine and methylphenidate are associated with insomnia. Guanfacine is less sedating than clonidine. Atomoxetine is less commonly associated with sedation than is clonidine, and is also variably associated with insomnia in some patients. 54-2. Answer: B. Requirement of regular dosing to sustain therapeutic blood levels. CHAPTER 55: Drug–Drug Interactions in Psychopharmacology 55-1. Answer: B. Reduction in the efficacy of pramipexole due to co-

prescription of risperidone. The D2 blocker risperidone interferes with the dopamine agonist properties of pramipexole, an example of a pharmacodynamic interaction at the site of drug action. In contrast, pharmacokinetic interactions, exemplified by the other options, involve changes in drug concentrations or effects due to interference with absorption, distribution, metabolism (tamoxifen, clozapine) and/or excretion (lithium). 55-2. Answer: D. Higher concentrations of the substrate. An individual who has a genetic polymorphism associated with lower levels of the active metabolic enzyme for a substrate is likely to have build-up of that substrate after administration because of reduced metabolic clearance. This may be associated with a higher burden of side effects when taking that substrate, lower concentrations of the substrat e’s metabolite normally produced through that enzyme pathway, and a typically less pronounced impact of inhibitors of the enzyme whose activity is already minimal. CHAPTER 56: Cardiovascular and Other Side Effects of Psychiatric Medications 56-1. Answer: C. Ziprasidone. Of the atypical antipsychotic medications, ziprasidone appears to cause the greatest degree of QTc prolongation. This is followed by iloperidone, risperidone, and olanzapine. In a recent meta-analysis (Leucht S. Lancet 2013; 382: 951–962), lurasidone, paliperidone, and aripiprazole were not associated with significant QTc prolongation compared to placebo. 56-2. Answer: B. Risperidone. Of the atypical antipsychotic medications, risperidone is the most likely to cause tardive dyskinesia. Olanzapine and ziprasidone also have been linked to tardive dyskinesia in case reports. Clozapine is minimally associated with tardive dyskinesia, and some providers recommend using clozapine in patients with tardive dyskinesia due to its low propensity to worsen symptoms of this disorder. CHAPTER 57: Natural Medications in Psychiatry

57-1. Answer: D. It has preparations that contain additional nutrients (vitamins B 2 , B 6 , B 12 , and n-acetyl cysteine) that are approved to treat dementia. All of the above are true, except that no 5-methyl tetrahydrofolate (Deplin) preparations are as of yet approved to treat dementia. 57-2. Answer: C. Omega-3 fatty acids may prevent depression in patients who are taking interferon therapy for hepatitis. The only true statement above is that Omega-3 fatty acids have been shown prevent depression in patients who are taking interferon therapy for hepatitis. S-adenosyl methionine was recently shown to be more effective in men than in women. St. John’s wort (hypericum) contains hypericin and hyperforin, but kavapyrones are found in kava. Inositol has shown benefit and safety in pediatric populations with bipolar illness. Ginkgo is not considered as effecti ve as cholinesterase inhibitors for dementia, but is better tolerated and may potentiate the effect of cholinesterase inhibitors when combined. CHAPTER 58: Suicide 58-1. Answer: B. Prior suicide attempt. The strongest single factor predictive of suicide is a prior suicide attempt. Half of all suicides occur in patients who have made at least one prior attempt. Patients with a prior suicide attempt are five to six times more likely to make another attempt. In fact, in the year following an attempt, the risk for suicide may be 100 times greater than that of the general population. 58-2. Answer: A. Use of a firearm. The use of a firearm is the most common means of completed suicide in the United States, accounting for up to 60% of annual suicides. Suffocation is the second most common means of suicide, followed by poisoning as the third most common means. Drug overdose is the most common means of failed suicide attempts. CHAPTER 59: Psychiatry and the Law I: Informed Consent, Competency, Treatment Refusal, and Civil Commitment

59-1. Answer: D. All of the above. All states provide for civil commitment where the person poses a substantial risk of harm to self or others, including an inability to provide for one’s own safety in the community. In addition, some states include the inability to make informed decisions as a commitment criterion. 59-2. Answer: C. 1, 2, and 3. Emergencies (where failing to act would result in likely substantial harm to the patient), incompetence, and waiver are well-established exceptions to informed consent. The fact that providing full information might dissuade the patient from accepting recommended treatment, even if the physician believes it is in the best interest of the patient, is not a justifiable reason for foregoing the informed consent process. CHAPTER 60: Psychiatry and the Law II: Criminal Issues and the Role of Psychiatrists in the Legal System 60-1. Answer: B. (2 and 4). The requirement of competence to stand trial ensures a fair trial, preserves the integrity of the criminal justice system, and serves the purpose of individual deterrence and retribution. 60-2. Answer: C. (1, 2, and 3). Unlike con fidentiality, which is an ongoing duty, the psychotherapist privilege must be claimed by the patient for it to have effect. If the patient claims the privilege, the psychiatrist will be barred from testifying unless one of several exceptions apply. These include express and implied waiver. CHAPTER 61: Patient Adherence 61-1. Answer: A. Optimal adherence increases the likelihood that patients will experience treatment response or remission, thereby reducing the burden of illness for patients, families and health-care systems. 61-2. Answer: A. Challenges to adherence are multi-level, including patient factors (e.g., cognitive impairment), clinician factors (e.g., approach to

patient care), structural issues (e.g., healthcare fragmentation), and social concerns (e.g., stigma of illness). CHAPTER 62: An Overview of the Psychotherapies 62-1. Answer: B. Resistance. Resistance is an unconscious process, in this instance manifest by the patient leaving too late to be timely because of the strong feeling that was generated in a previous session that the patient would rather not face. None of the other terms are consistent with unconscious processes. 62-2. Answer: D. Behavioral therapy. In this instance, learning to control the feelings generated by the behavior is modifying the patient’s behavior. Negative cognitions associated with CBT are not part of this intervention. There is only one patient, so this is not group treatment. The absence of exploring why the patient is worried he will faint rules out psychodynamic therapy. CHAPTER 63: Brief Psychotherapy 63-1. Answer: D. Sifneos. Psychodynamic short-term therapies were described by Sifneos (1992), Malan (1976), and Davanloo (1992). They featured psychoanalytic interpretation of defenses and unconscious conflicts as their main “curative” agent. Sifneos’ anxiety-provoking therapy treatment ran for 12–20 sessions and focused narrowly on issues such as the failure to grieve, fear of success, or triangular, futile love relationships. Cognitive-behavioral brief therapies described by Beck and Greenberg (1979), and by Dewan, Steenbarger, & Greenberg (2004) aimed to bring the patient’s “automatic” (pre-conscious) thoughts into awareness, and demonstrate how these thoughts impact behavior and feelings. Brief interpersonal therapy was developed by Klerman (1984) is a highly formalized (manualized) treatment. Interpersonal psychotherapy (IPT) focuses not on mental content but on the process of the patient’s interaction with others. “Eclectic” brief therapies are characterized by combinations and integrations of multiple theories and techniques. Budman and Gurman (1988) present one very popular version

of eclectic brief therapy which focuses on three dimensions of mental life: the interpersonal, the developmental, and the existential. 63-2. Answer: D. A significant risk of self-harm. Criteria for selection for brief therapy can be thought of as dimensions, with each patient being rated on how much of each dimension they have. The potential candidate for brief therapy should: be in moderate emotional distress (as this provides the motivation for treatment); want relief from his or her emotional pain (i.e., they should not have been sent to therapy reluctantly by a boss or spouse); be able to articulate a fairly specific cause of their pain or a circumscribed life problem (or be willing to accept your specific formulation of their difficulty); have a history of at least one positive (mutual) interpersonal relationship; still be functioning in at least one area of life; and, have the ability to commit to a treatment contract. The brief therapy patient should not be actively psychotic, abusing substances, or at significant risk for self-harm. The actively psychotic patient will not be able to make adequate use of the reality-oriented/logical aspects of the brief treatment. Substance-abusing patients should be directed to substance abuse treatment prior to undertaking any form of psychotherapy. Patients at significant risk for self-harm are not appropriate for brief therapy due to possible complications associated with the ending their treatment at a planned time. These factors should be considered categorical in nature; the presence of any one of them should rule-out a patient for brief psychotherapy. This is especially true for a therapist just beginning to learn brief treatment. 63-3. Answer: B. Executive dysfunction. Executive dysfunction. Four common treatment foci that are regularly utilized within planned brief treatments: losses, past, present, or pending; developmental desynchronies (being out of step with expected developmental stages); interpersonal conflicts; and symptomatic presentations. Neuropsychiatric dysfunction requires longer-term strategies. CHAPTER 64: Couples Therapy 64-1. Answer: C. The presence of defensiveness, criticism, stonewalling, and contempt during a fight is predictive of divorce.

Gottman has studied thousands of couples, particularly early in marriage, to discover what type of fighting puts them most at risk for divorce 10 years later. The presence of fighting itself is not a risk factor. Rather, when couples display certain characteristics during their fights—defensiveness, criticism, stonewalling, and contempt—couples are much more likely to divorce. In addition, when they use humor, make repair comments, and include positive remarks during a fight, the damage to the relationship is greatly reduced. Strategies, including teaching couples to paraphrase each other’s points of view, and learning to fight fairly, belong to the canon of behavioral couples therapy, but are not advocated by Gottman. 64-2. Answer: B. Talking to the individual therapists to find out any secrets about the couple’s relationship. During an evaluation, the couple’s therapist must focus on each individual’s perspective, history, and set of problems, as well as training an eye on the relationship. When a couple’s therapist learns secret information from an individual’s therapist, his/her ability to maintain a neutral stance toward the couple is compromised. Divulging the information betrays the individual’s therapeutic relationship. But, holding on to it, is also untenable as the therapist is then colluding with one partner against the other, and has lost trustworthiness and impartiality. During the evaluation, it is important to find out what else has been going in the lives of each individual, in the couple, and the larger family. Often when there are multiple stressors, a couple’s relationship can become destabilized. Asking about the sexual relationship is recommended because sexual problems so often co-exist with other marital problems. Couples can be reluctant to bring them up, so a therapist willingness to do so, is valuable. One of the main goals of any evaluation is to move from an individual description of the presenting problem to a relational, dyadic one. CHAPTER 65: Family Therapy 65-1. Answer: C. Negative reinforcement. 65-2. Answer: B. Externalization.

CHAPTER 66: Group Psychotherapy 66-1. Answer: D. The ability of the leader to be reimbursed in a timely fashion by group members. 66-2. Answer: D . Regular use of psychotropics. CHAPTER 67: Cognitive-Behavioral Therapy 67-1. Answer: A. Problem solving. Problem solving is a behavioral technique. 67-2. Answer: B. CBT is time-limited for both Axis I and Axis II disorders. Therapy for axis II disorders to create a more balanced perspective is generally long-term due to the over-abundance of maladaptive core beliefs and lack of adaptive core beliefs. CHAPTER 68: Mind–Body Medicine 68-1. Answer: D. Increased activity of the innate immune system. Stress causes increased activity of the innate immune system via upregulation of NF-κ B, stimulating high circulating levels of proinflammatory cytokines. Activity of these cytokines causes oxidative stress that leads to widespread cellular damage throughout the body. Research has shown that mind–body techniques decrease the activity of the innate immune system in response to stress. Mind–body techniques induce the relaxation response (decreased heart rate, vascular tone, respiratory rate and oxygen consumption). They dampen the reactivity of the innate immune system, which results in decreased oxidative stress. Research has shown that extended mind–body practice leads to epigenetic modifications in areas of the human genome associated with inflammation and metabolism. 68-2. Answer: B. Psychosis. Individuals experiencing major difficulties in reality testing, or who have experienced onset of psychosis during other introspective or isolating activities, are at greater risk of adverse events as a result of mindfulness

practice. CHAPTER 69: Geriatric Psychiatry 69-1. Answer: C. The risk of death after a suicide attempt in those > 65 years old is twice that of those in the United States population. Suicide is common in the elderly; it is most common in women of 50-65 years of age, and in men between the ages of 80-90 years. Roughly 1 in 9 suicide attempts in the elderly result in death. The risk of death after a suicide attempt in those > 65 years of age is twice that of the United States population at large. Statistics from the NIMH indicate that although older adults comprise only 12% of the population they accounted for 16% of the deaths by suicide. Moreover, since statistics report completed suicide and not passive efforts to die, suicide in the elderly is probably under-reported. Predictors of suicide risk include: advanced age; male sex; being separated, isolated, or divorced; having a debilitating illness; and abusing alcohol. 69-2. Answer: A. Cooking. Assessment of activities of daily living (ADLs) is crucial; this includes determination of the ability to transfer independently, dress oneself, bathe, maintain hygiene, feed oneself, use the bathroom, and maintain bladder and bowel continence. Assessment of instrumental activities of daily living (IADLs) includes determination as to whether the patient can live independently, go shopping for food, cook meals, use the telephone, do light housekeeping, manage medications, handle fnances, and arrange transportation. 69-3. Answer: B. Depression lowers the life expectancy of the elderly. Depression lowers the life expectancy of the elderly (from suicide and from medical co-morbidity). Rates of suicide increase as isolation increases. Lateonset depressive illness is associated with a higher rate of physical illness; depression also leads to psychiatric hospitalization in 50% of those afficted. Approximately 30% of those with dementia have co-morbid major depressive disorder (MDD), and those with a history of stroke, Parkinson’s disease, or multiple sclerosis are also vulnerable to depression. Grief and loss also contribute to depression. Nearly 60% of depressed patients have co-morbid anxiety; roughly 40% of anxious patients have co-morbid

depression related to medical illness (e.g., cardiac conditions [such as myocardial infarction], renal failure, cancer, endocrine disturbances, infections) and neurologic illness (e.g., stroke, Parkinson’s disease, cerebral neoplasm, multiple sclerosis). It is crucial to recall that undiagnosed medical illness can present as depression. 69-4. Answer: A. Alzheimer’s disease. An estimated 5.4 million people in the United States have Alzheimer’s disease (AD). Of the approximately 1.5 million patients occupying nursing home beds in this country, approximately 15.5% carry the diagnosis of AD. Lewy body disease (LBD) is often misdiagnosed as AD and it can complicate the use of medications. Patients with LBD have more hallucinations and a greater sensitivity to the side effects of antipsychotic medications, both typical and atypical, than do AD patients. LBD is characterized by widespread distribution of Lewy bodies in the brainstem, basal forebrain, and cortex. Reported as a fairly common form of degenerative dementia it is characterized by fuctuating cognitive impairment, transient episodes of marked confusion, prominent behavioral changes, a high incidence of visual and or auditory hallucinations and delusions, and a movement disorder similar to that of Parkinson’s disease. Extrapyramidal signs are present and there is an exquisite sensitivity to antipsychotic medication. Frontal lobe dementia (FLD) manifests prominent symptoms of disinhibition, self-neglect, compulsive behaviors, apathy or euphoria, neglect of personal hygiene and self-destructiveness. Vascular dementia usually presents with a stuttering course and the losses are more focal in the territory of the damage. The ratio of vascular dementia to AD is about 1:5. CHAPTER 70: Psychiatric Epidemiology 70-1. Answer: B. Nicotine dependence. In the NCS-R, the most prevalent psychiatric disorder was nicotine dependence. 70-2. Answer C. Older age. Alcoholism was correlated with male gender, younger ages, being separated

or divorced, having a low educational level, and low occupational level and income. CHAPTER 71: Statistics in Psychiat ric Research 71-1. Answer: B. Race. Race is a nominal value because race cannot be ranked and has no inherent numerical meaning. 71-2. Answer: C. d = 2.5, p = 0.002. Only two drugs have reasonable p -values (B and C) suggesting that the results observed in the study sample can be generalized to the population. Of those two candidates comparing the Cohen’s d as a measure of effect size drug C has a markedly larger effect on the outcome. CHAPTER 72: Psychiatric Research Metho dology 72-1. Answer: A. Randomized controlled trial. Randomization is the “gold standard” methodology for addressing confounding and improving internal validity. 72-2. Answer: C. Inter-rater reliability Inter-rater reliability is the extent to which a measure yields the same result in different investigator’s hands, whereas test-retest reliability is the extent to which a measure yields the same result in the hands of one investigator on two separate occasions. CHAPTER 73: Genetics and Psych iatry 73-1. Answer: B. Translation. Psychiatric disorders have been associated with mutations in both coding and non-coding DNA. Identified mutations include single nucleotide polymorphisms (SNPs), which are single base pair changes between alleles of the same gene and can be inherited or arise as de novo mutations, and copy number variants (CNVs) in which the number of copies of a sequence of base pairs (often an entire gene) varies from one individual to the next.

CNVs can include deletions (too few copies of a genetic sequence) or duplications (extra copies). CNVs can range from thousands to millions of base pairs, unlike SNPs which affect only one single nucleotide base. Many psychiatric illnesses, such as schizophrenia and autism spectrum disorder (ASD) show an increased number of SNPs and CNVs as compared to controls. Translation is the normal process by which mRNA is coded into proteins and is part of healthy functioning. Translation is not a type of DNA mutation. 73-2. Answer: D. Bipolar disorder. Although all of the choices show increased heritability, bipolar disorder has the highest rate of heritability at 60% to 85%. This is significantly higher than the heritability of unipolar depression which is estimated at 31% to 42%. Even among studies of monozygotic twins, the estimate of genetic heritability for unipolar depression does not exceed 69% (estimates range from 23% to 69% for monozygotic twins, and even lower for dizygotic twins). The estimated heritability of panic disorder is 40% to 45%. Heritability estimates for alcohol use disorder vary by the diagnostic criteria. Most twin and adoption studies of alcohol use disorder have supported the role of genetic influences, though many favor a strong environmental influence, as well. Among studies demonstrating genetic influence, estimated heritability has ranged from approximately 50% to 60% though environmental influences are consistently implicated. Importantly, the risk of inheritance by first degree relatives across all psychiatric disorders may differ from the heritability, as heritability is a study of genetic association in particular, whereas the total risk of inheriting a disorder includes both genetic and environmental factors. Thus, the risk to a first-degree relative of an affected proband might differ from the heritability estimate. 73-3. Answer: A. Hundreds or thousands of samples might be required to obtain sufficient statistical power. In GWAS, genomes from individuals with and without the disease are sequenced and compared to one another using sophisticated computer algorithms to analyze whether variations are associated with a psychiatric

disorder. Thousands of patients and controls are often required to achieve statistical power, and factors such as race/ethnicity, gender, and geographic distribution must be controlled for to reduce false positives. These genomes do not need to be from related individuals. The LOD score is a measurement linkage between two genetic loci. The LOD score compares the likelihood of obtaining the observed results if the two loci are indeed linked, to the likelihood of observing the same results by random chance. The higher the LOD score the higher the likelihood of genetic linkage. Traditionally, a LOD score of 3 (corresponding to odds of 1000:1 in favor of linkage) has been the threshold of declaring linkage. Fluorescent probes are used to bind to complementary strands of DNA in Fluorescence in situ hybridization (FISH), a cytogenetic technique that can localize where on the chromosome a gene is located, as well as any mutations within that gene. Prior knowledge of target genes is not required for GWAS. Such knowledge is required for a candidate gene approach, which uses prior knowledge of a gene’s biological function to focus studies on one or a small group of genes believed to play a role in causing disease states. 73-4. Answer: E. Obesity related to chronic hunger. Down syndrome, or trisomy 21, is the most common genetic cause of intellectual disability, occurring on average every 1 in 700 births. Common physical features include: a characteristic facial appearance of upslanting palpebral fissures (eye openings); epicanthal folds; a flat nasal bridge; lowset ears; a protruding tongue; short neck; and brushfield spots on the iris. Short stature, a single palmar crease, congenital heart disease, duodenal atresia, and hypothyroidism are also characteristic. The intellectual disability associated with Down syndrome is thought to be a static process; decline in cognition or change in behavior in patients with Down syndrome should raise suspicions for possible early-onset Alzheimer disease (AD) which has an increased incidence in this population. AD is thought to be increased in Down syndrome patients because the amyloid precursor protein is located on chromosome 21. The typical age of onset of AD in these individuals is around 40 to 50 years. Chronic hunger is characteristic of Prader Willi Syndrome, a rare disorder caused by a mutation on the paternally-inherited chromosome 15q11-13. The feeling of chronic hunger often leads to obesity in these individuals.

CHAPTER 74: Psychiatry and the Law III : Malpractice and Boundary Violations 74-1. Answer: D. Damages. Commonly referred to as “The 4 Ds,” the elements of a malpractice claim are D ereliction, of D uty, that D irectly causes D amages. 74-2. Answer: H. All of the above. Sexual relationships with patients have been deemed unethical by the American Medical Association and the American Psychiatric Association. They are the basis for license suspension or revocation in all states, and criminal charges in some. They are considered to be a violation of the standard of care and are a basis for malpractice claims. CHAPTER 75: Psychiatric Consultation to Me dical and Surgical Patients 75-1. Answer: C. Delusional disorder. Delusions can manifest in patients with severe depression, dementia, delirium, and other more commonly encountered phenomena in medically ill hospitalized patients; however primary, delusional disorder is an uncommon reason for psychiatric consultation. 75-2. Answer: B. It focuses on the here-and-now and attempts to bolster adaptive reactions to stress. Psychotherapy in medically ill hospitalized patients deals with current issues that may cause distress or interfere with effective coping or management. CHAPTER 76: Organ Transplantation 76-1. Answer: C. UNOS. In the United States, The United Network for Organ Sharing (UNOS) is the non-profit corporation endowed by Congress and reporting to the Department of Health and Human Services that regulates the allocation of organs. UNOS has the power to enforce its policies as federal regulations. UNOS is divided into two branches: Organ Procurement and Transplant

Network (OPTN), and Scientific Registry. 76-2. Answer: A. True. Pre-transplant evaluation of candidates requires recognition of common psychological symptom clusters and syndromes. Informed consent, teaching, and pre-operative management help ensure compliance with the requirements of transplant teams and thus more favorable post-operative outcomes. Unfortunately, there are no uniformly accepted psychiatric guidelines for acceptance or rejection of transplant candidates. Some centers routinely use self-report questionnaires, like the Beck Depression Inventory; others rely on a dynamically-informed clinical interview. One of the most promising standardized psychosocial assessment tool is the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) developed by Maldonado et al (2008), which can be used by any member of the transplant team as a way to determine patients’ psychosocial risk factors and highlights current issues that might translate into problems post-transplant. CHAPTER 77: Chronic Mental Illness 77-1. Answer: A. Being a victim of violence. Patients with schizophrenia are more likely to be a victim of violence, rather than a perpetrator of violence. Patients with schizophrenia are at increased risk of suicide, particularly early in the course of illness. 77-2. Answer: C. 25 years earlier. Patients with serious mental illness have increased mortality compared to the general population, and on average, they die 25 years earlier. The increased mortality is due to suicide, but also to chronic medical illnesses, many of which are treatable. CHAPTER 78: Intimate Partner Violence (IPV) 78-1. Answer: E. All of the above. A physician must be trained to identify the many potential physical and psychological signs of partner abuse, including a pattern of injury in the medical record. He or she must also know specific and direct questions to

ask the patient about abuse, and must do this when the patient is alone. Finally, if abuse is suspected, instead of intervening to “solve” the problem, a doctor should make clear statements about the abuse being unacceptable, that the patient is not to blame, and offer referrals to social services where patient can find help, shelter, and legal advice. However, the decision to act rests entirely with the patient. The physician should not notify police, as this might make the patient’s situation worse. Physicians are not mandated reporters of partner abuse. 78-2. Answer: C. Fibromyalgia. Fibromyalgia is not itself co-morbid with partner abuse; however, somatic complaints, such as headaches, pelvic and musculoskeletal pains are commonly associated with the stress of ongoing abuse. Before suspecting partner abuse, a physician must consider the totality of evidence, and also conduct patient screening for abuse using a methodology approved by the physician’s group, hospital or medical association. CHAPTER 79: Abuse and Neglect 79-1. Answer: C. Self-neglect. Although the elderly woman’s lack of interest in daily chores and self-care might be a sign of depression, more information would be needed to make that diagnosis. Based on the observations of the daughter, and the clinical signs of malnourishment, and with limited medical history, the best diagnosis at this point would be self-neglect. Dehydration is a component of self-neglect as well as malnourishment. Often self-neglect is paired with an illness or medical condition. Further medical examination, and a neuropsychological evaluation would be necessary to determine dementia or depression. 79-2. Answer: G. Depression. All of the above can be considered a potential sign of child neglect except depression. Although depression can be a consequence of neglect, it could be due to maternal depression, a significant loss, social difficulties, or stress. A physician must assess each sign of neglect and abuse (malnutrition, poor dentition, lack of immunization, untreated medical illness, chronic and unaddressed truancy, and substance abuse) individually, and consider the

totality of signs and symptoms in order to reach a conclusion. 79-3. Answer: F. All of the above. Each of these factors are challenges to detecting abuse in an elderly person. Frailty of mind makes abuse difficult to diagnose because the patient’s ability to provide an adequate history is somewhat compromised. Also, fear may be mistaken for frailty. Family members comprise 90% of the perpetrators of elder abuse, and financial exploitation is one of several types of abuse. CHAPTER 80: Lesbian, Gay, Bisexual, Transgender, and Queer (LGBTQ) Mental Health 80-1. Answer: B. 6 months. The minimum duration of gender dysphoria needed to meet DSM-5 diagnostic criteria is 6 months. This time-frame was selected to demonstrate adequate persistence of gender dysphoria while also preventing unnecessary delays initiating gender-affirming medical care for transgender people. 80-2. Answer: D. Treat the patient’s alcohol use disorder and schizophrenia; as these disorders become reasonably well controlled, gender-affirming cross-sex hormone therapy is indicated if the patient has capacity to make medical decisions. Untreated co-occurring psychiatric disorders often impede the process of gender identity discovery and gender dysphoria alleviation. Every effort must therefore be made to stabilize co-occurring psychiatric disorders. As with other medically necessary pharmacotherapies and surgeries, psychiatrists cannot ethically withhold gender-affirming medical care from patients who have medical decision-making capacity if their co-occurring psychiatric disorders are reasonably well controlled. CHAPTER 81: Culture and Psychiatry 81-1. Answer: B. Culture-bound syndrome. The term “culture-bound syndrome” does not take into account that some “syndromes” are actually variations in ways people experience distress

rather than distinct collections of symptoms (e.g., nervios ), while others are causal explanations for a range of symptoms (e.g., dhat syndrome). DSM-5 now emphasizes that all forms of distress, including the DSM disorders, are shaped by cultural influences. 81-2. Answer: C. Selective serotonin re-uptake inhibitors. The CYP (Cytochrome P450) 2D6 isoenzyme metabolizes many antidepressants, including the tricyclic and heterocyclic antidepressants, and the selective serotonin re-uptake inhibitors (SSRIs). CYP 2D6 also plays a role in metabolizing antipsychotics, including clozapine, haloperidol, perphenazine, risperidone, thioridazine, and sertindole. The incidence of poor metabolizers at the CYP 2D6 ranges from 3% to 10% in Caucasians, 1.9% to 7.3% in African-Americans, 2.2% to 6.6% in Hispanics, and approximately 0% to 4.8% in Asians. Another genetic variation of the metabolizer gene leads to “intermediate metabolizers,” or individuals who exhibit CYP2D6 activity that is between that of poor (little or no CYPD6 function) and extensive metabolizers (normal CYP2D6 function). Approximately 18% of Mexican-Americans and 33% of Asian-Americans and African-Americans have this gene variation. This might explain ethnic differences in the pharmacokinetics of neuroleptics and antidepressants. CHAPTER 82: Approaches to Collaborative Care Psychiatry and Primary Care 82-1. Answer B. A registered nurse who transferred from the inpatient care after 10 years of practice. Collaborative-care teams often comprise a primary-care physician, specialty physicians as indicated, as well as care managers. The care manager often plays the lead role in patient follow-up, performing check-ins, patient education, as well as tracking adherence and progress, promoting and arranging change in treatment plans for those who do not improve. Types of case managers are variable and models have included registered nurses, master’s-level mental health workers, and social workers. Data supports that those with more clinical experience, in particular registered nurses, lead to more effective outcomes. 82-2. Answer: A. Having a systematic way of identifying patients with

mental illness, where identified patients are followed by a team, who works together to deliver interventions and track his progress through specified monitoring. Despite the variety of models, collaborative programs have three essential components: (1) A systematic way of identifying patients with psychiatric disorders; (2) team-based delivery of mental health interventions; (3) implementation of trackable patient outcomes. In terms of the clinical approach, collaborative-care programs follow the three basic principles. First, collaborative care is based on measurement-based care in efforts to replicate a model used by primary care physicians for chronic medical conditions (e.g., hemoglobin A1c for type II diabetes or lipid panel tracking). Patient progress is monitored using validated clinical rating scales (e.g., PHQ-9 for depression). Second, treatment is designed with a targeted goal, for example specific improvement on PHQ-9 scores. Third, treatment is adjusted when patients do not improve. This is referred to as a stepped-up approach. CHAPTER 83: Community Psychiatry 83-1. Answer: A. Capitation. Capitation is a method of contracting for health care provision, for a given population, based on the up-front payment of a set monetary amount (i.e., cap), per member, per month. Capitation plans have tended to carve-out mental health and substance use services, which set the stage for costshifting between mental and physical health capitation pools. Cost-shifting refers to the practice of shifting the locus of care either for, or with the effect of, off-loading the cost of the care to another system or payment source, without necessarily affecting the quality or over-all cost of the care. Carve-out is a process to separate the benefit management of mental health and substance use services from the management of other (physical) healthcare benefits. Managed care (as opposed to care management) refers to organized attempts to control a population’s health care costs, and possibly quality, through management and monitoring of allocated services to individuals within that population. Managed-care organizations (MCOs) contract to provide this management

function for public or private insurers of a given population, sometimes with financial incentives to contain costs within a fixed budget, and/or financial penalties when the service budget is exceeded. 83-2. Answer: D. Phillipe Pinel. In the late 18th century, Phillipe Pinel, a French alienist (psychiatrist), removed the shackles of mental patients and promoted the notion that fresh air and work would restore mental health. This was the advent of “moral treatment,” considered the “first psychiatric revolution.” Adolph Meyer wrote about prevention and the social context in which mental illness occurred. This “mental hygiene” movement was parallel to the preventive, public health movement of the time, fueled by industrialization, urbanization, and the need for sanitation and infection control. In 1905, Clifford Beers published his first-person report of life and conditions inside the mental institution (A Mind that Found Itself ). Beers, along with Meyer and William James, formed the National Association for Mental Health in 1909. The movement promoted smaller hospitals, community-based outpatient evaluation, interdisciplinary training, greater affiliation with medical schools and mainstream medicine, and application of psychodynamic principles. In 1963, President Kennedy delivered the first presidential message concerning mental illness and retardation to Congress. Kennedy invited a “bold new approach,” to successfully treat the majority of the mentally ill in their communities, where they might resume productive roles. Kennedy opposed enhancement of the existent institutional system of care, and called for a “new type of health facility,” the community mental health center (CMHC). CHAPTER 84: Psychiatric Care of Military Personnel and Returning Veterans 84-1. Answer: C. Prolonged exposure. According to Institute of Medicine and VA/DoD guidelines, cognitivebehavioral therapy modalities, including prolonged exposure and cognitive processing therapy, are most efficacious in the treatment of PTSD based on

current evidence. Psychodynamic psychotherapy, stress inoculation training, and image rehearsal therapy have fewer studies indicating that benefits outweigh risks for their use. 84-2. Answer: B. Firearms. Firearms are the leading lethal means of suicide in the military and in veteran populations. More suicides occur using non-military-issue firearms than using military-issue firearms. CHAPTER 85: Sports Psychiatry 85-1. Answer: A. Eating disorder not otherwise specified (ED NOS). Eating disorders among athletes are better studied than other psychiatric disorders in this population. In particular in sports where leanness or low body weight is considered an advantage, researchers have found a higher prevalence of disordered-eating patterns. 85-2. Answer: C. Methylphenidate. Prescription of stimulants to athletes is controversial, as they are considered to have performance-enhancing effects and safety concerns. A physician who wishes to prescribe this class a medicine to an athlete at the elite level will likely need to complete a TUE. CHAPTER 86: Global Mental Health: Concepts and Personnel 86-1. Answer: B. Depression. 86-2. Answer: C. $4 86-3. Answer: D. All of the above. CHAPTER 87: Quality Assurance and Quality Improvement 87-1. Answer: B. Assist with the design of a quality improvement project. The Smart Aim statement was developed by the Institute of Medicine to outline a process for designing a QI plan. An ideal aim statement explicitly identifies the aim of a project with goals that are measurable and achievable,

and the success or failure of the project will be able to be determined during a specified period. 87-2. Answer: C. To investigate sentinel events. The fishbone diagram is a tool used to visually depict key components that might have contributed to an unwanted outcome or sentinel event. By looking at the components of the fishbone diagram, each aspect of the systems and processes is assessed. CHAPTER 88: Ethical Considerations in Psychiatry Throughout the Lifespan 88-1. Answer A. Respect for autonomy. The principle of respect for autonomy emphasizes the right of an individual to make decisions in accordance with their values. This patient was able to rationally weigh the relevant medical considerations and tie them to his religious values. Beneficence is acting in a patient’s best interests and nonmaleficence is not harming a patient by failing to take a helpful action. Although this patient had a poor outcome, he believed that it was more important to follow his religious doctrine. Justice is emphasizing fairness across society and is not clearly relevant to this case. Virtue is an ethical theory that emphasizes judging actions based on a person’s character rather than the action itself. 88-2. Answer C. Double effect. The principle of double effect justifies taking an action with foreseeably harmful effects (respiratory compromise) if the act itself is aimed at promoting good (causing relief of pain) and the good effect outweighs the bad effect (aiming for pain relief in a hospice patient with a terminal illness). Informed consent emphasizes making a patient aware of risks and benefits of proposed treatment. Multiple agentry refers to a physician having duties to interested parties beyond an individual patient. Therapeutic privilege is a principle justifying withholding relevant clinical information from a patient if disclosing that information would cause harm. Cultural relativism is a principle stating that an individual’s morality should be judged according to their own cultural context and not by the standards of an outside culture.

Index

A Ablative limbic system surgery, 540 Abnormal Involuntary Movement Scale (AIMS), 361 Absence seizures, 439, 586 Abulia, 335 Acamprosate, 143 Acceptance and commitment therapy (ACT), 215, 684 Acculturation and immigration, 785 Acetylcholine (ACh), 492 Acoustic/vestibular nerve, 414 Action tremors, 480, 482 Activities of daily living (ADL), 97, 106 Acute dystonia, 482 Acute intermittent porphyria (AIP), psychiatric differential diagnosis, 123 Acute meningitis, 453 Acute stress disorder (ASD), 219 Adderall, 66, 566 Addiction Severity Index (ASI), 361 Adherence, 633–636 Adjustment disorder clinical features of, 296 differential diagnosis, 178, 206, 296 epidemiology, 295 etiology, 296 evaluation of, 296 overview, 295 treatment, 296 Adolescent development. See Child and adolescent development Adrenal insufficiency, differential diagnosis, 124 Adrenoleukodystrophy (ALD), psychiatric differential diagnosis, 125 Adult separation anxiety disorder (ASAD), 209 Advanced sleep-phase disorder (ASPD), 284 Adzenys XR-ODT, 566 Affective disorders, co-morbid with intellectual disability, 114 Affordable Care Act (ACA), 808

Age-Associated Memory Impairment (AAMI), 698 Age-related cognitive decline, 698 Aggression, 114 Agoraphobia, 207 Ainsworth, Mary, 59 Akathisia, 479, 482, 507 Akinesia, 478 Akinetic mutism, 335 Alcohol hallucinosis, 135 Alcoholic hallucinosis, 134 Alcoholics Anonymous (AA), 141, 163 Alcohol use disorder (AUD) alcohol-induced disorders, 135 alcohol metabolism, 133 alcohol neurobiology, 133 alcohol physiologic effects, 134 alcohol-related syndromes, 135 chronic disease model, 141 co-morbidity, 133, 137 deaths and diseases associated with, 132 delirium associated with, 91 diagnosis, 133 differential diagnosis, 138–148 dual diagnosis patient management, 144 epidemiology, 132, 710 evaluation, 136–148 genetics and the biologic correlates of alcoholism, 135, 731 in geriatric patients, 699 laboratory evaluation, 138 motivational interviewing techniques, 141, 142 stages of behavioral change, 141 sub-types of alcoholics, 136, 137 treatment, alcohol withdrawal, 142 treatment, associated syndromes, 144, 145 treatment, inpatient and specialized, 145 treatment, long-term, 143 treatment, not FDA-approved, 143 treatment, pharmacological, 142 treatment, strategies for, 140 Type A and Type B alcoholics, 136 Type I and Type II alcoholism, 136 withdrawal and related syndromes, 134 Alcohol withdrawal delirium, 134 Alpha-adrenergic blockers dosing and preparations available, 572 drug interactions, 572 general effects, 571 indications, 571 side effects, 572 using, 571

Alzheimer’s disease (AD) assessment tools, 380 associated with intellectual disability, 114 atypical presentations of, 103 cost of care, 96 demographic factors, 96 diagnosis, 102 genetic heritability, 729 Amphetamine sulfate (Adderall), 66, 561 Amygdala, 403 Amyotrophic lateral sclerosis (ALS), psychiatric differential diagnosis, 125 Annual Oral Examination (AOE), 10–40 anxiety, coping with, 39 case presentation, 37 doctor–patient relationship element, 36 evaluation, 18 focus of, 35 format, 10 grading, 35 interviews, conducting, 36 practice for, 35 preparation and study guides, 35 script for, 35 treatment plan, 38 vs. CSV, 10 Anorexia nervosa (AN). See also Eating disorders diagnosis, 266 differential diagnosis, 267–278 epidemiology, 266 treatment, medical, 271 treatment, pharmacotherapy, 273–278 treatment, psychological, 272 Anterior circulation strokes, 472 Anticholinergic delirium, 339, 342 Anticholinergic effects, of psychiatric medications, 593 Anticonvulsants/antiepileptics (AEDs) added to antipsychotics, 514 carbamazepine, 557–560 eating disorder treatment, 275 gabapentin, 558 lamotrigine, 556–560 levetiracetam, 560 overview, 554 oxcarbazepine, 559 pharmacology of, 555 pregabalin, 559 side effects, 556 social anxiety disorder treatment, 501 suicidal ideation and, 560 topiramate, 559

use during pregnancy, 315 use of in psychiatry, 555 valproate, 554–560 Antidepressants added to antipsychotics, 514 alcohol-related anxiety, 144 alcohol-related depression, 144 atypical antidepressants, 521–524 bulimia nervosa treatment, 523 categories of, 181 classes of, 518 cocaine-related depression, 154 dosing, 518, 519, 520, 521 drug interactions, 519, 520, 521, 581 during menopause, 320 dysthymic disorder treatment, 523 eating disorder treatment, 275 efficacy of, 181 food interactions, 521 generalized anxiety disorder treatment, 524 geriatric patients, 523 laboratory monitoring of, 395 major depression treatment, 523 natural medications, 600–612 OCD treatment, 524 overview, 518 pain relief obtained from, 464, 523 panic disorder treatment, 524 PTSD treatment, 224, 524 risks in bipolar disorder, 523 side effects of, 182, 183, 197, 518, 519, 520 smoking cessation, 524 treatment-refractory depression and, 523 use during pregnancy, 314, 523 Antihypertensives, ADHD treatment with, 66 Antipsychotics autism treatment, 86 dosing schedules, 513 drug interactions, 510, 513, 583, 585 eating disorder treatment, 273 efficacy, 172, 522 extrapyramidal symptoms, 507–516 first-generation agents, 506, 506–516 in children and adolescents, 73 in dementia, 106 laboratory monitoring, 395 long-acting injectable antipsychotics (LAIs), 512 non-adherence, 513 overview, 506 poor treatment response, 513

second-generation agents, 508, 509 side effects, 506–516, 512–516, 588, 592 therapeutic drug monitoring (TDM), 513 Tourette’s treatment, 80 treatment resistance, 513 use during pregnancy, 316 Antiretroviral medications, 329 Antisocial personality disorder, 303–308 Anxiety. See also Anxiety disorders AIDs/HIV patients, 326 alcohol-induced, 135, 140, 144 coping with during residency, 39 managing prior to certification exams, 6 present in psychiatric disorders, 206 test-taking, 6, 39 that complicates medical illness, 206 Anxiety Disorder Interview Scale, Revised (ADIS-R), 359 Anxiety disorders adult separation anxiety disorder (ASAD), 209 agoraphobia, 207 anxiety that complicates medical illness, 206 AUD patient management, 144 chronic pain with, 460 cognitive-behavioral model, 204 co-morbidities, 206 co-morbid with bipolar disorder, 194 co-morbid with intellectual disability, 114 course of illness, 205 differential diagnosis, 205, 206, 392 epidemiology, 205 etiology, 204 generalized anxiety disorder (GAD), 69, 71, 208 genetic heritability, 731 in athletes, 821 in children and adolescents, 69, 71 in geriatric patients, 696 medical conditions associated with, 206 neurobiological model, 204 organic causes of anxiety, 205 overview, 204 panic disorder, 207 post-traumatic stress disorder (PTSD), 209 prevalence, 205, 709 primary psychiatric disorders, 207–210 psychodynamic model, 204 separation anxiety, 71 social phobia, 69, 71, 208 specific phobia, 208 treatment, 496–504 Applied behavioral analysis (ABA), 86

Aripiprazole ASD-related symptoms treatment, 86 dosing, 511 in children and adolescents, 71 side effects, 511 Tourette’s treatment, 80 Army Center for Enhanced Performance (ACEP), 817 Asenapine dosing, 512 in children and adolescents, 71 side effects, 511 Assertive community treatment (ACT), 172, 808 Assessment Instrument for Mental Health Systems (AIMS), 826 Assessment, neuropsychological. See also Neurologic examination ADHD, 381 approaches to, 376 brief neuropsychological assessment tools, 380 common neuropsychological assessment referral questions, 381 depression versus dementia, 381 goals of, 376–384 history of, 376 independent living, 381 methodology, 377–384, 419–426 neuropsychological assessment report, 382 of attention and concentration, 378 of emotional function, 380 of executive functions and abstract thinking, 379 of memory functioning, 378 of motor and sensory functioning, 380 of receptive and expressive language, 378 of visual-spatial constructional ability, 379 overview, 376 treatment planning, 377, 382 Assessment of Activities of Daily Living (ADLs), 381 Assessment, psychological. See also Diagnostic rating scales assessment consultation process and report, 372 behavior rating scale, 371 child and adolescent assessment, 371 chronically mentally ill patients, 760–764 history of, 366 integrating assessment data, 372 medical and surgical patients, 746–750 performance-based psychological tests, 370 projective drawings, 371 psychological test categories, 368 psychological tests defined, 368 psychometrics and test development, 366 reliability and validity, 367 reliability and validity of psychiatric diagnosis, 706 Rorschach inkblot method, 370

Rorschach Performance Assessment System (R-PAS), 371 routine outcome monitoring (ROM), 371 standardized instruments for case assessment, 706 tests of personality, psychopathology, and psychological functioning, 368–374 Thematic Apperception Test (TAT), 371 understanding assessment reports, 373 using test results, 373 validity scales and other considerations, 370 Ataxia, 480, 482 Athetosis, 479 Atomoxetine, 570 Atomoxetine (Strattera), 66 Attachment theory, 59 Attention Deficit Hyperactivity Disorder (ADHD) assessment tools, 381 characteristics and treatment, 69 co-morbid with AUD, 145 co-morbid with bipolar disorder, 194 co-morbid with intellectual disability, 114 co-morbid with mood disorders, 567 differential diagnosis, 71, 177, 195 genetic heritability, 728 in athletes, 821 non-stimulant treatments, 570, 571 overview of, 65 prevalence, 66 psychostimulant treatment, 66, 561, 563, 564, 565, 566 Tourette disorder link, 79 Autism diagnostic interview-revised (ADI-R), 85 Autism diagnostic observation schedule (ADOS), 85 Autism spectrum disorder (ASD) characteristics and treatment, 69, 86 clinical features, 84 co-morbidity, 84, 85 differential diagnosis, 85 epidemiology, 84 etiology, 84 evaluation, 85 genetic heritability, 728 overview, 84 pharmacotherapy, 86 Avoidant personality disorder, 306 Avoidant/restrictive food intake disorder (ARFID), 266. See also Eating disorders

B Baclofen, 143 Basal ganglia calcifications, 482 Basal pain, 458 Beauchamp and Childress, Four Principles of, 838

Beck Depression Inventory (BDI), 358 Bedside neuropsychological assessment, 409 Beery Visual Motor Integration Test, 379 Behavioral disorders, co-morbid with intellectual disability, 114 Behavioral disorganization, 166 Behavioral phenotype, 113 Behavioral therapy, opioid use treatment, 162 Behavioral Variant FTD (Bv-FTD), 104 Behavior therapy, 638 Benign ethnic neutropenia (BEN), 509 Benton Judgment of Line Orientation Test, 379 Benton Visual Form Discrimination Test, 379 Benzodiazepines added to antipsychotics, 514 alcohol withdrawal treatment, 134, 142 AUD-associated anxiety treatment, 144 AUD contraindication, 144 characteristics of commonly used, 499 cocaine use treatment, 153 contraindication in dementia, 106 drug-drug interactions, 584 electroconvulsive therapy and, 529 GABA withdrawal treatment, 93 generalized anxiety disorder treatment, 500 panic disorder treatment, 498 PTSD prevention, 222 PTSD treatment, 224 risks during pregnancy, 316 seizure disorder treatment, 444 Beta-adrenergic blockers atomoxetine, 570 dosing and preparations available, 569 drug interactions, 570 general effects, 568 guidelines for use, 568 half-life and route of elimination, 569 indications, 568 side effects, 569 use in selected conditions, 568 Bias, sources of, 718–722, 785 Binge-eating disorder (BED) diagnosis, 267 epidemiology, 266 treatment, overview, 271–278 treatment, pharmacologic, 275 Bio-ethical issues, 838. See Ethics and professionalism Biogenic amine hypothesis, 179 Bipolar disorder AIDs/HIV patients, 327 alcohol-induced, 135

antidepressant use in, 523 assessment strategies, 198 AUD dual diagnosis management, 144 breastfeeding and, 318 co-morbidity, 194 course of the illness, 196 differential diagnosis, 177, 195 epidemiology, 194, 709 evaluation, 196 genetic and environmental impacts, 196 genetic heritability, 730 in children and adolescents, 69, 70 in geriatric patients, 696 maintenance treatment, 200 mood stabilizers during pregnancy, 315 overview, 194 patient management, acute depression, 200 patient management, acute mania, 199 prevalence, 194 secondary mood disorders, 197 specific elements of mental status examination, 199 specific elements of patient history, 198 sub-types of, 195 Type I, 194, 195 Type II, 194, 195 Bisexual persons, 780 Black Cohosh (Cimicifuga Racemosa), 607 Blessed Dementia Scale (BDS), 360 Blood alcohol concentration (BAC), 133 Blood tests. See Laboratory testing Body dysmorphic disorder (BDD) differential diagnosis, 213 DSM-5 criteria, 212, 229 treatment, 215 Body mass index (BMI), 269 Borderline personality disorder, 304 Boston Naming Test, 378 Boundary violations, 742–744, 840 Bowlby, John, 59 Bradykinesia, 478 Brain-derived neurotrophic factor (BDNF ), 180, 508 Brain tumors, 127 Breastfeeding, 318 Breathing-related sleep disorders, 283 Brexpiprazole, 511 Brief Psychiatric Rating Scale (BPRS), 359 Brief psychodynamic psychotherapy, 186, 640 brief interpersonal therapy, 645 cognitive-behavioral brief therapies, 645 eclectic brief therapies, 645

essential features of, 646–650 history of, 644 overview of, 644 patient selection criteria for, 646 phases of, 648 psychodynamic short-term therapies, 644 reasons for brief therapy approach, 645 self-reflective mindset needed for, 646 types of therapist activity, 648 Bucharest Early Intervention Project (BEIP), 62 Bulimia nervosa (BN). See also Eating disorders diagnosis, 267 differential diagnosis, 267–278 epidemiology, 266 treatment, medical, 271 treatment, pharmacotherapy, 273–278, 523 treatment, psychological, 272 Bullying, 62 Buprenorphine buprenorphine/naloxone opioid substitution, 160 detoxification using, 158 implants, 161 pain management and, 161 pregnancy and, 161 Bupropion ADHD treatment, 66 contraindication in eating disorders, 273 overview, 521 panic disorder treatment, 499 smoking cessation, 524 use during pregnancy, 314 Buspirone generalized anxiety disorder treatment, 501 panic disorder treatment, 499 PTSD treatment, 224, 503

C CAGE questionnaire, 137, 138, 360 California Verbal Learning Test-II (CVLT-II), 379 Candidate gene approach, 726 Capacity to make treatment decisions, 621, 840 Capitation plans, 803 Carbamazepine drug-drug interactions, 580, 581 efficacy, 558 indications, 557 laboratory monitoring of, 395 pharmacology, 557 seizure disorder treatment, 445

toxicity, 557, 594 Carbohydrate-deficient transferrin (CDT), 138 Carbon monoxide (CO) poisoning, 126 Cardiovascular system cardiac conducting system, 591 hypertension, 588 managing treatment side effects, 588 medication concerns in patients with cardiovascular disease, 592 orthostatic hypotension (OH), 588 Cariprazine, 511 Carve-out process, 803 Catatonia defined, 166, 334 diagnosis, 335 differential diagnosis, 335 EEGs, neuroimaging, and laboratory tests, 337 epidemiology, 334 etiology, 334, 335 evaluation, 337 medical complications associated with, 337 pathophysiology, 336 symptoms, 336 treatment, 337 Central nervous system, effects of psychiatric medications on, 592–598 Central sleep apnea, 283 Cerebral amyloid angiopathy (CAA), 100, 103 Cerebral autosomal dominant arteriopathy (CADASIL), 103 Cerebrovascular disease, psychiatric differential diagnosis, 125 Chess, Stella, 61 Child abuse and neglect bullying, 62, 772 Child Abuse Prevention and Treatment Act (CAPTA), 772 deaths caused by, 62 defined, 772 emotional abuse, 772 epidemiology, 773 neglect, 772 overview, 772 physical abuse, 62, 772 risk factors for, 62, 773 sexual abuse, 772 sub-types of, 772 treatment, 773 Child Abuse Prevention and Treatment Act (CAPTA), 772 Child and adolescent development adolescence, 59 brain development, 63 bullying, 62 developmental milestones, 58 divorce, impact of, 62

eating disorders in, 273 environmental impacts on, 62–64 ethical issues in child and adolescent psychiatry, 839 fetal alcohol spectrum disorders (FASDs), 112, 115, 135 gender dysphoria, 778 infancy, 58, 157 laboratory tests and diagnostic procedures, 392 media immersion, 62 overview, 58 pharmacologic principles, 74 pre-school age, 59 psychological assessment, 371 risks associated with pharmacotherapy during pregnancy, 313–320 school age/latency, 59 theories of development, 58, 59–64 Child Behavior Checklist, 371 Childhood-onset fluency disorder (stuttering), 67 Children’s Apperception Test, 371 Chlordiazepoxide AUD-associated anxiety treatment, 144 GABA withdrawal treatment, 93 Chorea, 479 Chronic meningitis, 120, 453 Chronic mental illness assessment of chronically ill patients, 760 diagnostic issues, 762 history-taking, 761 mental status exam (MSE), 761 overview of, 760 treatment strategies, 762 Chronic pain antidepressant treatment, 523 buprenorphine treatment, 161 defined, 458 opioid use for, 464 treatment, 461 Chronic traumatic encephalopathy (CTE), 481 Citalopram, 274 Civil commitment, 623 Clinical Dementia Rating (CDR), 98, 105 Clinical Global Improvement (CGI) scale, 358 Clinical Institute Withdrawal Assessment for Alcohol-Revised scale (CIWA-r), 134, 143 Clinical Skills Verification (CSV), 10–40 anxiety, coping with, 39 case presentation, 37 doctor–patient relationship element, 36 evaluation, 18 focus of, 35 format, 10 grading, 35

interviews, conducting, 36 practice for, 35 preparation and study guides, 35 script for, 35 vs. AOE, 10 Clomipramine, 502 Clonazepam, 498 Clonidine, 66, 159, 503 Clonus, testing for, 417 Clozapine add-on strategies, 514 AUD co-morbid schizophrenia treatment, 145 dosing, 509 drug interactions, 509 efficacy of, 508 laboratory monitoring, 395 side effects, 508, 591, 594 time-limited trails, 514 treatment resistant schizophrenia, 172 Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program, 509 Cluster A personality disorders, 300, 302–308 Cluster B personality disorders, 195, 300, 303, 303–308 Cluster C personality disorders, 206, 300, 306–308 Cluster headaches, 452 Cobalamin deficiency, 122 Cocaine and cocaine use cocaine-induced disorders, 151 cocaine-related disorders, 151 co-morbid psychiatric disorders, 152 co-morbid substance use, 152 epidemiology of cocaine use, 152 medical complications associated with, 153 other substances of abuse used with cocaine, 152 patterns of cocaine use, 152 pharmacology of, 151 physical and psychological effects of, 152 relapse prevention, 154 treatment, 153 treatment, pharmacologic, 154 unspecified cocaine-related disorder, 151 Cocaine Anonymous (CA), 154 Cognitive–behavioral therapy (CBT) acceptance and commitment therapy (ACT), 684 adjustment disorder treatment, 296 AUD treatment, 141, 144 behavioral techniques, 681 cocaine use relapse prevention, 154 cognitive techniques, 680 co-morbidity, 230 depression treatment, 681

eating disorder treatment, 272, 683 generalized anxiety disorder treatment, 501 in children and adolescents, 71 MDD treatment, 181, 186 mindfulness-based cognitive therapy (MBCT), 684 OCD treatment, 503 OCRD treatment, 214 opioid use treatment, 162 overview of, 639 pain treatment, 466 panic disorder treatment, 500, 682 personality disorder treatment, 302, 684 principles of, 679 psychosis treatment, 683 psychotic symptoms treatment, 172 PTSD treatment, 223, 503 relapse prevention, 142 sleep disorder treatment, 282, 284 social anxiety disorder treatment, 502 somatic symptom and related disorders treatment, 230 substance use disorders treatment, 683 theoretical basis for, 678 Tourette’s treatment, 81 Cognitive development, Piaget’s model of, 61 Cognitive functioning, assessment of, 378, 421 Cognitive slowing, 593 Cognitive therapy, 639 Cogwheel rigidity, 415, 478 Collaborative care psychiatry barriers to treatment, 793 collaborative models, 795–800 collaborative model selection, 797 collaborative roles, relationships, and expectations, 794 defined, 792 epidemiology, 792 improvement goals of collaboration, 794 overview, 792 Collaborative management, 796 Colloid cysts, 127 Communication disorders, 67, 69, 85 Community/Continuous Treatment Team (CTT), 762, 808 Community Mental Health Center Acts of 1963 and 1965, 802 Community mental health (CMH), 802 Community psychiatry components and services of CMH systems, 806 definitions and terminology surrounding, 801 history of, 803–810 managed care terms and definitions, 803 models of public health, 802 political changes to mental health care, 808

trauma-informed care, patient-centered care, and the recovery model, 808 trends in, 807 underlying principles of CMH, 805 Competency criminal competency, 628–632 to make informed treatment decisions, 621, 840 Complementary and alternative medicine (CAM) cognition-enhancing remedies, 608–612 defined, 600 homeopathy, 608 medications for pre-menstrual syndrome (PMS)/menopausal symptoms, 607 natural antidepressants, 600–612 natural anxiolytics, 606–612 natural medications and their indications and usage, 601 popularity of, 600 problems associated with, 600 recommendations for practitioners, 609 Complex Regional Pain Syndrome (CRPS), 459 Composite International Diagnostic Interview (CIDI), 356 Comprehensive behavioral intervention for tics (CBIT), 80 Computed tomography (CT) headache evaluation, 451 indications, 347 risks of, 346 stroke evaluation, 471 Conduct disorder (CD) characteristics and treatment, 68 diagnosis, 290 differential, 290 epidemiology, 290 overview, 288 subclassification and specifiers, 290 treatment, 291 Confidentiality, 741, 840 Confusion Assessment Method (CAM), 422 Consensus Cognitive Battery (MCCB), 380 Conservatorship, 622 Consultation–liaison (C–L), 746–750 Consultation psychiatrists, 795 Conversion disorder, 228 Coordination testing, 416 Copraxia, 114 Correlation coefficient, 713 Corticobasal ganglionic degeneration, 105 Cost-shifting practices, 803, 807 Couples therapy evaluation process, 654–658 organizing principles for, 652–658 overview of, 652 treatment interventions, 656–658

Cranial nerves, 412–418 Creutzfeldt-Jakob disease (CJD), 121, 329 Criminal system, competency in, 628 Critical incident debriefings, 222, 503 Crossing the Quality Chasm, 833 Culture and psychiatry concept of culture, 784 cultural concepts of distress, 785, 787 cultural syndromes, idioms of distress, and perceived causes, 786 DSM-5 cultural formulation, 784 ethnicity and psychopharmacology, 786–790 impact of culture on psychiatric diagnosis, 785 overview, 784 recommendations for observed clinical exercises, 788 Culture-bound syndromes, 245, 785 Cytochrome P450 isoenzymes, 579, 580

D Deception syndromes, 233–240 Declaration of Helsinki, 841 Deep brain stimulations (DBS), 185, 539–544 Deep tendon reflexes (DTRs), 416, 417 Deep vein thromboses (DVTs), 471 Degenerative disorders, 127 Dehydroepiandrosterone (DHEA), 604 De-institutionalization, 802 Delayed ejaculation disorder, 253 Delayed sleep-phase disorder (DSPD), 284 Delirium AIDs/HIV patients, 324 alcohol withdrawal, 134 anticholinergic, 339 causes, 91 diagnosis, 90, 391, 392 differential diagnosis, 96 EEG in, 430 epidemiology, 90 GABA withdrawal, 93 in geriatric patients, 699 mechanism, 90 overview, 90 prevention, 92 treatment, 92 Delirium tremens, 134, 135 Delis Kaplan Executive Function Systems, 380 Delusional disorders, 206 Dementia assessment tests, 380 caregiver burden and burnout, 107

depression co-morbidity, 101 diagnostic criteria for, 101–110 differential diagnosis, 96, 177, 381 DSM-5 criteria, 96 epidemiology, 96 etiology, 96, 103–110 evaluation, 96–110 frontotemporal dementias (FTD), 104 identification of, 96 in geriatric patients, 697 laboratory evaluation, 98, 99 mechanisms of neurodegenerative diseases, 100 metabolic effects contributing to, 101 mixed dementias, 103 Parkinson’s disease is associated with, 104 pharmacologic treatment, 105 prevention, 105 related conditions, 103 research trials concerning, 106 semantic, 104 treatment, 105 vascular, 96, 103 young-onset, 105 Dementia Rating Scale (DRS-II), 380 Dementia with Lewy bodies (DLB), 96, 104, 481, 698 Dependent personality disorder, 306 Depersonalization/derealization disorder, 245 Depression and depressive disorders. See also Major Depressive Disorder (MDD) AIDs/HIV patients, 325 alcohol-induced, 135, 140, 144 anti-epileptic drugs and, 447 dementia co-morbidity, 101 depressive disorder due to another medical condition, 188 differential diagnosis, 381, 392 DSM-5 categories, 176 electroconvulsive therapy in, 527–534 female life cycle and, 310 in geriatric patients, 695 MacArthur Initiative on Depression in Primary Care, 796 other specified depressive disorder, 188 post-stroke depression (PSD), 474 substance/medication-induced depressive disorder, 188 Three-Component Model (TCM) of collaboration, 796 treatment-refractory depression, 523 unspecified depressive disorder, 188 Dermatological system, effects of psychiatric medications, 595 Descriptive statistics, 712 Developmental coordination disorder, 68 Dexmedetomidine, 93 Dextroamphetamine, 565

Dhat syndrome, 786 Diabetic ketoacidosis, psychiatric differential diagnosis, 123 Diadochokinesia, 416 Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition (DSM-5), 45–56 conceptual changes, 47 cultural formulation, 784 diagnostic changes, 47, 48–56 organization of, 46 overview, 45 revision process, 46 revision summary, 45 Diagnostic Interview Schedule (DIS), 356 Diagnostic process. See also Laboratory testing anxiety evaluation, 392 approach to, 386 electroencephalograms, 394 functional neuroimaging, 394 geriatrics evaluation, 392 impact of culture on psychiatric diagnosis, 785 mental status examination, 387 monitoring psychotropic medications, 395 mood disorders and depression evaluation, 392 neuroimaging, 393 pediatric evaluations, 392 physical examination, 386 psychosis and delirium evaluation, 391 reliability and validity of psychiatric diagnosis, 706 strategies for, 386 structural neuroimaging, 393 substance use, 393 test selection, 387–398 types of studies, 387 Diagnostic rating scales Abnormal Involuntary Movement Scale (AIMS), 361 Addiction Severity Index (ASI), 361 Antidepressant Treatment Response Questionnaire (ATRQ), 361 Anxiety Disorder Interview Scale, Revised (ADIS-R), 359 anxiety scales, 359 Beck Depression Inventory (BDI), 358 Blessed Dementia Scale (BDS), 360 Brief Psychiatric Rating Scale (BPRS), 359 CAGE Questionnaire, 360 Clinical Global Improvement (CGI) scale, 358 cognitive impairment scales, 360 depression scales, 357 drug side-effect scales, 361 fear questionnaire, 359 Global Assessment of Functioning Scale (GAF), 361 Hamilton Rating Scale for Anxiety (HAM-A), 359 Hamilton Rating Scale for Depression (HAM-D), 357

Inventory of Depressive Symptomatology (IDS), 358 mania scales, 359 Manic State Rating Scale (MSRS), 359 Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), 360 Massachusetts General Hospital Sexual Functioning Questionnaire, 361 Michigan Alcoholism Screening Test (MAST), 360 Mini-International Neuropsychiatric Interview (MINI), 357 Mini-Mental State Examination (MMSE), 360 Montgomery-Asberg Depression Rating Scale (MADRS), 358 overview, 356 Personality Disorder Examination (PDE), 360 personality disorder scales, 360 Positive and Negative Symptoms Scale (PANSS), 359 Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), 358 reliability and validity of, 356 Scale for the Assessment of Negative Symptoms (SANS), 359 Scale for the Assessment of Positive Symptoms (SAPS), 359 scales for assessing efficacy and adequacy of previous antidepressant trials, 361 schizophrenia scales, 359 Social Adjustment Scale (SAS), 361 social functioning scales, 361 Structured Clinical Interview for DSM-5 Personality Disorders (SCID-II), 360 structured clinical interview for DSM-5 (SCID), 356 substance abuse scales, 360 Symptoms of Depression Questionnaire (SDQ), 358 Systematic Assessment for Treatment Emergent Effects (SAFTEE), 361 types of, 356 uses for, 356 Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), 359 Young Mania Rating Scale (Y-MRS), 359 Dialectical behavioral therapy (DBT), 302, 639 Diazepam, 93 Diffusion-weighted MRI (DWI), 471 DiGeorge syndrome, 734 DIGFAST symptoms of mania/hypomania, 197, 198 Digit Span Backward (WAIS-IV), 380 Disease frequency, measuring, 707 Disenfranchisement, 807 Disinhibited social engagement disorder, 70, 72 Disorders due to another medical condition (DTAMC). See Mental disorders DTAMC (due to another medical condition) Disruptive, impulse-control, and conduct disorders conduct disorder, 290–294 intermittent explosive disorder, 289 kleptomania, 292 oppositional defiant disorder, 288–294 other specified and unspecified disruptive, impulse-control, and conduct disorders, 293 overview, 288 pyromania, 291–294 Dissociative disorders

culture-bound syndromes, 245 depersonalization/derealization disorder, 245 diagnosis, 244 differential diagnosis, 243, 244 dissociative amnesia including dissociative fugue, 243 dissociative identity disorder (DID), 241, 243 etiology, 242 false dissociative symptoms, 245 Ganser’s syndrome, 245 measurement scales, 243 other specified dissociative disorders (OSDD), 245 overview, 241 specific dissociative disorders, 243–246 symptoms, 244 treatment, 243, 244 unspecified dissociative disorders, 245 Dissociative Experience Scale (DES), 243 Distal motor latency, 432 Distal sensory polyneuropathy (DSP), 328 Disulfiram, 143, 586 Divalproex, 71 Divorce, impact on children, 62 Domestic violence. See also Intimate partner violence (IPV) Donabedian Triad Classification System, 833 Donepezil, 106, 586 Dopamine agonists, 154, 170, 340 Dopamine (DA), 151, 491 Dorsolateral prefrontal cortex (DLPFC), 402 Double effect principle, 841 Down syndrome, 112, 114, 733 Dronabinol, 274 Drug–drug interactions according to psychotropic drug class, 580–586 antidepressants, 581–586 antipsychotics, 583–586 anxiolytics, 584–586 classification, 577–586 common inducers of hepatic drug metabolism, 579 common inhibitors of drug metabolism, 579 disulfiram, 586 donepezil, 586 involving alpha-adrenergic blockers, 572 involving antipsychotics, 585 involving beta-adrenergic blockers, 570 involving carbamazepine, 581 involving cytochrome P450 isoenzyme, 579, 580 involving lithium, 581 involving SSRIs, 583 involving stimulants, 568 involving TCAs, 584

involving valproate, 581 methadone, 586 mood stabilizers, 580–586 overview, 576 zolpidem, 586 Drug-induced action tremor, 482 Drug-induced movement disorders, 482 Duloxetine, 465 Dyanavel XR, 566 Dysexecutive syndrome, 403 Dysmetria, 480 Dysthymic disorder antidepressant use in, 523 diagnosis, 187 differential diagnosis, 177 Dystonia, 479, 482, 483, 507

E Eating Disorder Inventory-2 (EDI-2), 274 Eating disorders assessment and management of, 276 co-morbid with bipolar disorder, 194 diagnosis, 266–278 differential diagnosis, 267–278 epidemiology, 266 evaluation, 267 evaluation, medical, 268–278 in athletes, 821 inpatient management, 276 laboratory analysis, 269 nutritional assessment, 269 nutritional counseling, 273 psychiatric evaluation, 269–278 sociocultural factors, 266 treatment, medical, 271 treatment, pharmacotherapy, 273 treatment, psychological, 272 Eating Disorders Clinical and Research Program (EDCRP), 372 Effect size, 714 Elder abuse, 700, 772, 774, 840 Electrocardiogram (EKG), 280, 387 Electroconvulsive therapy (ECT) added to antipsychotics, 514 anesthesia during, 529 catatonia treatment, 338 complications, 530 contraindications, 184 efficacy, 183, 527–534 indications, 183

indications for, 526 mechanism of action, 526 practical aspects of, 528–534 procedure, 184 risk factors, 527 safety profile, 526 seizure administration, 529–534 side effects, 184, 531 Electroencephalogram (EEG) abnormalities in, 428 characteristics of recordings, 428 diagnostic process and, 387 evoked potentials, 431 limitations of, 429 normal EEG, 428, 429 polysomnography and, 280 seizure disorder evaluation, 394, 442 use in clinical practice, 429 use in psychiatry, 430 Electromyogram (EMG), 280, 431–436 Electrooculogram (EOG), 280 Elimination disorders, 73 Encopresis, 70, 73 Endocrine system, effects of psychiatric medications, 596 End-of-life care, 840 Enuresis, 70, 73 Epidemiology, psychiatric alcohol use disorders, 710 bipolar disorder, 709 major depressive disorder, 710 measurement of disease frequency, 707 National Co-Morbidity Survey (NCS), 708 overview, 705 panic disorder, 710 prevalence estimates for specific mood and anxiety disorders, 709 reliability and validity of psychiatric diagnosis, 706–710 schizophrenia, 709 statistics describing, 714 study designs, 707–710 Epigenetic model of development, 60 Epilepsy behavioral changes in, 442 classification of, 438 diagnosis, 438 neuropsychiatric manifestations, 443 psychiatric differential diagnosis, 121 refractory, 445 treatment, 443–448 EQUATOR (Enhancing the Quality and Transparency Of Health Research) Network, 721 Erectile disorder, 253, 254

E-reflex, 433 Erikson, Erik, 60 Eslicarbazepine, 447 Essential hypertension, 588 estimated, 700 Estrogen, 310, 318. See also Female reproductive cycle and associated psychiatric disorders Eszopiclone, 316 Ethics and professionalism cultural relativism, 839 ethical aspects of forensic considerations, 839 Four Principles of Beauchamp and Childress, 838 in childhood/adolescence, 839 in genetic testing, 839 in geriatric patients, 840 in reproductive psychiatry, 839 Kantian and Utilitarian ethics, 838 managed care, insurance, and pharmaceutical company interactions, 841 physician-assisted suicide, 841 professional association guidelines, 838 research ethics, 841 Excoriation disorder, 212 Execution, competency evaluation prior to, 628 Experimental validity, 718 Exposure with response prevention (ERP), 214 Expressive psychotherapy, 638 External validity, 718 Extrapyramidal symptoms (EPS) avoiding, 92 dealing with, 592 differential diagnosis, 339 use of term, 478 with first-generation antipsychotics, 172, 506–516 Eye movement desensitization and reprocessing (EMDR), 223, 242, 504 Eye movement examination, 413

F Facial nerve, 414 Factitious disorders characteristic course, 235 clinical features, 235 clinical types of factitious disorder with physical symptoms, 238 diagnosis, 235, 238 differential diagnosis, 336 epidemiology, 234 etiology, 236 hallmarks of, 229 management, 237 overview, 234 pain and, 461

sub-types, 235 treatment, 230, 237 Fahr’s disease, 482 False–positive and false–negative errors, 713 Family studies, 726 Family therapy behavioral family therapy, 663 eating disorder treatment, 272 efficacy of, 664 experiential family therapy, 660 narrative family therapy, 662 opioid use treatment, 162 overview of, 659 psychodynamic family therapy, 659 psychoeducational family therapy, 664 psychotic relapse prevention, 172 strategic family therapy, 661 structural family therapy, 661 systemic family therapy, 662 Fasciculations, 480 Felbamate, 446 Female orgasmic disorder, 253, 256 Female reproductive cycle and associated psychiatric disorders depression, 310 estrogen and progesterone neuromodulatory effects, 310 gay women/lesbians, 780 menopause, 318–320 oral contraceptives and lamotrigine interactions, 581 overview, 310 post-partum, 316–320 pregnancy, 312–320 pre-menstrual dysphoric disorder (PMDD), 310–320 pre-menstrual syndrome (PMS), 310–320 Female sexual interest/arousal disorder (FSIAD), 253, 256 Festination, 480 Fetal alcohol spectrum disorders (FASDs), 112, 115, 135, 737 Fifth Edition (SCID-5), 356 Finger-Localization Test, 380 Finger-Tapping Test, 380 First-generation antipsychotics (FGAs), 506, 506–516. See also Antipsychotics Flibanserin, 256 Flumazenil, 585 Fluoro deoxyglucose (FDG) PET, 349, 394 Fluoxetine AUD treatment, 143, 144 eating disorder treatment, 274 in children and adolescents, 70 Focal seizures, 440–448 Folstein Mini-Mental State Examination. See Mini-Mental State Examination (MMSE) Forensic psychiatry

assessing capacity to make treatment decisions, 621 civil commitment, 623 criminal competency, 628–632 criminal responsibility, 629–632 informed consent, 620 informed consent, exceptions to, 622 overview, 620 role of psychiatrists in the legal system, 630–632 treatment refusal, 622 Four Principles of Beauchamp and Childress, 838 Fragile X syndrome, 112, 114, 735 F-response, 433 Freud, Sigmund, 60 Froment’s sign, 415 Frontotemporal dementias (FTD), 96, 103, 104, 698 Functional MRI (fMRI), 351 Functional neuroanatomy. See Neuropsychological functioning Functional somatic syndromes (FSSs), 230

G Gabapentin, 143, 144, 315, 501 efficacy, 558 indications, 558 pharmacology, 558 toxicity, 558 Gait testing, 416 Gamma-aminobutyric acid (GABA), 133, 171, 205, 490 Gamma-aminobutyric acid (GABA) agonists in delirium, 91 withdrawal treatment, 93 Gangliosidoses, psychiatric differential diagnosis, 125 Ganser’s syndrome, 245 Gastrointestinal (GI) system, adverse effects of psychiatric medications, 594 Gay men, 780 Gay women/lesbians, 780 Gegenhalten, 415, 479 Gender-affirming care, 779 Gender dysphoria, 259–264, 778 Gender identity, 777 Generalized anxiety disorder (GAD) diagnosis, 208 in children and adolescents, 69, 71 overview, 208 prevalence, 208 treatment, pharmacotherapy, 500–504, 524 treatment, psychosocial, 501 Genetic mapping, 725. See also Psychiatric genetics Genito-pelvic pain/penetration disorder, 254 Genome-wide association studies (GWAS), 727

Geriatric patients abuse of, 700, 772, 774, 840 acute behavioral problems in, 699 antidepressant use in, 523 anxiety in, 696 benzodiazepine use by, 498 bipolar illness in, 696 commonly used antipsychotic, 700 delirium in, 699 depression in, 695 drugs causing symptoms of depression, 696 estimated numbers in U.S., 694 ethical considerations for, 840 evaluation of, 694 functional assessment, 695 increased mortality with FGAs and SGAs, 512 laboratory tests and diagnostic procedures, 392 major neurocognitive disorder in, 697 metabolic changes associated with aging, 694 treatments recommended for depression, 697 Giant cell (temporal) arteritis, 453 Gilligan, Carol, 62 Ginkgo Biloba, 608 Glasgow Coma Scale, 410 Global Assessment of Functioning Scale (GAF), 361 Global Burden of Disease study, 825 Global Developmental Delay, 67 Global mental health capacity-building through training priorities, 826 integration of mental health into primary care, 828 mental health in humanitarian emergencies, 828 mental health policies and legislation, 827 overview, 825 Glossopharyngeal nerve, 414 Glutamate (Glu), 489 Grief and bereavement clinical features of, 297 evaluation and differential diagnosis, 297 management, 297 overview, 296 Grooved Pegboard Test, 380 Group A Strep infections, 80 Group therapy combination therapies, 673 common therapeutic assumptions, 668 consultation and supervision for, 674 creation and goals of groups, 669–676 for psychotic symptoms, 172 legal and ethical considerations in, 673 opioid use treatment, 162

overview of, 640, 668 patient selection for group therapy, 672 preparing and maintaining groups, 671–676 research outcome and evaluation, 674 roles of group leaders, 670 therapeutic factors in, 671 types of, 670 Guanfacine (Tenex), 66 Guardianship, 622

H Habit reversal therapy (HRT), 80, 215 Hair-pulling disorder. See Trichotillomania (TTM) Haloperidol delirium treatment, 92 Tourette’s treatment, 80 Halstead-Reitan (H-R) Neuropsychological Test Battery, 376 Hamilton Rating Scale for Anxiety (HAM-A), 359 Hamilton Rating Scale for Depression (HAM-D), 357 Hand Dynamomet, 380 Headache epidemiology, 450 evaluation, 450 headache syndromes, 451–454 Head trauma, 128 Hematologic system, effects of psychiatric medications, 594 Hemiballism, 480 Hemorrhagic stroke, 471 Hepatic encephalopathy, psychiatric differential diagnosis, 123 Herbal medications. See Complementary and alternative medicine (CAM) Heritability estimates, 727 Herpes simplex encephalitis, 453 Herpes simplex virus (HSV), 119 Histamine, 492 Histrionic personality disorder, 305 HIV-associated dementia (HAD), 324, 328 HIV-associated neurocognitive disorder (HAND), 327 Hoarding disorder, 212 Homeopathic medications, 608. See also Complementary and alternative medicine (CAM) Homocystinuria, 735 Hooper Visual Organization Test, 379 Hopkins Verbal Learning Test-Revised (HVLT-R), 379 Hormone fluctuations, 310. See also Female reproductive cycle and associated psychiatric disorders Hormone replacement therapy (HRT), 319, 320 H-reflex, 433 Human genome, 724 Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) anti-retroviral medications, 329–332 central nervous system infections, 329

diagnosis, 323 differential diagnosis of mental status alterations, 325 epidemiology, 322 general approach to psychiatric care, 324 HIV-associated meningitis, 328 HIV-associated neuropathies, 328 legal considerations for testing and management, 330 neurologic manifestations of, 327–332 neurosyphilis in patients with, 120 overview, 322 psychiatric differential diagnosis, 119 psychiatric illness in, 324–332 treatment side effects, 327 Huntington disease (HD), 481, 734 Huntington’s chorea, 128 Hyperkinetic signs, 479 Hyperprolactinemia, 508, 596 Hypersomnolence disorder, 283 Hypertensive (hyper-adrenergic) crisis, 582, 588 Hypertensive vasculopathy, 471 Hypoglossal nerve, 415 Hypoglycemic encephalopathy, psychiatric differential diagnosis, 123 Hypokinetic signs, 478 Hypoparathyroidism, 482 Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation, 179 Hypothalamic-pituitary-thyroid axis dysregulation, 180 Hypothesis testing, 713

I Idiopathic intracranial hypertension, 453 Idiopathic pain, 460 Idiopathic Parkinson’s disease (IPD), 480 Illness anxiety disorder (IAD), 228 Iloperidone, 512 Imipramine alcohol-related anxiety, 144 in children and adolescents, 73 Immigration and acculturation, 785 Infant development. See also Child and adolescent development attachment and separation stages, 58 breastfeeding and psychotropic medications, 318 neonatal abstinence syndrome (NAS), 157 perinatal toxicity with antipsychotics and antianxiety medications, 316 persistent pulmonary hypertension of the newborn (PPHN), 315 risks associated with pharmacotherapy during pregnancy, 313–320 Inferential statistics, 713 Informed consent, 620–626, 840 Insanity defense, 629–632 Insomnia disorder, 281–286. See also Sleep disorders

Insomnia, treating alcohol-induced, 144 Instrumental activities of daily living (IADLs), 97, 106 Integrative psychotherapy, 640 Integumentary system, effects of psychiatric medications, 595 Intellectual disabilities child-onset fluency disorder (stuttering), 67 communication disorders, 67 co-morbidity, 113–116 diagnostic features, 113 epidemiology and etiology, 112, 135 evaluation and differential diagnosis, 113 global developmental delay, 67 Intellectual Development Disorder, 66 language disorder, 67 overview, 112 severity specifiers, 113 specific learning disorder, 68 speech sound disorder, 67 treatment, 113 Intellectual Disability (Intellectual Developmental Disorder), 66 Intelligence Quotient (IQ), 378 Intelligence tests, 368 Intermittent explosive disorder (IED), 195 diagnosis, 289 epidemiology, 289 evaluation, 290 overview, 288 Internal validity, 718 International League Against Epilepsy (ILAE), 438 Interpersonal psychotherapy (IPT) MDD treatment, 186 overview of, 639 post-partum depression treatment, 317 Intimate partner violence (IPV) clinical presentation, 766 cycle of violence, 767 differential diagnosis, 769 epidemiology, 766 evaluation, 768 nature of violent relationships, 767 overview, 766 recognition and treatment of partner violence (RADAR), 769 risk factors, 766 treatment considerations, 769 Intra-cranial mass lesions, 453 Inventory of Depressive Symptomatology (IDS), 358 Ischemic stroke, 470

J

Jacksonian march, 440

K Kagan, Jerome, 61 Kantian ethics, 838 Kava (Piper Methysticum), 606 Kidney Donor Profile Index (KDPI), 752 Kindling, in cocaine use, 153 Klein, Melanie, 59 Kleptomania diagnosis, 292 differential diagnosis, 292 epidemiology, 292 evaluation/examination, 292 overview, 288 treatment, 292 Klerman, Gerald, 639 Klinefelter syndrome, 733 Kohlberg, Lawrence, 62 Korsakoff syndrome, 135 Kuru, 121

L Laboratory testing. See also Diagnostic process common studies used, 387 drug detection in serum and urine, 389 neuroendocrine and psychiatric manifestations, 389 psychosis and delirium evaluation, 391 role in diagnostic process, 386 routine screening tests, 387 serological studies and psychiatric manifestations, 390 serum chemistries and pertinent findings, 388 toxin detection, 391 Lacosamide, 446 Lacunar strokes, 473 L-alpha-acetylmethadol (LAAM), 160 Lamotrigine added to antipsychotics, 514 drug-drug interactions, 580 efficacy, 557 in children and adolescents, 71 indications, 556 pharmacology, 557 PTSD treatment, 224 seizure disorder treatment, 446 toxicity, 557, 595 use during pregnancy, 315 Language disorder, 67 Lead toxicity, 126

Learning disorders characteristics and treatment, 69 overview of, 68 stuttering, 67 Legal issues. See Forensic psychiatry Lesbian, Gay, Bisexual, Transgender and Queer (LGBTQ) mental health, 777–782 Lesch-Nyhan syndrome, 736 Lesions, neuropsychiatric dysfunction due to, 419–426 Letter-Number Sequencing (WAIS-III), 380 Level of consciousness evaluation, 409, 421 Levetiracetam, 315, 446, 560 Linkage studies, 727 Lisdexamfetamine dimesylate, 275, 566 Lithium added to antipsychotics, 514 AUD co-morbid bipolar disorder treatment, 145 breastfeeding and, 318 clinical effectiveness, 549 clinical factors affecting response, 550 dosing and titration, 546 drug interactions, 547, 580, 581 eating disorder treatment, 274 electroconvulsive therapy and, 528 history, 546 in children and adolescents, 71 indications, 546 laboratory monitoring of, 395 mechanisms of action, 547 monitoring, 548 overview, 546 pharmacology, 546 reasons for non-compliance, 548 side effects and toxicity, 547, 549, 591, 594 teratogenicity, 548 toxicity, 549 Locked-in syndrome, 335 Lofexidine, 159 Long-acting injectable antipsychotics (LAIs), 512 Long-term psychodynamic psychotherapy (LTPP), 186 Lorazepam GABA withdrawal treatment, 93 seizure disorder treatment, 444 side effects, 595 Lurasidone, 512 Luria hand sequence, 90 Luria-Nebraska Battery (L-NB), 376 Lyme disease, 119

M

MacArthur Initiative on Depression in Primary Care, 796 Magnetic resonance imaging (MRI), 347, 351, 387, 451 Mahler, Margaret, 60 Maintenance of Certification Examination (MOC), 3. See also Psychiatry Certification Examinations Major depression. See also Major Depressive Disorder (MDD) AIDs/HIV patients, 325 antidepressant use in, 523 chronic pain with, 460 genetic heritability, 730 Major Depressive Disorder (MDD) AUD co-morbid, 144 biochemical basis for, 179 brain-derived neurotrophic factor (BDNF), 180 course of, 178 diagnosis, 176 differential diagnosis, 96, 177, 195 epidemiology of, 178, 710 etiology, 178–192 family and genetic associations, 178 hormone dysregulation and, 179 in children and adolescents, 68, 70 inflammatory markers, 180 in military personnel and veterans, 816 sleep dysregulation and, 179 specifiers for, 176 structural abnormalities associated with, 180 treatment, CBT, 186 treatment, combination therapy, 187 treatment, DBS, 185 treatment, ECT, 183 treatment, IPT, 186 treatment, of MDD sub-types, 185 treatment, pharmacologic, 181–192 treatment, phases of, 181 treatment, psychodynamic therapy, 186 treatment, rTMS, 184 treatment, vagal nerve stimulation (VNS), 184 Major neurocognitive disorder, 697–702 Male erectile disorder. See Erectile disorder Male hypoactive sexual desire disorder, 252 Malignant hyperthermia, 336, 338, 339, 342 Malingering clinical features, 236 diagnosis, 236, 238 differential diagnosis, 236, 336 dissociative symptoms in, 245 epidemiology, 236 management, 237 overview, 234 pain and, 461

treatment, 237 Malpractice law, 739–744 Managed behavioral health organizations (MBHOs) Managed, 803 Managed care entities (MCEs), 807 Managed-care organizations (MCOs), 803 Manic State Rating Scale (MSRS), 359 Marine Resiliency Study (MRS), 817 Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), 360 Massachusetts General Hospital Sexual Functioning Questionnaire (ATRQ), 361 Measurement and Treatment Research to Improve Cognition in Schizophrenia’s (MATRICS), 380, 381 Médecins Sans Frontières (MSF), 828 Medial prefrontal cortex (MPFC), 403 Medical adherence, 633–636 Medical patients, psychiatric consultation to, 746–750 Medications, 497 Meditation, 689 Melatonin, 493, 607 Memantine, 106 Mendelian expression, 725 Menopause, psychiatric disorders during, 318–320 Mental disorders DTAMC (due to another medical condition) categories for, 119 cerebrovascular disease, 125 defined, 117 demyelinating disorders, 124 depressive disorder, 188 endocrine disorders, 123 evaluation, 129 head trauma, 128 immune diseases, 128 lipid storage disorders, 125 mitochondrial metabolic dysfunction, 125 neoplasms, 127 nutritional deficits associated with, 122 OCRD due to another medical condition, 212 personality change, 307 psychiatric differential diagnosis, 117 substance-induced disorders, 118 toxins, 126 treatment, 129 Mental retardation. See Intellectual disabilities Mental status exam (MSE), 129, 378, 387, 408–418, 761 Mercury toxicity, 126 Metabolic encephalopathy, psychiatric differential diagnosis, 122 Metachromatic leukodystrophy (MLD), 736 Metachromatic leukodystrophy (MLD), psychiatric differential diagnosis, 125 Methadone drug-drug interactions, 586 in pregnancy, 157

interaction with opioid receptors, 155 methadone maintenance, 160 opioid detoxification, 158 Methylphenidate (MPH), 66, 562–574 mhGAP (mental health Gap Action Programme), 826 Michigan Alcoholism Screening Test (MAST), 139, 360 Microtubule-associated proteins (MAP), 100 Migraine headaches, 451 Mild cognitive impairment (MCI), 101 Military personnel and returning veterans barriers to care, 813 major depressive disorder (MDD) in, 816 military service and culture, 812 overview, 812 post-traumatic stress disorder (PTSD) in, 814, 815 psychological trauma in, 813 substance misuse in, 816 suicide in, 817 traumatic brain injury (TBI) in, 816 understanding and enhancement of resilience in, 817 Miller Fisher Test, 105 Millon Clinical Multi-axial Inventory-IV (MCMI-IV), 369 Mind–body medicine clinical practice integration, 690 consequences of stress, 688 efficacy, 690 historical perspective, 688 manualized therapies, 690 mechanisms of mind–body interventions, 689 overview, 688 precautions, 690 primary mind–body techniques, 689 Mindfulness-based cognitive therapy (MBCT), 684 Mindfulness-Based Stress Reduction (MBSR), 690 Mini-International Neuropsychiatric Interview (MINI), 357 Mini-Mental State Examination (MMSE) common use of, 424 delirium diagnosis, 90 dementia diagnosis, 98, 380 overview of, 360 Minnesota Multiphasic Personality Inventory (MMPI), 243 Minor patients, 840 Mirtazapine, 499, 522, 583 Missing data, types of, 714 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), 125 MMPI-2, 369 MMPI-Adolescent, 371 Molecular genetics, 726 Monitoring tools, 377 Monoamine Oxidase Inhibitors (MAOIs)

contraindications in eating disorders, 273 dosing, 521 drug interactions, 521 efficacy, 520 electroconvulsive therapy and, 528 food interactions, 521 panic disorder treatment, 498 PTSD treatment, 224 side effects, 183, 498, 520, 588 social anxiety disorder treatment, 501 use during pregnancy, 314 Montgomery-Asberg Depression Rating Scale (MADRS), 358 Montreal Cognitive Assessment (MoCA), 90, 105, 424 Mood disorder chronic pain with, 460 differential diagnosis, 177, 392 genetic heritability, 730 in athletes, 820 prevalence, 709 secondary to bipolar disorder, 197 Mood stabilizers drug-drug interactions, 580 laboratory monitoring of, 395 use during pregnancy, 315 Mood swings, 195 Moral development models, 62 Motor nerve conduction, 432 Motor neuron disease, 104 Motor skills examination, 415 Movement disorders drug-induced, 482–484 hyperkinetic signs, 479 hypokinetic signs, 478 overview, 478 pathophysiology, 478 psychogenic movement disorders, 483 with psychiatric symptoms, 480–484 Multi-focal leukoencephalopathy (PML), 329 Multiple agentry, 840 Multiple personality disorder. See Dissociative disorders: dissociative identity disorder (DID) Multiple sclerosis (MS), psychiatric differential diagnosis, 124 Multiple system atrophy (MSA), 481 Multi-systemic treatment, 639 Muscle strength, grading of, 415 Myoclonic seizures, 440 Myoclonus, 479 Myofascial pain, 459

N

N-acetyl-cysteine (NAC), 605 Naloxone detoxification using, 158 interaction with opioid receptors, 155 response signs, 158 Naltrexone, 143, 144, 162 Narcissistic personality disorder, 305 Narcolepsy, 283 Narcotic Anonymous (NA), 163 National Center on Elder Abuse (NCEA), 774 National Committee for Quality Assurance (NCQA), 803 National Co-Morbidity Survey (NCS), 708 National Institute on Alcohol Abuse and Alcoholism (NIAAA), 137 National Institutes of Health Stroke Scale (NIHSS), 471 National Practitioner Data Bank (NPDB), 742 Natural medications. See Complementary and alternative medicine (CAM) Nefazodone AUD-associated MDD treatment, 144 AUD treatment, 144 overview, 522 panic disorder treatment, 499 PTSD treatment, 224 Nelson-Denny Reading Comprehension tests, 378 Neonatal abstinence syndrome (NAS), 157, 161 Neoplasm, 127 Nerve conduction studies, 431–436 Neurofibromatosis Type 1 (NF1), 734 Neuroimaging techniques applications in clinical psychiatry, 351–354 computed tomography (CT), 346, 393 CT scans vs. MRIs, 348, 349 factors to consider for use in psychiatry, 346–354 functional imaging, 349–354 functional MRI (fMRI), 351, 394 guidelines for use in psychiatric patients, 352 magnetic resonance imaging (MRI), 347, 394 MRIs resulting in treatable findings, 351 PET vs. SPECT, 350 plain films (X-ray) of the skull, 346 positron emission tomography (PET), 349, 394 single-photon emission computed tomography (SPECT), 350, 394 structural imaging, 346–354, 393 Neuroleptic malignant syndrome (NMS) defined, 338 diagnosis, 338 differential diagnosis, 339, 342 epidemiology, 338 etiology, 482 evaluation, 339 first-generation antipsychotics and, 507, 508

pathophysiology, 339 symptoms, 593 treatment, 340 Neurologic examination complete exam, 408 coordination testing, 416 cranial nerves, 412–418 Glasgow Coma Scale, 410 level of consciousness, 409 motor examination, 415 neurologic MSE, 409–418 overview, 407 psychiatric MSE, 408–418 reflex testing, 416 sensory examination, 415 Neuropathic pain, 459 Neuropsychiatric dysfunction ancillary information, 421 cognitive examination, 421–426 guiding principles, 420 history, 420 overview, 419 patient selection, 420 physical examinations and diagnostic test selection, 424–426 terminologies for temporal aspects of declarative memory, 424 Neuropsychological assessment. See Assessment, neuropsychological Neuropsychological functioning basic domains of, 401 cortical anatomy, 402–406 executive function and comportment, 402 hemispheric specialization, 403 keys to understanding neuropsychiatric pathophysiology, 404 language, 402 medial temporal structures, 403 memory and emotion, 402 neurotransmitter loci, 404 object identification, 401 overview, 401 prefrontal cortex and subdivisions, 402–406 principles of, 402 subcortical structures and the cerebellum, 404 visuospatial functioning, 401 Neurosyphilis, 120 Neurotherapeutics ablative limbic system surgery, 540 deep brain stimulation, 539–544 overview and classification, 536 transcranial magnetic stimulation, 536–544 vagal nerve stimulation, 538–544 Neurotransmitter systems, 489–494

Niacin deficiency, 122 Nociception, 457 Nocturnal penile tumescence (NPT) studies, 251 Non-convulsive status epileptics (NCSE), 430 Non–rapid eye movement (NREM) sleep, 280 Norepinephrine (NE), 151, 491 Normal pressure hydrocephalus (NPH), 105, 481 North American Adult Reading Tests (NAART), 378 NREM sleep arousal disorders, 285

O Object relations theory, 59 Obsessive-compulsive and related disorders (OCRD) diagnosis, 212 differential diagnosis, 213 gender differences, 213 onset and course of illness, 214 overview, 212 prevalence, 213 qualifiers to OCRD diagnoses, 212 treatment, pharmacological, 214 treatment, psychosocial, 214 Obsessive–Compulsive Disorder (OCD) differential diagnosis, 80, 307 DSM-5 criteria, 212 genetic heritability, 731 in children and adolescents, 69, 72 Tourette disorder link, 79 treatment, pharmacotherapy, 502, 524 treatment, psychosocial, 503 Obsessive-compulsive personality disorder (OCPD), 307 Obstructive sleep apnea (OSA), 283 Olanzapine dosing, 510 efficacy, 510 in children and adolescents, 71 side effects, 510 Older Americans Act (OAA), 774 Olfactory nerve, 412 Omega-3 fatty acids, 604 Ondansetron, 275 Open Dialogue practice, 808 Operational Stress Control and Readiness (OSCAR), 817 Opioids and opioid use adverse effects, 464 central opiate receptors, 458 chronic pain treatment, 464 co-morbid psychiatric disorders, 156 course of opiate use, 155

detoxification, 158 epidemiology of opiate abuse, 155 etiological factors associated with opiate use, 156 false-positive urine tests for, 155 medical complications of opiate use, 157 opioid antagonist therapy, 162 opioid-induced disorders, 154 opioid pharmacology, 155 opioid substitution, 160–164 opioid use disorders, 154 pain management using, 464 pharmacological treatment developments, 161 pregnancy and, 157 psychological treatments, 162 treatment, 158 unspecified opioid-related disorder, 155 urine testing for, 155 Oppositional defiant disorder (ODD), 68 diagnosis, 288 differential diagnosis, 289 epidemiology, 288 evaluation, 288 overview, 288 treatment, 289 Optic nerve, 412 Orbitofrontal (prefrontal) cortex (OFC), 403 Orexin, 493 Organ transplantation, 751–758 Orthostatic hypotension (OH), 588 Ospemifene, 256 Other specified dissociative disorders (OSDD, 245 Other specified feeding or eating disorders (OSFED). See also Eating disorders diagnosis, 267 epidemiology, 266 pharmacotherapy, 273 Outcomes monitoring, 371 Outpatient consultation models of collaborative care, 795 Oxazepam, 144 Oxcarbazepine, 315, 446, 559 Oxycodone, 155. See also Opioids and opioid use

P Paced Auditory Serial Addition Test, 378 Pain analgesic therapies, 462 categories of, 458–468 descending analgesic pain pathway, 458 endogenous analgesic system, 458 multi-disciplinary approach to management, 466

overview, 457 pathophysiology of, 457 psychopathology of, 460 treatment, analgesic adjuvants, 464, 523 treatment, analgesic therapies, 461–468 treatment, non-pharmacological, 466 treatment, NSAIDs, 463 treatment, opiates, 463, 465 Paliperidone, 510 Pancreatic cancer, 127 Panic disorder (PD) course of illness, 207 epidemiology, 207, 710 genetic heritability, 731 symptoms, 207 treatment, pharmacotherapy, 496–504 treatment, psychosocial, 500 Parallel care model of collaboration, 796 Parallel play, 59 Paraneoplastic syndromes, 127 Paraphilias, 248, 258, 257–264 Parathyroid dysfunction, psychiatric differential diagnosis, 124 Paratonia, 415, 479 Parkinsonianism, 478, 480, 482, 507 Parkinson’s disease (PD) dementia in, 104 onset of, 336 psychiatric differential diagnosis, 127 Parkinson’s Plus syndromes, 481 Paroxetine AUD treatment, 144 PTSD treatment, 224 Partners in Health (PIH), 828 Pathobehavorial syndrome, 113 Patient adherence, 633–636 Patient-centered care (PCC), 808 Pediatric Acute Onset Neuropsychiatric Syndrome (PANS), 80 Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS), 80 Penn Resilience Program (PRP), 817 Perampanel, 447 Perceptual Reasoning Subtests of the WAIS-IV, 379 Performance enhancing drugs, 822 Persistent (chronic) motor/vocal tic disorder, 70, 78 Persistent depressive disorder (dysthymia), 187 Persistent pulmonary hypertension of the newborn (PPHN), 315, 523 Persistent vegetative state, 335 Personality Assessment Inventory (PAI), 369, 380 Personality Disorder Examination (PDE0, 360 Personality disorders alternative DSM-5 model for personality disorders, 307

antisocial personality disorder, 303–308 avoidant personality disorder, 306 borderline personality disorder, 304–308 Cluster A personality disorders, 302 cluster C personality disorders, 306 current taxonomy, 300 defense mechanisms seen in, 301 definition and classification, 300 dependent personality disorder, 306 epidemiology, 300 etiology, 301 histrionic personality disorder, 305 narcissistic personality disorder, 305 obsessive-compulsive personality disorder (OCPD), 307 other personality disorders, 307 schizoid personality disorder, 302–308 schizotypal personality disorder, 303 treatment, 301 Personality Inventory for DSM-5 (PID-5), 370 Personality Inventory for Youth, 371 Phantom limb pain, 459 Pharmaceutical company interactions, 841 Phenelzine, 224 Phenobarbital alcohol withdrawal treatment, 134 GABA withdrawal treatment, 93 seizure disorder treatment, 445 Phenytoin, 444 Physical examination, 386. See also Diagnostic process; See also Laboratory testing Physician-assisted suicide, 841 Piaget, Jean, 61 Pica, 70, 73, 114 Pick’s disease, 104 PICO framework for research questions, 718 Pimozide, 80 Pituitary dysfunction, psychiatric differential diagnosis, 124 Plain films (X-ray), of the skull, 346 Plan-Do-Study-Act (PDSA), 835 PLISSIT model of sexual dysfunction treatment, 256 Polymorphisms, 724 Polysomnogram (PSG), 280, 387 Population-based psychiatry, 802 Porphyria, 735 Positive and Negative Symptoms Scale (PANSS), 359 Positron emission tomography (PET), 349, 387 Post-concussive syndrome (PCS), 129 Posterior circulation strokes, 473 Post-partum psychiatric illnesses, 316–320 categories of, 316 diagnosis, 317

epidemiology, 317 etiology, 317 overview, 316 treatment, 317–320 Post-stroke depression (PSD), 474 Post-transplant patients, 755 Post-traumatic headache, 452 Post-traumatic stress disorder (PTSD) AUD co-morbid, 144 clinical course of, 220 co-morbidity, 220 complex PTSD, 220 complications of, 209 diagnosis, 209 differential diagnosis, 209, 222 dissociative sub-type, 242 DSM-5 diagnostic criteria, 218–226 epidemiology, 220 evaluation, 222 in children and adolescents, 69, 72 in military personnel and veterans, 814–818 neurobiology of, 221 overview, 218 prevalence, 209 prevention, 222 risk factors, 209, 220 treatment, guidelines for, 222 treatment, overview of, 209 treatment, pharmacotherapy, 224, 503, 524 treatment, psychotherapeutic, 223, 503 vs. acute stress disorder (ASD), 219 Prader-Willi syndrome, 114, 733 Prazosin, 224, 503 Prefrontal cortex (PFC), 402. See also Neuropsychological functioning Pregabalin, 446, 559 Pregnancy antidepressant use in, 523 buprenorphine and, 161 cocaine use during, 153 electroconvulsive therapy during, 527 opiate-dependency treatment, 161 opioid use during, 157 psychiatric illnesses during, 312–320 risks associated with pharmacotherapy during, 313–320 valproate contraindication, 445 Premature (early) ejaculation disorder, 253, 255 Pre-menstrual dysphoric disorder (PMDD) assessment, 311 diagnosis, 310 epidemiology, 188, 311

etiology, 311 symptoms, 187 treatment, hormonal, 312 treatment, non-pharmacologic, 311 treatment, overview, 188 treatment, pharmacologic, 312 Pre-menstrual syndrome (PMS) defined, 310 diagnosis, 311 epidemiology, 311 etiology, 311 treatment, hormonal, 312 treatment, non-pharmacologic, 311 treatment, pharmacologic, 312 Present State Examination (PSE), 356 Pretransplant psychiatric evaluation, 753 Primary-care-driven model of collaboration, 797 Primary-care physicians (PCPs), collaboration with, 792–800 Primary prevention measures, 802 Prion diseases, 120 Privatization, 802 Professional boundaries, 742, 840 Progesterone, 310, 318. See also Female reproductive cycle and associated psychiatric disorders Prognosis, determining, 377 Program for Assertive Community Treatment (PACT), 762 Progressive supranuclear palsy (PSP), 105, 481 Prolactin elevation, 506, 508, 596 Prolonged exposure therapy, 223 Propofol, 134 Propranolol, 222 Provisional tic disorder, 78 Pseudobulbar affect (PBA), 474 Psychiatric biological axis, 37 Psychiatric genetics Alzheimer disease (AD), 729 attention deficit hyperactivity disorder (ADHD), 728 autism spectrum disorder (ASD), 728 basic principles of, 724–738 bipolar disorder, 730 Down Syndrome/trisomy 21, 733 Fetal Alcohol Syndrome (FAS), 737 Fragile X Syndrome (FXS), 735 genetic architecture of psychiatric disorders, 725 genetic linkage, 725 genetics of personality and temperament, 732 genetic syndromes and inborn errors of metabolism, 732 genotypes and phenotypes, 724 homocystinuria, 735 Huntington disease (HD), 734 implications of, 732

Klinefelter syndrome, 733 Lesch-Nyhan syndrome, 736 major depression, 730 metachromatic leukodystrophy, 736 neurofibromatosis type 1 (NF1), 734 obsessive-compulsive disorder, 731 panic disorder, 731 porphyria, 735 Prader-Willi syndrome (PWS), 733 psychiatric disorders arising from the interaction of genes and environment, 725 Rett Syndrome (RS), 735 schizophrenia, 730 substance use disorders, 731 tools of, 726–738 Tourette syndrome, 729 tuberous sclerosis complex (TSC), 734 Turner syndrome, 733 Velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS), 734 Williams syndrome (WS), 734 Wilson disease, 736 X-linked adrenoleukodystrophy, 736 Psychiatric instruments, 356. See also Diagnostic rating scales Psychiatric teleconsultation, 795 Psychiatry Certification Examinations, 3–8 accuracy, 5 anxiety regarding, 6 components, 3 difficult questions, 5 guessing, 4, 6 oral boards, 3, 10 preparation strategies, 4 question types, 3 stems, 5 test-taking skills, 4–8 video clips, 3 Psychiatry Residency in Training Examination (PRITE), 4 Psychoanalytic-based psychotherapy, 638 Psychodynamic psychotherapy, 638 Psychoeducational therapy, 639 Psychogenic movement disorders, 483 Psychogenic non-epileptic seizures (PNES), 438, 441 Psychogenic pain, 460 Psychological assessment. See Assessment, psychological Psychological factors affecting other medical conditions (PFAMC), 229 Psychological trauma, in military personnel and veterans, 813 Psychopathology Spectra Inventory (PSI), 369 Psychopharmacology cholinergic neurotransmitter system, 492 dopaminergic neurotransmitter system, 491 drug-drug interactions, 576–586

drug-induced movement disorders, 482 ethnicity and, 786–790 GABA-ergic neurotransmitter system, 490 glutamatergic neurotransmitter system, 489 histaminergic neurotransmitter system, 492 melatonin neurotransmitter, 493 natural medications, 600–612 neuronal anatomy and functioning, 488–494 neuronal circuitry, 489 neurotransmitter systems, 489–494 noradrenergic neurotransmitter system, 491 orexin neurotransmitter, 493 post-transplant patients, 756 serotonergic neurotransmitter system, 490 side effects, anticholinergic, 593 side effects, cardiovascular system, 588–598 side effects, central nervous system, 482–484, 592–598 side effects, dermatological, 595 side effects, endocrinological, 596 side effects, gastrointestinal, 594 side effects, hematological, 594 side effects, profiles of psychiatric medications, 589 side effects, renal, 594 side effects, sexual, 596 side effects, unique effects, 590 side effects, weight gain, 595 stimulants, 561–574 transplant recipients, 754 Psychosexual development, 60 Psychosis. See also Schizophrenia AIDs/HIV patients, 326 children and adolescents, 72 differential diagnosis, 167, 195 drugs and conditions associated with, 168 due to a medical condition, 168 due to another condition, 167 evaluation of, 169, 391, 392 in children and adolescents, 69 predictors of outcome, 171 symptoms, 166 treatment, 172

Psychostimulants dosing, 66 in children and adolescents, 66 side effects, 522 Psychotherapies behavior therapy, 638 brief psychodynamic psychotherapies, 640 cognitive therapy and CBT, 639, 678–686 couples therapy, 652–658 dialectical behavioral therapy (DBT), 639 family therapy, 659–666 future directions for, 640 group psychotherapy, 668–676 group therapies, 640 integrative psychotherapy, 640 interpersonal psychotherapy (IPT), 639 multi-systemic treatment, 639 overview of, 637 psychoanalytic-based psychotherapy, 638 psychoeducational therapy, 639 supportive psychotherapy, 639 transplant recipients, 755 Public health, models of, 802 Public psychiatry, 802 Pyromania diagnosis, 291 differential diagnosis, 291 epidemiology, 291 evaluation/examination, 291 overview, 288 treatment, 292

Q Qi gong, 690 QT prolongation, 508, 591 Quality improvement (QI) and quality assurance (QA) history of, 833 identifying QI goals, 834 implementing change for QI, 835 key characteristics in high-value health-care organizations, 834 maintaining change, 835 national efforts in, 833 overview of, 832 planning change for QI, 834 process of improving quality, 834 QI vs. research, 836 quality measures, 835 Quetiapine dosing, 511

in children and adolescents, 71 side effects, 510 Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), 181, 358

R Rabies, 119 Rapid eye movement (REM) sleep, 280 Rating scales. See Diagnostic rating scales Rational Recovery, 142 Reactive attachment disorder, 70, 72 Recognition and treatment of partner violence (RADAR), 769 Recombinant intravenous tissue plasminogen activator (rt-PA), 471 Recovery model approach, 808 Recovery Record app, 372 Reflex testing, 416, 417, 433 Refusal of treatment, 622 Relapse prevention, 142 REM sleep parasomnias, 285 Renal insufficiency, psychiatric differential diagnosis, 123 Renal system, effects of psychiatric medications, 594 Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), 380 Repetitive TMS (rTMS), 538 Repetitive transcranial magnetic stimulation (rTMS), 184 Reproductive safety. See also Pregnancy Research ethics, 841 Research methodologies ethics and professionalism, 841 experimental validity, 718 measurement tools, 720 overview of, 718 PICO framework for question formulation, 718 reporting guidelines, 721 schematic of, 720 sources of bias, 718–722 Resilience programs, 817 Restless legs syndrome (RLS), 285 Rett Syndrome (RS), 735 Rey-Ostereith Complex Figure Test, 379, 423 Risperidone added to clozapine, 514 ASD-related symptoms treatment, 86 dosing, 510 in children and adolescents, 71 overview, 509 side effects, 510 Ritalin, 66 Rivastigmine, 106 Roberts Apperception Test, 371 Rorschach inkblot method, 370, 371

Rorschach Performance Assessment System (R-PAS), 371 Routine outcome monitoring (ROM), 371 Rumination disorder, 70, 73, 114

S S-Adenosyl Methionine (SAMe), 603 Sampling bias, 718 Scale for the Assessment of Negative Symptoms (SANS), 359 Scale for the Assessment of Positive Symptoms (SAPS), 359 Scales, rating. See Diagnostic rating scales Schedule for Affective Disorders and Schizophrenia (SADS), 356 Schedules for Clinical Assessment in Neuropsychiatry (SCAN), 356 Schema-focused therapy (SFT), 302 Schizoid personality disorder, 302–308 Schizophrenia. See also Psychosis assessment, 760–764 awareness of illness, 172 biological abnormalities and, 170 co-morbid with AUD, 145 co-morbid with intellectual disability, 114 diagnosis, 167, 762 differential diagnosis, 85, 140, 167, 206 epidemiology of, 169, 709, 760 etiology theories, 170 genetic heritability, 730 genetics of, 170 history of the diagnostic classification of, 166 impact of culture on diagnosis of, 785 in children and adolescents, 72 morbidity and mortality, 171 negative symptoms, 172 predictors of outcome, 171 treatment, pharmacologic, 172, 762 treatment, psychosocial, 172, 762 Schizotypal personality disorder, 303 Schwartz, Carl, 61 Screening, brief intervention, and referral to treatment (SBIRT) model, 137 Seasonal affective disorder (SAD), 185 Secondary headaches, 452–454 Secondary prevention measures, 802 Second-generation antipsychotics (SGAs), 506, 508–516 Seizure disorders behavioral changes in epilepsy, 442–448 evaluation of, 441–448 focal seizures, 440–448 generalized seizures, 439–448 non-convulsive, 335 overview, 438 seizure classification, 438

side effects of psychiatric medications, 593 treatment, and suicidal ideation, 447 treatment, anti-seizure medications, 444 treatment, medications, 443–448, 445–448 treatment, surgical, 447 Selective mutism, 70, 71, 85 Selective serotonin re-uptake inhibitors (SSRIs) ASD-related behavior treatment, 86 AUD-associated anxiety treatment, 144 AUD-associated MDD treatment, 144 breastfeeding and, 318 dosing, 518 drug interactions, 519, 581, 583 during menopause, 320 eating disorder treatment, 274, 275 efficacy, 181, 518 in children and adolescents, 70, 71 in dementia, 106 mechanism of action, 518 OCD treatment, 502 OCRD treatment, 214 panic disorder treatment, 496 PTSD treatment, 224, 503 sexual dysfunction induced by, 254, 255 side effects, 182, 496, 518 social anxiety disorder treatment, 501 use during pregnancy, 314 Self-injurious behavior (SIB), 114 Self-medication hypothesis, 156 Sensitivity and specificity, 715 Sensory examination, 415, 432 Separation anxiety disorder, 69, 71 Separation-individuation, 60 Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial, 181 Serological studies. See Laboratory testing Serotonergic, 143 Serotonin (5-HT), 151, 490 Serotonin-norepinephrine re-uptake inhibitors (SNRIs) dosing, 519 drug interactions, 519 during menopause, 320 eating disorder treatment, 275 mechanism of action, 519 pain-relieving effect of, 465 side effects, 183, 519 use during pregnancy, 314 Serotonin syndrome (SS) course of illness, 342 defined, 340 diagnosis, 341

differential diagnosis, 339, 342 drug-drug interactions, 582 epidemiology, 341 evaluation, 342 Hunter criteria for, 342 pathophysiology, 342 serotonergic agent, 341 treatment, 343 Sertraline, 144, 224 Sexual abuse, childhood, 62 Sexual dysfunction alcohol-induced, 135 classification of, 249 diagnostic criteria, 252–264 drugs and medicines causing, 251, 596 evaluation, 248–264 gender dysphoria, 259–264 incidence, 248 interview techniques, 250 medical and surgical conditions causing, 250 medical history, 249 overview, 248 paraphilic disorders, 257–264 physical and laboratory examinations, 250 psychiatric differential diagnosis, 251, 252 psychologically based disorders, 252 sexual history, 249 treatment, gender dysphoria, 261 treatment, organically-based disorders, 254–264 treatment, paraphilic disorders, 259 treatment, psychologically based disorders, 256–264 treatment, SSRI-induced dysfunction, 255 Sexual orientation, 777 Sexual response biopsychosocial model of female sexuality, 248 changes associated with aging, 248 changes associated with physical and psychological status, 248 complexities in, 249 four-step model, 248 triphasic model, 248 Short-term psychodynamic psychotherapy (STPP), 186 Shy-Drager syndrome, 481 Similarities and Comprehension subtests of the WAIS-IV, 380 Single nucleotide polymorphisms (SNPs), 724, 727 Single-photon emission computed tomography (SPECT), 350 Six Sigma, 835 Skin-picking disorder. See Excoriation disorder Sleep disorders alcohol-induced, 135, 144 breathing-related sleep disorders, 283

circadian rhythm sleep disorders, 284 hypersomnolence disorder, 283 insomnia disorder, 281–286 MDD and, 179 medication related, 593 menopause-related, 320 narcolepsy, 283 parasomnias, 284–286 patterns of sleep, 281 polysomnography evaluation, 280 stages and cycles of sleep, 280 stages of sleep, 280 treatment, independent of co-existing disorders, 281 treatment, pharmacologic, 282 treatment, psychological, 284 Sleepwalking (somnambulism), 285 SMART Aim Statement, 834 Smartphones apps, 372 Smart Recovery, 142 Smoking cessation, 524 Smooth pursuit eye movements (SPEM), 170 Social Adjustment Scale (SAS), 361 Social anxiety disorder (social phobia) children and adolescents, 69, 71 overview, 208 treatment, pharmacotherapy, 501 treatment, psychosocial, 502 Social (pragmatic) communication disorder (SCD), 85 Somatic symptom and related disorders chronic pain in, 460 conversion disorder, 228 factitious disorders, 229, 230 functional somatic syndromes, 229 illness anxiety disorder (IAD), 228 management, 230 mechanisms, 231 overview, 228 psychological factors affecting other medical conditions (PFAMC), 229 somatic symptom disorder (SSD), 228, 460 Somatic therapies, 536 Somatosensory evoked potentials (SEPs), 431 Somatosensory seizures, 440 Spasticity, 478 Specialty psychiatric clinics, 795 Specific phobia, 208, 502 Speech sound disorder, 67 Spinal accessory nerve, 414 Sports psychiatry anxiety disorders in athletes, 821 attention deficit hyperactivity disorder in athletes, 821

doping/use of performance enhancing drugs, 822 eating disorders in athletes, 821 injury and recovery issues, 823 mental illness in athletes, 820 mood disorders in athletes, 820 overview, 819 psychology of athletes, 819 substance use disorders in athletes, 822 treatment, pharmacotherapy, 823 treatment, therapy, 823 Spousal abuse. See Intimate partner violence (IPV) Statistics descriptive statistics, 712 effect size, 714 epidemiological statistics, 714 inferential statistics, 713 levels of measurement, 712 missing data, 714 sensitivity and specificity, 715 Status epilepticus, 134, 335, 430, 445 Stereotypic movement disorders, 479 Stevens–Johnson syndrome, 446, 595 Steven’s taxonomy, 712 Stimulants Adderall, 566 ADHD treatment, 566. See Attention Deficit Hyperactivity Disorder (ADHD) amphetamines preparations, 565 approved ages of medications for ADHD, 564 AUD co-morbid ADHD treatment, 145 dextroamphetamine, 565 drug interactions, 568 ED formulations, 566 equivalent doses of Adzenys XR-ODT and Adderall XR, 567 FDA-approved treatments for ADHD, 563 general properties, 561 indications, 561 methylphenidate (MPH) preparations available, 564 narcolepsy and depression in the medically ill, 567 precipitating mania/hypomania, 197 side effects, 567 tolerance and abuse, 567 St. John’s Wort ( Hypericum Peforatum L.), 600 Strattera, 66 Stress, consequences of precautions, 688 Stroke classification and pathophysiology, 470–476 epidemiology, 470 psychiatric sequelae of, 473–476 stroke syndromes, 472

Stroop Color Word Test, 380 Structured Clinical Interview for Axis I Diagnostic and Statistical Manual of Mental Disorders, 356 Structured Clinical Interview for Dissociative Disorders-Revised (SCID-D-R), 243 Structured Clinical Interview for DSM-5 Personality Disorders (SCID-II), 360 Structured Clinical Interview for DSM-5 (SCID), 356 Study designs, 707–710, 719–722 Subacute sclerosing panencephalitis (SSPE), 120 Subarachnoid hemorrhage, 452, 471 Substance abuse. See also Alcohol use disorder (AUD); See also Cocaine and cocaine use; See also Opioids and opioid use AIDs/HIV patients, 326 benzodiazepine use in, 498 chronic pain and, 461 co-morbidity, 133, 194 drugs precipitating mania/hypomania, 197 genetic heritability, 731 headache evaluation, 453 in athletes, 822 in geriatric patients, 699 in military personnel and veterans, 816 laboratory testing and diagnostic procedures, 393 prevalence, 710 psychiatric differential diagnosis, 118 sleep disorders related to, 286 substance-induced mood disorder with depressive features, 177 substance/medication-induced depressive disorder, 188 substance/medication-induced OCRD, 212 Substance Abuse and Mental Health Services Administration (SAMHSA), 137 Substance/medication-induced sexual dysfunction, 254 Suicide AIDs/HIV patients, 326 antidepressant side effects, 182 anti-epileptic drugs and suicidal ideation, 447, 560 disposition and treatment of suicidal patients, 616 epidemiology, 614 evaluation, 616 in children and adolescents, 73 in military personnel and veterans, 817 involving alcohol use, 133 management of the suicidal patients, 615 neurobiology of, 615 risk factors, 614 risk in grieving survivors, 297 Supportive psychotherapy, 639 Surgical patients, psychiatric consultation to, 746 Symptoms of Depression Questionnaire (SDQ), 358 Systematic Assessment for Treatment Emergent Effects (SAFTEE), 361 Systemic exertion intolerance disease, 229 Systemic lupus erythematosus (SLE), 128

T Tachycardia, 591 Tai chi, 690 Tarasoff v. Regents of the University of California, 742 Tardive dyskinesia (TD), 483, 506, 507, 592 Tau proteins, 100 Teleconsultation/telepsychiatry, 795 Temperament, theory of, 61 Temporal arteritis, 453 Tenex, 66 Tension-type headaches (TTHs), 452 Teratogenesis, 313 Test-taking strategies, 3–8 The Boston Process Approach, 376 Thematic Apperception Test (TAT), 371 Thiamine deficiency, 122, 135 Thomas, Alexander, 61 Thought disorder, 166 Three-Component Model (TCM) of collaboration, 796 Three Shapes and Three Words Memory Test, 379 Thyroid dysfunction, psychiatric differential diagnosis, 123 Tiagabine, 315 Tic Douloureux, 454 Tics categorization of, 78 defined, 78 frequency of, 78 overview of, 479 secondary causes of, 79 tic disorders, 78 treatment, 80 To Err Is Human report, 833 Tonic–clonic seizures, 439, 529 Topiramate, 143, 224 eating disorder treatment, 274 efficacy, 559 indications, 559 pharmacology, 559 risks during pregnancy, 315 seizure disorder treatment, 446 toxicity, 559 Tourette disorder characteristics and treatment, 70, 80 co-morbidities, 79 diagnosis, 79 differential diagnosis, 80 frequency, 78 genetic heritability, 729 genetics of, 79

overview, 78, 482 pathophysiology of, 79 symptoms, timeline of, 79 tics in, 78 Toxic epidermal necrolysis, 595 Toxoplasmosis, 329 Trail-Making Test, 378, 380 Transcranial magnetic stimulation (TMS) definition and basic principles, 536 efficacy, 538 indications, 538 safety, 538 treatment parameters, 537 Transgender persons, 777, 779 Transient ischemic attack (TIA), 470 Trauma-informed care, 808 Traumatic brain injury (TBI) in military personnel and veterans, 816 Trazodone, 144, 522 Treatment, barriers to, 793 Treatment planning, 377, 382, 634 Treatment refusal, 622 Tremor, 479 Trichotillomania (TTM), 212, 214 Tricyclic antidepressants (TCAs) ADHD treatment, 66 cocaine dependence treatment, 154 dosing, 520 drug interactions, 520, 584 eating disorder treatment, 273 efficacy, 519 in depressed individuals with AUD, 144 laboratory monitoring of, 395 mechanism of action, 519 pain-relieving effect of, 464 panic disorder treatment, 497 PTSD treatment, 224 side effects, 182, 519, 588 TCAs, 318 use during pregnancy, 314 Trigeminal nerve, 413 Trigeminal neuralgia, 454 Tuberous sclerosis complex (TSC), 734 Turner syndrome, 733 Twin and adoption studies, 726 Two-Point Discrimination and Simultaneous Extinction test, 380

U United States Preventive Services Task Force (USPSTF), 768

Unspecified feeding or eating disorder (UFED), 267 Utilitarian ethics, 838

V Vagal nerve stimulation (VNS), 184, 447, 538–544 Vagus nerve, 414 Valerian (Valeriana Officinalis), 606 Validity, 718, 721 Valproate/Valproic acid added to antipsychotics, 514 AUD co-morbid bipolar disorder treatment, 144 drug-drug interactions, 580, 581 efficacy, 556 indications, 554 laboratory monitoring of, 395 pharmacology, 554 risks during pregnancy, 315 seizure disorder treatment, 445 side effects, 594 toxicity, 554 Vascular dementia (VaD), 96, 103 Vasopressin (ddAVP), enuresis treatment using, 73 Velocardiofacial syndrome, 734 Venlafaxine, 320, 588 Ventricular arrhythmias, 591 Veterans. See Military personnel and returning veterans Vicarious liability, 741 Vigabatrin, 446 Vilazodone, 522 Visual evoked potentials (VEPs), 431 Vitamin B1, 122, 135 Vitamin B12, 122 Von Recklinghausen Disease, 734 Vortioxetine, 522

W Wada test, 447 WAIS-IV Verbal Subtests, 378 Warrior Resiliency Program (WRP), 817 Waxy flexibility, 415 Wechsler IQ series, 368, 376, 378 Wechsler Memory Scale-IV (WMS-IV), 379 Weight gain, 595 Wernicke-Korsakoff Syndrome, 135, 393, 698 Whole-genome approach, 727 Wife beating. See Intimate partner violence (IPV) Williams syndrome, 115, 734 Wilson’s disease, 128, 481, 736 Winnicott, Donald, 59

Wisconsin Card Sorting Test (WCST), 379

X X-linked adrenoleukodystrophy, 736

Y Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), 359 Yoga, 690 Young Mania Rating Scale (Y-MRS), 359 Youth Self-Report, 371

Z Zaleplon, 316 Ziprasidone dosing, 511 side effects, 511 Zolpidem, 316, 586 Zonisamide, 315, 446