Clinical Aspects of Psychopharmacology in Childhood and Adolescence [1 ed.] 9781611227154, 9781611221350

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Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

HEALTH AND HUMAN DEVELOPMENT

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CLINICAL ASPECTS OF PSYCHOPHARMACOLOGY IN CHILDHOOD AND ADOLESCENCE

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

HEALTH AND HUMAN DEVELOPMENT JOAV MERRICK - SERIES EDITOR – NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT, MINISTRY OF SOCIAL AFFAIRS, JERUSALEM Adolescent Behavior Research: International Perspectives Joav Merrick and Hatim A. Omar (Editors) 2007. ISBN: 1-60021-649-8 Complementary Medicine Systems: Comparison and Integration Karl W. Kratky 2008. ISBN: 978-1-60456-475-4 (Hardcover) 2008. ISBN: 978-1-61122-433-7 (E-book)

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Pain in Children and Youth Patricia Schofield and Joav Merrick (Editors) 2008. ISBN: 978-1-60456-951-3

Obesity and Adolescence: A Public Health Concern Hatim A. Omar, Donald E. Greydanus, Dilip R. Patel and Joav Merrick (Editors) 2009. ISBN: 978-1-60456-821-9 Poverty and Children: A Public Health Concern Alexis Lieberman and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-140-6 Living on the Edge: The Mythical, Spiritual, and Philosophical Roots of Social Marginality Joseph Goodbread 2009. ISBN: 978-1-60741-162-8

Challenges in Adolescent Health: An Australian Perspective David Bennett, Susan Towns, Elizabeth Elliott and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-616-6 (Hardcover) 2009. ISBN: 978-1-61668-240-8 (E-book)

Alcohol-Related Cognitive Disorders: Research and Clinical Perspectives Leo Sher, Isack Kandel and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-730-9 (Hardcover) 2009. ISBN: 978-1-60876-623-9 (E-book)

Behavioral Pediatrics, 3rd Edition Donald E. Greydanus, Dilip R. Patel, Helen D. Pratt and Joseph L. Calles, Jr. (Editors) 2009. ISBN: 978-1-60692-702-1 (Hardcover) 2009. ISBN: 978-1-60876-630-7 (E-book)

Rural Child Health: International Aspects Erica Bell and Joav Merrick (Editors) 2010. ISBN: 978-1-60876-357-3 (Hardcover) 2010. ISBN: 978-1-61324-005-2 (E-book)

Health and Happiness from Meaningful Work: Research in Quality of Working Life Søren Ventegodt and Joav Merrick (Editors) 2009. ISBN: 978-1-60692-820-2

Children and Pain Patricia Schofield and Joav Merrick (Editors) 2009. ISBN: 978-1-60876-020-6 (Hardcover) 2009. ISBN: 978-1-61728-183-9 (E-book)

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Conceptualizing Behavior in Health and Social Research: A Practical Guide to Data Analysis Said Shahtahmasebi and Damon Berridge 2010. ISBN: 978-1-60876-383-2 Chance Action and Therapy: The Playful Way of Changing Uri Wernik 2010. ISBN: 978-1-60876-393-1 (Hardcover) 2011. ISBN: 978-1-61122-987-5 (Softcover) 2011. ISBN: 978-1-61209-874-6 (E-book) Adolescence and Chronic Illness. A Public Health Concern Hatim Omar, Donald E. Greydanus, Dilip R. Patel and Joav Merrick (Editors) 2010. ISBN: 978-1-60876-628-4 (Hardcover) 2010. ISBN: 978-1-61761-482-8 (E-book)

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Adolescence and Sports Dilip R. Patel, Donald E. Greydanus, Hatim Omar and Joav Merrick (Editors) 2010. ISBN: 978-1-60876-702-1 (Hardcover) 2010. ISBN: 978-1-61761-483-5 (E-book) International Aspects of Child Abuse and Neglect Howard Dubowitz and Joav Merrick (Editors) 2010. ISBN: 978-1-60876-703-8 (Hardcover) 2010. ISBN: 978-1-61122-049-0 (Softcover) 2010. ISBN: 978-1-61122-403-0 (E-book) Positive Youth Development: Evaluation and Future Directions in a Chinese Context Daniel T.L. Shek, Hing Keung Ma and Joav Merrick (Editors) 2010. ISBN: 978-1-60876-830-1 (Hardcover) 2010. ISBN: 978-1-61668-376-4 (E-book) 2011. ISBN: 978-1-62100-175-1 (Softcover)

Positive Youth Development: Implementation of a Youth Program in a Chinese Context Daniel T.L Shek, Hing Keung Ma and Joav Merrick (Editors) 2010. ISBN: 978-1-61668-230-9 (Hardcover) 2010. ISBN: 978-1-61209-091-7 (E-book) Pediatric and Adolescent Sexuality and Gynecology: Principles for the Primary Care Clinician Hatim A. Omar, Donald E. Greydanus, Artemis K. Tsitsika, Dilip R. Patel and Joav Merrick (Editors) 2010. ISBN: 978-1-60876-735-9 Understanding Eating Disorders: Integrating Culture, Psychology and Biology Yael Latzer, Joav Merrick and Daniel Stein (Editors) 2010. ISBN: 978-1-61728-298-0 (Hardcover) 2011. ISBN: 978-1-61470-976-3 (Softcover) Advanced Cancer Pain and Quality of Life Edward Chow and Joav Merrick (Editors) 2010. ISBN: 978-1-61668-207-1 (Hardcover) 2010. ISBN: 978-1-61668-400-6 (E-book) Bone and Brain Metastases: Advances in Research and Treatment Arjun Sahgal, Edward Chow and Joav Merrick (Editors) 2010. ISBN: 978-1-61668-365-8 (Hardcover) 2010. ISBN: 978-1-61728-085-6 (E-book) Environment, Mood Disorders and Suicide Teodor T. Postolache and Joav Merrick (Editors) 2010. ISBN: 978-1-61668-505-8

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Social and Cultural Psychiatry Experience from the Caribbean Region Hari D. Maharajh and Joav Merrick (Editors) 2010. ISBN: 978-1-61668-506-5 (Hardcover) 2010. ISBN: 978-1-61728-088-7 (E-book) Narratives and Meanings of Migration Julia Mirsky 2010. ISBN: 978-1-61761-103-2 (Hardcover) 2010. ISBN: 978-1-61761-519-1 (E-book)

Advances in Environmental Health Effects of Toxigenic Mold and Mycotoxins Ebere Cyril Anyanwu 2011. ISBN: 978-1-60741-953-2

Self-Management and the Health Care Consumer Peter William Harvey 2011. ISBN: 978-1-61761-796-6 (Hardcover) 2011. ISBN: 978-1-61122-214-2 (E-book)

Child and Adolescent Health Yearbook 2009 Joav Merrick 2011. ISBN: 978-1-61668-913-1 (Hardcover)

Sexology from a Holistic Point of View Soren Ventegodt and Joav Merrick 2011. ISBN: 978-1-61761-859-8 (Hardcover) 2011. ISBN: 978-1-61122-262-3 (E-book)

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Rural Medical Education: Practical Strategies Erica Bell, Craig Zimitat and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-649-2 (Hardcover)

Principles of Holistic Psychiatry: A Textbook on Holistic Medicine for Mental Disorders Soren Ventegodt and Joav Merrick 2011. ISBN: 978-1-61761-940-3 (Hardcover) 2011. ISBN: 978-1-61122-263-0 (E-book) Clinical Aspects of Psychopharmacology in Childhood and Adolescence Donald E. Greydanus, Joseph L. Calles, Jr., Dilip P. Patel, Ahsan Nazeer and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-135-0 (Hardcover) 2011. ISBN: 978-1-61122-715-4 (E-book) Climate Change and Rural Child Health Erica Bell, Bastian M. Seidel and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-640-9 (Hardcover) 2011. ISBN: 978-1-61209-014-6 (E-book)

Public Health Yearbook 2009 Joav Merrick 2011. ISBN: 978-1-61668-911-7 (Hardcover) Child Health and Human Development Yearbook 2009 Joav Merrick 2011. ISBN: 978-1-61668-912-4 (Hardcover) Alternative Medicine Yearbook 2009 Joav Merrick (Editor) 2011. ISBN: 978-1-61668-910-0 (Hardcover) The Dance of Sleeping and Eating among Adolescents: Normal and Pathological Perspectives Yael Latzer and Orna Tzischinsky (Editors) 2011. ISBN: 978-1-61209-710-7 (Hardcover) Child and Adolescent Health Yearbook 2010 Joav Merrick (Editor) 2011. ISBN: 978-1-61209-788-6 (Hardcover)

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Child Health and Human Development Yearbook 2010 Joav Merrick (Editor) 2011. ISBN: 978-1-61209-789-3 Public Health Yearbook 2010 Joav Merrick (Editor) 2011. ISBN: 978-1-61209-971-2 Living on the Edge: The Mythical, Spiritual, and Philosophical Roots of Social Marginality Joseph Goodbread (Editor) 2011. ISBN: 978-1-60741-162-8 (Hardcover) 2011. ISBN: 978-1-61122-986-8 (Softcover) Alternative Medicine Yearbook 2010 Joav Merrick (Editor) 2011. ISBN: 978-1-62100-132-4 (Hardcover) 2011. ISBN: 978-1-62100-210-9 (E-book)

Drug Abuse in Hong Kong: Development and Evaluation of a Prevention Program Daniel T.L. Shek, Rachel C.F. Sun and Joav Merrick (Editors) 2011. ISBN: 978-1-61324-491-3 (Hardcover) Human Development: Biology from a Holistic Point of View Søren Ventegodt, Tyge Dahl Hermansen and Joav Merrick (Editors) 2011. ISBN: 978-1-61470-441-6 (Hardcover) 2011. ISBN: 978-1-61470-541-3 (E-book) Our Search for Meaning in Life Søren Ventegodt and Joav Merrick (Editors) 2011. ISBN: 978-1-61470-494-2 (Hardcover) 2011. ISBN: 978-1-61470-519-2 (E-book)

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The Astonishing Brain and Holistic Conciousness: Neuroscience and Vedanta Perspectives Vinod D. Deshmukh 2011. ISBN: 978-1-61324-295-7 (Hardcover)

Translational Research for Primary Healthcare Erica Bell and Joav Merrick (Editors) 2011. ISBN: 978-1-61324-647-4 (Hardcover)

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

HEALTH AND HUMAN DEVELOPMENT

CLINICAL ASPECTS OF PSYCHOPHARMACOLOGY IN CHILDHOOD AND ADOLESCENCE

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

DONALD E. GREYDANUS JOSEPH L. CALLES, JR. DILIP P. PATEL AHSAN NAZEER AND

JOAV MERRICK EDITORS

Nova Science Publishers, Inc. New York

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.

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Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data

Clinical aspects of psychopharmacology in childhood and adolescence / editors, Donald E. Greydanus ... [et al.]. p. ; cm. -- (Health and human development book series) Includes bibliographical references and index. ISBN H%RRN 1. Pediatric psychopharmacology. 2. Adolescent psychopharmacology. I. Greydanus, Donald E. II. Series: Health and human development series. [DNLM: 1. Mental Disorders--drug therapy. 2. Adolescent. 3. Child. 4. Psychopharmacology--methods. 5. Psychotropic Drugs--therapeutic use. WS 350.2] RJ504.7.C55 2010 615'.780835--dc22 2010037337

Published by Nova Science Publishers, Inc. † New York

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Contents Foreword

ix Professor George P Chrousos, MD, MACP, MACE, FRCP

Introduction:

Pediatric psychopharmacology xi Donald E Greydanus, MD, Dr HC (ATHENS), FSAM, FAAP, FIAP (HON), Joseph L Calles Jr, MD, Dilip P Patel, MD, FAAP, FSAM, FAACPDM, FACSM, Ahsan Nazeer, MD and Joav Merrick, MD, MMedSci, DMSc

Section One: ADHD Chapter I

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Chapter II

Attention deficit hyperactivity disorder: pharmacologic management in children and adolescents Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD Attention deficit hyperactivity disorder and comorbid substance abuse Iliyan Ivanov, MD, Andrew Pearson, MD, Gabriel Kaplan, MD and Jeffrey Newcorn, MD

1 3 31

Section Two: Mental Health Aspects

51

Chapter III

Psychotherapy in the age of pharmacology Helen D Pratt, PhD

53

Chapter IV

Child and adolescent depression Joseph L Calles, Jr, MD and Ahsan Nazeer, MD

61

Chapter V

Pediatric bipolar disorder Ahsan Nazeer, MD and Joseph L Calles, Jr, MD

71

Chapter VI

Anxiety disorders in children and adolescents Dilip R Patel, MD and Donald E Greydanus, MD

83

Chapter VII

Oppositional defiant and conduct disorders Joseph L Calles, Jr, MD and Ahsan Nazeer, MD

95

Chapter VIII

Aggressive and violent behavior Joseph L Calles, Jr, MD and Ahsan Nazeer, MD

103

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

viii Chapter IX

Contents Tic disorders in children and adolescents Donald E Greydanus, MD, Dilip R Patel, MD and Daiva Olipra, MD

Section Three: Specific Disorders

127

Chapter X

Autistic spectrum disorders Ahsan Nazeer, MD and Joseph L Calles, Jr, MD

129

Chapter XI

Schizophrenia in children and adolescents Ahsan Nazeer, MD and Joseph L Calles, Jr, MD

145

Chapter XII

Cognitive-adaptive disabilities Joseph L Calles, Jr, MD and Ahsan Nazeer, MD

163

Section Four: Other Use

173

Chapter XIII

Substance abuse disorders in adolescents: pharmacologic management Donald E Greydanus, MD, Cynthia Feucht, PharmD and Dilip R Patel, MD

175

Chapter XIV

Smoking cessation and pharmacological agents Dilip R Patel, MD and Donald E Greydanus, MD

191

Chapter XV

Sleep disorders in children and adolescents Donald E Greydanus, MD and Bantu S Chhangani, MD

199

Section Five: Conclusions Chapter XVI

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115

225

Pediatric psychopharmacology: where do we go from here? 227 Donald E Greydanus, MD, Dr HC (ATHENS), FSAM, FAAP, FIAP (HON), Joseph L Calles Jr, MD, Dilip P Patel, MD, FAAP, FSAM, FAACPDM, FACSM, Ahsan Nazeer, MD and Joav Merrick, MD, MMedSci, DMSc

Section Six: Acknowledgements

235

Chapter XVII About the editors

237

Chapter XVIII About the department of pediatrics and human development, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, Kalamazoo, Michigan, United States Professor Donald E Greydanus, MD and professor Dilip R. Patel, MD Chapter XIX

Chapter XX

About the national institute of child health and human development in Israel Joav Merrick, MD, DMSc About the book series ―Health and human development‖ Professor Joav Merrick, MD, MMedSci, DMSc

Index

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

239

243 247 251

Foreword Professor George P Chrousos, MD, MACP, MACE, FRCP*

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(London), Chairman, First Dept of Pediatrics and Chief, Division of Endocrinology, Metabolism and Diabetes, University of Athens Medical School, Children's Hospital Aghia Sophia, Greece, Recent evidence has extended the developmental period of human beings well beyond the years of puberty. We know now that while the body has completed its sexual maturation by the age of 14-16 years, the brain continues to physically develop up to the age of 25-27 years. This knowledge is crucial, as the use of pharmacologic agents with activities in the central nervous system during this active developmental period of brain maturation, may have profound long-term effects on emotions and behavior that can last for life. A large proportion of children and youth have mental health problems that follow different trajectories over time. Adolescence is a period in which latent mental problems emerge, with as many as one third of adolescents presenting with complaints significant enough to warrant a visit to the doctor. Attention deficit hyperactivity disorder, conduct disorder, anxiety, depression, psychosis, substance abuse disorders, eating disorders, and other psychologic conditions, constitute a long list of diagnoses with which the pediatrician or primary care physician must be well acquainted. Since the mid-1950s, a considerable number of psychoactive medications have been developed, with primarily adults with mental health disorders being the main focus. Only a proportion of these drugs were subsequently studied in children and adolescents in welldesigned, controlled trials with a sufficiently long-term follow-up. This means that the treatment decision of the prescribing physician carries a unique burden of personal responsibility. The questions of whether to use medications, which ones to select, how to administer, and with what expected potential outcomes, are crucial. The bibliographic sources are scarce, hard to find, frequently confusing, and usually of limited value. This is where Pediatric and Adolescent Psychopharmacology has a place for use by the busy pediatricians and other clinicians who care for children, adolescents and young adults with mental health problems. The book presents succinctly and accurately the psychopharmacologic agents that are available for their patients. The book authors discuss the *

E-mail: [email protected] or [email protected]

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

x

Professor George P Chrousos, MD

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indications, pharmacology, pediatric dosages, side effects, drug interactions, and the indicated monitoring parameters of these medications. FDA approval, ages that are covered by this approval and other useful information is included. The editors and authors are well-known experts in pediatrics, adolescent medicine, behavioral-developmental and behavioral pediatrics, and child/adolescent psychiatry. Pediatric and Adolescent Psychopharmacology is a truly informative book, which I highly recommend to pediatricians and other primary care physicians who are caring for children, adolescents and young adults with mental health disorders. This book will also be of help to anybody that will seek solid, succinct, straightforward, accurate and truly evidencebased knowledge in this very sensitive field that concerns patients with still developing brains and a whole life ahead of them. It is a great addition to the armamentarium of pediatric and adolescent medicine.

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Introduction: pediatric psychopharmacology Donald E Greydanus*, MD, Dr HC (ATHENS), FSAM, FAAP, FIAP (HON)1, Joseph L Calles Jr, MD2,3, Dilip P Patel, MD, FAAP, FSAM, FAACPDM, FACSM1, Ahsan Nazeer, MD2,3 and Joav Merrick, MD, MMedSci, DMSc4,5

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Pediatrics and Human Development1, Department of Psychiatry2, Child and Adolescent Psychiatry, Michigan State University College of Human Medicine, Kalamazoo and East Lansing, Michigan United States of America3, National Institute of Child Health and Human Development, Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem4, Kentucky Children‘s Hospital, University of Kentucky, Lexington, United States of America5 ―He cures most successfully in whom the people have the greatest confidence‖ (Galen, 180 CE)

Concern with psychological or emotional problems of humans has probably existed ever since Homo sapiens emerged as a species over 50,000 years ago (1). History notes medical treatments dating back to the Ebers Papyrus (1500 BCE) that lists over 700 medicines made from various sources---animal, vegetable, mineral, others (2). Scholars in China and India developed large pharmacopoeias dealing with various disorders over several thousands of years (3). However, the ancient philosopher, Aristotle (384-322 BCE), was quite skeptical of the powers of medicine as noted with his opine: ―…the physician does not cure man, except in an incidental sense‖ (4). Distinguishing medical and psychological problems of children and adolescents required thousands of years of observation since most energy was spent on adult disorders. Health care advances usually were initially targeted for adults and gradually over the past 1,000 years, *Correspondence: Professor Donald E Greydanus, MD, Pediatrics and Human Development, Michigan State University College of Human Medicine, Pediatrics Program Director, Michigan State University/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, MI 49008-1284 United States. E-mail: [email protected]

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

xii

Donald E. Greydanus, MD, Joseph L. Calles, Jr., MD, Dilip P. Patel, MD et al.

considered the health of children. Rhazes (Muhammad ibn Zakariya Razi [865-925 CE]) was the most famous physician of ancient Persia and his brilliant observations as well as writings initiated the birth of pediatric knowledge with his book on children‘s disorders at the same time that Western civilization knowledge was lost in the Dark Ages. Eventually those in the West emerged from their intellectual abyss with textbooks covering children by Trotula Platearius of Salerno, Italy (De Mylierum Passionibus) in 1050 CE and by Thomas Phaer in 1544 CE (The Boke of Chyldren). Thomas Phaer was an English pediatrician, lawyer, and author of the first book on pediatrics in the English language; this landmark treatise was the first to provide a distinction between the critical stages of childhood and adulthood setting the stage for further research on problems of childhood. Four centuries later, medical problems of children were finally appreciated with the formation of the American Academy of Pediatrics in 1930. The American Academy of Child Psychiatry was formed in 1953 to study psychiatric problems of children and the Journal of the American Academy of Child and Adolescent Psychiatry began in 1962 to record research discoveries in mental health disorders of children and adolescents (5).

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Modern psychopharmacology The field of modern psychopharmacology began in the 1930s with the availability of various psychoactive medications such as barbiturates, antihistamines, and psychostimulants (6). The seminal work of Bradley in 1937 identified Benzedrine (racemic mixture of levoamphetamine and dextroamphetamine) as a drug that improved the behavior of 30 children in Providence, Rhode Island, USA who had various emotional and behavioral problems (7). In the same year Molitch and Eccles conducted what may be the first placebo-controlled work in child psychiatry to show the positive effect of Benzadrine on 93 males labeled as juvenile delinquents (8). Chlorpromazine was introduced in 1950 as the first of many future antipsychotic medications to treat psychosis in adults. Also, in the 1950s, there was the introduction of two antidepressant classes, a monoamine-oxidase inhibitor (iproniazid) and a tricyclic antidepressant (imipramine) (9,10). Methylphenidate (MPH) was first identified in 1959 by Knobel in Kansas, USA as medication that would improve the behavior of children with ―hyperkinesis and organicity‖ after MPH was first introduced to the market in 1957 (10). Lithium, antidepressants, and benzodiazepines were placed in the general market before 1965 and the use of psychopharmacology was then firmly placed in the armamentarium of adult psychiatrists dealing with adult mental disorders. Though pediatric psychopharmacology was developed first with the work of Bradley (1937) and Knobel (1959), further development of drugs to treat mental disorders of children and adolescents was essentially halted for most of the 20th century until the 1990s. This delay was due to a combination of factors including the belief that psychotherapy was best for management of pediatric patients with mental illness and the main emphasis by pharmaceutical companies on developing medications for adults with mental illness. Interest in treating children and adolescents with such medications began during the late 1970s and was further stimulated by the development of the selective serotonin reuptake inhibitor (SSRI) fluoxetine in the late 1980s (9). The development of such periodicals as the Journal of

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Introduction: Pediatric psychopharmacology

xiii

Child and Adolescent Psychopharmacology in 1990 was clear evidence of the growing science of pediatric psychopharmacology (6). This science continues to grow, though research trials remain limited and many studies are under the fiscal control of pharmaceutical companies who also heavily market their products to consumers and physicians alike (12-14). For example, ethical as well medical concerns complicate the desire of many to have unbiased, double-blind randomized placebo control trials in the pediatric population. However, evidence of the efficacy power of such treatment was noted in the well-conducted 1999 Multimodal Treatment (MTA) study of methylphenidate showing benefit in children with attention-deficit/hyperactivity disorder (ADHD) that was conducted by the US National Institute of Mental Health (NIMH) (15). The NIMH has continued its outstanding work in pediatric pharmacology with such studies as the TADS (Treating Adolescent Depression Study) that validates the use of SSRIs (fluoxetine) along with cognitive-behavioral therapy (16). Atypical antipsychotics are now approved by the US Food and Drug Administration for use in children and adolescents with bipolar disorders and schizophrenia (17). ―Those having torches will pass them on to others.‖ (Plato, The Republic)

Conclusions

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Indeed, the science of evidence-based pharmacotherapy for mental health disorders in children and adolescents is finally emerging and exciting discoveries await the researchers of this still early 21st century lead by the collaborative efforts of academicians, pharmaceutical scientists, and medical government authorities (18).

References (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)

Magner LN. A history of the life sciences, 3rd ed. New York:[z [Marcel Dekker], 2002. Porter R. The greatest benefit to mankind: A medical history of humanity. New York: [WW Norton], 1998. Grollman AP. Alternative medicine: The importance of evidence in medicine and medical evidence. Foreward: Is there wheat among the chaff? [Acad Med] 2001;76 (3):221-3. Wheelwright P. Aristotle. New York: [Odyssey Press], 1951:68. Musto DF. History of child psychiatry. In: Lewis M, ed. Child and adolescent psychiatry. A comprehensive text, 3rd ed. Philadelphia, PA: [Lippincott Williams Wilkins], 2002:1448-9. Werry JS, Aman MG. Preface to the first edition. Practitioner‘s guide to psychoactive drugs for children and adolescents. New York: [Plenum], 1999. Bradley C. The behavior of children receiving benzadrine. [Am J Psychiatry] 1937;94:577-85. Molitch M, Sullivan J: The effect of benzedrine sulfate on children taking the new Stanford achivement test. [Am J Orthopsych] 1937; 7: 519-22. López-Munoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. [Curr Pharm Des] 2009;15:1563-86. Delini-Stula A. Discovery of the tricyclic antidepressants. [Pharm Unserer Zeit] 2008;37:194-7. Knobel M, Wolman M, Mason A. Hyperkinesis and organicity in children. [Arch Gen Psychiatry] 1959;1(3):310-21.

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Greydanus DE, Patel DR. The role of pharmaceutical influence in education and research: The clinician‘s response. [Asian J Paediatr Pract] 2006;9:35-41. Tan JO, Koeich M. The ethics of psychopharmacological research in legal minors. [Child Adolesc Psychiatr Ment Health] 2008;2:39-43. Vitiello B, Heiligenstein JH, Riddle MA et al: The interface between publicly funded and industryfunded research in pediatric psychopharmacology: Opportunities for integration and collaboration. [Biol Psychiatry] 2004;56:3-9. MTA: A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal treatment study of children with ADHD. [Arch Gen Psychiatry] 1999;56:1073-86. March J, Silva S, Petrycki S. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. [JAMA] 2004;292:807-20. FDA panel OKs 3 antipsychotic drugs for pediatric use, cautions against overuse. [JAMA] 2009;302:833-4. DeVeaugh-Geiss J, March J, Shapiro M et al: Child and adolescent psychopharmacology in the new millennium: a workshop for academia, industry, and government. [J Am Acad Child Adolesc Psychiatry] 2006;45:261-70.

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Donald E. Greydanus, MD, Joseph L. Calles, Jr., MD, Dilip P. Patel, MD et al.

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Section One: ADHD

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In: Clinical Aspects of Psychopharmacology in Childhood… ISBN: 978-1-61122-135-0 Editors: D. Greydanus, J. Calles, Jr, D. Patel et al. ©2011 Nova Science Publishers, Inc.

Chapter I

Attention deficit hyperactivity disorder: pharmacologic management in children and adolescents Gabriel Kaplan*, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

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Department of Psychiatry, Hoboken University Medical Center, Hoboken, New Jersey, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey and Department of Psychiatry, Mount Sinai School of Medicine, New York, United States of America Attention deficit hyperactivity disorder (ADHD) used to be considered a mild childhood condition that manifested mostly in the school setting and remitted by adolescence. More recently, a large body of evidence has shown that it is a very frequent psychiatric problem in childhood, causes considerable suffering in patients and their families, and persists in adulthood 70% of the time. This chapter outlines current pharmacological treatment options available to office based clinicians who wish to provide treatment for ADHD. Each FDA approved agent is reviewed in detail focusing on the safety profile and efficacy data, as well as the monitoring tools that can be utilized to optimize treatment. This review also addresses recent controversies in the field and provides practical clinical advice within a Frequently Asked Question format.

*

Correspondence: Gabriel Kaplan, MD, Clinical Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey, Director of Psychiatry, Hoboken University Medical Center, Hoboken, 535 Morris Avenue, Springfield, NJ 07081 United States. E-mail: [email protected]

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

Introduction Attention deficit hyperactivity disorder (ADHD) used to be considered a mild childhood condition that manifested mostly in the school setting and remitted by adolescence. More recently, a large body of evidence has shown that ADHD is a very frequent psychiatric problem in childhood, causes considerable suffering in patients and their families, and persists in adulthood 70% of the time (1). Two large recent US epidemiological studies have placed the prevalence at 8.7% in children (2) and at 4.4% in adults (3). Since pathognomonic tests are not yet available, the clinical assessment (buttressed by use of validated and normed rating scales, and structured diagnostic interviews) remains the gold-standard diagnostic approach. However, the search for biological markers has produced very interesting findings that suggest such tests could be available in a not too distant future. For instance, research has shown that ADHD is a highly heritable condition for which potentially responsible candidate genes have been identified and characteristic neuroanatomical as well as neurophysiological findings have been confirmed (4). Furthermore, diagnostic criteria have been developed that when applied (5) yield similar prevalence rates across the US and Europe, and also show that the condition is found in most other parts of the world (6). The present paper outlines current pharmacological treatment options available to office based clinicians who wish to provide treatment for ADHD. It will focus on the safety profile and efficacy data for medications, as well as the monitoring tools that can be utilized to optimize treatment. Finally, the present review addresses recent controversies in the field and provides practical clinical advice within a Frequently Asked Question format.

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Assessment and treatment principles Diagnostic accuracy is paramount to the success of any treatment and ADHD is no exception. Children can show distractibility and agitation due to environmental stressors and other psychiatric or medical problems. In such instances, ADHD treatments may not help and could worsen symptoms, making diagnostic certainty especially important. While a comprehensive outline of assessment procedures and non pharmacological treatment choices is beyond the scope of this paper, it is important to mention here some basic parameters, which the reader can explore more deeply by consulting the ample literature (7).

Diagnostic criteria DSM IV TR (5) supplies the gold standard diagnostic criteria utilized worldwide. According to this nomenclature, for patients to qualify for the diagnosis, they must have either A: 6 or more from a list of 9 symptoms of inattention for at least 6 months, to a degree that is maladaptive or B: 6 or more of a list of 9 symptoms of hyperactivity-impulsivity for at least 6 months, to a degree that is maladaptive. Furthermore, some symptoms that cause impairment should have been present before age seven and some impairment from the symptoms must be present in two or more settings (e.g., at school/work and at home). In addition, there must be

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clear evidence of significant impairment in social, school, or work functioning and symptoms cannot be better accounted for by another mental disorder.

Diagnostic work up The most accurate diagnostic procedure for ADHD consists of obtaining comprehensive psychiatric/medical histories and relevant physical and mental status examinations. It is essential that information be carefully obtained from multiple sources. At a minimum, in addition to meeting with the patient, clinicians should also conduct an in person interview of the caretakers and seek information from teachers – either in person, by phone, or via completion of rating scales (7). A thorough medical history is mandatory and consultation with the pediatrician is recommended, especially when patients have a current or past medical problem. Psychological testing is not essential but can be helpful, especially if learning disorders are also present.

Comorbidity Patients with ADHD often have co-occurring psychiatric disorders which should be investigated. This is mandatory because the presence of additional conditions such as bipolar, substance abuse, oppositional defiant, anxiety, and other mood disorders will significantly influence the clinician's choice of treatment, as described in other papers elsewhere in this publication (8,9).

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Discussing medications and monitoring with patients and caretakers Due to increased ADHD awareness, diminished stigma and improved teacher education, by the time parents arrive in the physician's office, the possibility of medication has usually been entertained. However, very few parents have had the experience of giving medication to their child on a daily basis, as is the case with ADHD. In general, prior medication use would have been limited to antibiotics or other short term type of somatic treatment. Parents are not accustomed to bringing their child back to the physician for monitoring on a frequent basis, which is very different from visiting the pediatrician briefly for acute problems or for yearly checkups. In addition to discussing that ADHD treatment requires more frequent monitoring, it is essential that the clinician engage in a frank and realistic discussion regarding what medication can and cannot accomplish, as well as what potential adverse effects may occur. Medications are highly effective in treating current symptoms and will likely improve function in the future. But while they can help to improve family or peer relations moving forward, medications cannot repair what may have been damaged in the past as a result of ADHD symptoms. It is also essential that a therapeutic alliance be developed with both patient and caretakers to foster adherence, one of the most important features required for any successful treatment.

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

Treatment planning and multimodal options While medications often offer the best option for treatment of core ADHD symptoms, clinicians should not dismiss the potential benefits that psychosocial therapies can provide. Modalities such as summer treatment programs, teacher training and behavioral parent training are evidence-based approaches which can be used effectively in reducing symptoms (10). Psychosocial approaches can be offered alone or in conjunction with medications. Combination of medication and behavior therapy has been demonstrated to have some advantages in some cases (11). But other types of therapies aimed at improving self esteem, and peer and family relationships may be helpful as well. Occasionally, patients are maintained on psychotherapies alone due to caretaker preference, poor response to pharmacotherapy, or intolerable side effects. Although this paper focuses solely on psychopharmacology, it is important that each patient receive an individualized treatment plan based on a review of all available pharmacological, non pharmacological, and educational options. Ultimately, the options that are finally selected for implementation must be tailored to each patient‘s specific needs.

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Psychopharmacology of ADHD A brief outline of current thinking regarding the pathophysiology of ADHD is helpful in understanding the potential remedial role that pharmacological agents play. The cognitive and behavioral impairments experienced by ADHD patients can be viewed from a unifying neuropsychological perspective as representing deficits in executive functions (12). These functions encompass high level tasks such as organizing, prioritizing, focusing, sustaining effort, managing frustration, utilizing working memory, and monitoring and self regulating (13). The literature shows that the neuronal substrate for these functions is located in the prefrontal cortex (PFC) and its connections (14). Dopamine (DA) and Noradrenaline (NA) are so essential to PFC function that even small changes in these neurotransmitters can have marked effects. For instance, studies suggest that weaker neurotransmitter production may impair circuits regulating attention and behavior (14). All of the US Food and Drug Administration (FDA) approved agents are believed to potentiate catecholamine transmission in the PFC which would help explain why they are effective in improving ADHD symptoms. According to the American Academy of Child and Adolescent Psychiatry, the initial psychopharmacological treatment for ADHD should be a trial with an FDA approved agent (7). Fortunately, due to recent additions to the armamentarium, clinicians can choose from a wide variety of agents that belong either to the Stimulant or Non Stimulant categories, as described below. Non FDA approved agents will be listed because while much less frequently utilized, they provide alternative options of benefit to some patients.

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FDA approved stimulants The FDA has approved two types of stimulant agents for ADHD: Amphetamine (AMP) and Methylphenidate (MPH). In 1937, Charles Bradley published his now classical paper (15) describing a "spectacular" improvement in the school performance of behaviorally disordered children who were treated with d-l amphetamine (Benzedrine). In addition to marking the beginning of modern child psychopharmacology, this paper established amphetamines as a potentially effective and safe treatment for ADHD. Methylphenidate (Ritalin) followed with the first published reports by Knobel and others appearing in the late fifties (16). Stimulants are one the most researched categories of psychotropics and their high efficacy has been demonstrated in numerous randomized controlled studies (17). More specifically, these agents are effective in improving the cardinal symptoms of ADHD: hyperactivity, impulsivity, and inattention. In addition, research shows that they improve productivity, family interactions, aggression, school disruption, peer interactions, antisocial behaviors, and may even decrease the risk for subsequent comorbid psychiatric disorders and academic failure (17,18). Despite the significant and desirable improvements in behavioral and cognitive symptoms, evidence for long term improvement in academic achievement has been elusive (19). As will be discussed below, both AMP and MPH preparations are available in multiple generic and branded formulations in the US, which are similar in their therapeutic and safety profiles. They differ in their route of administration and mechanism of delivery which determines the specific preparation's duration of action. Both types of stimulants are equally efficacious at the group level, with a response rate of 65-75%. However, it appears that individual patients can show a preferential response to one of the types, so that the response rate increases to as much as 85% if both types are tried (7). Unfortunately, there is no current method to determine which patient will respond better to which type of stimulant. In contrast to other agents used to treat psychiatric illness, stimulant efficacy can usually be observed within 30 to 90 minutes of administration of an appropriate dose – though this may not occur until the right dose for that individual is reached. Most side effects tend to be mild, short-lived, and responsive to dose or timing adjustments. However, occasionally more problematic adverse effects can occur and there are specific serious risks to be considered such as cardiovascular risk which is examined below in more detail. Serious side effects of stimulants which include psychosis, obsessive ruminations, and movement disorders, are infrequent and usually abate if the medication dose is lowered or stopped (20). Table 1 shows the most common stimulant side effects, contraindications, and black box warnings. Despite recent concerns addressed later in this review, stimulants have enjoyed an unparalleled track record of over seven decades of demonstrated efficacy and low incidence of side effects when used according to clinical guidelines. Due to these characteristics of working quickly, safely, and effectively, there is probably no other mental health condition where patients, and more frequently their parents, offer the treating physician more laudatory comments for a job well done. And yet, despite the very high response rates and generally high level of tolerability, there are several adverse effects listed in Table 1 which can limit the palatability and long-term appeal of these agents. Perhaps at least in part, the development of

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

these untoward effects is the reason why, the majority of patients to whom stimulants are prescribed discontinue their medication within a year. Table 1. Stimulant side effects, contraindications and warnings (while essentially similar for all preparations, the package insert wording may vary from product to product). SIDE EFFECTS COMMON Insomnia Anorexia Headache Weight Loss New Onset Tics

LESS FREQUENT Nausea Abdominal Pain Palpitations Dizziness Drowsiness

RARE Tachycardia Fever Arthralgia Psychosis Depression

CONTRAINDICATIONS

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Advanced arteriosclerosis Symptomatic cardiovascular disease Moderate to severe hypertension Hyperthyroidism Known hypersensitivity or idiosyncrasy to sympathomimetic amines Tics/Tourette's Syndrome Glaucoma Agitated states History of drug abuse During or within 14 days following the administration of monoamine oxidase inhibitors (MAOI) BLACK BOXED WARNINGS MPH Drug Dependence. Should be given cautiously to patients with a history of drug dependence or alcoholism. Frank psychotic episodes can occur. Careful supervision is required during withdrawal. AMP Misuse may cause sudden death /serious cardiovascular adverse events. High potential for abuse. Administration for prolonged periods of time may lead to drug dependence.

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Table 2. MPH preparations main features. NAME /FORMULATION DURATION SHORT ACTING Ritalin, Methylin (MPH) Focalin (DexMPH)

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INTERMEDIATE ACTING Metadate ER (MPH ER) Ritalin SR (MPH SR) LONG ACTING Metadate CD (Diffucaps MPH) Ritalin LA (SODAS MPH) Concerta (OROS MPH) Focalin XR (SODAS DexMPH) MPH TRANSDERMAL SYSTEM Daytrana patch

DOSE FORMS

STARTING DOSE

REMARKS (Max dose may increase as per MD judgment)

5, 10, 20 mg tab

5 mg b.i.d.

Max dose=40 mg

2.5, 5, 10 mg cap

2.5 mg b.i.d.

Max dose=40 mg

10, 20 mg cap

10 mg q.a.m.

Max dose=60 mg

20 mg

20 mg q.a.m.

Max dose=60 mg

10, 20, 30, 40, 50, 60mg

20 mg q.a.m.

Max dose=60 mg; caps contents can be sprinkled

10, 20, 30, 40 mg

20 mg q.a.m.

Max dose=60 mg; caps contents can be sprinkled

18, 27, 36, 54 mg cap

18 mg q.a.m.

5,10, 15, 20, 30 mg cap

5 mg q.a.m.

tab

10, 15, 20, 30 mg patches 10 mg patch

Max dose=72 mg; do not cut/crush medication Max dose=30 mg; caps contents can be sprinkled

Max dose=30 mg; patch cannot be cut

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

Methylphenidate (MPH) preparations There are oral and transdermal formulations available. The oral preparations can be subclassified according to duration of action into short or immediate release (IR), intermediate, and long acting formulations. Table 2 shows their main features. The past few years have seen a change in the understanding of ADHD from a condition that requires treatment only during school hours to one that can impair the patient's functioning in all settings throughout the day. For this reason, the IR formulations, despite their high degree of efficacy, present some challenges because of the need for repeated administration over the course of the day. Longer acting preparations may improve compliance by reducing the number of times the patient must take the medication and protect confidentiality by obviating the need for administration during the school day (7). For this reason, a variety of technologies have been utilized to prolong the duration of action for both MPH and AMP.

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Oral short acting MPH formulations (3 - 5 hours duration) The short acting MPH formulations include d-l MPH IR (available in generic, Methylin branded generic, and Ritalin brand) and DexMPH IR (available in generic and Focalin brand). MPH's probable mechanism of action is to block the reuptake of NE and DA into the presynaptic neuron, thereby increasing the availability of these neurotransmitters to the synaptic cleft (14). MPH IR is a racemic mixture of its d and l threo enanthiomers. DexMPH IR is the d-threo enanthiomer by itself, considered to be more pharmacologically active, and thus administered at half the dose of the racemic compound. All the IR formulations are rapidly absorbed so that therapeutic action can often be observed within 30-60 minutes. However, since they have a half life of 3 to 5 hours, multiple doses are needed in order to achieve symptom control throughout the day. A large body of evidence documenting the short term efficacy of MPH IR has accumulated over the past 30 years. More recently, two large randomized multisite trials looking at longer time periods were sponsored by the US National Institute of Mental Health. These are the Multimodal Treatment Study of Children with ADHD (MTA) study (21) and the Preschool ADHD Treatment Study (PATS) (22).

Multimodal treatment study of children with ADHD (MTA) study The MTA study posed three questions: How do long-term medication and behavioral treatments compare with one another? Are there additional benefits when they are used together? What is the effectiveness of systematic, carefully delivered treatments vs. routine community care? In this study, 579 children with ADHD Combined Type, aged 7 to 9.9 years, were randomly assigned to 14 months of treatment with: rigorous medication management; intensive behavioral treatment; the two combined; or standard community care (delivered by community providers who in two thirds of the cases treated patients with medications).

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Seventy four percent of the MTA Study subjects in the medication management group received MPH IR three times per day with an average dose of approximately 31 mg/day which was well tolerated overall. Due to ethical concerns regarding the duration of the trial, a strict "placebo" no treatment control group was not included. The community care group served the purpose of control. While all groups showed reductions in symptoms over time, there were significant differences between the 4 groups. For core ADHD symptoms, children in the combined treatment and medication management groups showed significantly greater improvement than those given intensive behavioral treatment and community care. However, the combined treatment offered no significantly greater benefits than medication management alone for core ADHD symptoms. In addition, the medication management regimen was superior to community care treatments. The authors concluded that a carefully crafted medication management was superior to behavioral treatment alone and to routine community care that included medication. The MTA results validated the clinical experience that children who largely adhere to a well titrated regimen of stimulants significantly continue to benefit for at least 14 months. After completing the controlled study, children were free to continue treatment with community providers and were followed by the MTA group. While the initial study was not designed to demonstrate effects beyond 14 months, researchers had hoped that such effects would be nonetheless present at follow up. Data from an 8 year follow up were recently published, with overall findings showing that treatment-related improvements were generally maintained but differential treatment efficacy was lost (23). In other words, there were no differences between the four initially assigned treatment groups on repeated measures of psychiatric symptoms, academic function, and social functioning. The differential effects of study treatments, observed when the interventions were delivered during the controlled period, softened when the rigor of treatment was relaxed. Thus, in the MTA study follow-up, the outcome of children who had received an intensive treatment protocol years earlier was no different from that of children receiving community style treatment when assessed 8 years later. The study data did not address individual patient needs; in fact, the authors stated that "Decisions about starting, continuing, and stopping medication may have to be made on an individualized basis, avoiding untested assumptions about continuing benefit and using periodic trial discontinuations to check for need and benefit" (23:497). The findings, however, generated controversy and media reports were published questioning the efficacy of stimulants which resulted in a response from the American Academy of Child and Adolescent Psychiatry, asking families to consult with a doctor before discontinuing medication abruptly (24).

Preschool ADHD treatment study (pats) PATS is the largest and longest study of ADHD preschoolers to date (22). Children 3 to 5.5 years old were enrolled to participate in a complex series of phases including a five week randomized placebo controlled and a forty week open label maintenance, in order to assess the efficacy and safety of MPH IR. The results concluded that this agent was effective in a younger population at smaller doses than in the MTA study and that, overall, treatment was considered safe.

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Other MPH IR formulations A special formulation of MPH IR, Methylin, is available in chewable tablets and oral solution, which can be preferred by children unable or unwilling to swallow traditional pill formats. Studies with DexMPH found that this medication is also significantly more effective than placebo (17). Its side effect profile is the same as MPH's (Table I).

Oral intermediate acting MPH formulations (up to 8 hours duration) These agents are sustained release or extended release formulations of MPH and include MPH SR (generic), Metadate ER (branded generic), and Ritalin SR (brand). In order to achieve a longer duration, the MPH molecules are carried within a wax matrix which liberates the active ingredient slowly as it traverses the gastrointestinal (GI) tract thereby delaying absorption. This delivery method is also known as "single pulse" release in contrast to the more recent bimodal release preparations described below. While the duration of action of single pulse MPH is extended to approximately 6-8hrs, clinicians have noted that the onset of action can be delayed, so these formulations are no longer preferred (17). Side effects are the same as the immediate release formulation.

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Long acting MPH formulations (up to 12 hours duration) These include branded MPH agents (Ritalin LA and Concerta), branded generic (Metadate CD), and branded DexMPH (Focalin XR). The efficacy of all these agents has been established in multiple studies (17). Side effects are generally the same as for the immediate release formulations (see table 1), although there may be individual differences. These preparations utilize sophisticated delivery methods to prolong duration of action. For instance, Ritalin LA and Focalin XR use the Spheroidal Oral Drug Absorption System (SODAS) in which the active molecule is placed in beads inside a capsule. Each bead-filled capsule contains half the dose as immediate-release beads and half as entericcoated, delayed-release beads, thus providing an initial immediate release of the active agent followed by a second delayed release about 4 hours later. Metadate CD uses Diffucaps, a beaded formulation with 30% immediate release and 70% delayed beads. These agents are also known as "double pulse", because they deliver drug in two bursts. Patients who can not swallow the capsule may sprinkle its beads into applesauce, pudding, others for easier ingestion. Concerta uses the Osmotic-controlled Release Oral delivery System, (OROS) technology. In the OROS technology, MPH is delivered in two ways. Initially, medication is released after ingestion from the outer coat of the tablet to provide rapid onset of action. Once this immediate release overcoat is dissolved, an osmotic gradient is created that slowly releases the stimulant contained inside the tablet's core.

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Table 3. AMP preparations main features. NAME/FORMULATION DURATION

DOSE FORMS

STARTING DOSE

REMARKS (Max dose may increase as per MD judgment)

SHORT ACTING Adderall (Mixed AMP salts)

5, 7.5, 10, 12.5, 15, 20, 30 mg tab

3-5y: 2.5 mg q.d >6y: 5 mg q.d.

Max dose =40mg.

5 mg cap

3-5y: 2.5 mg q.d >6y: 5 mg q.d.

Max dose =40mg.

LONG ACTING Dexedrine Spansule

5, 10, 15 mg cap

>6y: 5-10mg q.d

Max dose =40mg.

Adderall XR (Mixed AMP salts XR)

5, 10, 15, 20, 25, 30 mg cap

>6y: 10 mg q.d.

Max dose =30mg; caps contents can be sprinkled

PRODRUG Vyvanse (LDX)

20, 30, 40, 50, 60, 70 mg cap

>6y: 20m q.d.

Max dose =70 mg: caps contents can be dissolved

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Dexedrine (d-AMP)

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

MPH transdermal formulation (MTS) Daytrana is the only available formulation of this kind. It consists of a skin patch with three layers, 1) a polyester/ethylene vinyl acetate laminate film backing, 2) a proprietary adhesive formulation consisting of an acrylic adhesive, a silicone adhesive, and methylphenidate (DOT Matrix transdermal technology), and 3) a protective liner which is attached to the adhesive surface to be removed before the patch can be used. MPH is absorbed transdermally and the total dose delivered is dependent on the patch size (which comes in four different strengths) and wear time. It is recommended that the patch be applied to the hip area, two hours before the desired onset of action. Because duration of action is observed for some time after the patch is removed, in order to achieve a 12 hour duration, the patch must be removed after 9 hours. The efficacy of the patch was demonstrated in laboratory classroom studies and long term studies (25). In addition to the usual side effects seen with orally delivered MPH, the patch may elicit skin reactions (usually mild but occasionally more problematic) so if it is worn every day, it is generally recommended that the patch be applied to the opposite hip the following day. MTS offers flexibility of therapeutic duration, which can be controlled by variations in the length of time the patch is worn. It is also helful for children who are unable to swallow oral preparations.

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Amphetamine (AMP) preparations There are two different AMP agents: dextromphetamine (d-AMP) and mixed amphetamine salts (MAS), a racemic formulation in which the medication is bound to a mixture of salts. AMP is believed to work in the same fashion as MPH by enhancing DA and NA neurotransmission (17). AMP preparations can be classified into Short Acting, Long Acting, and Prodrug Formulations. The main features are listed in table 3.

Short acting AMP formulations (up to 6 hours) These include generic d-AMP, branded d-AMP (Dexedrine, Dextrostat), generic mixed amphetamine salts or MAS (50% d-AMP plus 50% d/l AMP) and branded MAS (Adderall). The rationale for these different enanthiomer combinations is that while d-AMP is more potent, some patients respond to one enanthiomer but not the other (26). These agents have been widely used for decades with excellent safety and efficacy (17). In contradistinction to other medications for ADHD, the short acting AMP formulations are FDA approved for use in children as young as 3 years old. Side effect profile is listed in table 1.

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Long acting AMP formulations (up to 8-10hHrs) These include Dexedrine spansules, generic mixed amphetamine salts extended release (MAS XR), and branded MAS XR (Adderall XR). Dexedrine spansules are capsules that contain two types of beads: d-AMP IR beads account for the initial action while other beads are covered by a polymer substance resulting in a delayed release of d-AMP. The spansule efficacy and safety profile is comparable to that of d-AMP IR. MAS XR come in capsules containing Microtrol technology beads. Half of the beads in the capsule contain MAS IR while the other half are coated with a substance designed to release MAS IR once the beads reach a higher pH environment, usually in the intestine. The efficacy of extended-release mixed amphetamine salts has been well established in short controlled studies as well as in open label studies up to a 24-month period (27). The side effect profile of MAS XR is the same as other AMP preparations (see table 1).

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Prodrug formulation Lisdexamfetamine (LDX), brand name Vyvanse, is the only agent in this category. LDX is a therapeutically inactive molecule that, after ingestion, is hydrolyzed by endogenous enzymes to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for its therapeutic effect. Conversion of LDX to d-amphetamine and l-lysine occurs mostly in the blood (28). Thus, its long duration of action, measured up to 13 hours in school aged children in controlled research in a laboratory classroom (29), is perhaps due to a post absorption systemic biological conversion, in contrast to other stimulants that rely on pre absorption delayed release mechanisms. This may also make the agent less susceptible to GI tract variations (30). The efficacy of LDX has been documented in short and long term studies (31). The adverse effect profile of LDX is the same as for all stimulants (Table 1) and in studies of up to 12 months length, the medication has been generally well tolerated (32). There may be an advantage for LDX with regard to abuse potential. For instance, research shows that at an equivalent amount of amphetamine base taken orally, LDX 100 mg had attenuated responses on measures of abuse liability compared with immediate-release d-amphetamine 40 mg (33). Because LDX is highly soluble, the capsule can be opened and its content administered dissolved in water.

Special safety considerations regarding stimulants A significant increase in the number of patients treated with stimulants coupled with safety concerns raised by newly available data from large original and meta studies led to a reassessment of the stimulants' risk/benefit ratio. More specifically, interest has been focused on four areas: cardiovascular system, growth, substance abuse risk, and tics.

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

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Cardiovascular The dopaminergic and noradrenergic mechanism of action explains the undeniable severe and sometimes fatal cardiovascular consequences of acute stimulant toxicity and chronic non medical use. However, the degree of stimulant cardiovascular risk in patients medically supervised for the treatment of ADHD, in particular the risk of sudden death, has been more difficult to quantify. Although recent epidemiological work has revealed that ADHD is not the benign self limiting childhood disorder once thought (3), most clinicians would agree that its treatment should not include agents with significant cardiovascular risks. A review of the literature regarding hemodynamic effects in patients treated with stimulants showed that some studies found no differences between stimulant and placebo on blood pressure and heart rate while others did. The differences found in these studies, although statistically significant, were small and would not be considered clinically significant in healthy individuals. (34). The specific risk for sudden death has been the subject of considerable recent controversy. Twenty cases of sudden death during treatment with stimulants were recently reviewed by the US Food and Drug Administration (FDA). The estimated rate of sudden death during stimulant treatment was below estimated rates for the general population; thus, a direct relationship to drug treatment cannot be firmly established from the data (34). Two large retrospective cohorts, one British and the other US found no association between stimulants and sudden death (35,36). However, another recent report that utilized case control and sophisticated psychological autopsy methodology did find an association (37). An editorial on the sudden death controversy concluded that data suggesting a link between stimulants and sudden unexplained death cannot be dismissed because the sympathomimetic activity of stimulants provides biological plausibility for cardiovascular effects. However, sudden unexplained death is a rare event and it is not possible to quantify the risk beyond estimating that it is very small (38). This very small risk is likely to be significantly increased in children with pre existing cardiac pathology. For this reason, it is recommended that a diagnostic evaluation prior to initiating stimulant therapy include information from a physical examination and a detailed cardiac history in an effort to reasonably rule out the presence of such pathology. Clinicians agree that inquiries should be made regarding a history of congenital problems, severe heart palpitations, fainting, exercise intolerance, chest pain, previous cardiac consultations, or family history of sudden death. In addition, blood pressure and heart rate should be routinely monitored before and during stimulant treatment for every patient. More involved routine pre treatment tests are not universally accepted (39). In April 2008, the American Heart Association (AHA) recommended that ECGs be obtained as part of the routine assessment for children considered for treatment with stimulant medication, in order to identify children potentially at risk for sudden death. However, this recommendation was not sanctioned by pediatric or child psychiatric practice guidelines. In May of 2008, the AHA and American Academy of Pediatrics, cosponsored by the American Academy of Child and Adolescent Psychiatry, jointly issued a news release clarifying that obtaining an ECG before starting medication was ―reasonable‖ but not mandatory (40). Given the plausible danger of cardiac complications in children with heart problems, what has become mandatory, however, is to refer any patient with a history or current symptoms of heart disease for clearance by a cardiology specialist before initiating treatment.

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Attention deficit hyperactivity disorder

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Growth The appetite suppressant effects of stimulants that are used for treating children with ADHD were described as early as 1937 in Bradley‘s seminal paper. Adverse consequences on growth can be understood as stemming either directly from decreased appetite or stimulant effects on dopaminergic neurons in the pituitary and resultant effects on growth hormone. There is a suggestion that growth dysregulation may also be characteristic of ADHD itself, although there is disagreement about the direction of such a dysregulation, if it indeed exists (34). Clinicians investigating growth delay in earlier follow up studies had concluded that the loss in expected weight and height was small and drug discontinuation resulted in growth rebound. Furthermore, patients treated continuously for up to five years until the age of 13 showed no difference in height when compared to untreated peers (34). These results suggested that clinicians who instituted prudent weight/height checkups could reassure parents that the potentially adverse consequences of stimulants on growth were benign, while also monitoring for the appearance of any problems in selected individuals. Newly available follow up data documenting height differences between treated and non treated children (41) in conjunction with the increasingly accepted practice of continuing treatment beyond early adolescence, called for a re-examination of the issue. A recent comprehensive review (42) concluded, consistent with earlier findings, that treatment with stimulants in childhood can result in small reductions in expected height and weight that attenuate over time; also, although physicians should monitor for deficits in height and weight, these do not appear to be a clinical concern for most children. However, not all authors agree that the degree of concern is low. Since study results aggregate group effects rather than present individual changes, it is possible that more important growth delays could be noted in specific patients, or that even very small changes could be unacceptable for some patients. In such cases, strategies such as drug holidays or switching to a different agent could be entertained. The context for such a decision should be a carefully developed risk/benefit assessment, weighing concerns regarding stature against the potential consequences of modifying a treatment that was otherwise effective up to that point (42).

Abuse potential This topic is addressed in detail in another paper elsewhere in this issue of the journal (9). Briefly, it should be mentioned that all stimulants are classified as Controlled class II (CII) substances and carry a warning regarding their potential for abuse. At the same time, most studies have found that the risk of abuse in patients treated for ADHD under medical supervision is very low. Some studies have even concluded that there is perhaps greater risk of developing comorbid addiction in untreated patients. However, the issue is far from resolved. The prescribing of CII agents is tightly regulated; historically, prescriptions could not exceed a 30 day supply. Possibly in recognition of the protective nature of medical supervision, the Drug Enforcement Administration (DEA), a US Federal agency, recently eased regulations for CII agents allowing the issuing of multiple prescriptions authorizing the patient to receive a total of up to a 90 day supply. However, different states have different

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Gabriel Kaplan, MD, Jeffrey H Newcorn, MD and Iliyan S Ivanov, MD

policies regarding the way this regulation may be implemented at the local level, and some states still do not allow more than 30 days of medication per prescription. Other important related issues such as diversion are examined elsewhere in this journal (9).

Tics The nature of the relationship between stimulants and tics has been a controversial issue and is discussed in detail elsewhere (43). According to current labeling, stimulants are contraindicated in patients with tic disorders. This presents a clinical dilemma since ADHD children with tics are usually more impaired by symptoms of ADHD than tics, and stimulants are the most effective treatment for ADHD at the group level. Further, research shows that stimulants, in particular MPH, can benefit patients with comorbid tic disorder and ADHD (43) without detriment, and thus are often used in clinical practice. Atomoxetine and guanfacine are also alternatives found to be helpful in children with comorbid Tic/ADHD disorders.

FDA approved non stimulants At present, there are only two FDA approved non stimulant agents: atomoxetine (Strattera) and guanfacine XR (Intuniv). These medications target noradrenergic neurotransmission preferentially. Their main differences with stimulants are their DEA non controlled status, "24/7" duration, and slower onset of action. Table 4 shows the main features of these agents.

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Atomoxetine (strattera) Atomoxetine was the first non stimulant approved by the FDA in 2002 to treat children and adults, arriving in a therapeutic landscape long dominated by AMP and MPH preparations. Atomoxetine binds rather selectively to the norepinephrine transporter, thereby increasing synaptic norepinephrine diffusely and dopamine in the PFC (where dopamine re-uptake is achieved via norepinephrine transporters). It is well absorbed after oral administration and is metabolized primarily through the cytochrome P 450 2D6 pathway. Therefore, coadministration with some SSRIs (e.g., paroxetine and to a lesser extent fluoxetine) is not recommended due to drug/drug interactions. The efficacy of atomoxetine has been documented in many short and long term studies (7). Full therapeutic effect can take up to 4 weeks to develop (44).

Greydanus, Donald E., et al. Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Nova Science Publishers, Incorporated, 2011.

Table 4. FDA approved non stimulant preparations main features.

NAME/FORMULATION DOSE DURATION FORMS

STARTING DOSE

REMARKS

Strattera (Atomoxetine)

10, 18, 25, 40, 60, 80, 100 mg cap

500 ms. Often results from combinations with other medications that interact with neuroleptics and extend QTc.

Examine combination of medications taken by patient if QTc is > 500 ms. Watch for macrolide antibiotics which may be added by primary care provider.

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Depot injections of medication It should be noted that unpleasant side-effects of neuroleptics, including neuromuscular extrapyramidal side-effects and the blockade of pleasureable dopamine receptors, may make these drugs difficult to motivate someone to take. In addition, lack of insight into the social unacceptability of positive and negative symptoms of schizophrenia may further reduce adherence. Failure to achieve good medication management during childhood will likely impair educational progress and achievement, later vocational potential and social skills acquisition. Frequent bouts of instability also may lead to legal entanglements, violence and injury, drug involvement and addiction, and cognitive decline. Two typical neuroleptics and one atypical neuroleptic have been introduced in a depot injection formulation that provides several weeks of clinical efficacy. These include prolixin decanoate, haloperidol decanoate (where the medication is dissolved in a vegetable oil), and risperidone long-acting injection (where the medication is attached to microspheres made of suture material). These preparations are indicated in cases where medication adherence is inconsistent. Often, in adults, these medications form a part of the management strategy used along with case management and sometimes court treatment orders to reduce the frequency of hospitalization and other morbidities that interfere with life functioning in the community. For youth, especially adolescents, this approach may help when parental structure does not effectively provide good adherence or is unavailable.

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Psychosocial interventions Managing the psychosocial aspects of treatment is an extremely important part of schizophrenia management. Individual and family focused psychoeducation and therapies improve the long-term outcomes and increase medication adherence (56). Reduction of expression of hostility by family members has been shown in adults to markedly improve outcome. Skill training and long-term rehabilitation are other facets of psychosocial management. As schizophrenia is chronic and progressive, long-term planning for when the child reaches the age of majority should begin during adolescence. Larger communities have Assertive Community Management teams that may assist in managing the more difficult cases. One should be aware that some youth with childhood schizophrenia do manage to function as adults as long as they remain treatment adherent.

Conclusion Numerous strides have been made in the early 21st century to better understand childhood schizophrenia, its phenomenology, and its management. Second generation antipsychotics have proved to be safer in their use despite the notion that their comparative efficacy with conventional antipsychotics recently have came into question.

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Ahsan Nazeer, MD and Joseph L Calles, Jr, MD Mulholland C, Cooper S.The symptom of depression in schizophrenia and its management [Adv. Psychiatr. Treat]. 2000;6:169-77. Siris, S. G. Assessment and treatment of depression in schizophrenia. [Psychiatr Ann] 1994;24,463–7. Muller JE, Koen L, Soraya S, Emsley RA, Stein DJ. Anxiety disorders and schizophrenia. [Curr Psychiatry Rep]. 2004;6:255-61. Lykouras L, Alevizos B, Michalopoulou P, Rabavilas A: Obsessive-compulsive symptoms induced by atypical antipsychotics: a review of the reported cases. [Prog Neuropsychopharmacol Biol Psychiatry] 2003;27:333–46. BA Palmer, VS Pankratz, JM Bostwick. The lifetime risk of suicide in schizophrenia: A reexamination. [Arch Gen Psychiatry] 2005;62: 247-53. Calderoni D, Wudarsky M, Bhangoo R, et al. Differentiating childhood onset schizophrenia from psychotic mood disorders. [J Am Acad Child Adolesc Psychiatry] 2001;40(10):1190-6. Armenteros JL, Davies M. Antipsychotics in early onset Schizophrenia: Systematic review and metaanalysis. [Eur Child Adolesc Psychiatry]. 2006;15(3):141-8. Lieberman JA, Stroup TS, McEvoy JP. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. [N Engl J Med]. 2005;353(12):1209-23. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of effect on quality of life of second vs. first generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). [Arch Gen Psychiatry]. 2006;63:1079-87. Sikich L, Hamer RM, Bashford RA, Sheitman BB, Licberman A. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. [Neuropsychopharmacology] 2004;29:133-45. Kryzhanovskaya L, Schulz SC, McDougle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. [J Am Acad Child Adolesc Psychiatry] 2009;48(1):60-70. Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. [Am J Psychiatry] 2008;165:142031. Lieberman JA. Metabolic changes associated with antipsychotic use. [Prim Care Companion J Clin Psychiatry] 2004;6:8-13. De Hert MA, van Winkel R, Van Eyck D, et al. Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. [Schizophr Res] 2006;83(1):87-93. Consensus development conference on antipsychotic drugs and obesity and diabetes. [Diabetes Care] 2004;27(2):596-601 Laita P, Cifuentes A, Doll A, Llorente C, Cortés I, Parellada M, Moreno D, et al. Antipsychoticrelated abnormal involuntary movements and metabolic and endocrine side effects in children and adolescents. [J Child Adolesc Psychopharmacol]. 2007;17(4):487-502. Jin H, Meyer JM, Jeste DV. Phenomenology of and risk factors for new onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. [Ann Clin Psychiatry] 2002;14:59–64 Correll CU, Penzner JB, Parikh UH, Mughal T, Javed T, Carbon M. et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. [Child Adolesc Psychiatr Clin N Am] 2006;15(1):177-206. Castro-Fornieles J, Parellada M, Soutullo CA, Baeza I, Gonzalez-Pinto A, Graell M, Paya B, et al. Antipsychotic treatment in child and adolescent first-episode psychosis: a longitudinal naturalistic approach. [J Child Adolesc Psychopharmacol] 2008;18(4):327-36. Nasrallah HA, Newcomer JW. Atypical antipsychotics and metabolic dysregulation: evaluating the risk/benefit equation and improving the standard of care. [J Clin Psychopharmacol] 2004;24:S7-14. Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. [Can J Psychiatry] 2006;1;51(8):480-91. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. [CNS Drugs] 2005;19:1–93.

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In: Clinical Aspects of Psychopharmacology in Childhood… ISBN: 978-1-61122-135-0 Editors: D. Greydanus, J. Calles, Jr, D. Patel et al. ©2011 Nova Science Publishers, Inc.

Chapter XII

Cognitive-adaptive disabilities Joseph L Calles, Jr, MD* and Ahsan Nazeer, MD Department of Psychiatry, Michigan State University, College of Human Medicine, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan, United States of America

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There is an increased need for pediatricians and other primary care physicians to identify and treat psychiatric disorders in their patients with disordered cognitive development. The treatment of psychopathology in this clinical population is complicated by high rates of medical and psychiatric comorbidity, sensitivity to the adverse effects from medications, and non-compliance with prescribed medication. This chapter provides an overview of common psychiatric disorders seen in intellectually impaired individuals and makes recommendations for pharmacotherapy based on the best available evidence.

Introduction The early identification of, and interventions for, cognitive-adaptive disability (CAD) in children has become a priority issue in pediatrics. One effort in that regard is a policy statement by the American Academy of Pediatrics that includes a developmental screening algorithm (1). As the life spans of individuals with CADs continue to increase, primary care physicians need to be attuned to the high rates of physical and mental illnesses that can develop in their patients with CADs well into adulthood (2). This chapter provides an overview of the psychiatric disorders that are commonly encountered in those with CADs [also variously referred to in the medical literature as developmental disability (DD), intellectual disability (ID), learning disability (LD), or mental retardation (MR) with the term ID used internationally today].

*

Correspondence: Joseph L Calles, Jr, MD, Psychiatry Residency Training Program, Michigan State University/Kalamazoo Center for Medical Studies, 1722 Shaffer Road, Suite 3, Kalamazoo, MI 49048 United States. Tel: (269) 337-4413; Fax: (269) 337-6378; E-mail: [email protected]

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Epidemiology The estimation of prevalence rates of ID is complicated by methodological disagreements, leading to results that can be influenced by multiple factors (3) (see table 1). A review of prevalence studies of ID in the school-age population reported a fairly stable average prevalence rate of 3.8 per 1,000 for severe ID (IQ < 50) (4). Prevalence rates for mild ID (IQ 50-70) were highly variable, but a reasonable estimation is a figure of 29.8 per 1,000. Table 1. Factors influencing prevalence rates of ID*.

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How ID is defined (i.e., the IQ scores used) Selection criteria (e.g., IQ vs. functional capabilities) Populations surveyed (e.g., general vs. specialty samples) Ages surveyed (children, adults, or the elderly) Gender Socioeconomic class Ethnicity/race Etiology Others *Adapted from reference 3

The prevalence of mental disorders in those with IDs was determined in a United Kingdom study (5). The sample consisted of 1,023 individuals ages 16 years and older. The rates of psychiatric problems differed, depending on the method of assessment used. For example, rates of ―mental ill-health‖ (excluding problem behaviors, autistic-spectrum disorders and specific phobias) ranged from 22.4%, in those who were clinically assessed, to 13.9% using the American Psychiatric Association‘s DSM-IV-TR criteria (6). In that same study, the rates of clinically-determined diagnoses also varied by level of impairment, but not always in the same direction; thus, being in the moderate-profound range of disability was not always associated with a higher rate of psychopathology when compared to those in the mild disability range. Kerker et al reviewed the issue of inconsistent prevalence rates of mental illness in those with ID (7). They concluded that one of the main challenges to accuracy in this area is that health care providers struggle with diagnosing psychiatric disorders in people with MR. A resource that can aid in the identification of mental disorders in those with IDs is the Diagnostic Manual- Intellectual Disability (DM-ID), which is an adaptation of the DSMIV-TR criteria specifically for the intellectually disabled population (8).

Clinical features By definition, those with CADs have some degree of impairments in cognition and adaptive functioning. As total IQ scores are a composite of several, more specific subscale scores, individuals with cognitive impairment may have some relative strengths pertaining to cognition; these are sometimes referred to as ―splinter skills.‖ Overall, however, these individuals will have some level of difficulty in the areas of attention span, concentration,

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short- and long-term memory, comprehension (verbal and/or written), speech and language, mental organization, anticipation and planning, problem solving, and other skills. They will usually do better in an environment that is predictable and not overly-stimulating. The impairments in adaptive functioning are strongly related to the cognitive limitations, but are also commonly contributed to by emotional factors. Difficulties in academic, work, and social settings can be exacerbated by low frustration tolerance, anger dyscontrol, and impulsivity. All manner of training programs exist to help individuals with CADs improve their social and occupational skills. The best programs are comprehensive in nature, and will address emotional issues in their clients referring for formal mental health assessment if needed. Table 2. Developmental disorders and common psychiatric and behavioral problems. Problems

Aggression

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Self-injurious behaviors

Attention-deficit/hyperactivity disorder, or symptoms

Sleep disorders

Disorders CdCS DS FAS FXS PWS SMS TSC CdCS CdLS FXS LNS PWS SMS AS• CdCS• FAS• FXS• NF-1• SMS• TSC• VCFS• WS• AS CdLS DS FXS PWS SMS WS

Problems

Disorders

Eating disorders

AS DS PWS WS

Obsessive-compulsive disorder, or symptoms

DS FXS PWS VCFS WS

Other anxiety disorders, or symptoms

Depression

Psychosis

DS FAS• FXS• NF-1 PWS VCFS• WS• DS• FAS• FXS• NF-1 PWS TSC• VCFS• FAS• PWS• VCFS•

Abbreviations: AS= Angelman syndrome; CdCS= Cri du chat syndrome; CdLS= Cornelia de Lange syndrome; DS= Down syndrome; FAS= fetal alcohol syndrome; FXS= fragile X syndrome; LNS= Lesch-Nyhan syndrome; NF-1= neurofibromatosis, type 1; PWS= Prader-Willi syndrome; SMS= Smith-Magenis syndrome; TSC= tuberous sclerosis complex; VCFS= velocardiofacial syndrome; WS= Williams syndrome • Discussed in the chapter

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What follows is a general description of some common psychiatric problems that are seen in the CAD population, followed by more detailed prevalence data on selected and specific syndromes. Table 2 is an expanded list of psychiatric/behavioral problems and associated DDs, several of which are not discussed in this chapter.

Comorbid conditions Mood disorders

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Cooper et al examined the data that was obtained in a previously cited study (5); the goal of the companion analysis was to explore the epidemiology of affective (mood) disorders in adults with ID (9). They found that, per clinical diagnosis, 4.1% had a current unipolar depression and 0.5% had a current bipolar depression; for mania, 0.4% had bipolar disorder, while 0.2% was experiencing a first manic episode. These rates are higher than those seen in the general population. There are specific DD syndromes in which mood disorders appear at high rates. In Down syndrome (DS), major depressive disorder (MDD) tends to have its onset in early adulthood and has a prevalence of 6.1% to 11.3% (10). Children with velocardiofacial syndrome (VCFS) had a higher rate of MDD when compared to community and sibling controls (12% vs. 3%, respectively) (11). Based on structured interviews, 44% of adults with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) met criteria for MDD; 20% also met criteria for bipolar disorder (12). A small study of females with the Fragile X mutation found that 24% of those subjects had MDD vs. 6% of the control group (13). In a population-based study of adults with tuberous sclerosis complex (TSC), 23.3% of subjects were diagnosed with MDD (14).

Anxiety disorders A United Kingdom survey of 10,438 children (ages 5-15 years) identified 264 with ID (15). A standardized, multimodal assessment procedure determined that children with ID were 2.5 times more likely to have a diagnosable anxiety disorder than were those without ID. There are some DD syndromes in which anxiety disorders are prominent. The parents of patients (N= 51; ages 5-49 years) with Williams syndrome (WS) were administered a semistructured interview about their children (16). The highest rates of anxiety disorders were noted for specific phobias (35%) and for overanxious disorder/generalized anxiety disorder (GAD) (16%-18%). There were even higher rates of endorsement of anxiety symptoms that did not meet diagnostic criteria for a full disorder. Children with VCFS had a highly significant rate of simple phobias when compared to community and sibling controls (22.6% vs. 8.6%, respectively); they also had a numerically- but not statistically- higher rate of GAD (11). In addition to mood disorders, prenatal alcohol exposure increases the risk for developing anxiety disorders, which were seen in 18% of adults with FAS and 21% of adults with FAE (12). Females (ages 4-27 years) with the fragile X mutation showed high rates of anxiety, especially social avoidance (65% vs. 12% of controls) (13). Boys with fragile X

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syndrome (FXS) are also prone to anxiety, especially in response to environmental changes (78.8% of the sample) and social stimulation (39.4%) (17).

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Attention-deficit/hyperactivity disorder (ADHD) A study of three samples of children and adolescents with IDs of mixed etiologies utilized three different methods to determine rates of ADHD (18). In one sample (N=75; 3-19 years of age), 60% of those with IDs scored in the clinical range for hyperactivity, while only 2.7% of their non-ID siblings did so. Symptoms of ADHD were more likely to be present in children with autism than in those with MR without autism. The rates of hyperactivity reported in those with Angelman syndrome (AS) have varied between 50% and 94%. In order to try more accurately to determine the prevalence of hyperactivity in that population, Berry et al, compared a group with AS to those with ID of undetermined cause (19). Using standardized behavioral questionnaires, raters endorsed the ―overactive, restless, unable to sit still‖ item in 71.2% of the AS subjects, vs. in 49.3% of the comparison group; conversely, those with AS were less likely to be inattentive. Comparing individuals with three different genetic syndromes associated with MR, Clarke and Boer found that those with Cri du chat syndrome (CdCS) and those with Smith-Magenis syndrome (SMS) had much higher rates of hyperactivity (and non-compliance) than did subjects with Prader-Willi syndrome (PWS) (20). A study from the state of North Dakota in the US assessed three groups of children for ADHD relative to prenatal alcohol exposure (21). Comorbid ADHD was identified in 73% of those with FAS, in 72% with partial FAS, and in 36% with no FAS. Boys with Fragile X Syndrome (FXS), when compared to boys with either DS or non-specific IDs, are more highly rated as being restless, hyperactive, fidgety, and inattentive (22). Girls with FXS do not show similarly high rates of ADHD when compared to controls (13). In one study, children with VCFS had a significantly higher rate of ADHD (42.8%) when compared to community controls (26.3%) (11). Based on diagnostic interviews with the parents of 119 children (4-16 years of age) with WS, 64.7% of the children met criteria for ADHD; of those, over two-thirds had the inattentive type of ADHD (23). Mautner, et al. investigated the rate of ADHD in neurofibromatosis, type 1 (NF-1) (24). Comprehensive testing yielded a rate of 49.5% of those with NF-1 meeting DSM-IV criteria for ADHD. Finally, a retrospective review of 241 children and adults with TSC yielded a history of 30% having been diagnosed with ADHD (25).

Psychotic disorders Compared to the general population, one study found that adults with IDs have a high point prevalence (4.4%) of non-affective psychotic disorders (26). That same study calculated the 2-year incidence of psychotic disorders to be 10-times higher in the ID population vs. that in the general population. As previously noted, prenatal alcohol exposure increases the lifetime risk of developing mood, anxiety, and attention deficit disorders; it also increases the risk for developing psychosis. Of the 25 adults with FAS or FAE who were evaluated, 40% reported psychotic symptoms; brief psychotic disorder was the most common psychotic diagnosis (28% of

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subjects) (12). Vogels et al found that of 37 patients with PWS, 6 (i.e. 16.2% of the group) had developed a psychotic disorder; interestingly, 5 of those 6 had the uniparental (maternal) disomy type of PWS (27). Children with VCFS (also called 22q11.2 deletion syndrome) have high rates of psychotic symptoms (14%-28%), and are at risk for developing psychotic disorders, especially those in the schizophrenia spectrum (28).

Other disorders As a group, people with IDs are at high risk for developing other clinical disorders, such as dementia (29), aggression (30), sleep disturbances (31), and repetitive behaviors (including those in the obsessive-compulsive spectrum) (32).

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Treatment The literature on the treatment of psychiatric disorders in the CAD/DD/ID/MR population has primarily focused on adults. Individuals with IDs display high rates of behavioral disturbances, for which psychotropic medications are commonly used, especially in residential settings. A significant number of those medications are prescribed in the absence of clearly identified psychiatric diagnoses (33). Over time there has been a trend towards the use of polypharmacy in patients with DDs. Frequent changes in medication regimens are not uncommon, and there is a tendency for prescribers to increase medication dosages or to add medications upon other medications, either to try and achieve better results or to ameliorate adverse medication effects. One problem with this approach, that is often under-appreciated, is that psychotropic medications can themselves cause side effects that can mimic the psychopathology that is being treated (34). The caution to ―start low and go slow‖ with medications that we employ with children is even more important to keep in mind as we treat disabled patients of any age or with any diagnosis.

Mood disorders The treatment of depression in adults with MR has been addressed in consensus guidelines (35) and a review article (36). The two resources are in agreement that the pharmacotherapy of depression should begin with a selective serotonin reuptake inhibitor (SSRI) antidepressant. The guidelines also suggest that in the case of non-response to the first SSRI, the next step should be a trial of a second SSRI. If there is a partial response to the first SSRI, consideration should be given to the addition of either an anticonvulsant/mood stabilizer, lithium, or a different antidepressant, such as the serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine or duloxetine. These recommendations are also reasonable to follow for the treatment of depression in children and adolescents with ID. All medications should be started at doses even lower than the lowest doses recommended for depressed individuals without ID.

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Bipolar disorder For the treatment of bipolar disorder in those with ID, the consensus guidelines (35) are more complex, with choice of agent(s) dependent on the phase of illness (i.e., manic, hypomanic or depressed), the type of mania (i.e., classic/euphoric, mixed/dysphoric or rapid cycling), or whether the depression is psychotic or non-psychotic (see figure 1). An extensive literature review of psychopharmacologic agents for bipolar disorder in children and adolescents with DDs tentatively endorsed lithium for manic symptoms, valproic acid if electroencephalographic abnormalities are present, adjunctive use of carbamazepine (perhaps more so if depression is present), and possibly the atypical antipsychotics (AAs) (37) (see figure 1).

Anxiety disorders

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Environmental and psychological interventions are the methods of first-choice for the treatment of anxiety disorders. If they inadequately treat the anxiety symptoms, or if the anxiety is severe and debilitating, then psychotropic medications should be considered. In adults with comorbid MR and anxiety disorders, the preferred agents are the SSRIs for posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD), as well as for non-specific anxiety symptoms (35). Non-syndromal anxiety can also be treated with buspirone, which may be especially helpful when aggression is also present (38). The SSRIs are also first-line agents for the treatment of anxiety in children with DDs. The use of traditional anxiolytics, such as the benzodiazepines, should probably be avoided in individuals with MR/DD, as the side effects of sedation, impaired cognition, and behavioral disinhibition are more likely to occur in that population (39).

Attention-deficit/hyperactivity disorder The psychostimulants are the preferred medications for use in adults with both ID and ADHD or non-specific hyperactivity (35). Stimulants are also the primary medications used to treat ADHD in children with ID (40). The dosing of medications should follow the guidelines established for children without ID. Patients who do not respond to, or who cannot tolerate, the psychostimulants may do well with clonidine.

Psychotic disorders The preferred medications for the treatment of psychotic symptoms in the ID population are the atypical antipsychotics (AAs), with either risperidone or olanzapine as first-level choices and quetiapine as a second-level choice (35). The use of clozapine should be considered after two (or more) adequate, but failed, trials of AAs. Given the potentially serious adverse effects associated with clozapine (i.e., agranulocytosis, seizures, myocarditis, and marked orthostatic

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hypotension), its use should be reserved for those psychotic patients who are likely to be resistant to conventional treatment, such as individuals with VCFS (41).

Conclusions

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Individuals with cognitive-adaptive disabilities (CADs) are at risk for developing a large variety of psychiatric disorders at rates higher than those seen in the intellectually normal population. Mental illnesses which are associated with disturbances of mood, anxiety, hyperactivity/ impulsivity and/or psychosis can be identified in those with CADs. Pharmacotherapy can be a useful adjunct to behavioral treatments, and proper selection of patients and agents, along with careful dosing and monitoring, can alleviate mental suffering, improve functional capabilities, and reduce disturbing behaviors. This chapter presents bestevidence information on the psychotropic agents to choose for patients with comorbid CADs and common psychiatric disorders.

(Abbreviations: AA= atypical antipsychotics; AD= antidepressant; BD= bipolar disorder; Li= lithium; LTG= lamotrigine; VPA= valproic acid) * Adapted from Reference 35 Figure 1. Medications for Bipolar Disorder in CADs*.

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Council on Children With Disabilities; Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children With Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. [Pediatrics] 2006;118(1):405-20. [Erratum in: Pediatrics] 2006;118(4):1808-9. Sullivan WF, Heng J, Cameron D, Lunsky Y, Cheetham T, Hennen B, et al. Consensus guidelines for primary health care of adults with developmental disabilities.[ Can Fam Physician] 2006;52(11):14108. Erratum in: [Can Fam Physician] 2007;53(1):31. Leonard H, Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. [Ment Retard Dev Disabil Res Rev] 2002;8(3):117-34. Roeleveld N, Zielhuis GA, Gabreëls F. The prevalence of mental retardation: a critical review of recent literature. [Dev Med Child Neurol] 1997;39(2):125-32. Cooper SA, Smiley E, Morrison J, Williamson A, Allan L. Mental ill-health in adults with intellectual disabilities: prevalence and associated factors. [Br J Psychiatry] 2007;190(1):27-35. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, Fourth ed, text rev. Washington, DC: [APA], 2000. Kerker BD, Owens PL, Zigler E, Horwitz SM. Mental health disorders among individuals with mental retardation: challenges to accurate prevalence estimates. [Pub Health Rep] 2004;119(4):409-17. Fletcher R, Loschen E, Stavrakaki C, First M, eds. Diagnostic manual-intellectual disability (DM-ID): A clinical guide for diagnosis of mental disorders in persons with intellectual disability. Kingston, NY: [NADD Press], 2007. Cooper SA, Smiley E, Morrison J, Williamson A, Allan L. An epidemiological investigation of affective disorders with a population-based cohort of 1023 adults with intellectual disabilities. [Psychol Med] 2007;37(6):873-82. Pary RJ, Loschen EL, Tomkowiak SB. Mood disorders and Down syndrome. [Semin Clin Neuropsychiatry] 1996;1(2):148-53. Antshel KM, Fremont W, Roizen NJ, Shprintzen R, Higgins AM, Dhamoon A, et al.. ADHD, major depressive disorder, and simple phobias are prevalent psychiatric conditions in youth with velocardiofacial syndrome. [J Am Acad Child Adolesc Psychiatry] 2006;45(5):596-603. Famy C, Streissguth AP, Unis AS. Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. [Am J Psychiatry] 1998;155(4):552-4. Freund LS, Reiss AL, Abrams MT. Psychiatric disorders associated with fragile X in the young female. [Pediatrics] 1993;91(2):321-9. Raznahan A, Joinson C, O'Callaghan F, Osborne JP, Bolton PF. Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis. [J Intellect Disabil Res] 2006;50(Pt 8):561-9. Erratum in: [J Intellect Disabil Res] 2006;50(10):780. Emerson E. Prevalence of psychiatric disorders in children and adolescents with and without intellectual disability. [J Intellect Disabil Res] 2003;47(Pt 1):51-8. Dykens EM. Anxiety, fears, and phobias in persons with Williams syndrome. [Dev Neuropsychol] 2003;23(1-2):291-316. Woodcock K, Oliver C, Humphreys G. Associations between repetitive questioning, resistance to change, temper outbursts and anxiety in Prader–Willi and Fragile-X syndromes. [J Intellect Disabil Res] 2009;53(3):265-78. Hastings RP, Beck A, Daley D, Hill C. Symptoms of ADHD and their correlates in children with intellectual disabilities. [Res Dev Disabil] 2005;26(5):456-68. Berry RJ, Leitner RP, Clarke AR, Einfeld SL. Behavioral aspects of Angelman Syndrome: a case control study. [Am J Med Genet] 2005;132A:8-12. Clarke DJ, Boer H. Problem behaviors associated with deletion Prader-Willi, Smith-Magenis, and Cri du chat syndromes. [Am J Ment Retard] 1998;103(3):264-71.

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Joseph L Calles, Jr, MD and Ahsan Nazeer, MD Burd L, Klug MG, Martsolf JT, Kerbeshian J. Fetal alcohol syndrome: neuropsychiatric phenomics. [Neurotoxicol Teratology] 2003;25(6):697-705. Turk J. Fragile X syndrome and attentional deficits. [J Appl Res Intellect Disabil] 1998;11(3):175-91. Leyfer OT, Woodruff-Borden J, Klein-Tasman BP, Fricke JS, Mervis CB. Prevalence of psychiatric disorders in 4 to 16-year-olds with Williams syndrome. [Am J Med Genet Part B] 2006;141B:615-22. Mautner VF, Kluwe L, Thakker SD, Leark RA. Treatment of ADHD in neurofibromatosis type 1. [Dev Med Child Neuro]l 2002;44(3):164-70. Muzykewicz DA, Newberry P, Danforth N, Halpern EF, Thiele EA. Psychiatric comorbid conditions in a clinic population of 241 patients with tuberous sclerosis complex. [Epilepsy Beh] 2007;11(4):50613. Cooper SA, Smiley E, Morrison J, Allan L, Williamson A, Finlayson J, et al. Psychosis and adults with intellectual disabilities: Prevalence, incidence, and related factors. [Soc Psychiatry Psychiatr Epidemiol] 2007;42(7):530-6. Vogels A, De Hert M, Descheemaeker MJ, Govers V, Devriendt K, Legius E, et al. Psychotic disorders in Prader-Willi syndrome. [Am J Med Gene]t 2004;127A:238-43. Jolin EM, Weller RA, Weller EB. Psychosis in children with velocardiofacial syndrome (22q11.2 deletion syndrome). [Curr Psychiatry Rep] 2009;11:99-105. Strydom A, Hassiotis A, King M, Livingston G. The relationship of dementia prevalence in older adults with intellectual disability (ID) to age and severity of ID. [Psychol Med] 2009;39:13-21. Tyrer F, McGrother CW, Thorp CF, Donaldson M, Bhaumik S, Watson JM, et al. Physical aggression towards others in adults with learning disabilities: prevalence and associated factors.[ J Intellect Disabil Res] 2006;50(4):295-304. Erratum in: [J Intellect Disabil Res] 2006;50(5):395. Doran SM, Harvey MT, Horner RH. Sleep and developmental disabilities: Assessment, treatment, and outcome measures. [Ment Retard] 2006;44(1):13-27. Barnhill J. What exactly is obsessive-compulsive disorder in individuals with intellectual and developmental disabilities? Ment Health [Aspects Dev Disabil] 2008;11(3):85-93. Unwin GL, Deb S. Use of medication for the management of behavior problems among adults with intellectual disabilities: a clinicians' consensus survey. [Am J Ment Retard] 2008;113(1):19-31. Valdovinos MG, Caruso M, Roberts C, Kim G, Kennedy CH. Medical and behavioral symptoms as potential medication side effects in adults with developmental disabilities. [Am J Ment Retard] 2005;110(3):164-70. Aman MG, Crismon ML, Frances A, King BH, Rojahn J, eds. Treatment of psychiatric and behavioral problems in individuals with mental retardation: An update of the Expert Consensus Guidelines© for mental retardation/developmental disability populations. Englewood, CO: [Postgraduate Institute for Medicine; 2004. Available at: http://www.psychguides.com/mental_retardation] Accessed November 23, 2009 Janowsky DS, Davis JM. Diagnosis and treatment of depression in patients with mental retardation. [Curr Psychiatry Rep] 2005;7(6):421-8. Gutkovich ZA, Carlson GA. Medication treatment of bipolar disorder in developmentally disabled children and adolescents. [Minerva Pediatr] 2008;60(1):69-85. Ratey J, Sovner R, Parks A, Rogentine K. Buspirone treatment of aggression and anxiety in mentally retarded patients: a multiple-baseline, placebo lead-in study. J Clin Psychiatry 1991;52(4):159-62. Werry JS. Anxiolytics in MRDD. [Ment Retard Dev Disabil Res Rev] 1999;5(4):299-304. Huang H, Ruedrich S. Recent advances in the diagnosis and treatment of attentiondeficit/hyperactivity disorder in individuals with intellectual disability. [Mental Health Aspects of Developmental Disabilities] 2007;10(4):121-8. Gladston S, Clarke DJ. Clozapine treatment of psychosis associated with velo-cardio-facial syndrome: benefits and risks.[ J Intellect Disabil Res] 2005;49(7):567-70.

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Section Four: Other Use

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In: Clinical Aspects of Psychopharmacology in Childhood… ISBN: 978-1-61122-135-0 Editors: D. Greydanus, J. Calles, Jr, D. Patel et al. ©2011 Nova Science Publishers, Inc.

Chapter XIII

Substance abuse disorders in adolescents: pharmacologic management Donald E Greydanus, MD*1,2, Cynthia Feucht, PharmD3 and Dilip R Patel, MD1,2

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Michigan State University (MSU) College of Human Medicine, Department of Pediatrics and Human Development1 MSU/Kalamazoo Center for Medical Studies, Pediatrics Program, Kalamazoo, Michigan2 Ferris State University College of Pharmacy, Big Rapids, Michigan, United States of America3 Substance abuse is a major public health conundrum of adolescents and adults throughout the world. The major problem of addiction in the world has intensified since the unfortunate biochemical isolation of cocaine, heroin, and morphine in the 19th century. The role of pharmacologic agents in the management of substance abuse disorders in adolescents is secondary or adjunctive, with psychological therapies serving as the primary methods of treatment. Medications may serve a more primary role in the transient issue of helping in acute management of drug intoxication or withdrawal states. This article discusses current pharmacologic management of specific illicit drugs in which research indicates drug treatment can be beneficial; these drugs include alcohol, heroin, and cocaine.

*

Correspondence: Professor Donald E Greydanus, MD, Pediatrics and Human Development, Michigan State University College of Human Medicine, Pediatrics Program Director, MSU/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, Michigan 49008-1284, United States. E-mail: [email protected]

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Donald E Greydanus, MD, Cynthia Feucht, PharmD and Dilip R Patel, MD

Introduction

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Substance abuse is a major public health conundrum of adolescents and adults throughout the world (1-42). The major problem of addiction in the world has intensified since the unfortunate biochemical isolation of cocaine, heroin, and morphine in the 19th century. Research over the past decade has noted that addiction is not an illness that is simply inherited, but a complex illness in which various genes combine with each addict‘s environment that includes influences of peers and family. Addiction is a chronic disorder that involves using drugs that provide euphoric effects in diverse ways, including enhancing the neurotransmitter dopamine in the areas of the brain involved in reward and motivation- such as the mesocorticolimbic pathway (8,12,13). The role of pharmacologic agents in the management of substance abuse disorders in adolescents is secondary or adjunctive, with psychological therapies serving as the primary methods of treatment (13-16). Medications may serve a more primary role in the transient issue of helping in acute management of drug intoxication or withdrawal states. Nonpharmacologic management of substance abuse disorders in adolescents include motivational interviewing, cognitive-behavioral therapy, behavior motivation therapy, family therapy, and group counseling. Adolescents may require outpatient treatment, partial hospitalization, inpatient management, detoxification management, acute residential management, and even management in long-term residential programs. This article discusses current pharmacologic management of specific illicit drugs in which research indicates drug treatment can be beneficial; these drugs include alcohol, heroin and cocaine. The literature on psychopharmacologic management of drug abuse mainly focuses on adults, and there are no medications that are FDA-approved for those with substance abuse disorder under 18 years of age. Many of these medications, however, are used by various clinicians dealing with adolescents who have drug withdrawal and dependence problems. Medications used to treat nicotine addiction are reviewed in another chapter (21-29).

Alcohol Treatment of acute alcohol consumption includes gastric emptying, intravenous fluids along with glucose, respiratory support, and, if necessary, dialysis (11,12,17,18). A number of medications have been used to treat alcohol withdrawal syndrome, as noted in table 1; benzodiazepines are sedation-inducing drugs and include diazepam, chlordiazepoxide, and lorazepam that are given every 1-4 hours (depending upon the agent) until withdrawal symptoms cease (11,12,16,18). Table 1. Medications for management of alcohol withdrawal syndrome.     

Lorazepam Chlordiazepoxide Diazepam Clorazepate Various antipsychotics

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Table 2 lists drugs approved for treatment of adults with alcohol dependence in the United States; there are no FDA approved medications for adolescents (6,7,19). The United States Food and Drug Administration (FDA) approved the use of disulfiram for the management of adult alcohol dependence nearly a half century ago. In 1994, the FDA approved naltrexone (opioid-receptor antagonist) for management of adult alcohol dependence, followed in 2004 by acamprosate. Other drugs (see table 2) have been used in adults with alcohol dependence but are not FDA-approved and not discussed here. Table 2. Drugs for management of adults with alcohol dependence.

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Approved  Disulfiram  Naltrexone  Acamprosate Used but not officially approved (off label)  Buspirone  Carbamazepine  Oxcarbazepine  Gabapentin  Nalmefene (opioid antagonist)  Ondansetron  Quetiapine  Selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline)  Tiapride (Orphan drug status)  Topiramate (anticonvulsant)  Tricyclic antidepressants

Table 3 reviews the mechanism, side effects, and dosages of disulfiram, naltrexone and acamprosate; liver function tests (aminotransferase levels) must be monitored when taking disulfiram or naltrexone.

Drug interactions Disulfiram may interfere with the metabolism of certain medications, such as phenytoin (causing phenytoin intoxication), oral anticoagulants (can prolong prothrombin time), benzodiazepines which undergo oxidative metabolism (i.e., diazepam & chlordiazepoxide) and isoniazid (can induce mental status changes and unsteady gait). Naltrexone blocks opioid effects and can precipitate an acute opioid withdrawal syndrome if given to someone taking opioids; the individual must be off opioids for at least 710 days before taking naltrexone. Combining naltrexone with acamprosate increases serum acamprosate levels, but dosage adjustments are not necessary. Naltrexone is hepatotoxic at higher than recommended levels. Acamprosate is a safe medication when added to other medications; serum levels are increased when added to naltrexone, but without known adverse consequences.

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Table 3. FDA medications approved for adult alcohol dependence (39,40). Agent

Mechanism

Adverse Effects Drinking alcohol while on disulfiram leads to flushing, headache, nausea, palpitations, chest pain, vertigo & hypotension. Side effects apart from alcohol ingestion: sedation, allergic dermatitis, headache, metallic or garlicky taste in mouth.

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Disulfiram (Antabuse, others)

Interferes with alcohol metabolism by inhibition of acetaldehyde dehydrogenase.

Rare: peripheral neuropathy, optic neuritis, polyneuritis, cardiac arrhythmias & psychosis. Can be hepatotoxic with rare idiosyncratic fulminant hepatitis with death (Must monitor liver function tests). Caution use in hepatic cirrhosis / insufficiency.

Dosage

Comments

Small amount of alcohol consumed while taking disulfiram, the concentration of acetaldehyde can be 5-10 x higher than if alcohol is consumed without the disulfiram. Not approved for age