Bipolar II Disorder: Recognition, Understanding, and Treatment 1615371788, 9781615371785

Table of contents :
Dedications
Contents
Contributors
Preface • Holly A. Swartz and Trisha Suppes
Part I: Recognition
1 A Neglected Condition • Holly A. Swartz and Trisha Suppes
2 Diagnosing Bipolar II Disorder • Nicole Kramer and Trisha Suppes
3 Interface Between Borderline Personality Disorder and Bipolar II Disorder • Mark Zimmerman and Theresa A. Morgan
4 Psychiatric and Medical Comorbidities With Bipolar II Disorder • Joshua D. Rosenblat, Michael J. Ostacher, and Roger S. McIntyre
5 Suicide and Bipolar II Disorder • Ayal Schaffer and Mark Sinyor
Part II: Understanding
6 Genetics of Bipolar II Disorder • Melvin McInnis
7 Functional Brain Imaging and Neural Determinants in Bipolar II Disorder • Anna Manelis, Adriane M. Soehner, and Mary L. Phillips
Part III: Treatment
8 Mood Stabilizers and Antipsychotic Medications in Bipolar II Disorder • Eva Solé, Marina Garriga, and Eduard Vieta
9 Antidepressant Medications in Bipolar II Disorder • Susan L. McElroy and Alex Israel
10 Psychosocial Interventions in Bipolar II Disorder • Danielle M. Novick and Holly A. Swartz
Part IV: Special Populations
11 Bipolar II Disorder in Childhood and Adolescence • Manivel Rengasamy and Boris Birmaher
12 Reproductive-Age Women With Bipolar II Disorder • Eydie L. Moses-Kolko, Crystal T. Clark, Sarah DeBrunner, and Katherine L. Wisner
Index

Citation preview

Recognition, Understanding, and Treatment

Edited by

Holly A. Swartz, M.D. Trisha Suppes, M.D., Ph.D.

BIPOLAR II DISORDER RECOGNITION, UNDERSTANDING, AND TREATMENT

BIPOLAR II DISORDER RECOGNITION, UNDERSTANDING, AND TREATMENT Edited by

Holly A. Swartz, M.D. Trisha Suppes, M.D., Ph.D.

Note: The authors have worked to ensure that all information in this book is accu­ rate at the time of publication and consistent with general psychiatric and medical

standards, and that information concerning drug dosages, schedules, and routes of

administration is accurate at the time of publication and consistent with standards set

by the U.S. Food and Drug Administration and the general medical community. As

medical research and practice continue to advance, however, therapeutic standards

may change. Moreover, specific situations may require a specific therapeutic response

not included in this book. For these reasons and because human and mechanical er­ rors sometimes occur, we recommend that readers follow the advice of physicians di­ rectly involved in their care or the care of a member of their family.

Books published by American Psychiatric Association Publishing represent the find­ ings, conclusions, and views of the individual authors and do not necessarily repre­ sent the policies and opinions of American Psychiatric Association Publishing or

the American Psychiatric Association.

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Library of Congress Cataloguing-in-Publication Data Names: Swartz, Holly A., editor. | Suppes, Trisha, editor. | American Psychiatric Association Publishing, issuing body. Title: Bipolar II disorder : recognition, understanding, and treatment / edited by Holly A. Swartz, Trisha Suppes. Other titles: Bipolar II disorder (Swartz) Description: First edition. | Washington, D.C. : American Psychiatric Association Publishing, [2019] | Includes bibliographical references and index. | Identifiers: LCCN 2019011723 (print) | LCCN 2019012924 (ebook) | ISBN 9781615372591 () | ISBN 9781615371785 (pbk. : alk. paper) Subjects: | MESH: Bipolar Disorder—diagnosis | Bipolar Disorder—therapy Classification: LCC RC516 (ebook) | LCC RC516 (print) | NLM WM 171.7 | DDC 616.89/5—dc23 LC record available at https://lccn.loc.gov/2019011723 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

To Steven, Sophie, and Eli—each special, for different reasons. H.A.S. To my sisters and brothers Deborah, John, Alexandra, and Michael with great appreciation you are in my life. T.S.

To our patients and colleagues who taught us about bipolar II disorder; you made this book possible.

Contents Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

Holly A. Swartz, M.D., and Trisha Suppes, M.D., Ph.D.

Part I

Recognition

1

A Neglected Condition . . . . . . . . . . . . . . . . . . . . . . 3

Holly A. Swartz, M.D., and Trisha Suppes, M.D., Ph.D.

2

Diagnosing Bipolar II Disorder. . . . . . . . . . . . . . .17

Nicole Kramer, M.A., M.S., and Trisha Suppes, M.D., Ph.D.

3

Interface Between Borderline Personality

Disorder and Bipolar II Disorder . . . . . . . . . . . . .51

Mark Zimmerman, M.D., and Theresa A. Morgan, Ph.D.

4

Psychiatric and Medical Comorbidities

With Bipolar II Disorder . . . . . . . . . . . . . . . . . . . .71

Joshua D. Rosenblat, M.D., Michael J. Ostacher, M.D., M.P.H., M.M.Sc., and Roger S. McIntyre, M.D., F.R.C.P.C.

5

Suicide and Bipolar II Disorder . . . . . . . . . . . . . .99

Ayal Schaffer, M.D., F.R.C.P.C., and

Mark Sinyor, M.Sc., M.D., F.R.C.P.C.

Part II

Understanding

6

Genetics of Bipolar II Disorder . . . . . . . . . . . . .121

Melvin McInnis, M.D.

7

Functional Brain Imaging and

Neural Determinants in Bipolar II Disorder . . .139

Anna Manelis, Ph.D., Adriane M. Soehner, Ph.D., and Mary L. Phillips, M.D., M.D.(Cantab.)

Part III

Treatment

8

Mood Stabilizers and Antipsychotic

Medications in Bipolar II Disorder. . . . . . . . . . .165

Eva Solé, M.D., Marina Garriga, M.D., and Eduard Vieta, M.D., Ph.D.

9

Antidepressant Medications in

Bipolar II Disorder . . . . . . . . . . . . . . . . . . . . . . .183

Susan L. McElroy, M.D., and Alex Israel, M.D.

10 Psychosocial Interventions in

Bipolar II Disorder . . . . . . . . . . . . . . . . . . . . . . .203

Danielle M. Novick, Ph.D., and Holly A. Swartz, M.D.

Part IV

Special Populations

11 Bipolar II Disorder in Childhood and

Adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . .241

Manivel Rengasamy, M.D., and Boris Birmaher, M.D.

12 Reproductive-Age Women With

Bipolar II Disorder . . . . . . . . . . . . . . . . . . . . . . .263

Eydie L. Moses-Kolko, M.D., Crystal T. Clark, M.D., M.Sc., Sarah DeBrunner, M.D., and Katherine L. Wisner, M.D., M.S.

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

Contributors

Boris Birmaher, M.D. Professor of Psychiatry and Endowed Chair in Early Bipolar Disorder, Di­ rector of the Child and Adolescent Bipolar Services Program, Co-Director of Psychiatry Research Pathway Program, Department of Psychiatry, Uni­ versity of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Crystal T. Clark, M.D., M.Sc. Assistant Professor of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Asher Center for the Study and Treatment of Depressive Disorders, Northwestern Feinberg School of Medicine, Chicago, Illinois Sarah DeBrunner, M.D. Clinical Assistant Professor, University of Pittsburgh School of Medicine, Department of Psychiatry, University of Pittsburgh Medical Center, Pitts­ burgh, Pennsylvania Marina Garriga, M.D. Psychiatrist, Department of Psychiatry and Psychology, Institute of Neuro­ science, University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain Alex Israel, M.D. Graduate Medical Resident in Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania Nicole Kramer, M.A., M.S. Doctoral Candidate and Research Assistant, Prevention and Intervention Laboratory, Stanford University School of Medicine, Stanford, California

ix

x

Bipolar II Disorder: Recognition, Understanding, and Treatment

Anna Manelis, Ph.D. Assistant Professor, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Susan L. McElroy, M.D. Chief Research Officer, Lindner Center of HOPE, Mason, Ohio; Profes­ sor of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio Melvin McInnis, M.D. Thomas B. and Nancy Upjohn Woodworth Professor of Bipolar Disorder and Depression, Professor of Psychiatry, University of Michigan Medi­ cal School, Ann Arbor, Michigan Roger S. McIntyre, M.D., F.R.C.P.C. Professor of Psychiatry and Pharmacology, University of Toronto; University Health Network, Mood Disorder Psychopharmacology Unit (MDPU), Toronto, ON, Canada Theresa A. Morgan, Ph.D. Clinical Assistant Professor of Psychiatry, Brown University; Staff Psy­ chologist, Rhode Island Hospital, Providence, Rhode Island Eydie L. Moses-Kolko, M.D. Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Danielle M. Novick, Ph.D. Clinical Psychologist, Outpatient Mood Disorders Clinic, Clinical Su­ pervisor, Clinical Training Committee, VA Pittsburgh Healthcare Sys­ tem, Pittsburgh, Pennsylvania Michael J. Ostacher, M.D., M.P.H., M.M.Sc. Associate Professor of Psychiatry, Department of Psychiatry and Behav­ ioral Sciences, Stanford University School of Medicine; Medical Direc­ tor, VA/Stanford Bipolar and Depression Research Program, Veterans Affairs Palo Alto Health Care System, Palo Alto, California

Contributors

xi

Mary L. Phillips, M.D., M.D.(Cantab.) Pittsburgh Foundation-Emmerling Endowed Chair in Psychotic Disor­ ders, Professor in Psychiatry and Clinical and Translational Science, and Director of the Mood and Brain Laboratory, The Clinical and Transla­ tional Affective Neuroscience Program, Department of Psychiatry, Uni­ versity of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Manivel Rengasamy, M.D. Child Psychiatry Fellow, Department of Psychiatry, University of Pitts­ burgh Medical Center, Pittsburgh, Pennsylvania Joshua D. Rosenblat, M.D. Chief Resident of Psychiatry, Clinician Scientist Program, University of Toronto; University Health Network, Mood Disorder Psychopharma­ cology Unit (MDPU), Toronto, ON, Canada Ayal Schaffer, M.D., F.R.C.P.C. Deputy Psychiatrist-in-Chief, Head, Mood and Anxiety Disorders Pro­ gram, Sunnybrook Health Sciences Centre; Professor, Department of Psy­ chiatry, University of Toronto, Toronto, Ontario, Canada Mark Sinyor, M.Sc., M.D., F.R.C.P.C. Psychiatrist, Sunnybrook Health Sciences Centre; Assistant Professor, De­ partment of Psychiatry, University of Toronto, Toronto, Ontario, Canada Adriane M. Soehner, Ph.D. Assistant Professor, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Eva Solé, M.D. Psychiatrist, Department of Psychiatry and Psychology, Institute of Neuro­ science, University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain Trisha Suppes, M.D., Ph.D. Professor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; VA Palo Alto Health Care System, Palo Alto, California

xii

Bipolar II Disorder: Recognition, Understanding, and Treatment

Holly A. Swartz, M.D. Professor, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Eduard Vieta, M.D., Ph.D. Professor of Psychiatry, Chair, Department of Psychiatry and Psychol­ ogy, Institute of Neuroscience, University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain Katherine L. Wisner, M.D., M.S. Norman and Helen Asher Professor of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology; Director, Asher Center for the Study and Treatment of Depressive Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois Mark Zimmerman, M.D. Professor of Psychiatry and Human Behavior, Brown University; Direc­ tor of Outpatient Psychiatry and Partial Hospital Program, Rhode Island Hospital, Providence, Rhode Island

Disclosure of Competing Interests The following contributors to this book have indicated a financial interest in or other affiliation with a commercial supporter, a manufacturer of a commercial product, a provider of a commercial service, a nongovernmental organization, and/or a government agency, as listed below:

Boris Birmaher, M.D.—Research funding: National Institute of Mental Health; Royalties: Lippincott Williams & Wilkins, Random House, UpToDate Marina Garriga, M.D.—Grants and/or consultant/advisor: Centro de Investigación Biomédica en Red de salud Mental (CIBERSAM), FEDER, Ferrer, Instituto de Salud Carlos III, Janssen, Lundbeck Susan L. McElroy, M.D.—Principal investigator or co-investigator on re­ search studies sponsored by: Allergan, Brainsway, Marriott Foundation, Myriad, National Institute of Mental Health, Novo Nordisk, Shire, Su­ novion; Consultant or scientific advisory board: Bracket, F. Hoffmann-La Roche, MedAvante, Mitsubishi Tanabe Pharma America, Myriad, Novo Nordisk, Shire, Sunovion; Patents: Inventor on U.S. Patent 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders,

Contributors

xiii

and along with the patent’s assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson Pharmaceutical Research and Development, L.L.C., which has exclusive rights under the patent Melvin McInnis, M.D.—Research support: National Institute of Mental Health (R21 MH114835), Prechter Bipolar Research Fund, Richard Tam Foundation, University of Michigan Depression Center; the author has consulted with Janssen and Otsuka Pharmaceuticals Eydie L. Moses-Kolko, M.D.—Site Principal Investigator for Sage Phar­ maceuticals trial of brexanolone for treatment of postpartum depression (period of study approximately November 1, 2016, to November 1, 2017) Ayal Schaffer, M.D., F.R.C.P.C.—Research grants: American Foundation for Suicide Prevention; Canadian Institute of Health Research; Ontario Mental Health Foundation; Ontario Ministry of Health and Long-Term Care (IMPACT Award); Honoraria of other fees: Allergan, Asofarma, Lundbeck, Sunovion Eva Solé, M.D.—Grants and/or consultant/advisor: Centro de Investi­ gación Biomédica en Red de salud Mental (CIBERSAM), Instituto de Salud Carlos III Holly A. Swartz, M.D.—Grant support: Myriad Genetics, National Insti­ tute of Mental Health; Consultant: Myriad Genetics; Royalties: UpToDate Eduard Vieta, M.D., Ph.D.—Grants and consultant/advisor/CME speaker: AB-Biotics, Actavis, Allergan, AstraZeneca, Bristol-Myers Squibb, Ferrer, Forest Research Institute, Geodon Richter, Glaxo-SmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Ser­ vier, Shire, Sunovion, Takeda, Telefónica, Brain and Behavior Founda­ tion, Spanish Ministry of Science and Innovation (Centro de Investigación Biomédica en Red de salud Mental; CIBERSAM), Seventh European Framework Programme (ENBREC), Stanley Medical Research Institute The following contributors to this book have indicated no competing interests to disclose:

Crystal T. Clark, M.D., M.Sc. Sarah DeBrunner, M.D. Anna Manelis, Ph.D. Manivel Rengasamy, M.D. Trisha Suppes, M.D., Ph.D.

Preface

W

hat is bipolar II disorder? Are there really different types of bipolar disorder? Why does it matter? Even many experienced clinicians may know surprisingly little about bipolar II disorder. Despite being a common illness, bipolar II disorder is misunderstood, neglected, and rarely receives the attention it deserves. When working with individuals diagnosed with bipolar II disorder, many clinicians have no clear roadmap for identifying or treating the disorder. As a result, bipolar II disorder often goes undiagnosed. Once the disorder is recognized, many clinicians use therapies that were tested in patients with bipolar I disorder to treat bipolar II disorder, even though the latter is quite different from the former. Shared frustrations about how little in­ formation is available to professionals about bipolar II disorder led us to write this book with the goal of providing a comprehensive resource for those interested in learning more. We hope it will serve as a resource for clinicians who care for individuals with bipolar II disorder, researchers who study bipolar II disorder, supporters who are concerned about some­ one with bipolar II disorder, and those who wish to learn more about their own diagnosis. All of these groups will find much to interest them in these chapters; the book, however, is written primarily for professionals rather than a lay audience. The book is divided into four parts: 1) Recognition, focused on differ­ ential diagnosis of bipolar II disorder; 2) Understanding, focused on biol­ ogy; 3) Treatment, focused on pharmacotherapy and psychotherapy; and 4) Special Populations, focused on bipolar II disorder in youth and women. Individual chapters are written by experts in the fields of phenomenol­ ogy, genetics, neuroimaging, psychopharmacology, psychotherapy, child psychiatry, and reproductive mental health, who review what is currently xv

xvi

Bipolar II Disorder: Recognition, Understanding, and Treatment

known about bipolar II disorder and its management. Throughout the book, readers will find case vignettes illustrating clinical applications of the research literature discussed in each chapter. The main messages of each chapter are summarized as Key Points for easy reference and review. We are thrilled to see that many advances have been made in under­ standing bipolar II disorder since the diagnosis was first codified in 1994. We are also humbled by the many holes that remain in the evidence base, particularly related to optimal treatments and neurobiology. This collec­ tion of writings highlights not only what we have learned about bipolar II disorder but also how much more we have yet to discover. This book seeks to answer many of the pressing, unresolved questions about bipolar II dis­ order facing those working in psychiatry. Our greatest hope, however, is that we will spur others to ask even more questions and find even better answers in the future. Holly A. Swartz, M.D.

Trisha Suppes, M.D., Ph.D.

Part I Recognition

1 A Neglected Condition Holly A. Swartz, M.D. Trisha Suppes, M.D., Ph.D.

D

espite being common and impairing, bipolar II disorder (BD II) is a neglected condition. Using conservative estimates, studies show that BD II affects approximately 0.4% of the population (Merikangas et al. 2011) and causes significant suffering and functional difficulties (Rosa et al. 2010; Ruggero et al. 2007). Evidence supports that BD II exists as a phenotype, distinct from bipolar I disorder (BD I) and other spectrum bipolar conditions (American Psychiatric Association 1994). But com­ pared with BD I, we know far less about BD II and how to treat it. Clini­ cians may not recognize the illness, and many do not know how to manage it. Consequently, thousands are unaware they have BD II and receive no treatment or inappropriate treatment. This book provides a comprehensive overview of our current under­ standing of BD II. We review phenomenology, discuss biologic under­ pinnings, and summarize management strategies to provide readers with state-of-the-art knowledge about BD II. By increasing awareness of BD II and disseminating information about it, we hope that more people will get the right diagnosis and receive appropriate treatments sooner. Be­ cause BD II is a neglected condition, however, there are many gaps in our knowledge. We hope, therefore, that this book will also encourage research that may ultimately lead to better recognition, understanding, and treatment of BD II. 3

4

Bipolar II Disorder: Recognition, Understanding, and Treatment

In this chapter we introduce BD II, including its clinical importance and historical origins. We then describe the four main topic areas of the book: recognition, understanding, treatment, and special populations. A case vignette at the end of this chapter illustrates the main themes ex­ plored in this book through the lived experiences of someone with BD II. Throughout this book, all names, details, and identifying information have been changed to ensure patient privacy.

Why Is the Bipolar II Subtype Important? Despite its relatively late arrival on the diagnostic scene, BD II has pub­ lic health significance. Associated with morbidity comparable to that of BD I (Forte et al. 2015), BD II is characterized by marked impairment in psychosocial functioning (Rosa et al. 2010), a chronic course of illness (MacQueen and Young 2001), and high rates of suicide (Novick et al. 2010). Cognitive impairment is common (Torrent et al. 2006), and mul­ tiple comorbidities are the rule rather than the exception (Merikangas et al. 2011). Economic burden associated with BD II is four times higher than that associated with BD I (Dilsaver et al. 2011). Absent the pathognomonic feature of mania that makes BD I among the most easily identified psychiatric disorders (Regier et al. 2013), BD II is admittedly less dramatic than BD I but no less impairing. Some erro­ neously refer to it as a “less severe” form of bipolar disorder, but that is a misnomer. BD II is characterized by multiple recurrent depressive epi­ sodes punctuated by infrequent hypomanic episodes. In one longitudinal study, the ratio of depressive to hypomanic episodes over time was 3:1 (Kupka et al. 2007). Thus, the BD II phenotype is dominated by depres­ sion, which, although less striking than mania, can be the more prob­ lematic pole of the disorder (Drancourt et al. 2013; Hlastala et al. 1997). Bipolar depression is notoriously difficult to treat and drives much of the morbidity and mortality associated with bipolar disorder (Kessler et al. 2006). BD II is also important because it is overlooked. Hypomania, the sine qua non of BD II, may be difficult to elicit from those who perceive these episodes as “positive,” leading to an overdiagnosis of major depres­ sive disorder (MDD). Many clinicians also do not recognize the energized depressions that occur in the context of depression with mixed symp­ toms. It takes, on average, 5 years for individuals to receive an accurate diagnosis of BD I, but over 10 years for those with BD II to receive an

A Neglected Condition

5

accurate diagnosis (Drancourt et al. 2013; Ghaemi et al. 2000). Thus, in­ dividuals with BD II often suffer for more than a decade with an inaccu­ rate diagnosis and inappropriate care.

Why Is Bipolar II Disorder Misunderstood and Overlooked? Bipolar disorders, including BD II, are characterized by fluctuating mood states. Descriptions of individuals who experience alternating periods of elevated and low moods have been documented since the Greco-Roman period (Jackson 1986). Modern conceptualizations of bipolar disorder, however, began in part with the German psychiatrist Emil Kraepelin in the early twentieth century (Goodwin and Jamison 2007). Kraepelin, working with European colleagues to catalog and classify abnormal hu­ man behavior, developed two categories to describe chronic psychotic disorders based on episodicity and course. Dementia praecox (later re­ named schizophrenia) was used to characterize nonepisodic psychotic disorders with a poor prognosis. Manic-depressive illness was defined as an episodic condition (i.e., characterized by discrete mood episodes followed by symptom-free intervals) with a comparatively benign prog­ nosis (relative to dementia praecox). The manic-depressive illness cate­ gory included those with recurrent mood episodes, be they manias or depressions. By the middle of the twentieth century, phenomenologists advanced the concept of a bipolar-unipolar dichotomy based on the presence or absence of a prior history of mania. Thus, individuals with recurrent de­ pressive episodes and at least one episode of mania were placed in the bi­ polar category; those with depression only (recurrent or not) were placed in the unipolar category (Leonhard 1979). In the United States, these con­ cepts were reified in the third edition of the Diagnostic and Statistical Man­ ual of Mental Disorders (DSM-III; American Psychiatric Association 1980). Thus, individuals with depression were diagnosed with either un­ ipolar disorder or bipolar affective disorder, depending on whether or not they had a prior episode of mania. In the 1960s, David Dunner became interested in patients who did not belong in either the unipolar or bipolar affective disorders category. Examining data from depressed patients who had been hospitalized at the National Institute of Mental Health, Dunner and colleagues identified

6

Bipolar II Disorder: Recognition, Understanding, and Treatment

“an interesting group of subjects who had been hospitalized for depres­ sion and who clearly had hypomanic but not manic episodes” (Dunner 2017, p. 520). He coined the term bipolar II disorder to describe these in­ dividuals’ illness. These individuals were distinct from those with BD I by virtue of never having had a manic episode, and distinct from those with unipolar disorder by virtue of having had at least one hypomanic episode. Patients with BD II were as likely as those with BD I and more likely than those with unipolar disorder to have relatives with histories of mania. These patients also had higher rates of suicide compared with the other groups (Dunner et al. 1976). Because of data showing differ­ ences from BD I in clinical features, family history, longitudinal illness course, and outcomes with pharmacology, BD II was officially recognized in 1994 as a distinct disorder in DSM-IV (American Psychiatric Associ­ ation 1994). The World Health Organization’s International Classifica­ tion of Disorders recognized BD II in its 10th and most recent revision (ICD-10), which was gradually released globally during the first decade of the twenty-first century. The phenomenology of bipolar disorder was first described in the fifth century B.C.E., but BD II was not formally recognized until 1994. Thus, for almost 2,500 years, BD II was subsumed under nonspecific categories such as manic-depressive illness, unipolar disorder, and bipolar affective disorder. Until Dunner and colleagues described evidence of biologic, ge­ netic, and clinical differences between BD I and II, little information was available about those with alternating depression and hypomania only. Without an operationalized diagnosis, research was not conducted on BD II treatments. Thus, it is not surprising that little was known about this population before 1994. But even once the diagnosis was formalized, the field of psychiatry has been slow to catch up. The admittedly subtle distinctions between mania and hypomania are confusing for clinicians and patients alike. Clinicians used to the framework of unipolar depres­ sion versus bipolar affective disorder are slow to adopt new concepts, such as an intermediary BD phenotype. Nuanced understanding of psy­ chopathology is needed to make a correct diagnosis of BD II. Research­ ers and pharmaceutical companies have been reluctant to wade into this “messy” disorder, limiting accumulation of new evidence about BD II. Thus, the halo of misunderstanding and misinformation about BD II per­ sists, even though BD II has been recognized as a distinct phenotypic en­ tity for a quarter century.

A Neglected Condition

7

How Is This Book Organized? This book is divided into four parts: recognition, understanding, treat­ ment, and special populations. Below we describe each of the four book parts, summarizing themes covered and pointing the reader to individ­ ual chapters on specific topics.

Part I: Recognition Part I grapples with the thorny issues of BD II diagnosis and comorbid­ ities. Diagnosis of BD II can be difficult and can be made even more complicated by the fact that psychiatric comorbidity is the rule rather than the exception. These factors have important implications for course and outcome. Part I focuses on differential diagnosis, medical and psychi­ atric comorbidities, and risk for suicide. Diagnosis of BD II is somewhat controversial. Conceptually, some authors favor a spectrum view of mood disorders, positioning BD I at one end of the continuum and MDD at the other end, with recurrent de­ pression plus any other feature of bipolarity (i.e., hypomania, family his­ tory of mania, antidepressant-induced mania, poor antidepressant response) in the middle (Ghaemi et al. 2002). This model invokes the conceptualization of Kraepelin, who identified mood episode recurrence (rather than mood episode type) as the most salient feature of these ill­ nesses. Others favor a categorical approach to diagnosis, identifying BD I, BD II, and MDD as distinct entities that are distinguished by presence or absence of mood episode types (mania, hypomania). This latter approach is used in clinical practice and is codified currently in DSM-5 (American Psychiatric Association 2013). Because DSM-5 provides a common lan­ guage for identifying patients and, more importantly, identifies groups that have well-characterized epidemiology, outcomes, and treatment re­ sponse, we use DSM-5 criteria in this book. We anticipate that with fur­ ther advances in understanding the biology of bipolar disorder, DSM will continue to evolve. Although the future is hard to predict, it seems un­ likely that the categories of BD I, BD II, and so forth will ever fully lose their utility. Differential diagnosis of BD II using DSM-5 criteria is a nontrivial matter. As previously discussed, hypomania may be underreported by patients, who do not perceive it to be a problem or simply do not rec­ ognize it as a distinct mood state, leading to an overdiagnosis of MDD. Hypomania can also be difficult to distinguish from mania, leading to

8

Bipolar II Disorder: Recognition, Understanding, and Treatment

potential misdiagnosis of BD II as BD I. Careful review of symptomatol­ ogy, illness course, family history, and treatment response is an impor­ tant part of the BD II diagnostic assessment. These issues are discussed in depth in Chapter 2, “Diagnosing Bipolar II Disorder.” Distinguishing BD II from borderline personality disorder (BPD) rep­ resents a different type of challenge (Zimmerman et al. 2013). As dis­ cussed in Chapter 3 (“Interface Between Borderline Personality Disorder and Bipolar II Disorder”), both disorders are characterized by mood instability, chronic illness course, suicide risk, irritability, lability, and interpersonal difficulties. Transient episodes of affective instability and emotional lability associated with BPD may be mistaken for hypomanic episodes. To make matters more complicated, these conditions often co­ occur; about 20% of individuals with BD II also have BPD (Zimmerman and Morgan 2013). Improved familiarity with diagnostic criteria and in­ creased understanding of the sources of diagnostic error can help improve diagnostic accuracy, ultimately leading to better ability to distinguish BPD from BD II. In addition to risk for BPD, individuals with BD II are at increased risk for multiple psychiatric comorbidities. Indeed, comorbidity is the rule rather than the exception in BD II. Almost all individuals with BD II have at least one psychiatric comorbidity, and over half have at least three (Merikangas et al. 2011). Anxiety disorders co-occur most com­ monly with BD II, followed by impulse-control disorders and substance use. Similarly, almost all individuals with BD II have at least one medical comorbidity, and about 40% have at least three (Sylvia et al. 2015). Both BD I and II are associated with elevated risk for cardiovascular disease and metabolic/endocrine disorders, with these comorbid condi­ tions occurring more frequently than in the general population. Although rates of cardiometabolic disorders are similar in BD I and BD II (Amann et al. 2017), individuals with BD II appear to be at greater risk for gastro­ intestinal disorders (Forty et al. 2014), perhaps related to dysfunction of the gut microbiota. Because most individuals with BD II experience many other illnesses in addition to their mood disorder, developing strategies to identify and address comorbidities is essential to the clinical management of BD II. Chapter 4 (“Psychiatric and Medical Comorbidities With Bipolar II Dis­ order”) describes psychiatric and medical comorbidities associated with BD II and proposes strategies to address them.

A Neglected Condition

9

Patients with BD II are also at increased risk for suicide attempts and completion. Risks for suicide attempts and completed suicide in BD II are at least comparable to those in BD I and are much higher than those in the general population (Novick et al. 2010). Chapter 5 (“Suicide and Bipolar II Disorder”) describes a framework for understanding risk and a clinical model for conducting a BD II–specific suicide risk assessment. The authors of this chapter underscore factors associated with increased risk in BD II and identify strategies to mitigate risk.

Part II: Understanding Part II focuses on the biologic determinants of BD II. A growing body of evidence suggests that the underlying biology of BD II is distinct from that of other mood disorders (BD I, MDD). The genetics of psychiatric disorders are complex and multifactorial, and BD II is no exception. Risk for psychiatric diseases, including BD II, appears to represent a mani­ festation of broad-based susceptibility coupled with environmental risk factors (Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium 2018). As reviewed in Chapter 6 (“Genetics of Bipolar II Disorder”), increased understanding of polygenic risk coupled with improved recognition of other determinants of dis­ ease will, it is hoped, improve specificity in disease prediction models in the future (Brainstorm Consortium et al. 2018). BD II is characterized by abnormalities in the neural systems that subsume reward and cognitive control of emotion regulation. Neuroim­ aging studies show similar alterations in brain regions responsible for reward anticipation, reward processing, and executive function in indi­ viduals with BD I and II in comparison to healthy control subjects (Phil­ lips and Swartz 2014). Some differences are noted between BD I and II, however. For instance, differences were found between BD I and II in the ventral striatum in response to reward anticipation, with BD II patients having significantly greater left putamen volume, which in turn correlated positively with left ventral striatal activity to reward (Caseras et al. 2013). As discussed in Chapter 7 (“Functional Brain Imaging and Neural De­ terminants in Bipolar II Disorder”), neuroimaging may play an increas­ ingly important role in the diagnosis and understanding of BD II as this research progresses.

10

Bipolar II Disorder: Recognition, Understanding, and Treatment

Part III: Treatment Part III focuses on how to better manage BD II. It provides an up-to-date review of medication options and psychosocial treatments for patients with BD II. Chapters 8, 9, and 10 summarize both what is known and what is not known about current treatments for BD II and point toward next steps needed to develop even better management strategies for BD II. For many years, individuals with BD II have been treated as if they have BD I, that is, with mood-stabilizing medications, including antipsy­ chotic medications, as the mainstay of treatment. What is the evidence supporting this approach? What is the role of medications such as lith­ ium, divalproex, lamotrigine, and carbamazepine in the management of BD II? What about the atypical antipsychotic medications? Chapter 8 (“Mood Stabilizers and Antipsychotic Medications in Bipolar II Disor­ der”) reviews evidence needed to answer these questions and provides clinical examples of how to use these medications for patients with BD II. Historically, antidepressant medication has been viewed with suspicion as a treatment for BD, including BD II. Recent data, however, show that antidepressant monotherapy may be superior to lithium as a treatment for BD II depression (Amsterdam et al. 2016). Chapter 9 (“Antidepressant Medications in Bipolar II Disorder”) reviews controversial evidence about antidepressant use (including as monotherapy) for BD II, weaving in clin­ ical examples. Psychosocial interventions play an important role in the management of BD II, both as medication augmentation strategies and, as supported by recent studies, as an alternative to medication (Swartz et al. 2018). Chapter 10 (“Psychosocial Interventions in Bipolar II Disorder”) reviews evidence-based psychosocial interventions for BD II, focusing on novel recent information showing that for some individuals with BD II, psy­ chotherapy alone may suffice. A case vignette describing treatment of BD II with interpersonal and social rhythm therapy (IPSRT; Swartz et al. 2012) is presented.

Part IV: Special Populations We recognize the irony in identifying women (who make up 50% of the population) and children and adolescents (who at one point in time are appropriate classifiers for 100% of the population) as “special” populations. We do not wish to imply that the material in Parts I through III does not apply to these large groups; rather, the intent of Part IV is to cover issues specific to these populations that were not discussed in earlier parts.

A Neglected Condition

11

Chapter 11 (“Bipolar II Disorder in Childhood and Adolescence”) brings us up to date on current thinking around the evolution of BD II from childhood through early adulthood. This chapter grapples with the challenges of diagnosing and managing BD II in youth. Mood insta­ bility, a defining feature of BD II, often begins in childhood. For some, the mood instability in childhood does not progress and thus perhaps represents a distinct phenotype from that seen in individuals at risk for BD II in adulthood. Because early presentations may not be the final state of illness, there may be discontinuities in diagnosis between child­ hood and adulthood. For instance, one longitudinal study of at-risk youth found that in approximately 25% of those with BD II, the disorder had converted to BD I by 4-year follow-up, and in 35% of youth with BD not otherwise specified (NOS), the illness had converted to BD II (Axel­ son et al. 2011). There are no randomized controlled trials of treatments for youth with BD II, but potential strategies for managing these chil­ dren and adolescents are discussed. Management of BD II in women during reproduction transitions poses special challenges. Women with BD II are more likely to experience men­ strual cycle–related mood worsening relative to those with BD I and MDD (Joffe et al. 2006) and, in pregnancy, are more likely than women with BD I to stop medication, experience episode recurrence, and have a depressive or mixed episode (versus a euphoric hypomanic episode) (Driscoll et al. 2017). Chapter 12 (“Reproductive-Age Women With Bi­ polar II Disorder”) discusses the challenges women with BD II face in the context of reproductive transitions such as pregnancy, childbirth, lac­ tation, and the menstrual cycle. Chapter 12 proposes a personalized decision-making framework to address the complexity of managing BD II during these epochs. Hormonal contraception is explored for stabili­ zation of mood symptoms across the menstrual cycle and in the context of potential drug-drug interactions when coadministered with moodstabilizing medication. Case material illustrates clinical decision-mak­ ing and management strategies.

Case Vignette Tina is a 30-year-old web designer. She supports herself performing odd web design jobs for small companies. She was admitted to inpatient psychiatric services following an ingestion of old prescription medica­ tions, deemed a suicide attempt by self-poisoning. She stated that the self­

12

Bipolar II Disorder: Recognition, Understanding, and Treatment poisoning was precipitated by growing frustration about her chronic low mood and belief that she was not “living up to [her] potential.” It fol­ lowed an altercation with her boyfriend. Tina reported that over the past 5 years, she had felt sad and irritable “most of the time.” She had also experienced low energy, increased sleep, suicidal thoughts, poor concentration, restlessness, loss of interest, and poor appetite. During these periods, which typically lasted 2–4 months, her work performance dropped and she lost clients because of irritability and delays in website construction. She also reported high levels of anx­ iety and worries about finances, her parents’ health, her relationship, and her web design business. Her mood would typically worsen during the week before her period, leading her to engage in self-injurious behaviors (cutting) in an attempt to alleviate these feelings. Tina had been followed by her primary care physician and was diag­ nosed with MDD; trials of several antidepressant medications, including bupropion 400 mg/day, fluoxetine 20 mg/day, and venlafaxine 225 mg/ day, were undertaken. None of these medications had been especially helpful. Frustrated by sexual side effects and lack of efficacy, Tina stopped all medications 6 months prior to her admission. Additional information was obtained about Tina’s history. In college, Tina was a computer science major who impressed her professors with her stellar coding skills and creative programming projects. She would have several weeklong periods when she worked especially hard on com­ plicated computer science projects, felt energetic, required little sleep (2–3 hours per night), and bragged to others about her outstanding skills and aptitude. She conceded that some thought she was arrogant, but she believed that her confidence was commensurate with her high perfor­ mance. She also admitted that over the past 5 years, she had experienced at least four episodes described as “a burst of energy” that lasted for about 1 week, during which she slept very little, worked feverishly on projects, and had lots of ideas about how to expand her business. During these ep­ isodes, she felt a return of her old self-confidence and enjoyed flirtatious interactions with a neighbor, even though she worried that her boyfriend might find out. Tina has a family history of depression, anxiety, and possible bipolar disorder. Her mother was treated in the past for depression with fluoxe­ tine. Her maternal grandmother was known for having mood swings and a “mean temper.” The grandmother died at age 63 from a heart at­ tack. Her younger sister is being treated with lorazepam for an unspec­ ified anxiety disorder. Tina’s history of recurrent depressive episodes alternating with epi­ sodes of hypomania suggests a diagnosis of BD II. Additional factors sup­ port this diagnosis. A family history of depression is very common in BD II. In addition, there is a probable family history of bipolar disorder

A Neglected Condition

13

(unconfirmed) in her maternal grandmother, which should raise suspi­ cion for a bipolar diagnosis. Late-luteal-phase worsening of mood symp­ toms is also consistent with BD II. BPD should be included in the dif­ ferential diagnosis because of the history of self-injurious behaviors and a suicide attempt occurring in an interpersonal context; however, other symptoms of BPD, such as a pattern of unstable and intense interper­ sonal relationships, efforts to avoid abandonment, identity disturbance, and chronic feelings of emptiness, were not endorsed. In addition, Tina’s mood was chronically low (except during periods of hypomania), and she did not show evidence of affective instability. This makes a diagno­ sis of BPD less likely. Comorbid generalized anxiety disorder is highly likely, given a pervasive pattern of excessive worry accompanied by phys­ ical symptoms (which could also be caused by BD II) such as irritability, restlessness, and poor concentration. The psychiatrist formally makes a diagnosis of BD II. She recom­ mends to Tina a trial of quetiapine, given the data supporting its effi­ cacy in BD II depression. She explains that this medication would also be helpful for her secondary diagnosis, generalized anxiety disorder. She also recommends a course of IPSRT to address the psychosocial de­ terminants of her illness. Tina agrees.

Conclusion It is our hope that reading this book will facilitate an appreciation for the complexity of BD II. By the end of the book, readers will be able to rec­ ognize Tina’s story as a “classic” depiction of BD II. For instance, the disorder usually begins well before it is recognized. Tina likely began ex­ periencing hypomanic symptoms in college, but the correct diagnosis was not made until over 10 years later, when she was 30 years old,. It is always important to ask about prior history of hypomania, because many patients do not offer this information spontaneously (see Chapter 2). During the intervening years, Tina had trials of several antidepressant medications, none of which worked. Nonresponse to antidepressant medication should always raise the question of bipolarity (Chapter 2). BPD was considered as an alternative explanation for Tina’s presentation. Although it was ruled out, the BPD–BD II differential is a common co­ nundrum (see Chapter 3). Tina also has an anxiety disorder, a frequent cotraveler with BD II (see Chapter 4). Risk for suicide is elevated, espe­ cially during the depressive phase (see Chapter 5). Tina’s grandmother likely had bipolar disorder, and her mother had depression. Although we do not know the specific gene or sets of genes that cause BD II, it is a

14

Bipolar II Disorder: Recognition, Understanding, and Treatment

heritable disorder (Chapter 6). Tina’s mood worsened in the late luteal phase of menses. Women with BD II have the added challenge of mood worsening related to hormonal changes, such as those that occur during the menstrual cycle and pregnancy (see Chapter 12). The psychiatrist recommended that Tina start taking quetiapine and also participate in IPSRT. Treatments for BD II include atypical antipsychotics, moodstabilizing medication (see Chapter 8), antidepressant medications (see Chapter 9), and psychotherapy (see Chapter 10). This book integrates state-of-the art information from well-established bipolar disorders researchers with practical information from clinical ex­ perts to provide a comprehensive overview of BD II. By the end of the book, readers will be better equipped to recognize BD II in patients like Tina, will be familiar with the genetics of and neurocircuitry underlying BD II, will understand the evidence supporting BD II treatments, and will recognize the many areas where more information is needed. This book is not an end but a beginning; it starts us on a path that someday may reduce or even prevent the suffering caused by BD II in individuals like Tina.

KEY POINTS • Bipolar II disorder (BD II) is characterized by recurrent depressive episodes, punctuated by less frequent hypomanic episodes. • BD II is a common disorder, affecting approximately 0.4% of the population. • Levels of impairment and risk for suicide are comparable in bipolar I disorder and BD II. • It takes, on average, 10 years for BD II to be diagnosed, despite the presence of debilitating symptoms. • BD II was formally recognized in 1994 as a distinct diagnostic category.

References Amann BL, Radua J, Wunsch C, et al: Psychiatric and physical comorbidities and their impact on the course of bipolar disorder: a prospective, naturalistic 4-year follow-up study. Bipolar Disord 19(3):225–234, 2017 28544558 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Publishing, 1980

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American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA, American Psychiatric Publishing, 2013 Amsterdam JD, Lorenzo-Luaces L, Soeller I, et al: Short-term venlafaxine v. lithium monotherapy for bipolar type II major depressive episodes: effectiveness and mood conversion rate. Br J Psychiatry 208(4):359–365, 2016 26892848 Axelson DA, Birmaher B, Strober MA, et al: Course of subthreshold bipolar disorder in youth: diagnostic progression from bipolar disorder not otherwise specified. J Am Acad Child Adolesc Psychiatry 50(10):1001.e3–1116.e3, 2011 21961775 Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium: Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell 173(7):1705.e16–1715.e16, 2018 29906468 Brainstorm Consortium; Anttila V, Bulik-Sullivan B, et al: Analysis of shared heritability in common disorders of the brain. Science 360(6395), 2018 29930110 Caseras X, Lawrence NS, Murphy K, et al: Ventral striatum activity in response to reward: differences between bipolar I and II disorders. Am J Psychiatry 170(5):533– 541, 2013 23558337 Dilsaver SL: An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. J Affect Disord 129 (1–3):79–83, 2011 20888048 Drancourt N, Etain B, Lajnef M, et al: Duration of untreated bipolar disorder: missed opportunities on the long road to optimal treatment. Acta Psychiatr Scand 127(2):136–144, 2013 22901015 Driscoll KE, Sit DK, Moses-Kolko EL, et al: Mood symptoms in pregnant and postpartum women with bipolar disorder: a naturalistic study. Bipolar Disord 19(4):295–304, 2017 28665044 Dunner DL: Bipolar II disorder. Bipolar Disord 19(7):520–521, 2017 29205722 Dunner DL, Gershon ES, Goodwin FK: Heritable factors in the severity of affective illness. Biol Psychiatry 11(1):31–42, 1976 1260075 Forte A, Baldessarini RJ, Tondo L, et al: Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders. J Affect Disord 178:71–78, 2015 25797049 Forty L, Ulanova A, Jones L, et al: Comorbid medical illness in bipolar disorder. Br J Psychiatry 205(6):465–472, 2014 25359927 Ghaemi SN, Boiman EE, Goodwin FK: Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry 61(10):804–808, quiz 809, 2000 11078046 Ghaemi SN, Ko JY, Goodwin FK: “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 47(2):125–134, 2002 11926074 Goodwin FK, Jamison KR: Manic-Depressive Illness. New York, Oxford University Press, 2007 Hlastala SA, Frank E, Mallinger AG, et al: Bipolar depression: an underestimated treatment challenge. Depress Anxiety 5(2):73–83, 1997 9262937 Jackson SW: Melancholia and Depression: From Hippocratic Times to Modern Times. New Haven, CT, Yale University Press, 1986 Joffe H, Kim DR, Foris JM, et al: Menstrual dysfunction prior to onset of psychiatric illness is reported more commonly by women with bipolar disorder than by women with unipolar depression and healthy controls. J Clin Psychiatry 67(2):297–304, 2006 16566627

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Bipolar II Disorder: Recognition, Understanding, and Treatment

Kessler RC, Akiskal HS, Ames M, et al: Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. Am J Psychiatry 163(9):1561–1568, 2006 16946181 Kupka RW, Altshuler LL, Nolen WA, et al: Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord 9(5):531–535, 2007 17680925 Leonhard K: The Classification of Endogenous Psychoses. New York, Irvington Publish­ ers, 1979 MacQueen GM, Young LT: Bipolar II disorder: symptoms, course, and response to treatment. Psychiatr Serv 52(3):358–361, 2001 11239105 Merikangas KR, Jin R, He J-P, et al: Prevalence and correlates of bipolar spectrum disor­ der in the world mental health survey initiative. Arch Gen Psychiatry 68(3):241–251, 2011 21383262 Novick DM, Swartz HA, Frank E: Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord 12(1):1–9, 2010 20148862 Phillips ML, Swartz HA: A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry 171(8):829–843, 2014 24626773 Regier DA, Narrow WE, Clarke DE, et al: DSM-5 field trials in the United States and Canada, part II: test-retest reliability of selected categorical diagnoses. Am J Psychiatry 170(1):59–70, 2013 23111466 Rosa AR, Bonnín CM, Vázquez GH, et al: Functional impairment in bipolar II disorder: is it as disabling as bipolar I? J Affect Disord 127(1–3):71–76, 2010 20538343 Ruggero CJ, Chelminski I, Young D, et al: Psychosocial impairment associated with bipolar II disorder. J Affect Disord 104(1–3):53–60, 2007 17337067 Swartz HA, Levenson JC, Frank E: Psychotherapy for bipolar II disorder: the role of interpersonal and social rhythm therapy. Prof Psychol Res Pr 43(2):145–153, 2012 26612968 Swartz HA, Rucci P, Thase ME, et al: Psychotherapy alone and combined with medica­ tion as treatments for bipolar II depression: a randomized controlled trial. J Clin Psy­ chiatry 79(2):16m11027, 2018 28703949 Sylvia LG, Shelton RC, Kemp DE, et al: Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE). Bipolar Disord 17(2):212–223, 2015 25130321 Torrent C, Martínez-Arán A, Daban C, et al: Cognitive impairment in bipolar II disorder. Br J Psychiatry 189:254–259, 2006 16946361 Zimmerman M, Morgan TA: The relationship between borderline personality disorder and bipolar disorder. Dialogues Clin Neurosci 15(2):155–169, 2013 24174890 Zimmerman M, Martinez JH, Morgan TA, et al: Distinguishing bipolar II depression from major depressive disorder with comorbid borderline personality disorder: demographic, clinical, and family history differences. J Clin Psychiatry 74(9):880– 886, 2013 24107761

2 Diagnosing Bipolar II Disorder Nicole Kramer, M.A., M.S. Trisha Suppes, M.D., Ph.D.

A

lternating states of mania and melancholia are among the earliest described human diseases, first noted by ancient Greek physi­ cians, philosophers, and poets (Angst and Marneros 2001). Hippocrates (460–337 B.C.E.), who formulated the first known classification of men­ tal disorders, systematically described bipolar mood states—namely, melancholia, mania, and paranoia. More than two millennia later, Emil Kraepelin, recognized as one of the founders of modern psychiatry, viewed manic-depressive illness as a unitary concept. Since then, a range of pre­ sentations of bipolar disorder (BD) have been observed, which led to the concept of a bipolar spectrum that encompasses different clinical presen­ tations (Benazzi and Akiskal 2008). Today the term bipolar spectrum has two, complementary meanings: a spectrum of severity across BD symp­ toms and a combination of mood states comprising manic/hypomanic and depressive components (Angst 2007). Both of these concepts reflect a more dimensional view of mood disorders compared with the older categorical approaches. Ongoing deliberations about diagnostic bound­ aries inform research and clinical discussions about BD II. Bipolar II disorder (BD II) is a mood disorder that is characterized by cycles of major depressive and hypomanic episodes. First accepted for 17

18

Bipolar II Disorder: Recognition, Understanding, and Treatment

inclusion in DSM-IV in 1994 (American Psychiatric Association 1994), BD II is a clinically heterogeneous condition (Hozer and Houenou 2016) that may result in diagnostic uncertainty, although it appears to be a reli­ able and consistent diagnosis when made by experienced clinicians (Simpson et al. 2002). BD II is often conceptualized as a less severe bipolar spectrum disorder relative to bipolar I disorder (BD I) absent the latter’s characteristic manic episodes. However, evidence suggests that both pre­ sentations have similar impacts on quality of life, functioning, and risk of suicide (Judd et al. 2003; Novick et al. 2010). BD II is defined by at least one hypomanic episode and one major de­ pressive episode. It can be difficult to diagnose, however, for several rea­ sons. First, the diagnostic criteria for a depressive episode associated with BD II are identical to those for a depressive episode associated with major depressive disorder (MDD), which makes them cross-sectionally indistinguishable. Second, hypomania, which is by definition a less severe form of mania, may be difficult for patients to distinguish from a “nor­ mal” mood state accompanied by extra energy and happiness or excite­ ment. Third, mixed mood states are very common in BD II. Hypomanic episodes with mixed depression symptoms or an energized depression are complex mood states that are easily missed by patients and clinicians alike. Finally, in comparison to BD I, BD II can be difficult to diagnose be­ cause of the lack of a defining event, such as a manic episode. Despite the challenges associated with recognizing BD II, the diagnos­ tic construct fared relatively well in DSM field trials. When the DSM-5 criteria were tested before adoption, BD I disorder was one of the most recognizable psychiatric illnesses, whereas BD II was somewhat less recognizable, but its reliability was considered to be in the good range. Notably, the reliability of BD II was higher than that of MDD, which fell in the “questionable” range for ability of the interviewer to recognize and correctly diagnose with DSM-5 criteria (Regier et al. 2013). Research suggests misdiagnosis of BD II can be due to both over- and underdiagnosis (Phelps and Ghaemi 2012; Zimmerman et al. 2008), but it is widely accepted that more accurate and timely diagnosis of BD II is needed. This chapter aims to improve readers’ BD II diagnostic acumen by examining key diagnostic factors, features, and fumbling points. In this chapter we review diagnostic criteria for BD II, changes made to BD II criteria during the transition from DSM-IV to DSM-5, and pertinent new specifiers critical to understanding the range of BD II presentations.

Diagnosing Bipolar II Disorder

19

We also discuss common pitfalls in making a differential diagnosis of BD II, including ruling out other mood disorders and identifying pre­ sentations of BD II with commonly occurring conditions such as anxiety, substance use, and personality disorders. Course modifiers, including rapid cycling, are reviewed as well. A case vignette illustrates some of the key points of the chapter.

Diagnosis of Bipolar II Disorder A diagnosis of BD II requires an individual to have experienced at least one hypomanic episode and one depressive episode within the lifetime course of illness (Box 2–1). Criteria for each episode type are summarized in Table 2–1. Box 2–1.

DSM-5 diagnostic criteria for bipolar II disorder

For a diagnosis of bipolar II disorder, it is necessary to meet the following criteria for a current or past hypomanic episode and the following criteria for a current or past major depressive episode:

Hypomanic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or en­ ergy, lasting at least 4 consecutive days and present most of the day, nearly every day. B. During the period of mood disturbance and increased energy and activity, three (or more) of the following symptoms have persisted (four if the mood is only irritable), represent a noticeable change from usual behavior, and have been present to a significant degree: 1. Inflated self-esteem or grandiosity. 2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 3. More talkative than usual or pressure to keep talking. 4. Flight of ideas or subjective experience that thoughts are racing. 5. Distractibility (i.e., attention too easily drawn to unimportant or irrel­ evant external stimuli), as reported or observed. 6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation. 7. Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments).

20

Bipolar II Disorder: Recognition, Understanding, and Treatment

C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization. If there are psy­ chotic features, the episode is, by definition, manic. F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, other treatment) or another medical condition. Note: A full hypomanic episode that emerges during antidepressant treat­ ment (e.g., medication, electroconvulsive therapy) but persists at a fully syn­ dromal level beyond the physiological effect of that treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is indicated so that one or two symptoms (particularly increased irritability, edginess, or agitation following antidepressant use) are not taken as sufficient for diagno­ sis of a hypomanic episode, nor necessarily indicative of a bipolar diathesis.

Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to a medical condition. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, or hopeless) or ob­ servation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2. Markedly diminished interest or pleasure in all, or almost all, activi­ ties most of the day, nearly every day (as indicated by either subjec­ tive account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others; not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).

Diagnosing Bipolar II Disorder

21

8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, a suicide attempt, or a specific plan for committing suicide. B. The symptoms cause clinically significant distress or impairment in so­ cial, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a sub­ stance or another medical condition. Note: Criteria A–C above constitute a major depressive episode. Note: Responses to a significant loss (e.g., bereavement, financial ruin, loss­ es from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor ap­ petite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered ap­ propriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should be carefully considered. This decision inevitably requires the exercise of clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the context of loss.1

Bipolar II Disorder A. Criteria have been met for at least one hypomanic episode (Criteria A– F under “Hypomanic Episode” above) and at least one major depressive episode (Criteria A–C under “Major Depressive Episode” above).

1In

distinguishing grief from a major depressive episode (MDE), it is useful to con­ sider that in grief the predominant affect is feelings of emptiness and loss, while in an MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These waves tend to be associated with thoughts or reminders of the deceased. The depressed mood of an MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of grief may be accompanied by positive emotions and humor that are uncharacteristic of the per­ vasive unhappiness and misery characteristic of an MDE. The thought content associ­ ated with grief generally features a preoccupation with thoughts and memories of the deceased, rather than the self-critical or pessimistic ruminations seen in an MDE. In grief, self-esteem is generally preserved, whereas in an MDE feelings of worthlessness and self-loathing are common. If self-derogatory ideation is present in grief, it typically involves perceived failings vis-à-vis the deceased (e.g., not visiting frequently enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks about death and dying, such thoughts are generally focused on the deceased and possibly about “joining” the deceased, whereas in an MDE such thoughts are focused on ending one’s own life because of feeling worthless, undeserving of life, or unable to cope with the pain of depression.

22

Bipolar II Disorder: Recognition, Understanding, and Treatment

B. There has never been a manic episode. C. The occurrence of the hypomanic episode(s) and major depressive ep­ isode(s) is not better explained by schizoaffective disorder, schizophre­ nia, schizophreniform disorder, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder. D. The symptoms of depression or the unpredictability caused by frequent alternation between periods of depression and hypomania causes clini­ cally significant distress or impairment in social, occupational, or other important areas of functioning. Coding and Recording Procedures Bipolar II disorder has one diagnostic code: 296.89 (F31.81). Its status with respect to current severity, presence of psychotic features, course, and other specifiers cannot be coded but should be indicated in writing (e.g., 296.89 [F31.81] bipolar II disorder, current episode depressed, moderate severity, with mixed features; 296.89 [F31.81] bipolar II disorder, most re­ cent episode depressed, in partial remission). Specify current or most recent episode: Hypomanic

Depressed

Specify if: With anxious distress With mixed features With rapid cycling With melancholic features With atypical features With mood-congruent psychotic features With mood-incongruent psychotic features With catatonia. Coding note: Use additional code 293.89 (F06.1). With peripartum onset With seasonal pattern Specify course if full criteria for a mood episode are not currently met: In partial remission

In full remission

Specify severity if full criteria for a major depressive episode are currently met: Mild

Moderate

Severe

Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Arlington, VA, American Psychiatric Association, 2013. Copyright © 2013 American Psychiatric Association. Used with permission.

aRequired for diagnosis. bOne or both required for diagnosis. Source. Adapted from American Psychiatric Association 2013.

Criterion A: Depressed moodb Loss of interest in activities or pleasureb

Criterion A: Distinct period of abnormally and persistently elevated, expansive, or irritable mooda Increased activity or energya Criterion B: Pressured speech Increased self-esteem or grandiosity Excessive involvement in activities with a high potential for painful consequences Distractibility Increased goal-directed activities Racing thoughts or flight of ideas Decreased need for sleep Depression Number of Criterion B ≥5 symptomsa Durationa 2+weeks Causes significant distress or Functioninga impairment in functioning Mania ≥3

7+days or hospitalization Disrupts social and occupa­ tional functioning or hospitalization or psychotic features

Hypomania ≥3 4+days Not severe enough to disrupt functioning or require hospitalization

Criterion B: Decreased movement Decreased energy or increased fatigue Feelings of guilt or worthlessness Suicidality Lack of concentration; indecisiveness Sleep disturbance: insomnia, hypersomnia Change in appetite or weight (3 >3

Manic with mixed features

Mixed

Depressed mood or loss of interest >3 >5

Depressive with mixed features

Elevated mood + depressed mood or loss of interest >3 >5

Conceptualization of pure and mixed states in DSM-IV and DSM-5.

Core Elevated mood symptoms + energy >3 Manic Depressive 3 3 >5

Depressive

Depressive

Depressed mood or loss of interest >3 >5

Diagnosing Bipolar II Disorder 29

30

Bipolar II Disorder: Recognition, Understanding, and Treatment

TABLE 2–2.

Mixed features specifiers

Hypomania with mixed features specifier

Depression with mixed features specifier

Meets criteria for hypomanic episode plus 3 of the following symptoms present for most days: • Dysphoric or depressed mood • Diminished interest or pleasure • Worthlessness or inappropriate guilt • Psychomotor retardation • Fatigue or loss of energy • Thoughts of death

Meets criteria for depressive episodeplus 3 of the following symptoms present most days: • Elevated or expansive mood • Increased goal-directed activity • Inflated self-esteem • Increased energy • Decreased need for sleep • Risky behavior

depressive episode with mixed features, it is important to first establish whether the dominant mood state in the episode is hypomania or depres­ sion. To distinguish BD II depression from MDD with mixed features, a history of a hypomanic episode is necessary. As with BD II more broadly, once a hypomanic episode has been diagnosed, the patient no longer qualifies for an MDD diagnosis and criteria have been met for BD II. If there is a history of hypomania or hypomania is the dominant mood state, and the individual is experiencing co-occurring mixed symptoms, hypomania with a mixed features specifier would be applied. Differentiating a MDD episode with mixed features from a BD II depressive episode with mixed features requires a thorough history of the patient’s other symp­ toms and past episodes in order to confirm the diagnosis. Ample evidence suggests that episodes with mixed features represent a common (Miller et al. 2016b) and yet potentially more severe clinical presentation associated with adverse health outcomes and suicidality (Balázs et al. 2006). In a sample of more than 900 patients followed nat­ uralistically across more than 14,000 visits, Miller et al. (2016b) found that approximately 64% of patients with BD I or BD II experienced at least one visit with mixed depression, defined broadly as the presence of subthreshold hypomania concurrent with at least mild depression. Bi­ polar subtype (e.g., I or II) did not predict the likelihood of subthreshold hypomania during visits with depression, which may further complicate the clinical presentation and, necessarily, the diagnosis. Although most

31

Diagnosing Bipolar II Disorder

TABLE 2–3.

Symptoms excluded from mixed features specifier diagnosis

Depressive episode symptoms excludeda

Hypomanic episode symptoms excluded

• Diminished ability to think/concentrate • Irritability • Loss or gain of body weight • Distractibility • Insomnia or hypersomniab • Psychomotor agitationa aPsychomotor bNeeding

retardation is not excluded.

less sleep is not excluded.

patients with BD II will experience some degree of mixed symptoms, women may be more prone than men to mixed symptoms (Miller et al. 2016b; Suppes et al. 2005). In general, these episodes may be associated with worse treatment outcomes, higher suicide rates, and considerably higher rates of psychiatric and medical comorbidities (Angst et al. 2012; Betzler et al. 2017; Suppes et al. 2005).

Rapid Cycling and Other Course Modifiers Rapid cycling is more prevalent with BD II than with other bipolar disor­ ders, particularly among women (Kupka et al. 2003). Rapid cycling is specified in BD II when the patient has had at least four mood episodes in the previous 12 months that meet diagnostic criteria for depressive or hypomanic episodes. It is also common for rapid-cycling patients to have labile emotions during nondistinct mood episodes. Rapid cycling often reflects a worsening of the underlying disorder and potentially an end-stage of the illness, because cycles may get closer together over time (Carvalho et al. 2014). In some cases, there is ultrarapid cycling, which is defined by cycles that last less than 24 hours. In these cases, switches typically occur between morning and evening (Carvalho et al. 2014). Rapid-cycling BD II is viewed as a more treatment-resistant variant of the illness that may lead to significant clinical deterioration, including increased risk for suicidality. Case Vignette Anita is a 35-year-old woman with a history of at least three depressive episodes, as well as lingering depressive symptoms severe enough to

32

Bipolar II Disorder: Recognition, Understanding, and Treatment impact her life at home with her partner and her life at work with her colleagues. She has a tendency to isolate herself from others and avoid social interactions when feeling low. She has a past history of a hypomanic episode in her early 20s unrelated to substance use, which was followed by a depression. During this hypomanic period, lasting about 6 days, friends noticed that she seemed different from her usual self. Anita ini­ tially enjoyed feeling much more productive in her work, needing less sleep, having extra energy, and starting new projects. Toward the end of this period of decreased need for sleep and heightened productivity, Anita started going out more often than usual and drinking more alcohol than was customary for her. After this hypomanic period, she experi­ enced a severe depressive period lasting almost 2 months. Since then she has experienced periods of mood instability when she might have 2 or 3 days of symptoms similar to the hypomania (increased energy, risky behavior, inflated self-esteem) accompanied by ongoing depressive symptoms (increased appetite, low interest, irritability, hypersomnia, poor concentration, suicidal thoughts). There have been no other episodes of hypomania lasting 4 or more days. There is no history of mania or psy­ chosis. She rarely drinks alcohol, and typically only in small amounts, because drinking tends to make her more depressed and anxious later. She uses no other substances and limits her caffeine use because this also leads to an increase in anxiety. She has a history of symptoms that meet criteria for general anxiety disorder, but no history of panic attacks. She finds the anxiety returns if she drinks too much caffeine or does not exercise regularly.

Anita would be diagnosed with BD II because criteria for at least one major depressive episode lasting at least 2 weeks and one hypomanic ep­ isode lasting 4 or more days have been met. Her functioning was im­ paired during her depressive episode, but not in her hypomanic period. Yet, her hypomanic presentation reflected an unequivocal change in functioning that was noted by others and not caused by substance use or a medical etiology. Her current episode would be characterized as a ma­ jor depressive episode with mixed features because, in addition to the symptoms of depression, she experiences some concurrent symptoms of hypomania. This is very common for individuals with BD II. Anita also has anxiety symptoms, which may be prodromal for an anxiety disorder or may be part of the BD II illness. Interestingly, most individuals with BD II experience some anxiety symptoms over the course of illness. If her clinical assessment had focused only on her current depressive epi­ sode, key information about her past hypomanic episode would possibly have been missed because it is unlikely that she would have “complained”

Diagnosing Bipolar II Disorder

33

about her prior episode of elevated mood. It is important to educate pa­ tients about hypomanic symptoms, since some patients experience them as ego-syntonic, particularly when the symptoms represent a break from the dysphoria of depressive states, although the majority of hypomanic periods are as likely to be mixed as to be euphoric or irritable only (Sup­ pes et al. 2005).

Differential Diagnosis in Bipolar II Disorder Diagnosing BD II can be challenging because of the subtleties of this disorder’s hypomanic symptoms. Patients with BD II and subsyndromal hypomania may be at particular risk of misdiagnosis because symptoms may not be associated with stress or suffering, may not be noticed as problematic by the patient or family members, or may be misattributed to personality features (Nusslock and Frank 2011). More recent studies suggest that the lag in diagnosing BD II is worse than the lag in diag­ nosing BD I, with the average period between onset of BD II until the beginning of treatment found to be a decade or more (Drancourt et al. 2013). Patients in hypomanic episodes may underreport hypomanic symp­ toms, both because many patients may be unable to recognize their own hypomanic symptoms (Regeer et al. 2015) and because the symptoms may be ego-syntonic for some individuals with BD II, particularly in contrast to those of impairing depressive episodes (Keck et al. 2008; Nus­ slock and Frank 2011). BD II depressive episodes are associated with more severe distress and last more than twice as long as hypomanic ep­ isodes (Bschor et al. 2012; Judd and Akiskal 2003; Kupka et al. 2007). Hypomanic symptoms may, in contrast, be perceived as pleasant by some patients, particularly among those who experience elevated mood as a welcome relief from the intractable low mood and hopelessness of their depressive episodes. In one qualitative study of bipolar patients’ symptomatology, patients described their “hypomanic self” as a desir­ able, idealized self that contrasted with their “normal” or “real” self that was generally perceived as shy, lacking self-esteem and confidence, and more associated with depressive symptomatology (Fletcher et al. 2013). In contrast to pure hypomania, in a majority of cases, patients experi­ encing hypomania with mixed features of depression, often described as an “energized depression,” are likely to be rather uncomfortable (Gold­ berg et al. 2009; Miller et al. 2016b).

34

Bipolar II Disorder: Recognition, Understanding, and Treatment

Clinical interviews are a vitally important tool in diagnosing hypomanic episodes and BD II. Differential diagnosis requires pairing clini­ cal interviewing with patient psychoeducation so that individuals can understand that periods of hypomania are part of BD II illness and that the potentially pleasurable periods of increased energy may in fact be hy­ pomanic symptoms that could lead to further destabilization and impair­ ment over time. It is important to conduct a thorough history of mood symptoms by using easy-to-understand language while listening for cul­ tural differences in meaning of illness that could impact patient reporting of symptoms in Western medical terms. Because of the high genetic her­ itability of BDs (see Chapter 6, “Genetics of Bipolar II Disorder”), probing for a family history of bipolar and depressive disorders can meaningfully contribute to the diagnostic picture. BD II is a lifelong illness that impacts all aspects of a patient’s life, in­ cluding family relationships, social functioning, work productivity, and overall longevity. Because depression is the predominant mood episode type for BD II and patients most commonly seek medical attention when depressed, clinicians must look beyond the current depressive episode in order to arrive at the correct diagnosis. When a patient presents with de­ pressive symptoms, diagnoses that must be entertained include BD II, MDD, BD I, cyclothymia, and other bipolar and related disorders, which include conditions arising from substances or medications or another medical condition, other specified bipolar and related disorder, personality disorders, and conditions for further study. Below we discuss clues that can be used to distinguish BD II from other, overlapping psychiatric disorders.

Differential Diagnosis With Major Depressive Disorder Depressive symptoms dominate the longitudinal course of BDs (Kupka et al. 2007). As a result, many individuals with BD II are misdiagnosed as having unipolar rather than bipolar depression. Reanalyses of large epidemiological studies demonstrated that MDD is clearly heteroge­ neous and includes about 20%–40% of hidden BDs depending on the definition of hypomania (Angst 2013). A prospective cohort study found that in one-fifth of patients diagnosed with MDD, the depressive dis­ order progressed to BD, with a cumulative probability of one-quarter in survival analyses (Fiedorowicz et al. 2011). Although their symptom constellations and patterns are different, di­ agnostic criteria for a major depressive episode are identical for the two

Diagnosing Bipolar II Disorder

35

disorders, making it difficult to differentiate unipolar from bipolar de­ pression solely on the basis of the clinical picture during an acute de­ pressive episode. Most BD II patients first seek treatment for depression, increasing the likelihood of an inaccurate diagnosis of unipolar depres­ sion (Nusslock and Frank 2011). Furthermore, at the early stages of ill­ ness, there is usually little information available about the patient’s course of illness over time or the presence of prior hypomanic episodes that would point to a BD II diagnosis (Hantouche and Akiskal 2005). Time and careful observation are needed to differentiate BD II from MDD. Diagnosing BD II often requires looking beyond formal criteria. Empir­ ically based clinical hints can help guide differentiation between BD II and MDD. For example, BD II typically has a younger age at onset than MDD and is marked by higher rates of trait mood lability (Akiskal and Benazzi 2005). Family history also plays an important diagnostic role, given that family, twin, and adoption-based studies have found heritabil­ ity rates of 63%–79% in BD (Smoller and Finn 2003). In light of its high heritability, BD II diagnosis should rarely proceed without a thorough clinical interview with the patient or family members about any known family mental health history, including instances of bipolar spectrum disorders, problematic substance use, and possible untreated BD. It is also important to consider cultural factors and perceived stigma that may impact patient and family willingness to disclose mental health informa­ tion (Clement et al. 2015). Ethnicity, specifically, has been found to have a differential impact on attitudes and stigma associated with seeking men­ tal health services (Turner et al. 2015). Building a strong therapeutic al­ liance, providing accessible patient education about BD II, and leaving space in the clinical encounter for patients to ask questions or try to inte­ grate past experiences with an education of what constitutes hypomania are critical for diagnosing BD II.

Differential Diagnosis With Bipolar I Disorder BD I is the modern derivative of manic-depressive illness, and mania is its defining feature. The classic features of a manic episode include per­ sistently elevated, expansive, or irritable mood and abnormally and per­ sistently increased activity or energy lasting a period of at least 1 week (Table 2–1). There is no requirement for the patient to have experienced a major depressive episode or psychosis for diagnostic criteria for BD I to be met, but most individuals with BD I will experience one or more

36

Bipolar II Disorder: Recognition, Understanding, and Treatment

major depressive episodes over the lifetime course of their illness. These symptoms must cause marked impairment in functioning and/or re­ quire hospitalization. The primary characteristic separating BD II from BD I is absence of mania. Hypomania must be present in BD II but may also be present in BD I. How is mania distinguished from hypomania? The minimum duration for hypomania is 4 days, whereas a manic episode must last for at least 1 week. However, this distinction is not only one of duration. In mania’s most classic presentations, an episode is marked by euphoria, changed behavior from one’s normal baseline, grandiosity, pressured speech, a lack of sleep without loss of energy, and impulsive decision making with significant consequences. When a patient’s experience is less clearly manic, it is important to consider Criterion C under the DSM-5 mania diagnostic category (American Psychiatric Association 2013), which states that the symptoms (in Criteria A and B) must be severe enough to cause “marked impairment in social or occupational functioning or to ne­ cessitate hospitalization” (p. 124). In contrast, the criteria for a DSM-5­ defined hypomanic episode require that the episode be associated with “unequivocal change in functioning” that is observable by others but does not cause marked impairment (American Psychiatric Association 2013, p. 125). The presence of any psychotic symptoms during hypomania immediately changes the diagnosis to mania and thus a BD I diagnosis. Although these differences may seem clear in principle, in practice they may be hard to discern. There are many gradations between these two states. The difference between mania and hypomania is perhaps best clarified by examining the consequences of the person’s actions to assess severity and impairment caused by the episode, with less severe consequences more typically associated with BD II. In particular, examining the impact of actions taken and decisions made during episodes can differentiate ma­ nia from hypomania. Two patients’ impulsive spending habits elucidate the differences between a hypomanic and manic episode. One patient who recently completed graduate school and lived on a limited budget re­ ported buying several rounds of drinks for friends during an evening of celebrating. Although this put a strain on her budget and was uncharac­ teristic for her, it did not result in dire financial problems such as inability to pay rent or make credit card payments. In contrast, a 65-year-old patient drained his 401(k) account to pay for a lavish weekend in Las Vegas that

Diagnosing Bipolar II Disorder

37

he could not afford. Because of this behavior, his financial security in re­ tirement was jeopardized. The first patient’s spending spree, although beyond her means, was not associated with significant consequences and was consistent with hypomania. The second patient incurred sig­ nificant problems as a result of his impulsive spending, a feature that is consistent with mania. Additionally, it is important to recognize that sui­ cidal actions cannot be used to distinguish mania from hypomania (see below). Several demographic and clinical factors have been examined in an effort to better identify those at risk of BD I and BD II, with limited utility. A systematic review of literature found that age at onset may not reliably differentiate BD I from BD II patients (Dell’Osso et al. 2016). A meta­ analysis of suicide behaviors in BD I and BD II found no differences be­ tween these two bipolar subtypes on rate of suicide attempts (Novick et al. 2010). Compared with BD I, BD II is characterized by a higher num­ ber and frequency, greater severity, and longer duration of depressive episodes, and shorter euthymic periods (Judd et al. 2003), as well as more frequent rapid cycling and lower overall functioning (Vinberg et al. 2017).

Differential Diagnosis With Other Bipolar Diagnoses In some BD presentations, mood patterns are chronically mercurial, fluctuating between subclinical hypomanic symptoms and depressive symptoms without ever fulfilling the criteria for an episode of mania, hypomania, or major depression (American Psychiatric Association 2013). BD II may be difficult to distinguish from these other types of BD, as discussed below.

Cyclothymic Disorder Cyclothymic disorder is defined as alternating depressive and hypomanic symptoms for a least 1 year in children and adolescents or 2 years in adults, without any symptom-free periods lasting more than 2 months in duration during the initial index period (American Psychiatric Asso­ ciation 2013; Meter et al. 2012, 2017). Key diagnostic criteria are out­ lined in Table 2–4. In addition to duration and nonremittance criteria, cyclothymic disorder can be principally distinguished from other mood disorder diagnoses by the lack of full episode criteria being met for either a hypomanic episode or depressive episode. Thus, BD II is distin­ guished from cyclothymic disorder by the presence of at least one distinct

38

Bipolar II Disorder: Recognition, Understanding, and Treatment

major depressive episode and one hypomanic episode (American Psychi­ atric Association 2013). If a major depressive and hypomanic episode occurs after criteria for cyclothymic disorder are met, an additional di­ agnosis of BD II is given. Notably, about 30% of individuals first diagnosed with cyclothymia will go on to develop syndromal BD (Akiskal 2001). Cyclothymic disorder is not diagnosed if symptoms are better explained by a schizophrenia spectrum or other psychotic disorder, effects of chronic substance use, or a medical illness.

Other Specified Bipolar and Related Disorder In DSM-5, the category of not otherwise specified (NOS) disorder was replaced with a new category of other specified disorder that is used across all diagnostic categories to describe clinical presentations in which characteristic symptoms cause clinically significant distress or functional impairment but do not meet the full criteria for any of the disorders in the diagnostic class (American Psychiatric Association 2013). The other specified category is used in situations in which the clinician chooses to communicate the specific reason the presentation does not meet diagnos­ tic criteria for a specific disorder by recording “Other Specified Bipolar and Related Disorder,” followed by the specific reason, such as “Hypomanic episode without prior major depressive episode.” Other specified diagnoses include the following: 1. Short-duration hypomania (2–3 days meeting full hypomanic symp­ tom criteria) and major depressive episodes (also in DSM-5 under “Conditions for Further Study”) 2. Hypomanic episodes with insufficient symptoms and major depres­ sive episodes 3. Hypomanic episode without prior major depressive episode 4. Short-duration cyclothymia (i.e., lasts less than 24 months) Short-duration hypomania (2–3 days) and major depressive episodes is a diagnosis that should receive careful attention. If the patient is young, it would be reasonable to wonder whether this is the beginning of BD II despite there not yet being a syndromal hypomanic episode lasting at least 4 days. When DSM-5 was being developed, there was early evidence to suggest that this might be an ongoing pattern in some patients: they ex­ perience the full symptoms of hypomania but the minimum duration

Diagnosing Bipolar II Disorder

TABLE 2–4.

39

Diagnosing cyclothymic disorder: key criteria

• Numerous periods of subthreshold hypomanic and depressive symptoms that do not meet criteria for a hypomanic episode or major depressive episode have occurred. • Symptoms have persisted for 2+ years (1+ in youth). • Symptoms were present at least 50% of the time. • Symptoms have not remitted for more than 2 months at a time. • Criteria for a manic, hypomanic, or major depressive episode have never been met.

criterion is not met. The categorization of shorter-duration hypomania as a separate bipolar variant reflects the consensus of the DSM-5 Task Force that this clinical presentation could represent a phenotype that is distinct from both MDD and BD II (Miller et al. 2016a). On the basis of this empirical evidence, this category was placed in Section III of DSM-5, “Conditions for Further Study,” to encourage research to determine whether the presentation reflects a distinct bipolar phenotype. In the in­ terim, these symptoms must be examined carefully to assess if there was a longer period of hypomania, which would change the diagnosis to BD II. Several cross-sectional (e.g., Angst et al. 2012) and longitudinal (e.g., Bauer et al. 2011) studies have suggested that shorter courses of hypomania (e.g., 1–3 days in duration) may be far more common than the ≥4-day duration required to meet criteria for a hypomanic episode and syndromal BD II. Despite the meaningful findings of these initial stud­ ies, controlled studies examining the construct of shorter-duration hypomania are sparse and demonstrate considerable methodological variability (Miller et al. 2016a). Further research, including larger, meth­ odologically rigorous studies, is needed to expand our understanding of shorter duration hypomania and subsyndromal bipolar states. The hypomanic episodes with insufficient symptoms and major depres­ sive episodes category can be difficult to distinguish from BD II. This symptom presentation would not be viewed as MDD with mixed features specifier because by definition the hypomanic symptoms occurred not in the context of a major depressive episode but during a time separate and distinct from past episodes of major depression.

40

Bipolar II Disorder: Recognition, Understanding, and Treatment

The two other specified diagnoses listed above—hypomanic episode without prior major depressive episode and short-duration cyclothymia— may be difficult to distinguish from BD II, because it is common for BD II patients to experience at least one or two clear hypomanic episodes, although later many patients experience primarily subthreshold hypomania. Mood lability, rather than a full hypomanic episode, may be the main experience patients are able to identify, thinking of these in terms of “rocky patches” rather than psychopathology. Sometimes hypomanic epi­ sodes will not be defined as such in the patient’s review of history with­ out education around what constitutes hypomania, particularly if the symptoms are perceived as a respite from distressing depressive symp­ toms or in continuum of depressive symptoms (“energized depression”). When the clinician is attempting to characterize the symptomatology, it is helpful to distinguish between mood and emotional lability. Although mood dysregulation is a key marker of BDs, with degree and duration of mood instability diagnostically defining BDs, the closely related concept of emotion dysregulation is increasingly emerging as a third domain of impairment in BD. Mood typically refers to one or more enduring states such as depression or hypomania that last for days or weeks, whereas emo­ tions are more transient states lasting minutes or a couple of hours. These terms are often used interchangeably, although it can be helpful from a clinical perspective to distinguish emotion dysregulation, especially when it is reactive to environmental or interpersonal triggers, from mood changes. Mood episodes are the sine qua non of BD II; emotion dys­ regulation is common but may also be caused by other factors such as personality disorders or anxiety.

Differential Diagnosis With Anxiety Disorders Anxiety disorders and anxious symptoms are among the most prevalent comorbidities associated with BDs. Epidemiological studies, such as the National Comorbidity Survey, have found that as many as 62%–89% of individuals with BD II have at least one anxiety disorder at some point in their lives (Merikangas et al. 2007, 2011). Among patients with comorbid BDs and anxiety, social anxiety (37.8%), specific phobia (35.5%), and generalized anxiety (29.6%) are the most common disorders. GAD can be particularly problematic for patients with BD II, as it has also been associated with worse outcomes, including more depressive symptoms, more rapid cycling, and a significantly greater proportion of the year being

Diagnosing Bipolar II Disorder

41

spent ill (Boylan et al. 2004). Patients with comorbid BD II and GAD were found to have worse health-related quality of life than those with other bipolar spectrum disorders (Albert et al. 2008). Other prevalent anxiety and related disorders include panic disorder (20.1%). Several clinical and epidemiological studies have noted a high comorbidity between panic disorder and BD (Logue et al. 2009). Panic attacks have been found to be among the most common anxiety symptom among patients with BD II (Merikangas et al. 2011). As many as one in five patients may develop co­ morbid panic disorder during their lifetime (Hirschfeld et al. 2007). Comorbid anxiety disorders can have a substantial impact on the course of bipolar illness (Provencher et al. 2012). Compared with patients without an anxiety disorder, anxious patients with BD have an earlier onset of illness, higher rates of mixed states, more rapid cycling, more sui­ cidal behavior, and higher rates of treatment resistance, and are signifi­ cantly less likely to achieve remission (Parker and Graham 2017; Suppes et al. 2017). Although anxiety disorders may commonly co-occur with BD II, anx­ iety symptoms can also represent manifestations of depressive and hypomanic episodes. Table 2–5 highlights some of these overlapping symptoms that need to be differentiated from one another through a clinical interview.

Differential Diagnosis With Attention-Deficit/Hyperactivity Disorder Attention-deficit/hyperactivity disorder (ADHD) is a frequent comorbid­ ity with BD. Up to 43% of youth diagnosed with BD II will present with comorbid ADHD (Scheffer 2007). Although ADHD and BD II may fre­ quently occur together, they can also be difficult to distinguish diagnos­ tically because of the high prevalence of both disorders and several overlapping symptoms. Individuals with BD have also been found to have attentional control and executive functioning deficits—key diagnostic features of ADHD— with varying impacts across hypomanic, depressive, or mixed episode phases of illness (Ryan et al. 2012). Greater executive functioning im­ pairment typically occurs during a hypomanic episode. Furthermore, both hypomanic phases of BD and hyperactivity and combined subtypes of ADHD share impulsivity as a common symptom (Taylor et al. 2008). These overlaps contribute to the complexity of the clinical presentations

42

Bipolar II Disorder: Recognition, Understanding, and Treatment

TABLE 2–5.

Overlap between symptoms of anxiety, depression, and hypomania

Symptom

GAD

Panic

X

X

Diminished ability to think or concentrate Uncontrollable or racing thoughts Depressed mood Loss of interest or pleasure Irritability Psychomotor agitation Easily fatigued Decreased need for sleep Sleep disturbance Risky behavior or impulsivity Inflated self-esteem or grandiosity Note.

Depression Hypomania X

X

X X

X X X X X

X X

X

X

X

X X X X X

X X X

X X X

GAD= generalized anxiety disorder.

and create difficulties in differential diagnosis and treatment approach (Perugi et al. 2017). Examining the patterns of these overlapping symptoms can be helpful in determining if a patient has ADHD, BD II, or both (Table 2–6). Hypomanic symptoms not associated with ADHD such as grandiosity, hypersexuality, and racing thoughts and flight of ideas (Scheffer 2007) can be especially helpful in distinguishing ADHD from BD II. Patients with untreated ADHD often have dysphoria related to their frustrations with attentional deficits and poor achievement (e.g., in school; Scheffer 2007). When concentration difficulties are also present, it can be difficult to delineate the concurrent presence of ADHD and a depressive episode, but the distinction is an important one. It is notable that there are several symptoms commonly observed in depressive epi­ sodes that are not present in ADHD, including psychomotor retarda­ tion, fatigue or loss of energy, hypersomnia, loss of interest or pleasure, and thoughts of death and suicidality (Scheffer 2007). If these symptoms

43

Diagnosing Bipolar II Disorder

TABLE 2–6.

Overlapping symptoms among bipolar depression, hypomania, and attention-deficit/hyperactivity disorder (ADHD)

Depression symptoms ADHD symptoms Depressed mood Irritability Difficulty concentrating Psychomotor agitation — —

Dysphoria and frustration Irritability Inattention Hyperactivity Impulsivity Talks quickly

Hypomanic symptoms — Irritability Distractibility Psychomotor agitation Risky behavior Talkative

are present or persist after treatment has stabilized attentional problems, a depressive episode may be co-occurring. Furthermore, the dysphoria associated with ADHD is typically less severe than that typically ob­ served in a depressive episode. The key to differential diagnosis of ADHD versus BD II is that de­ pressive symptoms are often differently patterned: in ADHD, they tend to be more persistent, whereas they are usually more cyclic and variable in BD II episodes. If the symptoms that potentially overlap between these two syndromes wax and wane, they are more likely to be due to BD II. If the symptoms remain ongoing regardless of life conditions or mood states, they are more likely to be due to ADHD. Regardless of over­ lapping symptoms, a hypomanic episode can be diagnosed if the symp­ toms reflect a change from a patient’s norm, such as having periods of worsening attention, especially if accompanied by a change in mood/ irritability and increased activity.

Differential Diagnosis With Steroid-Induced Mood Fluctuations and Substance Use Disorders Corticosteroids administered in high doses may induce neuropsychiat­ ric symptoms that can be difficult to differentiate from bipolar symptoms. Individuals with psychiatric responses to corticosteroids can experience mood fluctuations, depression, irritability, restlessness, agitation, ag­ gression, anxiety, and manic symptoms as a result of impacts of steroids on the brain (Bhangle et al. 2013). Among those individuals who experi­ ence psychiatric symptoms following high-dose corticosteroid use, more

44

Bipolar II Disorder: Recognition, Understanding, and Treatment

than one-third will develop manic or hypomanic symptoms; depressive symptoms are slightly less prevalent (Sirois 2003). Suicidality has been estimated to increase sixfold during steroid psychosis (Brown 2012), but hypomanic symptoms appear most commonly, including irritability, pressured speech, hyperactivity, restlessness, agitation, and a sense of euphoria (Brown 2012). Anxiety is also frequently reported. A thorough clinical history and chart review of prescription medications is essential, particularly in light of the prevalence of steroid use in treating inflam­ matory-based medical comorbidities. Inflammatory and autoimmune conditions are also frequent comorbidities among patients with BD, which may contribute to exacerbation of patients’ depressive symptoms (Hamdani et al. 2013; Rosenblat and McIntyre 2016; Rosenblat et al. 2014). A number of substances can produce BD II–like symptoms, including amphetamine-based drugs, prescribed medications such as corticoste­ roids, or even psychedelics such as MDMA (3,4-methylenedioxymeth­ amphetamine). In fact, there is some debate about whether to prescribe amphetamines as part of an ADHD treatment regimen when ADHD co­ occurs with a BD because of concern about their potential destabilizing effects on the course of the illness (Perugi et al. 2017). However, there is some evidence that patients with comorbid BD and ADHD who are clin­ ically stable may experience improved functioning when they receive stimulants in conjunction with mood stabilizers (Perugi et al. 2017). Comorbid substance use and abuse are common in patients with BD II, who sometimes believe that substances improve their symptoms (Weiss et al. 2004). Epidemiological studies have found that more than onethird of patients diagnosed with BD II have been diagnosed with a comor­ bid substance use disorder (Hirschfeld et al. 2007; Merikangas et al. 2011). It is therefore important to ask patients to quantify their drug and alcohol use, clarifying, for example, whether a drink means an 8-ounce glass or 30-ounce pitcher. Regardless of the substance, more specific questioning about how much, when, and with whom they are using sub­ stances is important to differential diagnosis and identification of co­ morbid substance risks.

Differential Diagnosis With Personality Disorders Personality disorders overlap with and co-occur with BD II. Emotional lability occurring in the context of interpersonal stressors may raise ques­

45

Diagnosing Bipolar II Disorder

tions about the possibility of borderline personality disorder, while high levels of grandiosity may suggest narcissistic personality disorder. Diag­ nostically, it can be challenging to determine whether mood instability is an expression of BD, a personality disorder, or both (Nusslock and Frank 2011). The overlap of personality disorders with BD II and consid­ erations of differential diagnosis are discussed in greater detail in Chap­ ter 3 (“Interface Between Borderline Personality Disorder and Bipolar II Disorder”).

Conclusion It is clinically important to consider whether depressive symptoms, especially in a younger person, are manifestations of BD II or MDD. Ac­ curate diagnosis early in the illness course has implications for long-term illness trajectory and treatment choices. Accurate diagnosis is also essen­ tial to helping patients manage expectations about frequency and severity of symptoms. In all psychiatric illness, later diagnosis and management of symptoms appears to be related to a more difficult course of illness and, in many cases, may contribute to treatment resistance. The increased fo­ cus on biologic studies and the continued search for biomarkers hold the possibility of advancing our diagnostic armamentarium and, eventually, matching treatments to patients. The increased focus on precision med­ icine across psychiatric illnesses can only benefit patients with BD II.

KEY POINTS • Bipolar II disorder (BD lI) is characterized by cycles of at least one major depressive and one hypomanic episode in a patient’s lifetime. • Hypomanic symptoms are less severe than manic symptoms, and a duration of at least 4 days is required to meet episode criteria. • All mood disorders are longitudinal diagnoses. The diagnosis of BD II remains unchanged with time, unless the individual has a manic episode, in which case bipolar I disorder (BD I) would be diagnosed. • The DSM-5 revisions ushered in several diagnostic changes to BD II, including the requirement that to meet Criterion A, ab-

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Bipolar II Disorder: Recognition, Understanding, and Treatment

normally and persistently increased activity and energy must be present in addition to changes in mood. • Other key changes to bipolar disorder diagnostic criteria in DSM-5 include the addition of mixed features and anxious features specifiers. • A diagnosis of BD II may be made following an antidepressant-induced hypomania if the full episode criteria are met after the physiological effects of the medication have ended. • Anxiety disorders, attention-deficit/hyperactivity disorder, and substance use disorders are frequently comorbid with BD II and should be considered as part of the differential diagnosis. • Differential diagnosis requires a thorough history of mood symptoms and family history of mood disorders.

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Machado-Vieira R, Luckenbaugh DA, Ballard ED, et al: Increased activity or energy as a primary criterion for the diagnosis of bipolar mania in DSM-5: findings from the STEP-BD study. Am J Psychiatry 174(1):70–76, 2017 27523498 Malhi GS: Diagnosis of bipolar disorder: who is in a mixed state? Lancet 381(9878):1599–1600, 2013 23663937 Malhi GS, Lampe L, Coulston CM, et al: Mixed state discrimination: a DSM problem that won’t go away? J Affect Disord 158:8–10, 2014 24655759 Malhi GS, Berk M, Morris G, et al: Mixed mood: the not so United States? Bipolar Disord 19(4):242–245, 2017 28722274 McIntyre RS, Soczynska JK, Cha DS, et al: The prevalence and illness characteristics of DSM-5-defined “mixed feature specifier” in adults with major depressive disorder and bipolar disorder: results from the International Mood Disorders Collaborative Project. J Affect Disord 172:259–264, 2015 Merikangas KR, Akiskal HS, Angst J, et al: Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64(5):543–552, 2007 17485606 Merikangas KR, Jin R, He J-P, et al: Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 68(3):241–251, 2011 21383262 Meter AR, Van EA, Youngstrom BB, et al: Cyclothymic disorder: a critical review. Clin Psychol Rev 32(4):229–243, 2012 22459786 Meter AR, Van EA, Youngstrom BB, et al: Longitudinal course and characteristics of cyclothymic disorder in youth. J Affect Disord 215:314–322, 2017 28365522 Miller S, Dennehy EB, Suppes T: The prevalence and diagnostic validity of shortduration hypomanic episodes and major depressive episodes. Curr Psychiatry Rep 18(3):27, 2016a 26830885 Miller S, Suppes T, Mintz J, et al: Mixed depression in bipolar disorder: prevalence rate and clinical correlates during naturalistic follow-up in the Stanley Bipolar Network. Am J Psychiatry 173(10):1015–1023, 2016b 27079133 Novick DM, Swartz HA, Frank E: Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord 12(1):1–9, 2010 20148862 Nusslock R, Frank E: Subthreshold bipolarity: diagnostic issues and challenges. Bipolar Disord 13(7–8):587–603, 2011 22085472 Parker GB, Graham RK: Clinical characteristics associated with treatment-resistant bipolar disorder. J Nerv Ment Dis 205(3):188–191, 2017 27105455 Perugi G, Angst J, Azorin J-M, et al; BRIDGE-II-Mix Study Group: Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study. J Clin Psychiatry 76(3):e351–e358, 2015a 25830457 Perugi G, Hantouche E, Vannucchi G, et al: Cyclothymia reloaded: a reappraisal of the most misconceived affective disorder. J Affect Disord 183:119–133, 2015b 26005206 Perugi G, Vannucchi G, Bedani F, et al: Use of stimulants in bipolar disorder. Curr Psychiatry Rep 19(1):7, 2017 28144880 Phelps J, Ghaemi SN: The mistaken claim of bipolar “overdiagnosis”: solving the false positives problem for DSM-5/ICD-11. Acta Psychiatr Scand 126(6):395–401, 2012 22900986 Provencher MD, Guimond AJ, Hawke LD: Comorbid anxiety in bipolar spectrum disorders: a neglected research and treatment issue? J Affect Disord 137(1–3):161– 164, 2012 22209124

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Regeer EJ, Kupka RW, Have M, et al: Low self-recognition and awareness of past hypomanic and manic episodes in the general population. Int J Bipolar Disord 3(1):22, 2015 26440507 Regier DA, Narrow WE, Clarke DE, et al: DSM-5 field trials in the United States and Canada, part II: test-retest reliability of selected categorical diagnoses. Am J Psychiatry 170(1):59–70, 2013 23111466 Rosenblat JD, McIntyre RS: Bipolar disorder and inflammation. Psychiatr Clin North Am 39(1):125–137, 2016 26876323 Rosenblat JD, Cha DS, Mansur RB, et al: Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 53:23–34, 2014 24468642 Ryan KA, Vederman AC, McFadden EM, et al: Differential executive functioning performance by phase of bipolar disorder. Bipolar Disord 14(5):527–536, 2012 22834461 Scheffer RE: Concurrent ADHD and bipolar disorder. Curr Psychiatry Rep 9(5):415– 419, 2007 17915082 Simpson SG, McMahon FJ, McInnis MG, et al: Diagnostic reliability of bipolar II disorder. Arch Gen Psychiatry 59(8):736–740, 2002 12150650 Sirois F: Steroid psychosis: a review. Gen Hosp Psychiatry 25(1):27–33, 2003 12583925 Smoller JW, Finn CT: Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet 123C(1):48–58, 2003 14601036 Suppes T, Mintz J, McElroy SL, et al: Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sexspecific phenomenon. Arch Gen Psychiatry 62(10):1089–1096, 2005 16203954 Suppes T, Eberhard J, Lemming O, et al: Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials. Int J Bipolar Disord 5(1):36, 2017 29105003 Taylor CT, Hirshfeld-Becker DR, Ostacher MJ, et al: Anxiety is associated with impulsivity in bipolar disorder. J Anxiety Disord 22(5):868–876, 2008 17936573 Tohen M, Gold AK, Sylvia LG, et al: Bipolar mixed features—results from the Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study. J Affect Disord 217:183–189, 2017 28411507 Turner EA, Jensen-Doss A, Heffer RW: Ethnicity as a moderator of how parents’ attitudes and perceived stigma influence intentions to seek child mental health services. Cultur Divers Ethnic Minor Psychol 21(4):613–618, 2015 25894834 Vieta E, Valentí M: Mixed states in DSM-5: implications for clinical care, education, and research. J Affect Disord 148(1):28–36, 2013 23561484 Vinberg M, Mikkelsen RL, Kirkegaard T, et al: Differences in clinical presentation between bipolar I and II disorders in the early stages of bipolar disorder: a naturalistic study. J Affect Disord 208:521–527, 2017 27816324 Weiss RD, Kolodziej M, Griffin ML, et al: Substance use and perceived symptom improvement among patients with bipolar disorder and substance dependence. J Affect Disord 79(1–3):279–283, 2004 15023508 Zimmerman M, Ruggero CJ, Chelminski I, et al: Is bipolar disorder overdiagnosed? J Clin Psychiatry 69(6):935–940, 2008 18466044

3 Interface Between Borderline Personality Disorder and Bipolar II Disorder Mark Zimmerman, M.D. Theresa A. Morgan, Ph.D.

Both bipolar II disorder (BD II) and borderline personality disorder (BPD) are serious illnesses resulting in significant psychosocial impairment, chronic symptom burden, and excess mortality (Angst et al. 2002; Bryant-Comstock et al. 2002; Comtois and Carmel 2014; Gun­ derson et al. 2011; Morgan et al. 2005; Oldham 2006; Ruggero et al. 2007; Skodol et al. 2002). It is clinically important to recognize and dis­ tinguish between BD II and BPD because the empirically supported treat­ ments for each differ. Patients with both disorders most often seek treatment when depressed (Zimmerman et al. 2017). Depressive symptoms of both disorders may also be more frequent, prominent, and present with shorter episodes of well-being compared with bipolar I disorder (BD I) (Benazzi 2007). The diagnosis of BD II in patients who present with depression requires elic­ iting information about a previously experienced hypomanic episode in addition to the current depressive episode. Because patients’ memories 51

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are fallible, and since clinicians may fail to adequately inquire about a history of manic or hypomanic episodes, the underrecognition of bi­ polar disorder in patients presenting for the treatment of depression has been identified as a significant clinical problem (Angst et al. 2011; Bowden 2001; Ghaemi et al. 2000; Ghaemi et al. 2002; Hantouche et al. 1998; Hirschfeld 2001; Hirschfeld and Vornik 2004; Manning et al. 1997; Perugi et al.1998; Yatham 2005). The clinical implications of fail­ ure to recognize BD II in depressed patients are significant and include the underprescription of mood-stabilizing medications, an increased risk of rapid cycling, and increased costs of care (Birnbaum et al. 2003; Ghaemi et al. 2000; Matza et al. 2005; Shi et al. 2004). As a result of the potential morbidity associated with a delay in diagnosis, many experts have called for improved recognition of bipolar disorder (Bowden 2001; Ghaemi et al. 2002; Hirschfeld 2001; Yatham 2005). The emphasis on improving recognition of bipolar disorder during the past several years may have resulted in the emergence of the oppo­ site problem: bipolar disorder overdiagnosis. Phenomenological simi­ larities between bipolar disorder and BPD sometimes make differential diagnosis difficult. This may be particularly true for BD II, in which mood states may be less severe and pervasive than in BD I. Phenomenological similarities have led some experts to consider BPD as part of the bipolar spectrum (including BD I and II), therefore contributing to the underrecognition of bipolar disorder (Akiskal 2004; Perugi et al. 2003). Con­ versely, others have found that BPD contributes to the overdiagnosis of bipolar disorder broadly (Zimmerman et al. 2010b), although no study has examined this with regard to BD II specifically. A separate but much smaller literature has focused on the underrecog­ nition of BPD, delay in its diagnosis, and resultant consequences (Com­ tois and Carmel 2014; Magnavita et al. 2010; Zimmerman and Mattia 1999b). In this chapter we focus on four aspects of the relationship between BPD and BD II. First, we examine the most studied question on the re­ lationship between these two disorders: their diagnostic concordance. Next, we consider the issue of diagnostic boundaries, and whether BPD should be considered part of the “bipolar spectrum” and is therefore diagnostically related to BD II. Third, we discuss the problem of both under- and overdiagnosis of BD II, with a specific focus on the contribu­ tion of BPD to overdiagnosis. Finally, we discuss efforts to improve the

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recognition of both BD II and BPD through the development of screening scales, including a discussion of the potential risks and benefits to this approach.

Comorbidity Between Borderline Personality Disorder and Bipolar II Disorder Frequency of BPD in Patients With Bipolar II Disorder Can patients with BD II also have BPD? Diagnostic concordance is im­ portant to the issue of separating BD II from BPD because it speaks to the possibility and frequency of cases meriting one or both diagnoses. Zimmerman and Morgan (2013) reviewed the literature on the fre­ quency of co-occurring personality disorders in bipolar disorder. Across seven studies of 261 patients with BD II, the prevalence of BPD was 22.9% (n=60). This was twice as high as that reported for BD I (10.7%). Importantly, only two groups of investigators have reported data on both BD I and II, Vieta and colleagues in Spain and Zimmerman and colleagues in the United States. Vieta et al. (2000, 2001) found that BPD was diagnosed two times more frequently in patients with BD II than with BD I (12.5% vs. 6.2%), although this difference was not statistically significant. Similarly, Zimmerman and Mattia (1999a) reported a nonsignificantly higher prevalence of BPD in patients with BD II. Thus, al­ though aggregation of data across studies suggests that BPD is twice as common in patients with BD II compared with BD I, the only two studies that allowed for a direct comparison did not find a statistically significant difference.

Is BPD the Most Frequent Personality Disorder in Patients With Bipolar II Disorder? With so much attention paid to the association between BPD and bipo­ lar disorder, one might assume the BPD is the most common personal­ ity disorder in patients with BD II. We were only able to identify two studies examining this issue in BD II exclusively, and both reported BPD as the most frequently diagnosed personality disorder. In contrast, BPD was the most frequent diagnosis in only 4 of the 15 studies that exam­ ined the full range of personality disorders in patients with bipolar dis­ order more broadly defined (Zimmerman and Morgan 2013).

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Is BPD More Common in Patients With Bipolar II Disorder Than in Major Depressive Disorder Control Groups? Patients with major depressive disorder (MDD) have elevated rates of per­ sonality disorders. Thus, a different way of looking at the specificity of the BPD–bipolar disorder connection is to compare the frequency of BPD in patients with bipolar disorder versus patients with MDD. Four studies examined rates of personality disorder in BD II and MDD, and three of these studies found higher rates of BPD in the BD II group com­ pared with the MDD group (Zimmerman and Morgan 2013). Case Vignette: Co-occurring BPD and BD II Steve is a 22-year-old single white man who was referred to the partial hospital by his outpatient therapist because of worsening depression after breaking up with his girlfriend. At admission he indicated that he had been previously diagnosed with bipolar disorder, and this was confirmed by his description of multiple hypomanic episodes. However, his chief complaint was “My heart is destroyed, and I can’t trust anyone.” Steve de­ scribed numerous ups and downs in the relationship. “I would go from hating her and then telling her I love her.” When he feared that she would break up with him, he reported “I kick, and scream. I cut myself last week on the arm and showed her because I thought she would stay. It’s my big­ gest problem. I’m used to getting my way and this was the first time I didn’t get my way.” He described his mood as “happy and sad and snappy. I hate and then I love.” He reported that he “doesn’t know who [he] is,” and felt this way before the relationship’s end (“I’ve never explored who I am”). He described a history of difficulties controlling anger. He noted that he would “yell at [his] dog and snap.” He reported that he feels “aggravated daily” and that this anger stems from disrespect. He identified his temper as overall difficult to control and his anger “comes off in different ways.” When under stress, he feels as though the room is spinning, and he will have periodic blackout periods (“I once went to the hospital because of it. I got worked up and then woke up on the ground in the bathroom. They told me they weren’t seizures. The last time it happened was last week”). He also said he sees “shadows” out of the corner of his vision when stressed, and experiences paranoia (“I got really suspicious of the relation­ ship. I always thought she was lying, especially about the texts”). He has made suicidal threats (“I said it to get her attention”), and sometimes punches himself out of frustration. Recently he cut the top of his arm (“I’m not going to lie to you, it felt really good. It was like a release of tension”). He reported impulsivity in several areas, including buying unnecessary things (“I buy things and then I don’t know why I buy them, and then I sell them”), reckless driving (“I love driving fast”), and eating binges.

Interface Between BPD and Bipolar II Disorder

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Since the breakup, he has been in a depressive episode. “I’ve never felt this bad before.” Over the past month, he reported daily low mood (“it’s 24/7”), and anhedonia (“I don’t want to do anything. I haven’t enjoyed anything”). He described low appetite and subsequent weight loss (“I barely eat, it’s like my body won’t let me. I’ve lost 15 pounds”). He re­ ported difficulties sleeping (“I only get 5 hours now”) and significant psy­ chomotor agitation (“I’m always moving, but no one notices because they don’t care. They ignore me”). Of note, Steve was noticeably restless in the interview (i.e., shaking his leg vigorously). He described experienc­ ing daily fatigue, difficulties concentrating, and indecisiveness (“I can’t decide what to eat, whether to get a coffee, if I should walk my dog”). He described feelings of worthlessness (“I don’t feel good enough”) and guilt related to his recent relationship ending (“I feel guilty I ruined the relationship. I feel guilty when I’m eating because I used to eat with her”). He described currently experiencing passive thoughts of death (“I think I’d be better off not around”).

Frequency of Bipolar II Disorder in Patients With BPD Thus far we approached the comorbidity issue from the perspective of how often BPD occurs in patients with BD II. Approximately 20% of pa­ tients diagnosed with BPD receive bipolar disorder as the principal di­ agnosis (Zimmerman et al. 2017); thus, it is relevant to ask how often bipolar disorder occurs in patients with a primary diagnosis of BPD. A problem in summarizing this literature is that studies vary in the breadth of their diagnosis of bipolar disorder and often do not differen­ tiate between BD I and II. Six studies reported rates of BD II in patients diagnosed with BPD (Zimmerman and Morgan 2013). Across these six studies the rate of BD II was 10.2%, approximately the same as that for BD I (8.9%).

Three Takeaways From the BPD–Bipolar Disorder Comorbidity Literature 1. The prevalence of BPD in individuals diagnosed with bipolar disorder is approximately twice as high in patients with BD II compared with BD I (20% vs. 10%). However, this represents a summary of data across studies. Only two studies directly compared rates of BPD in patients diagnosed with BD I and II. 2. The prevalence of BD II in patients diagnosed with BPD is approxi­ mately 10%, with an additional 10% of patients with BPD diagnosed with BD I.

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3. BPD may be the most frequently diagnosed personality disorder in patients with BD II. However, this is drawn from only two studies. BPD is not the most frequently diagnosed personality disorder in pa­ tients with bipolar disorder broadly defined.

Should Borderline Personality Disorder Be Considered Part of the Bipolar Spectrum? The Spectrum Concept In recent years, there has been a growing literature on the bipolar spec­ trum. Although researchers differ in what they think should be included in this framework, there is a general consensus that bipolar spectrum dis­ orders are those characterized by manic symptomatology that is not as se­ vere in intensity, duration, or psychosocial impairment as that manifested during an episode of mania. These include BD II, cyclothymia, and other specified and unspecified bipolar and related disorders. The validity of the construct has been established by demonstrating that the correlates (e.g., comorbidity, personality, family history, longitudinal course) of bipolar spectrum conditions are similar to those of bipolar disorder (Angst et al. 2010, 2011; Benazzi and Akiskal 2003; Zimmermann et al. 2009). Some authors have argued that BPD should be included on the bipo­ lar spectrum (Akiskal 2004; Perugi et al. 2003; Smith et al. 2004). This suggestion, in part, stems from the superficial resemblance of phenom­ enological features, particularly with BD II. Both disorders are character­ ized by fluctuations in mood. However, the strong and intense emotions of individuals with BPD are often time-limited reactions to external con­ ditions, whereas the mood dysregulation in BD II is sustained and less reactive to environmental influences. Individuals with BPD may engage in impulsive behaviors that can cause problems such as gambling, exces­ sive spending, sexual promiscuity, drug and alcohol use, stealing, or reckless driving, often as an emotion regulation strategy. Individuals with BD II may engage in similar behaviors; however, these usually occur during distinct mood episodes. Given the overlap in the features charac­ teristic of these two disorders, it is not surprising that they frequently co-occur, as per the literature reviewed previously.

The DSM Diagnostic Criteria: A Test, Not a Decree BD II, like most disorders defined in DSM-5 (American Psychiatric Asso­ ciation 2013), is a symptom-based diagnosis. A biological test for BD II

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does not yet exist. The absence of a biological diagnostic test means that the DSM-5 symptom criteria for BD II are an approximation of the dis­ ease entity whose underlying pathophysiology we hope to one day under­ stand and identify with a valid test. It is helpful to take a step back and understand what the DSM diagnos­ tic criteria actually represent. DSM-5, like its predecessors, is a categor­ ical system that provides descriptive diagnostic criteria of psychiatric syndromes. The definition of mental disorder in DSM-5 notes that these descriptions represent underlying behavioral, psychological, or biologi­ cal dysfunction, albeit imperfect representations of the unknown, un­ derlying core dysfunction. Although DSM-5 has several valuable uses, such as the efficient communication of important clinical information, the descriptive diagnostic criteria should not be reified and considered the last word on whether a patient has the illness in question. Instead, the criteria should be conceptualized as a type of test for the underlying, eti­ ologically defined illness (although the etiology has not yet been discov­ ered). Accordingly, as with any other diagnostic test, diagnoses based on the DSM-5 criteria produce some false positive and some false negative results. That is, some patients with symptoms that meet the DSM-5 diag­ nostic criteria do not have the illness (i.e., false positives), and some whose symptoms do not meet the criteria because they fall below the DSM-5 diagnostic threshold have the illness but incorrectly do not receive the di­ agnosis (i.e., false negatives). It should be noted that there are other causes of diagnostic error. A second cause of diagnostic error is related to assessment methodology. There are limits to the accuracy of retrospective recall of prior hypomanic episodes. A clinician might ask all the right questions, but pa­ tients might not recall or report prior episodes, thus resulting in false negative diagnoses. False negative diagnoses could also result from the clinician failing to inquire about a history of manic or hypomanic epi­ sodes. Clinicians also might not ask the right questions needed to elicit helpful responses (Akiskal and Benazzi 2005; Benazzi 2003; Benazzi and Akiskal 2003). Similarly, false positive diagnoses may be a problem. For example, it is sometimes difficult to determine if prior hypomanic epi­ sodes occurred independent of substance use, thereby resulting in false positive diagnoses (Goldberg et al. 2008; Stewart and El-Mallakh 2007). Because this chapter focuses on the interface between BD II and BPD, it is worth reemphasizing that transient episodes of affective instability

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and emotional lability associated with BPD might be confused with hy­ pomanic episodes, thereby resulting in false positive diagnoses (Paris 2004; Zimmerman et al. 2010a). Diagnostic error is inherent in a system in which diagnoses are based on retrospective recall of symptom episodes. The question is not whether diagnostic error exists, but rather whether one of the types of error pre­ dominates, and whether shifting the diagnostic threshold would impact the number of each of these diagnostic errors, and if so, to what extent. Also important to consider are the clinical consequences of each type of error, and which error is more difficult to undo after it has been made. Let us now consider the potential consequences of expanding the bipo­ lar spectrum to include BPD.

Implications of Expanding the Boundary for Diagnosing Bipolar Disorder to Include BPD To date, no studies have examined the potential impact that expansion of criteria for bipolar spectrum would have on diagnosis and outcome in real-world clinical practice. The impact of overdiagnosis due to lowering the diagnostic threshold must be compared with the impact of underdi­ agnosing “true” bipolar disorder because reported symptoms did not last long enough to qualify as a DSM-5 hypomanic episode—that is, one must weigh the risk of a false positive diagnosis versus the risk of a false negative diagnosis. Although underdiagnosis due to insufficient duration is a real possibility, there is evidence that clinicians do not apply DSM-5 diagnostic thresholds rigidly (Zimmerman and Galione 2010). Thus, it is likely that patients who manifest recurrent hypomanic episodes of pre­ sumably insufficient duration are likely to be diagnosed with BD II none­ theless and treated accordingly. Both false positive and false negative diagnoses are associated with ad­ verse consequences. Underdiagnosed bipolar disorder—including BD II, which may be at highest risk of underdiagnosis for the reasons noted above—is associated with the underprescription of mood stabilizing medications, an increased risk of rapid cycling, and increased costs of care (Birnbaum et al. 2003; Ghaemi et al. 2000; Matza et al. 2005). Overdiagnosed BD II may be associated with overtreatment with un­ needed medications and consequent exposure to potential side effects and medical risk as well as the potential failure to offer more appropriate treatments.

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In trying to decide where to set the threshold for diagnosing BD II and minimize diagnostic errors of all types, another question is whether one type of diagnostic error is likely to be more long lasting and difficult to undo than another. Diagnosis is a dynamic, fluid process that is (hopefully) reconsidered as additional clinical material becomes available. However, when diag­ nosis is based, in part, on the presence of past episodes, it is more diffi­ cult to take away the diagnosis once it has been established than to add the diagnosis after another episode occurs in the future. Once a patient is diagnosed with BD II, the reoccurrence of hypomania is not necessary to retain the diagnosis. In fact, the lack of recurrence could be viewed as treatment success. The patient with a false positive diagnosis of BD II who is doing well while taking an antidepressant and a mood stabilizer is un­ likely to have the mood stabilizer discontinued or the diagnosis cor­ rected. On the other hand, a patient with a false negative diagnosis is more likely to have it changed from MDD to BD II on the emergence of a hypomanic episode. Thus, a false negative diagnosis of nonbipolar de­ pression is easier to correct than a false positive diagnosis of BD II. Ex­ panding the diagnostic boundary for BD II to include BPD may or may not reduce the overall number of diagnostic errors. However, the error due to false positive diagnoses, which would increase when the diagnos­ tic boundary is broadened, will be more likely to persist in clinical settings than the error due to false negative diagnoses. In the face of diagnostic uncertainty, we recommend erring on the side of choices that are easier to undo and correct.

Underdiagnosis of Bipolar II Disorder, Possible Overdiagnosis, and the Role of Borderline Personality Disorder Underdiagnosis of Bipolar II Disorder Is BD II underdiagnosed? Absolutely. Sometimes. If you take a cohort of patients diagnosed with MDD and interview them to elicit a history of hypomanic episodes, some of them will be rediagnosed as having BD II. Several studies have shown that bipolar disorder generally is sometimes underdiagnosed. The question is why? For example, a third-year resident in psychiatry asked one of us for the Structured Clinical Interview (SCID) module assessing hypomania.

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When he was asked why, the resident said that he was describing a pa­ tient to his supervisor, who speculated that the patient might have BD II. The resident noted he had inquired already about past hypomanic epi­ sodes. We reviewed together the questions he had asked his patient to elicit this information, and they seemed appropriate. When asked why, then, the resident wanted the SCID module, he indicated that his supervi­ sor recommended it. Instead of discussing the SCID specifically, we dis­ cussed instead diagnostic accuracy, ending on the realization that there were no special questions on the SCID that magically uncover a prior history of hypomania but were known only by the members of the secret society of SCIDDERS. The “right” questions can be asked as easily in clinical practice as in a research setting. Although some research demonstrates that BD II is underdiagnosed, the reasons that clinicians miss the diagnosis are not well understood. Do clinicians fail to inquire? Do they not know what questions to ask? We are not aware of any research that has fully examined this issue with re­ spect to BD II, although the clinical challenges of diagnosing BD II have been well discussed (see, e.g., Fletcher et al. 2018). Akiskal and Benazzi (2005) found that many patients with bipolar disorder initially respond negatively when asked about a history of sustained euphoric or irritable mood. Rather, patients are more likely to recall sustained periods of hy­ peractivity. Therefore, clinicians screening for BD II may find it helpful to inquire about hyperactivity and excess productivity in addition to ask­ ing questions about a change in mood. Do clinicians misinterpret patients’ responses to appropriate ques­ tions? Are clinicians concerned about pathologizing normal happiness or hyperproductivity and therefore discount positive responses? Are they reluctant to make a diagnosis that potentially consigns a patient to a life­ time of mood stabilizer medication when uncertainty about the diagnosis remains? Case Vignette A 42-year-old businessman presented for treatment of depression of several months’ duration that met the criteria for a major depressive ep­ isode. He reported that in the past, at the initiation of a new venture, his mood was elevated, and during this time he slept only 2–3 hours and did not feel tired (described as an “unthrottled expenditure of energy”), reportedly worked 16–18 hours per day, felt much more confident than usual, asserted his creativity and clarity of thought was enhanced, and

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described his thoughts as going much faster than usual. He reported two such episodes of a few months’ duration, each time coinciding with a new business initiative and associated with enhanced productivity. Both episodes were followed by periods of major depression.

Although this patient’s presentation clearly meets the DSM-5 criteria for past hypomania, and he was diagnosed with BD II, it was unclear if these episodes represented a normative response in a driven, successful businessman or true hypomania. In the language of testing, was this a false positive or a true positive? We have seen a number of other patients who describe what sounds like a history of one or two hypomanic epi­ sodes at the initial evaluation but, when followed longitudinally, never experienced a recurrence. What is the valid diagnosis in these patients? It is likely that some clinicians will not make a BD II diagnosis in this situation—despite the fact that patients’ presentations meet DSM-5 crite­ ria for the illness—and this could account for some of the underdiagno­ sis of BD II.

Overdiagnosis of Bipolar II Disorder? To date, no research has systematically examined the rate of overdiagnosis of BD II. However, given the phenomenological similarities between BD II and BPD, the ease of establishing false positives (and subsequent dif­ ficulty in discomfirming these cases), and a long history of viewing BD II as a “dustbin diagnosis” (Fletcher et al. 2018), it is certainly likely that overdiagnosis and misdiagnosis are relevant clinical concerns. Moreover, overdiagnosis of bipolar disorder broadly defined has been established, and it is likely cases of BD II diagnosis contribute to these at least in part. The largest study of bipolar disorder overdiagnosis was conducted by our clinical research group (Zimmerman et al. 2008). We used the Struc­ tured Clinical Interview for DSM-IV (SCID-IV) to interview 700 psy­ chiatric outpatients presenting for treatment. Slightly more than 20% of the sample reported that they had been previously diagnosed as having bipolar disorder, although no distinction was made between BD I and II. More than half of these patients were not diagnosed with bipolar disor­ der on the basis of administration of SCID-IV. A follow-up report exam­ ined whether there was a particular diagnostic profile associated with bipolar disorder overdiagnosis (Zimmerman et al. 2010b). The patients overdiagnosed with bipolar disorder were four times more likely to be diagnosed with BPD compared with patients who were not diagnosed with

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bipolar disorder (24.4% vs. 6.1%). That means nearly 40% of the patients with symptoms that met criteria for DSM-IV BPD (American Psychiat­ ric Association 1994) had been overdiagnosed with bipolar disorder. Why might the phenomenon of false positive BD II diagnoses be a spe­ cific concern? In addition to the aforementioned issues, we believe that the increased availability of medications to treat bipolar disorder, and the accompanying marketing efforts, contribute to risk. Many continu­ ing medical education programs on bipolar disorder begin with a sum­ mary of research suggesting bipolar disorder is underdiagnosed, and this is followed by a discussion of methods that clinicians can use to im­ prove the detection of the disorder. These discussions of diagnostic prac­ tice are usually not balanced by a summary of studies demonstrating overdiagnosis, nor do the discussions mention the risks associated with overdiagnosis. Because clinicians are probably inclined to diagnose dis­ orders that they feel more comfortable treating, we hypothesize that in pa­ tients with mood instability whose symptoms do not meet criteria for a DSM-5 hypomanic episode, physicians are more inclined to diagnose a potentially medication-responsive disorder such as bipolar disorder than to diagnose a disorder such as BPD that is less medication responsive.

Screening Scales: A Method of Improving Diagnostic Recognition The Concept of Screening Taking a thorough, comprehensive history is time consuming. Given the time demands of clinical practice, it is not surprising that diagnoses are sometimes missed. To improve diagnostic recognition, self-adminis­ tered screening scales have been recommended. When screening for a disorder, the clinician initiates a two-stage diag­ nostic process. The application of the screening test is the first stage, with the goal of casting a net broad enough to ensure that all patients with the disorder of interest are identified. In statistical terms, a screening proce­ dure should have high sensitivity. The second stage is more definitive, consisting of a full diagnostic evaluation that is generally more expensive and invasive than the first-stage screening procedure. It is important for a screening test to have high sensitivity because the more time-inten­ sive/expensive follow-up diagnostic inquiry will presumably only occur in patients who test positive on the initial screen.

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In psychiatry, the self-administered screening questionnaire (stage 1) is followed by a diagnostic interview (stage 2). In research, a semistruc­ tured interview such as the SCID is the usual gold standard diagnostic procedure.

Performance of Screening Scales for Bipolar II Disorder There are several screening scales for bipolar disorder. However, consis­ tent with the broader literature, the majority of these scales do not clearly distinguish among BD I, BD II, and other related disorders. An excep­ tion is the Hypomania Checklist–32 (HCL-32; Angst et al. 2005), which was specifically designed to capture past experiences of hypomania and “soft” symptoms that may be indicative of BD II cases. In at least one study the HCL-32 did show better discrimination of cases of BD II as compared with BD I (Lee et al. 2016). However, the measure overall per­ formed poorly at discriminating cases of bipolar disorder from nonclin­ ical controls. The most widely studied and promoted screening scale for bipolar disorder is the Mood Disorder Questionnaire (MDQ). Of note, this scale does not differentiate potential cases of BD I and II; however, we believe it merits brief discussion because of the pervasiveness of its use. Reviews of the MDQ have found that its sensitivity for detecting BD II was 38.8%, lower than its sensitivity for detecting BD I at 66.3% (Zimmerman and Galione 2011). This raises significant concerns about using the MDQ as a screening scale in clinical practice, because approximately one-third of the patients with BD I and two-thirds with BD II would not make it to the stage 2 clinical evaluation. In addition, the positive predictive value of the scale is less than 50%, meaning that more than half of patients who screen positive do not have any true bipolar disorder (Zimmerman and Galione 2011). This is not necessarily a problem as long as the clini­ cian understands the difference between a screening and diagnostic test. If a high percentage of patients who screen positive do not have bipolar disorder, it is imperative that a competent clinical evaluation follow the screening test to avoid overdiagnosis.

Problem With Screening Scales for (Any) Bipolar Disorder Per the principle of medical screening described above: If used, screening scales should be administered prior to the clinical evaluation, with the clinician following up on positive screens with a more comprehensive

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assessment. No research group has advocated an alternative manner of using the scale. The developers of these scales likewise do not recommend otherwise. Therefore, a clinical interview is always necessary regardless of the results of the scale. This is particularly important in the diagnosis of BD II, for which no adequate screening scale currently exists. Importantly, there is also a concern that the use of screening scales could result in false positive diagnoses if the clinical evaluation is not sufficiently rigorous. If a clinician relies too much on the scale and views the scale as a case-finding or diagnostic measure instead of as a screening scale, then some (perhaps many) patients will be incorrectly diagnosed with bipolar disorder. There are multiple examples of researchers mis­ construing a positive result on a bipolar disorder screening measure as indicating caseness (Zimmerman 2012). Clinicians should be wary of making this error. To draw attention to the limitations of bipolar disorder screening scales in clinical practice, our clinical research group examined whether patients who screened positive were more likely to be diagnosed with bi­ polar disorder or BPD (Zimmerman et al. 2010a). A sample of nearly 500 psychiatric outpatients were evaluated with semistructured inter­ views and completed the MDQ. Among patients who screened positive on the MDQ, as many were diagnosed with BPD as were diagnosed with bipolar disorder, although no breakdown was given of the number of pa­ tients diagnosed with BD I or II. Therefore, we do not recommend the use of bipolar disorder screening scales as a method to differentiate BPD and any bipolar disorder diagnoses.

Screening Scales for BPD The literature on underdiagnosis and screening for BPD is much less ro­ bust than it is for bipolar disorder generally, although perhaps larger than that for BD II specifically. In an early report from our clinical re­ search program, BPD diagnoses derived from structured and unstruc­ tured clinical interviews were compared in two groups of psychiatric outpatients seen in the same practice (Zimmerman and Mattia 1999b). In the structured interview cohort, individuals were 35 times more often diagnosed with BPD than individuals evaluated with an unstructured clin­ ical interview. Other studies have similarly found that the rate of BPD diagnoses was higher when the diagnosis was based on a semistructured diagnostic interview in comparison with an unstructured clinical inter­

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view, and that clinicians were reluctant to diagnose BPD during their in­ take diagnostic evaluation (Comtois and Carmel 2014; Magnavita et al. 2010). The most commonly studied self-report scale specific for BPD is the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) (Zanarini et al. 2003). Across the seven studies of the MSI-BPD, the sen­ sitivity of the scale was 80%. The above-described conceptual concerns regarding the use of a selfadministered screening scale for bipolar disorder apply as well to the use of such a scale for BPD. Screening scales should always be followed up with careful diagnostic interviewing and should not be used as a proxy for clinical diagnosis.

Conclusion Our goal in this chapter was to examine the relationship between BD II and BPD. How frequent is BPD in bipolar patients? Across studies, ap­ proximately 10% of patients with BPD had BD I and another 10% had BD II. Thus, a total of about 20% of patients with BPD were diagnosed with BD I or II. Similarly, approximately 20% of BD II patients were diagnosed with BPD, although only 10% of BD I patients were diag­ nosed with BPD. Much has been written about the link between bipolar disorder and BPD, and some authors have suggested that BPD is on the bipolar spec­ trum (Akiskal 2004; Perugi et al. 2003). It was therefore surprising that in the 15 studies examining the full range of personality disorders in pa­ tients with bipolar disorder, BPD was the most frequent in only 4 stud­ ies. However, BPD was the most frequent personality disorder in the only two studies of BD II. Why is there a seemingly stronger link between BD II and BPD than between BD I and BPD? We believe that this is primarily related to diag­ nostic error. Transient episodes of affective instability and emotional lability associated with BPD might be confused with hypomanic epi­ sodes, thereby resulting in false positive diagnoses (Paris 2004; Zimmer­ man et al. 2010a). This error is more common with BD II than with BD I, and we would hypothesize errors would be even greater if the diag­ nostic thresholds for BD II were lowered below the current standard, as some have proposed (Akiskal et al. 2000; Dunner 2003). Thus, some pa­ tients diagnosed with both BPD and BD II are likely to have false positive

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BD II diagnoses. Of course, some are also likely to have false positive BPD diagnoses. In clinical practice additional sources of diagnostic error include clini­ cal unfamiliarity with personality disorders, the perception that BD II is more easily treated (thus “erring on the side of caution”), the desire to protect patients from a stigmatizing diagnosis (Lewis and Appleby 1988), or lower reimbursement rates for treating personality disorders versus other psychiatric disorders (Gunderson et al. 2006). To us, the question is not whether diagnostic error exists, but rather which type of error pre­ dominates, as well as what can be done to reduce such error and which type of error is easier to reverse in the future. Screening scales, which have the potential of increasing recognition of BD II or BPD, also have the potential of increasing false positive diag­ noses. Screening scales need to be followed by a competent clinical eval­ uation, particularly for disorders like BD II and BPD, for which highly specific scales do not exist. Thus, there is little conceptual justification for recommendations for mental health clinicians to use screening question­ naires for BD II disorder in their clinical practice (Zimmerman 2012). Despite all the data, despite the considerations of risks of false positive and false negative diagnoses, and despite the alternative conceptualiza­ tions of what the DSM diagnostic criteria represent, in the final analysis the differential diagnosis of BD II and BPD may come down to a matter of diagnostic bias. Unfortunately, in the presence of diagnostic uncer­ tainty, clinicians are probably likely to diagnose the disorder they feel most comfortable treating.

KEY POINTS • About 20% of individuals with bipolar II disorder (BD II) also have borderline personality disorder (BPD). • BPD is twice as common in BD II as in bipolar I disorder (BD I). • About 10% of individuals with BPD also have BD II; another 10% have BD I. • Up to 40% of the patients with symptoms that meet criteria for BPD are overdiagnosed with bipolar disorder.

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• Transient episodes of affective instability and emotional lability associated with BPD can be confused with hypomanic episodes. • When the clinician is screening for BD II, it is helpful to inquire about hyperactivity and excess productivity in addition to asking questions about a change in mood. • Screening scales need to be followed by a competent clinical evaluation, particularly for disorders like BD II and BPD, for which highly specific scales do not exist.

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4 Psychiatric and Medical Comorbidities With Bipolar II Disorder Joshua D. Rosenblat, M.D.

Michael J. Ostacher, M.D., M.P.H., M.M.Sc.

Roger S. McIntyre, M.D., F.R.C.P.C.

In bipolar II disorder (BD II), comorbidity is the rule rather than the exception. Because core features of BD II are often the most dominant and disabling symptoms, comorbid disorders (both medical and psychiatric) are often missed, hidden in the shadows of the promi­ nent mood symptoms (MacQueen and Young 2001). However, unrec­ ognized and untreated comorbid disorders may contribute greatly to suffering, functional impairment, and prevention of full remission and recovery (McIntyre et al. 2012). Comorbidity is also associated with a more severe BD II illness course with more severe mood symptoms, in­ creased suicidality, increased treatment resistance, and shortened life expectancy (Jerrell et al. 2010; Undurraga et al. 2012; Valtonen et al. 2005). As such, an understanding and appreciation of the common co­ morbid conditions of BD II is essential for effective management of BD II itself. Screening, diagnosis, and treatment of comorbid disorders should be considered an integral part of the management of all patients with BD II. 71

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Bipolar II Disorder: Recognition, Understanding, and Treatment

The present chapter focuses on the epidemiology, phenomenology, and management of common medical and psychiatric comorbidities in BD II. The epidemiology and impact of comorbidity in BD II are relatively understudied compared with bipolar I disorder (BD I) and major depres­ sive disorder (MDD) (Blanco et al. 2017; Merikangas et al. 2007). It is sometimes necessary to extrapolate comorbidity data from studies that include both BD I and BD II participants in the absence of recent, robust data for BD II; however, an appreciation for potential differences in co­ morbidity rates and phenomenology is required. Treatment of comorbid psychiatric disorders in BD II is also understudied, at times requiring ex­ trapolation from BD I data along with expert opinion (McIntyre et al. 2012).

Case Vignette Joan is a 32-year-old woman with a 4-month history of low mood, an­ hedonia, poor sleep, and low energy. She also reports having negative thoughts about herself, feeling that she is worthless and “empty,” and that “I don’t even know who I am.” She has frequent thoughts that life is not worth living; however, she has never tried to end her life. She fre­ quently self-harms, cutting herself on her thighs to feel relief from her emotional suffering. She has withdrawn from her friends and thinks that “they all hate me.” Over 3 months, she gained 20 pounds, because she has had an increased appetite, “especially for junk food,” and at times, binges, eating more than 2,000 calories in a single sitting. She feels very guilty, however, and cannot stop herself. She does not purge or restrict after. She also reports feeling anxious and unable to control her worries “for as long as I can remember.” Her anxiety has worsened and is now negatively impacting her sleep because she is restless at night and thinks about all the mistakes she has made and worries about what the next day will hold. When she falls asleep, she gets up multiple times through­ out the night, often waking up during nightmares of childhood abuse (physical and sexual) she experienced from the age of 6–10. To help fall sleep, she sometimes drinks a bottle of wine (4–5 times per week). At times, she will also have a drink when she wakes up, “to help get through the day.” On review of past psychiatric history, she reports having simi­ lar depressive episodes before, “probably four or five times starting when I was 12,” with these episodes lasting 6 months to 1 year. She has not received treatment before and has often rejected the help when of­ fered. She also reports having had two episodes during which she “felt great! I didn’t need to sleep for 2 weeks and still had tons of energy. I had so many ideas and was incredibly productive, cleaning my entire house and finishing numerous projects for school. My friends thought

Psychiatric and Medical Comorbidities With Bipolar II Disorder

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I was acting weird though, talking too quickly, jumping from topic to topic and acting more impulsively. But I am always impulsive so I don’t know why they were so concerned.” She has never been admitted to hospital and never had psychotic symptoms. She also reports having lifelong difficulties with focusing. On past medical history, she reports having asthma, irritable bowel syndrome, migraines, and that she is overweight. She is not currently taking any medications.

Psychiatric Comorbidities Epidemiology and Phenomenology As illustrated in the case vignette above and supported by numerous studies (Amann et al. 2017; Angst et al. 2011, 2013; Forty et al. 2014; Merikangas et al. 2007, 2011), psychiatric comorbidity is present in al­ most all patients with BD II. In the largest international study to assess and report comorbidity rates of BD II, the World Health Organization (WHO) World Mental Health Survey Initiative performed cross-sectional, face-to-face household surveys of 61,392 community adults in 11 coun­ tries in the Americas, Europe, and Asia, assessing participants with the World Mental Health version of the WHO Composite International Di­ agnostic Interview (version 3.0), a fully structured, lay-administered psy­ chiatric diagnostic interview (Merikangas et al. 2011). In this study, 83% of participants diagnosed with BD II had at least one comorbid psychi­ atric diagnosis, yielding an odds ratio of 10.3 (95% confidence interval [CI] 7.1–14.9) compared with the general population. Furthermore, 58.3% of participants with BD II had three or more comorbid psychiat­ ric diagnoses. The most common diagnostic comorbidity category was anxiety disorders (75%), followed by impulse control disorders (52%) and substance use disorders (37%). Rates of specific comorbidities are further summarized in Table 4–1 along with comorbidity rates identi­ fied by the National Comorbidity Study (specific to the United States) (Merikangas et al. 2007, 2011). Given the high co-occurrence of BD II with anxiety disorders, numer­ ous investigators have proposed that this comorbid pattern may be better understood as a single disorder with overlapping etiological and patho­ physiological pathways rather than two separate disorders occurring in parallel (Pavlova et al. 2015). Indeed, some studies have shown specific genetic differences between BD II with versus without comorbid anxiety, further suggestive of a biological subtype (Wang et al. 2014). Prospective

Lifetime prevalence 8% 27% 73% 34% 37% 51% 55% 21% 43% 89% 23% 42%

Anxiety disorders Agoraphobia Panic disorder Panic attacks PTSD GAD Specific phobia Social phobia OCD SAD Any anxiety disorder

Impulse-control disorders IED ADHD 4 10

7 8 7 7 8 8 9 17 8 18

ORa

NCS (U.S. only)

19% 28%

9% 17% 64% 25% 33% 41% 36% 12% 39% 75%

Lifetime prevalence

4 9

10 8 7 6 9 6 7 6 8 9

ORa

WMHIS (11 countries)

Summary of common comorbidities with estimated lifetime prevalence in bipolar II disorder compared with general population based on the National Comorbidity Survey (NCS; Merikangas et al. 2007) and World Mental Health Initiative Survey (WMHIS; Merikangas et al. 2011)

Comorbid disorder

TABLE 4–1.

74 Bipolar II Disorder: Recognition, Understanding, and Treatment

36% 19% 24% 9% 40% 96% 7% 3% 86%

Substance use disorder Alcohol abuse Alcohol dependence Drug abuse Drug dependence Any substance

Any disorder Any disorder Exactly 1 disorder Exactly 2 disorders ≥3 Disorders 25 5 3 58

4 4 4 3 4

7 3 8

83% 14% 11% 58%

34% 17% 17% 8% 37%

29% 16% 52%

10 4 6 Not available

4 5 4 5 4

7 4 7

Note. All prevalence and odds ratio (OR) data are rounded without confidence intervals for simplicity. ADHD = attention-deficit/hyperactivity disorder;

CD=conduct disorder; GAD= generalized anxiety disorder; IED=intermittent explosive disorder; OCD=obsessive-compulsive disorder; ODD =oppositional defiant

disorder; PTSD= posttraumatic stress disorder; SAD= social anxiety disorder.

aAll reported ORs (compared with general population) were statistically significant.

38% 19% 70%

Summary of common comorbidities with estimated lifetime prevalence in bipolar II disorder compared with general population based on the National Comorbidity Survey (NCS; Merikangas et al. 2007) and World Mental Health Initiative Survey (WMHIS; Merikangas et al. 2011) (continued)

Impulse-control disorders (continued) ODD CD Any impulse control disorder

TABLE 4–1.

Psychiatric and Medical Comorbidities With Bipolar II Disorder 75

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Bipolar II Disorder: Recognition, Understanding, and Treatment

studies have also revealed that symptoms of anxiety are often present prior to onset of initial mood symptoms, suggestive of anxiety poten­ tially being part of the prodrome of bipolar disorder in some individuals (Nabavi et al. 2015). The presence of comorbid anxiety disorders is also associated with increased suicidal ideations and attempts, greater severity and frequency of mood episodes, treatment resistance, and higher rates of substance use disorders (Nabavi et al. 2015). Intriguingly, some earlier research also suggested poorer response to lithium when comorbid anxi­ ety was present (Young et al. 1993). Given the genetic, phenomenologi­ cal, and treatment response differences, patients with comorbid anxiety may represent an important subpopulation of BD II with a unique phe­ notype and potentially dissimilar pathophysiology, requiring different treatment approaches than are used in the treatment of patients with BD II in the absence of comorbid anxiety. Substance use disorders are also common and greatly complicate the treatment of BD II and comorbid anxiety. Alcohol use disorder is the most common substance use disorder, affecting approximately one-third of pa­ tients with BD II (Di Florio et al. 2014). Comorbid substance use may also lead to diagnostic challenges, because it may be unclear whether the substance use triggered the mood episode (e.g., cocaine-induced hypomania) or whether the mood episode led to increased substance use through impulsivity related to hypomania or reported “self-medicating” related to depression or anxiety. Importantly, even in the absence of diag­ nostic clarity, treating both the mood and substance use disorder con­ temporaneously is essential for full recovery. Historically, providers often took a sequenced treatment approach and asked patients to seek help for their substance use disorder before they could have their mood disorder treated, or vice versa. More recently, this approach has been found to be largely ineffective, and the simultaneous treatment of both disorders has been shown to be the optimal approach (to be further discussed in the section “Principles of Management of Comorbid Psychiatric Disorders”). Indeed, a guiding principle for the treatment of all BD II comorbidities is concurrent, rather than sequenced, treatment. Disorders associated with significant impulsivity (e.g., attention-deficit/ hyperactivity disorder [ADHD], intermittent explosive disorder, bingeeating disorder [BED]) affect approximately half of BD II patients, with ADHD being the most common of these (Wingo and Ghaemi 2007). Comorbid ADHD has also been associated with earlier age at onset of bi­

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polar disorder (Sachs et al. 2000) and increased suicidality, as well as de­ pressive, cyclothymic, irritable, and anxious temperaments (Harmanci et al. 2016). Comorbid ADHD can also create diagnostic challenges be­ cause there is significant symptomatic overlap with mood symptoms, such as distractibility, impulsivity, psychomotor agitation, and hyperac­ tivity in hypomania and poor concentration and executive dysfunction in depression. Understanding the temporality of symptoms is impor­ tant, because untreated ADHD entails longitudinal and continual symp­ toms, whereas mood disorders occur episodically and their symptoms cluster contemporaneously with other mood symptoms. Notably, un­ treated ADHD symptoms can worsen mood symptoms because of the significant functional impairments arising from untreated ADHD and sequelae of these impairments, leading to worsening mood symptoms (Harmanci et al. 2016). Although not classified as an impulse-control dis­ order, BED is another important comorbidity with significant neuro­ biological overlap with impulse-control disorders (Ely and Cusack 2015). Moreover, BED is very common in BD II, especially in females, with sig­ nificant medical sequelae, such as obesity, insulin resistance, and delayed recovery from depressive episodes (Boulanger et al. 2018). Approximately 10%–20% of bipolar disorder patients have comorbid BED with similar rates of comorbidity in BD I and BD II (Hudson et al. 2007). For a discussion of co-occurring borderline personality disorder and BD II, see Chapter 3, “Interface Between Borderline Personality Disorder and Bipolar II Disorder.” Taken together, psychiatric comorbidity is present in a majority of BD II cases. Anxiety disorders, ADHD, impulse-control disorders, sub­ stance use disorders, binge-eating disorder, and borderline personality disorder are particularly common. A thorough evaluation of common comorbid symptoms/disorders is essential in the evaluation and treat­ ment of BD II. Rates of psychiatric comorbidity are similar in BD I and BD II with the exception of borderline personality disorder, which is sig­ nificantly more common in BD II than in BD I.

Explanatory Models for High Rates of Psychiatric Comorbidity Numerous explanatory models have been proposed to explain the high rates of psychiatric comorbidity in mood disorders in general and in BD II specifically. These models broadly fall into the following four categories:

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Bipolar II Disorder: Recognition, Understanding, and Treatment

1. Overlapping symptoms. Comorbid diagnoses are an epiphenomena of misdiagnosis given the complexity of symptoms associated with BD II and the overlap of symptoms (i.e., diagnostic criteria) with nu­ merous other disorders. 2. Overlapping pathophysiology. BD II has pathophysiological overlap with numerous other disorders (e.g., shared dysfunctional neural circuits, genetic contributions, environmental factors). 3. Premorbid conditions as predisposing factors for BD II. Comorbid symptoms/disorders predate the onset of BD II, playing an etiological role in the onset and progression of disease. 4. BD II as a predisposing factor for comorbid disorders. BD II predates comorbidity, as comorbid psychiatric diagnoses are downstream se­ quelae of the bipolar disorder disease process. The issue of overlapping symptoms is often problematic and requires careful attention, because symptoms may “count” (i.e., be best explained by) toward diagnostic criteria for a mood episode (i.e., depression, hypomania, or a mixed state), or be better explained by a comorbid condition (e.g., chronic impulsivity as part of ADHD or borderline personality disorder), or may have contributions from both BD II and the comorbid condition (e.g., chronic impulsivity as part of borderline personality disorder along with periods of marked increases in impulsivity with in­ creased energy and decreased need for sleep during hypomanic episodes). Because BD II is an episodic illness characterized by syndromal mood episodes, understanding the timing of symptoms is often the key to at­ tributing symptoms to BD II versus comorbid disorders. Comorbid dis­ orders that wax and wane over minutes or hours may be separated from mood episodes that last for days to months. For example, as illustrated in the case vignette earlier in this chapter, the patient reported chronic impulsivity, which may be secondary to ADHD and/or borderline personality; however, she also reported sus­ tained periods of increased impulsivity (which her friends noticed) that were contemporaneously associated with other symptoms of hypoma­ nia (e.g., increased energy, decreased need for sleep, more talkative). In Joan’s case, impulsivity may be secondary to both hypomania and comor­ bid diagnoses; however, these disorders are variably contributory to symptoms at different points in her history. Common overlapping symp­ toms are further summarized in Table 4–2. For each of these examples,

Psychiatric and Medical Comorbidities With Bipolar II Disorder

TABLE 4–2.

Comorbid disorder

79

Overlapping symptoms of bipolar II disorder mood episodes and common comorbid disorders Overlapping symptoms Overlapping symptoms with depressive episodes with hypomanic episodes

Irritability, psychomotor Anxiety disorders Irritability, psychomotor agitation, racing thoughts, agitation, poor sleep, low cognitive dysfunction energy (easy fatigability), negative cognitions, rumination, social avoidance, cognitive dysfunction Hyperactivity, irritability, Psychomotor agitation, Impulse control psychomotor agitation, cognitive dysfunction disorders distractibility, inattention, impulsivity Substance use described as Impulsive excessive Substance use substance use “self-medicating” disorders Impulsivity, angry Negative cognitions, Personality outbursts, irritability, interpersonal problems, disorders mood lability, affective social withdrawal, dysregulation rejection sensitivity, suicidality, subjective emptiness Change in eating patterns Change in eating patterns Eating disorders (increased or decreased) (increased or decreased)

careful attention to a patient’s baseline, timing of symptoms, and co­ occurring symptoms may help to ascertain the most appropriate diag­ nostic explanation of symptoms. Notably, making this determination is much more than an academic exercise: it facilitates an understanding of the underlying disorder causing current symptoms (even if multiple dis­ orders are present) and has direct treatment implications. Studies have demonstrated overlapping pathophysiology of BD II and common comorbidities (Frías et al. 2016; Krishnan 2005; Wang et al. 2014). Both genetic and environmental risk factors have been identified that increase the risk of developing BD II and common comorbid disor­

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Bipolar II Disorder: Recognition, Understanding, and Treatment

ders (Post et al. 2016). For example, early childhood adversity has been shown to interact with genetic risk factors to increase risk for bipolar dis­ order, as well as anxiety, impulse control, substance use, and personality disorders (Benjet et al. 2010; Binder 2017). For patients with BD II plus multiple comorbidities, this presentation may be a phenotypic manifesta­ tion of the same underlying processes, rather than separate parallel pro­ cesses leading to different diagnoses (i.e., specific environmental risk factors interacting with genetic and epigenetic risk factors to lead to com­ plex presentation of numerous symptoms that would receive numerous different comorbid diagnoses under current diagnostic nosology). The concept of overlapping pathophysiology as an explanation for high rates of comorbidity is not unique to BD II. High rates of comorbid­ ity in psychiatric disorders and overlapping symptomatology have led the National Institute of Mental Health to create the Research Domain Criteria (RDoC) framework to try to identify common factors or “ele­ ments” (e.g., genes, molecules, networks) that may lead to dysfunction in various domains (e.g., cognitive systems, arousal/regulatory systems) and that manifest in a plethora of symptoms and diagnoses (Insel et al. 2010). In the future, understanding these transdiagnostic processes may allow for “precision medicine,” with treatment tailored to underlying pathophysiology rather than targeting symptoms that likely have het­ erogeneous etiologies (Insel 2014). In addition to overlapping pathophysiology underpinning comor­ bidity, comorbid disorders may also be a complication of BD II or vice versa. Stressful life experiences resulting from living with BD II may increase the risk of developing anxiety or substance use disorders. De­ velopment of comorbid disorders may also be a consequence of neuro­ progression of neuropsychiatric dysfunction associated with recurrence of mood episodes (Berk et al. 2011). Similarly, the neuropsychiatric ef­ fects of comorbid disorders may increase risk of developing BD II later in life. For example, anxiety disorders often precede initial mood symp­ toms of BD II, leading some investigators to suggest that anxiety may be part of a BD II prodrome (Hafeman et al. 2016). Taken together, several evidence-based explanatory models have been identified to account for high rates of comorbidity in BD II. It is likely that all models are contributory in this heterogeneous population, and under­ standing the underlying reasons for comorbidity in a specific patient might provide further insights into more personalized treatments.

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Principles of Management of Comorbid Psychiatric Disorders Effective management of comorbid disorders begins with effective screening for relevant comorbidities. All patients with BD II should be thoroughly screened for common psychiatric comorbidities, including but not limited to anxiety disorders, ADHD, substance use disorders, borderline personality disorder, and BED. Once identified, comorbid disorders must be treated concurrently with BD II. Previous clinical lore suggested that a sequenced treatment approach (i.e., treating the mood disorder first and then comorbidities or vice versa) was preferable; how­ ever, improved outcomes have been demonstrated with the simultane­ ous treatment of comorbid disorders (Pettinati et al. 2013; Tolliver and Anton 2015). Moreover, ineffective treatment of a comorbidity may lead to treatment resistance in BD II and vice versa. Both psychosocial and psychopharmacological treatments should be utilized to treat comorbid conditions. For anxiety disorders, cognitive-behavioral therapy and mindfulness are effective options (Stratford et al. 2015). For anxiety disorders in the absence of BD II, antidepressants are the usual first-line evidence-based treatment. When anxiety disorders are comorbid with BD II, conven­ tional wisdom has argued that treatment with antidepressants may carry the risk of destabilization, leading to a hypomanic switch (Leverich et al. 2006). However, it is increasingly apparent that antidepressant medica­ tions carry a significantly lower risk of destabilization in BD II com­ pared with BD I (Altshuler et al. 1995, 2017; Liu et al. 2017) (see Chapter 9, “Antidepressant Medications in Bipolar II Disorder”). Nevertheless, for patients with current symptoms of hypomania, or a propensity for hypomanic episodes (or hypomanic symptoms as part of mixed features during depressive episodes), antidepressants should be avoided. If hy­ pomanic symptoms emerge, all antidepressants should be discontinued because they may be worsening these symptoms. Quetiapine is the most robustly studied treatment in BD II. All other pharmacological treatments (e.g., other antipsychotics, conventional mood stabilizers) have showed minimal evidence of efficacy and are thus used off-label based on clinician experience. If these off-label treat­ ments are already being used, doses of antipsychotics and/or conven­ tional mood stabilizers may be optimized to control comorbid symptoms of anxiety (Rakofsky and Dunlop 2011). Atypical antipsychotics are

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Bipolar II Disorder: Recognition, Understanding, and Treatment

often effective at mitigating comorbid anxiety during depression, hypomania, mixed states, and euthymic periods. Optimizing currently pre­ scribed mood stabilizers (rather than adding an antidepressant) to treat anxiety may also have the added benefit of limiting polypharmacy, which is common and frequently problematic in BD II. Gabapentin and pre­ gabalin represent additional off-label alternatives that do not carry the same risk as antidepressants for destabilization (Houghton et al. 2017; Keck et al. 2006). These agents may also help treat comorbid alcohol use disorder and pain disorders given the demonstrated anticraving and an­ algesic effects of gabapentin and pregabalin (Mason et al. 2018; Moore et al. 2011). For more severe symptoms of anxiety, intermediate or longer half-life benzodiazepines may be required for the short term. However, given the high rates of comorbidity with substance use disorders, use of benzodiazepines must be carefully monitored and might not be appro­ priate for patients with comorbid alcohol or benzodiazepine use disorders. Notably, benzodiazepine prescribing may be associated with an in­ creased risk of relapse and increased symptom severity in BD I and BD II (Perlis et al. 2010). For comorbid substance use disorders, comprehensive addiction pro­ grams should be utilized that provide biological (e.g., anticraving med­ ications), psychological (e.g., motivational interviewing, integrated psychotherapy), and social (e.g., peer support, community programs) interventions. For these cases, the effective collaboration between mood disorder and addiction teams is often required to effectively and simul­ taneously treat these often treatment-resistant disorders (McIntyre et al. 2012). For ADHD, stimulants are the most efficacious options when used with added caution to monitor for the potential emergence of hypomanic symptoms (Scheffer et al. 2005). To prevent treatment emergent hypomania, stimulants should only be used along with adequate moodstabilizing treatment and avoided in patients with current hypomanic symptoms, rapid-cycling, or mixed features (Klassen et al. 2010). For patients with a low propensity for hypomanic symptoms and a greater propensity for depressive symptoms (as is frequently the case in BD II), stimulants may be appropriate ADHD treatment while also having po­ tential antidepressant effects (McIntyre et al. 2013, 2017). The use of stimulants (specifically lisdexamfetamine) has also been shown to be ben­ eficial for the treatment of comorbid BED with a low propensity for de­ stabilization in BD (McElroy et al. 2015).

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For comorbid personality disorders, dialectical behavioral therapy may be particularly effective, specifically for borderline personality dis­ order and chronic suicidality (Goldstein et al. 2015b; Linehan et al. 2015). In some cases, long-term psychodynamic psychotherapy may also be indicated. An essential part of treating comorbid borderline per­ sonality disorder is determining whether the symptoms are better ex­ plained by the personality disorder or by core mood symptoms of BD II. If the symptoms are better explained by BD II, optimization of medica­ tion is usually indicated. However, if symptoms are more related to the personality disorder, medications will likely have limited effect. Indeed, medications might be inappropriately increased (or added to), leading to polypharmacy and oversedation with continued, perceived treatment resistance. Medications may still play an important role in managing over­ lapping symptoms of BD II and borderline personality (Frankenburg and Zanarini 2002). Therefore, within the context of BD II with border­ line personality disorder, the clinician’s formulation must be continually questioned when symptoms persist despite a well-executed treatment plan. Taken together, effective treatment of comorbidities starts with effec­ tive screening and diagnosis (McIntyre et al. 2012). Contemporaneous treatment of BD II, along with identified comorbidities, with biological, psychological, and social interventions is required to achieve remission of all disorders. The use of mood stabilizers to treat both core BD II symp­ toms along with comorbidities may be an effective approach that limits polypharmacy. Continual questioning of initial diagnoses and formula­ tion should occur within the context of inadequate response to evidencebased treatments.

Medical Comorbidities Epidemiology Significant medical comorbidity is also common in both BD I and BD II (Carlborg et al. 2015; Forty et al. 2014; Jerrell et al. 2010). Greater than 90% of BD II patients have significant medical comorbidity, with ap­ proximately 40% having three or more significant medical comorbidi­ ties over their lifetime (Crump et al. 2013; Sylvia et al. 2015). Increased rates of medical comorbidity, specifically cardiovascular disease, are responsible for the 10- to 20-year decrease in life expectancy in bipolar

84

Bipolar II Disorder: Recognition, Understanding, and Treatment

disorder compared with the general population (Kessing et al. 2015). Given the high rates of cardiovascular disease, the American Heart As­ sociation has now recognized bipolar disorder as a risk factor for early cardiovascular disease (Goldstein et al. 2015a). Larger studies have reported rates of medical comorbidity for BD, combining participants with BD I and BD II in their sample. The smaller studies that separated results based on BD I versus BD II showed similar rates of medical comorbidity for the two subtypes (Sylvia et al. 2015) with few exceptions, such as migraines (Fornaro and Stubbs 2015) and irritable bowel syndrome (IBS) being more prevalent in BD II (Bortolato et al. 2017; Lee et al. 2015; Tseng et al. 2016; Walker et al. 1990). Medical comorbidities of bipolar disorder span numerous different systems, as shown in Table 4–3. Notably, there are different rates of comorbidity, with U.S. samples having greater medical comorbidity compared with Eu­ ropean samples (Post et al. 2014b). Cardiovascular disease (e.g., early atherosclerosis) (Goldstein et al. 2015a; Swartz and Fagiolini 2012) and metabolic/endocrine disorders (e.g., overweight, obesity, type 2 diabetes mellitus, dyslipidemia, thyroid disorders) (Elmslie et al. 2001; Mansur et al. 2015) are particularly com­ mon and problematic in BD and have been associated with a greater number of mood episodes, more frequent psychiatric hospitalizations, suicidality, increased depression severity, decreased probability of symp­ tomatic remission, substance use disorders, and shorter time to episode recurrence (Fagiolini et al. 2003; Post et al. 2014a; Schaffer et al. 2015; Undurraga et al. 2012; Valtonen et al. 2005). Both BD I and BD II have also been associated with increased rates of inflammatory disorders, affecting multiple systems (Table 4–3). For example, BD has been associated with significantly increased rates of systemic lupus erythematosus, environmental allergies, asthma, inflam­ matory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, multiple sclerosis, and psoriasis (Rosenblat and McIntyre 2015; SayuriYamagata et al. 2017). Numerous other conditions that have inflamma­ tion as a key pathophysiological factor have also been associated with increased rates of BD and vice versa. These include, but are not limited to, chronic infections (Benros et al. 2013; Horrobin and Lieb 1981), pain disorders (migraines and fibromyalgia) (Fornaro and Stubbs 2015; Kudlow et al. 2015), and, as previously discussed, cardiovascular and metabolic disorders, which are also associated with a more severe illness

Psychiatric and Medical Comorbidities With Bipolar II Disorder

TABLE 4–3.

85

Medical comorbidities associated with both bipolar I and bipolar II disorders

Category

Specific Conditions

Classic inflammatory disorders

Inflammatory bowel disease, systemic lupus erythematosus, autoimmune thyroiditis, Guillain-Barré syndrome, autoimmune hepatitis, rheumatoid arthritis, multiple sclerosis, psoriasis, allergies and asthma, chronic obstructive pulmonary disease Irritable bowel syndrome, peptic ulcer disease, liver disease, inflammatory bowel disease Toxoplasma gondii, HIV/AIDS, cytomegalovirus, human herpes virus 6, possibly herpes simplex virus 1 Myocardial infarction, cerebral vascular disease, atherosclerosis, hypertension Type II diabetes mellitus, dyslipidemia, obesity/overweight, metabolic syndrome, gout Fibromyalgia, migraines

Gastrointestinal disorders

Chronic infections

Cardiovascular disease Metabolic disorders

Pain disorders

course and greater cognitive dysfunction (Perugi et al. 2015; Rosenblat et al. 2015).

Explanatory Models of High Rates of Medical Comorbidity The underlying causes for the high rates of medical comorbidity are mul­ tifactorial as illustrated in Figure 4–1. Previously it was unclear if medical comorbidity was only secondary to the adverse effects of BD treatments (e.g., metabolic side effects of mood stabilizers) (Krishnan 2005). Nu­ merous investigators debated the role of BD pathophysiology in itself as a contributing factor to increased rates of medical comorbidity (Goldstein et al. 2009). The association between BD II and increased rates of

86

Bipolar II Disorder: Recognition, Understanding, and Treatment

medical comorbidity and mortality can be partially explained by unhealthy behaviors (e.g., smoking, physical inactivity, poor diet) and iatrogenic effects of mood stabilizers (Kupfer 2005; McElroy and Keck 2014); how­ ever, the association remains significant after these factors are controlled for, suggesting additional mechanisms underlying the association, which may be intrinsic to BD pathophysiology itself (Leboyer et al. 2012). The role of immune dysfunction in the etiology and pathophysiology of BD has been increasingly shown to be important (Rosenblat and McIntyre 2017a). Numerous studies have shown increased levels of proinflammatory cytokines centrally and peripherally in BD I and BD II, suggestive of chronic low-grade inflammation with further immune dysregulation occurring during depressive episodes (Goldsmith et al. 2016). Preclinical and clinical models have also demonstrated numerous mechanisms whereby dysfunction of the immune system may lead to the mood and cognitive dysfunction observed in bipolar disorder. These mechanisms have been extensively summarized elsewhere and include microglial dysfunction, monoamine changes, oxidative stress, and hy­ pothalamic-pituitary-adrenal axis dysregulation, among others (Rosen­ blat and McIntyre 2016, 2017a). Inflammation has also been proposed as one of the mediators of neuroprogression and the kindling phenome­ non observed in bipolar disorder whereby mood episodes have a cumula­ tive effect on brain function through the neuroinflammatory effects of each mood episode (Berk et al. 2017). Most comorbid disorders have inflammation as a key pathophysio­ logical mechanism of disease progression (e.g., cardiovascular disease, metabolic disorders, autoimmune disorders, chronic infections, pain disorders). As such, immune dysfunction may be a common underlying mechanism precipitating and perpetuating BD II symptomatology while also manifesting systemically in the form of inflammatory medical condi­ tions (Leboyer et al. 2012; Rosenblat and McIntyre 2015). Causality is likely bidirectional because inflammatory conditions have been shown to predate initial presentations of bipolar disorder and to worsen following bipolar disorder illness onset (Marrie et al. 2018). Given the inflamma­ tory nature of both bipolar disorder and its medical comorbidities, tar­ geting the immune system shows promise for simultaneously improving bipolar disorder along with its medical comorbidities. Indeed, research suggests that anti-inflammatory medications may have antidepressant effects in bipolar disorder (Rosenblat et al. 2016).

FIGURE 4–1.

• Increased binge-eating disorder • Chronic low-grade inflammation • Dysfunctional reward pathways

Intrinsic factors

• Weight gain • Insulin resistance • Hypertension • Dyslipidemia • Renal dysfunction • Thyroid dysfunction

Treatment side effects

• Sedentary lifestyle • Poor dietary habits • Increased smoking • Increased alcohol use

• Metabolic syndrome • Cardiovascular disease • Lung disease • Renal disease • Liver disease • Autoimmune disorders

Increased medical comorbidity

Factors impacting increased rates of medical comorbidity in bipolar II disorder (BD II).

• Increased suicidality • More relapse/recurrence • Treatment resistance • Increased hospitalizations • Increased depression severity

Worse prognosis

BD II

Underlying etiological factors

Lifestyle factors

Psychiatric and Medical Comorbidities With Bipolar II Disorder 87

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Bipolar II Disorder: Recognition, Understanding, and Treatment

The high rate of gastrointestinal (GI) disorders in BD II is also of in­ terest. In one study, involving a clinic sample of 136 patients, BD II was associated with increased rates of inflammatory bowel disease, IBS, pep­ tic ulcer disease, and hepatitis (Karling et al. 2016). Furthermore, rates of GI disorders are higher in BD II compared with BD I or MDD for an unknown reason (Forty et al. 2014; Lee et al. 2015; Tseng et al. 2016). Dysfunction of the gut microbiota has been implicated as a potential mediator of the high co-occurrence of GI disorders and BD (Alam et al. 2017; Cryan and Dinan 2012). Abnormalities in the gut microbiota have been shown to increase the risk of numerous GI disorders (due to the lo­ cal negative effects of the bacteria) and additionally may negatively im­ pact brain function through the gut-brain axis (Cryan and Dinan 2012). As such, abnormalities in the gut microbiota may be simultaneously having deleterious effects directly in the GI tract along with negatively impacting mood and cognitive function in the brain directly through gutbrain neuroendocrine tracts and indirectly through the GI release of pro-inflammatory cytokines (Rios et al. 2017). Abnormal microbiota is of particular interest in IBS because this is the only “organic” GI etiology that has been identified in this disorder, which is often characterized as a “functional bowel disorder” with primarily psychological origins. With the known dysfunction of the gut microbiota, intriguingly, IBS has been consistently associated with significantly elevated rates of bipolar disor­ der, as indicated by numerous large epidemiological studies and meta­ analyses (Forty et al. 2014; Lee et al. 2015).

Principles of Management of Medical Comorbidities When the clinician is screening for treatable medical comorbidities, the following information should be obtained at initial assessment: list of known medical comorbidities, smoking status, alcohol use, pregnancy status, current medications, and family history of cardiovascular risk factors. Obtaining this information may allow for establishing an initial index of suspicion for possible comorbidities. Knowledge of comor­ bidities may also influence selection of treatments, as numerous mood stabilizers may worsen specific comorbidities (e.g., quetiapine and olan­ zapine worsening cardiometabolic profiles) (Rosenblat and McIntyre 2017b). Prior to any pharmacological treatments being started, the fol­ lowing investigations should also be conducted to establish baseline val­ ues: waist circumference, body mass index (weight and height), blood

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pressure, complete blood count, electrolytes, urea, creatinine, liver func­ tion tests, fasting glucose, and fasting lipid profile. After initiation of mood stabilizer(s), treatment-specific monitoring should be conducted to allow for early detection of new onset (or worsening) of medical dis­ orders as recommended by monitoring guidelines (Ng et al. 2009). In addition to this screening and monitoring, psychoeducation should be provided specifically about the risks of cardiometabolic effects of most treatments and the importance of a healthy lifestyle in this population (e.g., heart healthy diet, exercise and limiting alcohol, smoking and other substance use) (Bauer et al. 2016). If history or investigations are suggestive of any medical comorbidities, collaboration with the primary care physician and/or relevant medical specialist (e.g., endocrinologist, nephrologist, cardiologist, rheumatolo­ gist) would be required for further assessment and management of medical comorbidities. Although the management of these medical co­ morbidities would usually not fall under the care of the psychiatrist, of­ ten the psychiatrist may be seeing the patient most frequently (compared with other providers) and so may still play an important role in advocat­ ing for appropriate medical care. Advocating for medical care in BD II is of particular importance given the clear evidence that patients with BD receive suboptimal medical care compared with the general population, even though their medical burden is much greater (Bahorik et al. 2017; Phelps and James 2017). In addition to collaborations with medical specialists to effectively manage comorbidity, there is also a role for preventative medicine through careful selection of mood stabilizers to limit iatrogenic medical disor­ ders. Most notable and modifiable are the metabolic effects of mood sta­ bilizers, because there is a large range of metabolic effects, as shown in Figure 4–2. Selecting mood stabilizers with minimal metabolic effects for all patients may be beneficial when possible (balancing the need for effectiveness), especially for patients with known risk factors for cardio­ vascular disease. If significant metabolic effects are detected (e.g., weight gain, insulin resistance), switching to a more metabolically neutral treatment would be advisable if possible (Rosenblat and McIntyre 2017b). Additionally, several weight loss medications (e.g., metformin, liraglutide) may be of benefit; however, these are outside of the scope of the current chapter (de Silva et al. 2016; Khera et al. 2016; Mizuno et al. 2014).

Lithium Risperidone Paliperidone

Quetiapine Valproate Chlorpromazine

Cardiometabolic side effects of commonly used mood-stabilizing medication.

Carbamazepine Oxcarbazepine Asenapine Haloperidol

Olanzapine

Clozapine

Greatest cardiometabolic side effects

This medication includes conventional mood stabilizers (lithium, valproate, carbamazepine, oxcarbazepine), second-generation antipsychotics (aripiprazole, lurasidone,

cariprazine, ziprasidone, brexpiprazole, asenapine, risperidone, paliperidone, quetiapine, olanzapine, clozapine), select first-generation antipsychotics (haloperidol,

chlorpromazine), and lamotrigine (used primarily for bipolar depression; however, has limited evidence for treatment of hypomanic episodes).

Source. Reprinted from Rosenblat JD, McIntyre RS: “Pharmacological Approaches to Minimizing Cardiometabolic Side Effects of Mood Stabilizing Medications.” Cur­ rent Treatment Options in Psychiatry 4(4):319–332, 2017b. Copyright 2017, Springer Nature. Used with permission.

FIGURE 4–2.

Aripiprazole Lurasidone Cariprazine Ziprasidone Brexpiprazole Lamotrigine

Least cardiometabolic side effects

90 Bipolar II Disorder: Recognition, Understanding, and Treatment

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Conclusion Both medical and psychiatric comorbidities are extremely common in BD II, affecting most patients. Common psychiatric comorbidities in­ clude anxiety disorders, substance use disorders, ADHD, BED, and bor­ derline personality disorder. Common medical comorbidities include cardiovascular disease, type II diabetes, dyslipidemia, migraines, auto­ immune disorders, and GI disorders. Moreover, psychiatric and medical comorbidities are associated with a more severe BD II illness course with increased treatment resistance, episode relapse and recurrence, and in­ creased suicidality. A careful assessment with sensitive screening meth­ ods is the first step in early detection, which may allow for timely remediation of comorbidities. Concurrent management of comorbid psychiatric and medical disorders, along with BD II–specific treatments, is essential. A collaborative care approach may be particularly beneficial in this patient group to treat all relevant comorbidities effectively. Future research is still needed to determine optimal treatments for BD II and its comorbidities.

KEY POINTS • In bipolar II disorder (BD II), comorbidity is the rule rather than the exception. • In BD II, greater than 80% of individuals will have at least one psychiatric comorbidity and greater than 90% at least one medical comorbidity. • The most common psychiatric comorbidities are anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), impulsecontrol disorders, and substance use disorders. • High rates of psychiatric comorbidity in BD II may be secondary to overlapping pathophysiology and shared genetic, epigenetic, and environmental risk factors. • The first step to the effective management of comorbid disorders is effective screening. • Psychiatric comorbidities should be treated contemporaneously, simultaneously targeting core BD II symptomatology and comorbid disorders.

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• Optimization of currently prescribed mood stabilizers (e.g., second-generation antipsychotics and anticonvulsants) often effectively decreases comorbid symptoms of anxiety during all phases of illness in BD II. • Stimulants may be used to effectively treat comorbid ADHD or binge-eating disorder; however, to prevent treatment emergent symptoms of hypomania, stimulants should always be prescribed along with adequate mood-stabilizing treatment and should be avoided when symptoms of hypomania or mixed features are present.

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5 Suicide and Bipolar II Disorder Ayal Schaffer, M.D., F.R.C.P.C. Mark Sinyor, M.Sc., M.D., F.R.C.P.C.

T

he topic of suicide risk and prevention in bipolar II disorder (BD II) is very important from a number of perspectives. In recent years there has been increased clinical and research interest in this area, driven by the disheartening data showing high rates of suicide in patients with BD II. It is no longer reasonable to accept that suicide is an unavoidable outcome for some people. Initiatives such as the Zero Suicide Model have been at the forefront of a renewed effort to establish systems of care that systematically assess for suicide risk and implement appropriate management strategies. Solely focusing on treating the underlying ill­ ness is not enough, with a strong evidence base emerging to support broad-based use of suicide prevention strategies. In this chapter we first examine the available epidemiological data on suicide in bipolar disorder, and when available in BD II specifically. We follow this discussion with an introduction to a bipolar disorder– specific suicide risk assessment model, informed by the latest infor­ mation on how specific clinical factors influence risk assessments for patients with BD II. Finally, we review management approaches. Be­ cause the focus of this chapter is on BD II, we highlight data specific to 99

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this subtype. Excluding data on combined bipolar I disorder (BD I) and BD II samples would leave too many gaps in the review, so we have also included these for context and comprehensiveness.

Epidemiology Overall Suicide Rates in Bipolar Disorder There is widespread evidence that rates of suicide attempts and suicide deaths are elevated in people with bipolar disorder. In this section, we review the epidemiology of suicide in bipolar disorder in general, and then move to what is known specifically about those with BD II. The two most common outcomes studied are suicide attempts and suicide deaths. Although the former is of interest because attempts can cause substan­ tial morbidity and are themselves a key risk factor for eventual death by suicide, there is also evidence that those who attempt suicide differ from those who die by suicide, and many suicide deaths are not preceded by a history of attempts. Therefore, when possible, we have emphasized data on suicide deaths rather than attempts as the most important outcome for informing prevention efforts. Numerous studies have reported on various aspects of the epidemiol­ ogy of suicide in bipolar disorder, with results influenced by factors such as characteristics of the sample (e.g., population-based vs. clinical), du­ ration of follow-up, and ascertainment of records of suicide death. In a seminal prospective study of a population-based Swedish sample, Osby et al. (2001) reported that suicide was the second most common cause of death among people with bipolar disorder after deaths from cardio­ vascular disease. Tondo et al. (2003) later conducted a pooled analysis of all published articles up to 2001 on bipolar disorder in general and reported an over­ all standardized mortality ratio (SMR) compared with the general pop­ ulation of 22.1 (95% CI=20.0–24.1). Although this ratio has been widely cited, it must be interpreted with caution, since important methodo­ logical aspects likely influenced the results. Even at face value, there is concern that an SMR of 22.1 may not be accurate. In the United States, suicide accounts for approximately 1.4% of all deaths. If those with bipo­ lar disorder have a 22-fold increased likelihood of dying by suicide at any point in their lives, this would translate into an approximately 30% likelihood of dying by suicide (taking into account that those with bipo­

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lar disorder account for a portion of the overall 1.4% of deaths), a risk of suicide that is much higher than suicide rates in any reported study in bipolar disorder or indeed of any specific clinical population. This dis­ crepancy may be largely due to the distinction between high-risk peri­ ods versus risk over an entire lifetime. Most population-based studies are not birth cohorts and track people from the time at which they have been identified as “patients” with bipolar disorder following contact with health care services. This selects for a subgroup of those with bipolar disorder who have come to clinical attention and may represent a more severe cohort, which may be especially relevant for those with BD II. Furthermore, the studies examine an epoch of monitoring that begins with active illness, and the period of time after a diagnosis of bipolar dis­ order and first contact with treatment services, such as hospitalization, is known to be associated with higher risk of suicide; therefore, extrap­ olation from this period to a lifetime will lead to an overestimate of risk. A large Swedish cohort study by Nordentoft et al. (2011) partially ad­ dressed this limitation by including an unusually long follow-up period. The epidemiological analysis included people with International Classi­ fication of Diseases, 10th Revision (ICD-10)–defined bipolar affective disorder and followed them for over 35 years from the time they were identified as a “patient” (i.e., entered into mental health treatment ser­ vices). Cumulative incidence of suicide deaths among individuals with bipolar disorder was 7.77% of men and 4.78% of women. This provides a reasonable estimate of the long-term risk of suicide among patients with bipolar disorder and can provide a foundational level of risk onto which other modifying factors may be added (discussed below in the subsection “Identifying General Suicide Risk Factors”). Another avenue of study focuses on reporting rates of suicide during specific periods of follow-up rather than comparison with the general population. The International Society for Bipolar Disorders (ISBD) Task Force on Suicide in Bipolar Disorder (Schaffer et al. 2015b) conducted a pooled analysis of all publications from 1980 to 2012 that reported on rates of suicide in both BD I and II samples. When pooled data were weighted for duration of exposure, a suicide rate of 164 per 100,000 per year was identified (in contrast to the reported global average rate of 10.6 per 100,000 per year). The same limitations noted above apply to these data, given that the average duration of follow-up in the included studies was 8.5 years.

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Suicide Methods An understanding of suicide deaths in people with bipolar disorder should also incorporate available information on specific methods of suicide. This has clear implications for potential suicide prevention strat­ egies. Four large studies have reported on suicide methods among bipo­ lar disorder samples in Sweden (Osby et al. 2001), Taiwan (Chen et al. 2009), the United Kingdom (Hunt et al. 2006), and Canada (Schaffer et al. 2014). Across the four studies there was surprising consistency of re­ sults, with 17.1%–32.5% deaths by hanging, 24.9%–33.5% by selfpoisoning, and 13.7%–18.9% by jumping from a height. It is worth not­ ing that these are common methods of suicide in general and that those with BD I and II constitute a small proportion of all suicide deaths. Nev­ ertheless, means restriction strategies targeting these specific methods are likely to confer specific protection to those with bipolar disorder.

Suicide Rates in Bipolar II Disorder There are limited epidemiological data on the impact of bipolar disorder subtype on rates of suicide deaths. In his seminal study of the Zurich co­ hort, Angst et al. (2002) compared mortality rates between 113 patients with BD I and 46 patients with BD II. Suicide deaths were recorded in 12 patients with BD I (SMR=11.53) and 6 patients with BD II (SMR= 14.15), a nonsignificant difference. Notably, he found that treatment re­ duced overall mortality rates in both groups and suicide mortality in particular. Within the BD II group, treatment reduced the suicide SMR from 27.63 to 9.51; however, a note of caution must be taken in inter­ preting these results because the sample size in both groups was small. In a follow-up study of a large Italian sample of 1,765 hospitalized pa­ tients (Sani et al. 2011), death by suicide occurred in 4.2% of patients with BD II and 2.8% of patients with BD I. This difference was nonsignif­ icant, and the findings were notable for lower rates of suicide compared with the Zurich cohort, likely accounted for by a shorter follow-up win­ dow, and potentially attributable also to personal and/or clinical risk fac­ tors (other than bipolar disorder diagnosis and subtype) that may have differed between the samples. Overall, these studies point to an absence of consistent data support­ ing any difference in risk of suicide death in patients with BD II versus BD I. Although the limitations in the extant data prevent any definitive conclusions from being drawn, evidence suggests that the bipolar disor­

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der subtype in and of itself is unlikely to have a meaningful impact on the suicide risk assessment in clinical settings.

Suicide Attempts in Bipolar I and II Disorders A much larger literature exists on the likelihood of a suicide attempt in BD I and II samples. A comprehensive review by Novick et al. (2010) in­ cluded 24 studies reporting data on both retrospective and prospective suicide attempts during follow-up periods ranging from 18 months to 44 years. Among subjects with BD II (n=1,099), 30.1% had a retrospec­ tively identified lifetime suicide attempt, a nonsignificant difference com­ pared with BD I samples (36.3%). Using a random effects meta-analytic model, Novick et al. reported an odds ratio for BD I compared with BD II of 1.21 (95% CI=0.98–1.48), which came close to significance (P=0.073). When examining only prospective data, those authors found that 19.8% of subjects with BD II had made a suicide attempt during the follow-up period, compared with 23.8% of subjects with BD I—again a nonsignif­ icant difference. Since 2010, there have been a number of additional studies comparing suicide attempts on the basis of bipolar disorder subtype. To revisit the question of potential differences in risk of suicide attempts, the ISBD Task Force (previously referred to) conducted a meta-analysis incorpo­ rating these newer data (Schaffer et al. 2015c). This analysis included a total of 6,047 BD I subjects and 2,407 BD II subjects, and found an OR of 0.96 (95% CI=0.64–1.44, P=0.83) for suicide attempts in BD I versus II samples. This finding further reinforced the conclusion that there do not appear to be significant differences based on subtype.

Summary of Epidemiological Data Overall findings have repeatedly demonstrated no consistent, signifi­ cant differences in rates of suicide attempts or suicide deaths between patients with BD II and those with BD I. However, the most important outcome of this area of research is that both groups, collectively, are at substantially higher risk of suicide compared with the general popula­ tion. This suggests that rather than focusing solely on disorder subtype, future studies ought to aim to more precisely incorporate higher risk time periods and/or clinical presentations that may be amenable to tar­ geted prevention strategies in both or either subtype.

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Clinical Factors Case Vignette Sophia, a 31-year-old woman, was brought by her parents for assessment to the emergency department. She reports experiencing suicidal thoughts with a plan to ingest a large number of her prescribed medications. She has been drinking alcohol excessively over the past few days, following a major argument with her fiancé. She has a 10-year history of BD II and is followed in the outpatient de­ partment. She has a history of four to five past major depressive episodes, managed by a variety of pharmacological and psychotherapeutic ap­ proaches. Two months before this presentation she had a hospitalization for a depressive episode with psychotic features and suicidal ideation. Desvenlafaxine 50 mg was started in addition to her usual treatment with quetiapine 400 mg at bedtime. Since starting the antidepressant, she has noted increased irritability, with some racing thoughts and anxiety at night that interfere with her sleep. Sophia endorses a family history of suicide death in her paternal grand­ father; he had been diagnosed with an alcohol use disorder. There is also suspicion of suicide death in her paternal aunt, who had been hos­ pitalized and treated with lithium.

There are numerous clinical issues involved in the care of a patient such as Sophia. 1. What are her short-term and long-term risks of suicide attempts and death? 2. How should this influence her current and future care? 3. How does her BD II diagnosis influence her risk and the treatment she should be provided? In the following subsections, we explore a framework model for un­ derstanding Sophia’s risk of suicide attempts and family history of sui­ cide death. We then review specific clinical factors that influence risk. In the final section of the chapter we move to an examination of manage­ ment approaches for Sophia and other patients with BD II, specifically related to suicide prevention.

A Framework Model for Understanding Suicide Risk There are a number of well-known models in the literature that explore factors associated with suicidal behavior (Hawton et al. 2013; Joiner et

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al. 2017; Mann 2002). A comprehensive review of these models is be­ yond the scope of this chapter, but for many patients across diagnostic groups, the various models provide important perspectives on the de­ velopment and progression of suicidal thoughts and behaviors. Models specific to bipolar disorder have been proposed, with recent work by Malhi et al. (2018) being particularly notable for its emphasis on puta­ tive neurobiological mechanisms interacting with the clinical and envi­ ronmental factors. Earlier work by Hawton et al. (2005) summarized meta-analytic results for specific clinical factors of interest. Our work within the ISBD Task Force on Suicide in Bipolar Disorder (Schaffer et al. 2015a, 2015b, 2015c) focused on a clinical model that grouped fac­ tors under distinct headings that would result in a bipolar disorder– specific suicide risk assessment (Figure 5–1). This rests on the premise not just that the diagnosis of bipolar disorder is relevant for a baseline estimation of elevated suicide risk, but that numerous relevant factors are inherent to the illness of bipolar disorder itself, with others being modified by the disorder’s presence. It then follows that understanding and incorporating the contribution of each of these factors into the risk assessment will result in a more individualized determination of risk.

Identifying General Suicide Risk Factors From the general literature it is possible to identify a number of sociode­ mographic and clinical factors associated with suicide attempts and deaths. Factors discussed below such as age, race, psychosocial stressors, past and current suicidal ideation, prior suicide attempts or deliberate self-harm, contact with mental health services, and family history of sui­ cide are important in understanding risk (McClatchey et al. 2017; Schaf­ fer et al. 2015a, 2015c; Teti et al. 2014). These factors are relevant irrespective of diagnosis; for instance, capacity to harm the self, as evi­ denced by past suicide attempts, is a significant factor in suicide risk for patients with major depressive disorder (Hawton et al. 2013), schizophre­ nia (Gómez-Durán et al. 2012), and bipolar disorder (Guillaume et al. 2010; Valtonen et al. 2006). From a clinical perspective, these factors should always be incorpo­ rated into the suicide risk assessment. As new information is added to the model, a refinement of the overall risk is achieved. If we return to Sophia, simply based on the diagnosis of BD II in a female patient who had contact with mental health services, we understand that her long­

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Known baseline risk in people with BD II

Identify impact of general suicide risk factors

• e.g., past suicide attempts

Identify impact of BD II on general risk factors

• e.g., sex effects

Identify impact of BD II–specific factors

• e.g., polarity of first mood episode

SUICIDE RISK ESTIMATE IN A PATIENT WITH BD II

FIGURE 5–1.

Clinical model for developing a suicide risk assessment specific to bipolar II disorder (BD II).

term suicide risk is estimated at 4.8%. General risk factors can then be added. Some of these—namely, presence of suicidal ideation with a plan and a psychosocial stressor (argument with fiancé)—would increase her acute risk, whereas others, such as the absence of past suicide attempt and regular contact with treatment services, may reduce her risk. The fact that she has been brought to the emergency department by her parents could be an area of further exploration, because it may be evidence that Sophia has some strong social supports (potentially lowering her risk) and/or a sign that she lacks insight into her disorder or is reluctant to engage in further treatment (potentially increasing her risk).

Identifying the Impact of Bipolar Disorder on General Risk Factors For some of the general risk factors, another layer of complexity results from the interaction between bipolar disorder and these factors. The most notable example is sex-based differences in suicide attempts and

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deaths. The general literature on suicide generally identifies a threefold or higher ratio of suicide deaths in men compared with women. This, however, is not the case in bipolar disorder, as several lines of research have reported a much narrower sex-based difference in risk. The Swed­ ish studies by Nordentoft et al. (2011) and Osby et al. (2001) identified a 1.4–1.7 to 1 ratio of incidence of male to female suicide deaths. The ISBD Task Force on Suicide in Bipolar Disorder meta-analysis included 11 studies that identified 1,149 suicide deaths among 75,055 bipolar dis­ order subjects, and reported an odds ratio of 1.83 (95% CI=1.41–2.39) (P=0.00001) for males compared with females. Therefore, although males with bipolar disorder are certainly at higher risk of dying by suicide, the ratio is notably reduced compared with the general population. This im­ plies that the impact of a BD II illness on suicide risk in women is rela­ tively higher than the impact on men. So rather than applying the standard ratio of 3:1, males to females, in the context of BD II, the 1.8:1 ratio is more accurate, although it has been identified from mixed sub­ type samples. Returning to our proposed model, sex is therefore a factor that is impacted by the presence of BD II. The presence of psychosis is another example of this type of interac­ tion, with psychotic symptoms or disorders identified as general risk factors for suicide attempts and deaths (Chan et al. 2018; Dutta et al. 2011). However, in the context of bipolar disorder, this does not appear to be the case. Large clinical and epidemiological studies of combined BD I and BD II samples did not find any association between the pres­ ence of lifetime psychosis and suicide attempts (Dennehy et al. 2011; Finseth et al. 2012; Ryu et al. 2010), with one exception being a Korean study that identified an association between lifetime auditory hallucina­ tions and suicide attempts in a clinical combined (BD I and BD II) sam­ ple (Song et al. 2012). Similarly, the presence of psychotic features has also been quite consistently shown to not be associated with suicide deaths in bipolar disorder samples (Black et al. 1988; Tondo et al. 2007), with the exception of a Taiwanese study that found that the presence of mood-incongruent psychosis at onset of illness was significantly less common among those that eventually died by suicide (Tsai et al. 2002). Psychosis, therefore, provides another example of how general risk factors cannot simply be extrapolated to bipolar disorder without first ex­ ploring for the presence of an interaction. Furthermore, within the con­ text of BD II, psychosis can only be present in the context of a depressive

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episode, with a paucity of data specifically examining this subsample of presentation. For factors such as sex and psychosis, the impact of the ill­ ness on these features can provide a refined and more accurate assess­ ment of risk, but there remain gaps in data specific to BD II. The relationship between substance use disorders and risk of suicide attempts and death in bipolar disorder is also complex. The overarching suicide literature has mostly found an impact of alcohol and drug use disorders on suicide risk (Kim et al. 2012; Porsteinsson et al. 1997). The heterogeneity in the nature and specifics of substance use makes it diffi­ cult to come up with broad generalizations, but most studies have found an effect. The ISBD Task Force examined this in some detail by first con­ ducting meta-analyses using a broadly defined substance use measure, with follow-up analyses specifically for alcohol use, any illicit substance use, and specifically cannabis use. Eighteen studies were included in the broad substance use analysis, with a total combined BD I and BD II sample size of 39,139 subjects. The presence of a lifetime substance use disorder was associated with an increased likelihood of suicide attempts (OR=1.81, 95% CI=1.31–2.50). Consistent results were obtained for the first two subanalyses, with lifetime alcohol use disorder (OR=1.60) and lifetime illicit substance use disorder (OR = 1.72) both being signifi­ cantly associated with lifetime suicide attempts. Four studies were avail­ able for the analysis of cannabis use, with the largest study reporting a positive association, but the other three finding no difference, resulting in an overall nonsignificant OR=1.29. The data on substance use and suicide deaths in bipolar disorder sam­ ples are also mixed. The ISBD Task Force meta-analysis found a small (OR=1.20) but nonsignificant association between lifetime substance use disorder and suicide death. The data were heavily weighted by large epidemiological samples that did not find an association, in contrast to data from the mixed BD I and BD II clinical sample in the Systematic Treatment Enhancement Program (STEP)–BD, which reported a strong association (Dennehy et al. 2011). Many questions remain, as the timing of substance use could not be consistently elucidated. Returning again to Sophia, we now have further information for the model. Factors such as the presence of psychosis in her last depressive episode are understood to not necessarily impact her long-term suicide risk. Unfortunately, no further conclusions can be drawn here, and this is indicative of the need for more high-quality information to include in

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the model. This includes further data not only on the impact of specific factors but also on how the synergy of individual risk factors may mod­ ify risk. One of the key limitations at present is the absence of an accu­ rate risk calculator that can combine the numerous general and bipolar disorder–specific risk factors into a single risk assessment estimate. Al­ though extensive data do exist for a number of individual factors, there are few examples of two-factor analyses. Any further calculations are nec­ essarily only blunt approximations based on single-factor effects, and there has been insufficient separation of BD II subanalyses to develop a more specific data signature for this group. This does not negate the value of applying a model for estimating suicide risk, but it must be un­ derstood that the level of precision is fairly poor, and that it is still pru­ dent to eschew broader categories such as “low,” “moderate,” and “high” risk to avoid pseudoprecision.

Identifying Impact of Factors Specific to Bipolar Disorder There is a substantial and growing literature examining the impact of bipolar disorder–specific clinical factors on risk of suicide attempts and deaths. These include variables such as age at illness onset, duration of illness, polarity of first episode, predominant polarity, polarity of most recent/current episode, the presence of mixed features, frequency of ep­ isodes, anxious distress, and atypical depressive features. A few studies have tested for differences in impact of these variables in BD II compared with BD I samples. Undurraga et al. (2012) prospec­ tively examined 290 patients with bipolar disorder (BD II: n=86) fol­ lowed for a median of 9 years. Patients with BD II were numerically but nonsignificantly more likely to develop suicidal ideation (54% vs. 37%). Other than depressive predominant polarity being overrepresented in the BD II group, there were no differences in risk factors for developing suicidal ideation or suicide attempts between patients with BD II and those with BD I. Bobo et al. (2018) conducted a very well designed and com­ prehensive comparison of suicide attempt risk factors in a large (N = 1,465) clinical sample of BD II and I subjects. They found only modest differences, with binge-eating behavior and comorbid binge-eating dis­ order being significantly associated with suicide attempts only in the BD II group; however, comorbid bulimia nervosa was a significant risk factor in both BD II and I groups, underscoring the challenge in interpreting these findings. Using machine modeling, they ranked the contribution of

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each variable by percentage of the total risk within both BD II and BD I samples but found only minimal differences between groups. Finally, in a STEP-BD subsample (Stanford site only) comprising 240 BD I outpa­ tients and 254 BD II outpatients, several differences were found in cor­ relates of suicide attempts (Goffin et al. 2016). Factors associated with suicide attempts in the BD I, but not the BD II, sample included lifetime history of eating disorder, current antidepressant use, lifetime history of an anxiety disorder, and first-degree relative with a mood disorder. In contrast, factors associated with suicide attempts in the BD II, but not the BD I, sample included childhood onset of bipolar disorder and lifetime history of psychosis. Phase of illness is also an important aspect of suicide risk assessment in bipolar disorder. Within BD II, not surprisingly, there is no significant in­ creased risk during periods of pure hypomania, but there is an additive contribution of both depression and hypomania during mixed periods (Persons et al. 2018). Of note, this analysis of data from the National In­ stitute of Mental Health Collaborative Depression Study found that a past history of mixed states was associated with risk of suicidal behavior during periods of depression in the BD I, but not the BD II, group. Overall, these data comparing risk factors between BD I and II show modest and sometimes inconsistent results. To date, there is insufficient evidence to suggest that differential contribution of specific factors be considered in clinical settings. Inclusion of bipolar disorder–specific clinical variables into the model shown in Figure 5–1 would then provide a comprehensive estimate of suicide risk. As noted earlier, this process does not lead to an exact esti­ mate, because the field does not have the equivalent of a Framingham risk score. However, these factors can be used to inform the assignment of a categorical level of risk both acutely and in the long term. A manage­ ment plan can be then developed on the basis of the assigned risk cate­ gories. In the next section we explore the management approach for a patient such as Sophia.

Management Overview The management approach for suicide prevention in patients with BD II should ideally incorporate two aspects. First, effective treatment for the

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underlying symptoms of BD II will undoubtedly have a positive effect on reducing risk of suicide (Angst et al. 1998; Khan et al. 2013). Second, there are specific pharmacological and nonpharmacological approaches to reducing risk of suicide that can complement treatment focused on symptom and episode reduction as well as functional improvement. A detailed discussion of management of BD II is covered in other sections of this textbook (see Chapters 8, “Mood Stabilizers and Antipsychotic Medications in Bipolar II Disorder”; 9, “Antidepressant Medications in Bipolar II Disorder”; and 10, “Psychosocial Interventions in Bipolar II Disorder,” respectively) and in published treatment guidelines (Yatham et al. 2018). The vast majority of treatment studies in BD II focus on symptomatic treatment, with suicide-related outcomes at times included as secondary measures or most commonly only addressed in the context of serious adverse events. It has been very difficult to indirectly glean any specific clinically relevant findings, even from pooled analyses of psychophar­ macological trials in bipolar disorder (Khan et al. 2013). This leaves a smaller but growing literature that analyzes the impact of various interventions, not just on symptom reduction but on a variety of suicide-related outcomes such as suicidal ideation, suicide attempts, and deaths by suicide. This line of research begins with the study of the overall impact of any treatment on suicide-related outcomes. In studies of combined bipolar disorder samples, treatment to reduce symptom bur­ den has been consistently associated with a significant decrease in sui­ cidal behavior (Rucci et al. 2002; Yerevanian et al. 2007a, 2007b, 2007c). Fewer data are available with regard to prevention of suicide deaths, but what data are available suggest that mood stabilizer treatment likely re­ duces the risk (Angst et al. 1998; Khan et al. 2013).

Pharmacological Treatments From a clinician’s perspective, what is of utmost importance is to under­ stand how the various evidence-based treatments for mood episodes in the context of bipolar disorder differ in terms of their effects on suicid­ ality. Among treatments for bipolar disorder, lithium has been the best studied with regard to a reduction in suicide attempts and deaths. A re­ cent meta-review of 16 systematic reviews (Smith and Cipriani 2017) summarized the putative antisuicidal effect of lithium treatment in bi­ polar disorder but also highlighted the limitation from the absence of

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large comparative randomized controlled trial (RCT) data. Although lithium treatment has been shown to be associated with a reduced rate of suicide in patients with bipolar disorder compared with treatment with placebo or with lithium discontinuation, and numerous epidemiological analyses have replicated the finding that suicide-related events are less frequent when patients are treated with lithium compared with other med­ ications, there are no prospective RCT data showing lithium to be supe­ rior to other mood-stabilizing agents. One RCT analysis found lithium treatment to be associated with reduced risk of deliberate self-harm com­ pared with carbamazepine, but this has yet to be replicated (Cipriani et al. 2013). This remains the one aspect of research on lithium and suicide in bipolar disorder that would confirm the extent and specificity of the antisuicidal effects of lithium in this disorder. Prospective studies are also needed to determine lithium’s effect within specific clinical situations and subgroups of patients such as those with BD II. In this context, there are again very limited data on the differen­ tial effects of treatment on reducing suicide across bipolar disorder sub­ types. In a Swedish national registry study (Song et al. 2017), lithium treatment was associated with a reduction in rate of suicide-related events in both BD I and BD II groups. The BD II group had a numeri­ cally larger reduction in risk (hazards ratio=0.62, 95% CI=0.46–0.82) than the BD I group (hazards ratio=0.85, 95% CI=0.67–1.09); however, the confidence intervals overlapped. Apart from lithium, anticonvulsants have the next largest literature specifically on reduction of suicide-related behavior in bipolar disorder. Following a 2009 U.S. Food and Drug Administration warning on anti­ convulsant medications being associated with an increased risk of sui­ cide thoughts or actions, several studies investigated this potential but found no evidence to support this concern (Arana et al. 2010; Leon et al. 2012). Furthermore, epidemiological studies have reported evidence of lower rates of suicide attempts and/or suicides during the month after starting an anticonvulsant medication (Marcus et al. 2013) and repeat purchases of anticonvulsant medications (Søndergård et al. 2008). Pa­ tients who receive anticonvulsants have been consistently found to have higher rates of suicide-related behavior compared with patients who are receiving lithium (Collins and McFarland 2008; Goodwin et al. 2003), but again, these are nonrandomized studies. The findings may be biased by selective use of anticonvulsants for patients at increased risk of a sui­

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cide, related to the perception that this class may be more effective for “complicated” cases, including psychiatric comorbidities and rapid cycling. Additionally, the perception of higher lethality in lithium overdose may paradoxically lead clinicians to avoid lithium use in their highest-risk patients. After lithium and anticonvulsants, there is an enormous decline in the availability of data on antipsychotics or antidepressants and suiciderelated events in bipolar disorder. Small clinical datasets and lack of RCT data make clinical interpretation of available data nearly impossible. Antipsychotic use has been associated with increased risk of suicide at­ tempts (Ahearn et al. 2013; Yerevanian et al. 2007c), but these studies did not control for factors such as severity of illness and high-risk peri­ ods. Similarly, recent treatment with an antidepressant has been associ­ ated with increased likelihood of a suicide attempt (Marangell et al. 2008; Yerevanian et al. 2007b), yet for the same reasons as above, it is very difficult to interpret this finding with any confidence.

Nonpharmacological Treatments Within the field of suicide prevention, significant attention has been given to the effectiveness of a variety of suicide prevention strategies. To date, there is a paucity of data exploring these interventions within bipo­ lar disorder and certainly for subtypes such as BD II. We will therefore only review these briefly, because they can still serve as key components to a suicide prevention strategy for patients with BD II. Recent data suggest that the inclusion of a number of complementary strategies may be most advantageous. Prevention approaches that include coordinated aftercare, means restriction, publication of media guide­ lines on reporting of suicides, public awareness campaigns, gatekeeper training, general practitioner training, and availability of psychosocial treatments have each been shown to be effective, and when combined are estimated to have the potential to reduce suicide by 20%–25% (Krysinska et al. 2016). Specific psychotherapy modalities have also been shown to reduce suicide-related behaviors. Dialectical behavioral therapy (DBT; Linehan et al. 2015), cognitive-behavioral therapy for suicide prevention (Brown et al. 2005), and Collaborative Assessment and Management of Suicid­ ality (CAMS; Jobes 2012) all show evidence of reducing suicide-related behaviors. Replicated data on novel interventions such as “caring contacts”

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TABLE 5–1.

Management options to consider for case vignette of patient with bipolar II disorder

Standard treatment options

Specific suicide prevention options

Use evidence-based treatment to treat BD II depression. Discontinue antidepressant in context of mixed features. Consider use of lithium as monotherapy or in combination with an atypical. Ensure appropriate follow-up.

Institute means restriction with regard to access to a large amount of medications. Use psychotherapy modality with evidence for suicide prevention (i.e., CBT, DBT, CAMS). Initiate caring contacts after ED visit. Develop written safety plan.

Note. CAMS= Collaborative Assessment and Management of Suicidality; CBT = cognitive­ behavioral therapy; DBT=dialectical behavior therapy; ED=emergency department.

after delivery of acute mental health services have also been shown to re­ duce risk of suicide-related behavior and even suicide deaths (Luxton et al. 2013). There has also been great interest in strategies to enhance cop­ ing, with different local versions developed based on the framework of the Stanley and Brown safety planning intervention (Boudreaux et al. 2017).

A Management Approach for Sophia A number of targeted management steps can be considered for patients such as Sophia. Table 5–1 below provides a summary of management options to consider.

Conclusion Bipolar II disorder is clearly associated with an increased risk of suicide attempts and death; however, epidemiological data suggest limited, if any, impact of bipolar disorder subtype on absolute risk. Models that in­ corporate both general and illness-specific clinical factors can enhance estimation of suicide risk in patients with BD II, yet these are inherently limited by large gaps in the data and the known poor predictive capacity of suicide prediction models. Ultimately, management approaches should therefore not just incorporate treatment for BD II symptoms and episodes but also include broad-based nonpharmacological interven­ tions for all patients with BD II considered at risk of suicide.

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KEY POINTS

• Rates of suicide attempts and deaths are comparable in bipolar I disorder and bipolar II disorder (BD II) groups and much higher than those in the general population. • Impact of a BD II illness on suicide risk in women is relatively higher than its impact on men. • Individuals with BD II are at higher risk for suicide during depression and mixed periods rather than during pure hypomania. • Models that incorporate both general and illness-specific clinical factors can enhance estimation of suicide risk in patients with BD II. • Risk reduction should include evidence-based treatments for BD II as well as suicide prevention strategies such as means restriction, a written safety plan, and psychosocial interventions.

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Part II Understanding

6 Genetics of Bipolar II Disorder Melvin McInnis, M.D.

B

ipolar II disorder (BD II) is a heritable illness. Early family and twin studies showed that bipolar disorder runs in families, with the risk of developing bipolar disorder being between 5 and 10 times higher in first-degree relatives of affected individuals compared with the gen­ eral population (Craddock and Sklar 2013). Estimates of the heritabil­ ity of bipolar disorder are in the range of 85% (McGuffin et al. 2003), meaning that the vast majority of variance in susceptibility to bipolar disorder is likely due to genetic factors. The rationale for defining BD II as a distinct subtype of bipolar disorder rests at least in part on evidence showing high family loading for the BD II phenotype (Dunner et al. 1976). Indeed, when bipolar subtypes are considered, no differences in heritability are observed (Edvardsen et al. 2008), suggesting that herita­ bility is comparable across bipolar I disorder (BD I) and BD II. A recent large comparative family aggregation study (Parker et al. 2018) showed that the prevalence of a bipolar disorder diagnosis in any family mem­ ber of a bipolar disorder proband was similar for the BD I and BD II subsets (41% vs. 36%), adding further credence to this literature. Heri­ tability provides an estimate of the proportion of the disorder that can be attributed to genetic variation but does not identify individual genes or combinations of genes that cause or increase susceptibility to a dis­ 121

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order. Recent advances in genetics, however, have begun to enable an exploration of these important questions. Psychiatric genetics is a specialty field that focuses on psychiatric dis­ orders and studies patterns of inheritance with the ultimate goal of find­ ing etiological mechanisms that cause disease. In this chapter I review the genetics of BD II. The review will highlight the challenges intrin­ sic to the study of complex human disease, including the controversy around the validity of the BD II phenotype and evolving research meth­ odologies in psychiatric genetics. In this review I underscore the finding that BD II, like most other heritable psychiatric disorders, is not a singlegene disorder but likely a manifestation of complex polygenic risk inter­ acting with environmental factors. I also examine methodological diffi­ culties that have arisen in elucidating the genetics of BD II as the field has moved from small linkage studies to examination of large datasets. In the earlier studies, for example, small sample sizes limited conclu­ sions that could be drawn about the contribution to risk of individual genes. In the current era of “big data,” different kinds of challenges arise. For instance, in order to accumulate large samples, genetic studies often include both BD I and BD II, making it difficult to make definitive state­ ments about genetic variants specific to one subtype versus another. The matter is confounded further by arguments about the validity of the BD II phenotype. As discussed in Chapter 2 (“Diagnosing Bipolar II Disor­ der”), most would agree that BD II is a unique clinical entity that can be reliably identified in clinical settings (Regier et al. 2013; Simpson et al. 2002). Nevertheless, as with any diagnosis based solely on clinical eval­ uation, there are ongoing debates surrounding the validity of the BD II diagnosis (Ghaemi et al. 2002) that complicate the evaluation of genes and genetic markers within the genome for association with the clinical phenotype (Schrodi 2017). The goal of psychiatric genetics is to identify molecular mechanisms that will form the basis for the discovery of novel interventions. With few evidence-based interventions available to treat BD II, the tools of psychiatric genetics may play an especially important role in expanding the therapeutic armamentarium for this neglected psychiatric condi­ tion. This chapter lays the foundations for understanding basic princi­ ples of psychiatric genetics, especially as they apply to BD II, with the goal of preparing readers to understand new genetic studies as they become available.

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History of Genetics What Is Genetics? Genetics is a core discipline in the study of human disease that examines the transmission of traits (inheritance) from one generation to the next. It is a fascinating and rapidly evolving field (Harper 2008) with direct rel­ evance to all life forms because it describes the fundamentals (content and mechanism) in transmission of essential biological information to the next generation. Scholars in the classical era (e.g., Hippocrates, Aristo­ tle) appreciated the importance of observed hereditary features (Vinci and Robert 2005). Similarities of temperament and moods across gener­ ations were described in the seventeenth-century writings of Burton’s The Anatomy of Melancholy (Burton 1859). The modern understanding of genetics was established by Gregor Mendel, who described the laws of segregation and independent assortment, collectively known as Mendel’s laws of inheritance (Glass 1953). The law of segregation states that each individual has two copies of any given genetic unit and during meiosis the resulting gamete has one copy (allele); the law of independent as­ sortment implies that the segregation of each allele is independent from other genetic units. These laws form the basis for the fields of both quantitative (population-based) and molecular (laboratory-based) genet­ ics (Plomin et al. 2009).

Why Is Phenotype Important? Genetic studies test the statistical association between a phenotype (what is clinically or otherwise observed) and the genotype (the genetic variant at a specific location on the genome). It is essential that these measures be accurate and consistently measured across all individuals in any given study. Capacity for increasingly sophisticated genetic anal­ yses has surged with advances in the biochemistry and analytic methods in genetics (Mattson 2018). However, assessment of clinical phenotypes remains tied to clinical observations and based on clinician driven eval­ uations of study participants. Concerns about reliability and validity of clinical diagnoses, particularly in a class of disorders where there are no established biological markers associated with disease states (Scarr et al. 2015), has created stumbling blocks to advancing genetic research. For these reasons, debates about the validity of the BD II diagnosis have im­ pacted our ability to elucidate the underlying genetics of the disorder.

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Early Studies The genetics of psychiatric disorders was inspired by early observations of inheritance patterns among families of affected individuals. Kraepelin es­ tablished the increased frequency of psychiatric illnesses among family members (Jablensky 2007), and Slater’s twin studies in affective disorder demonstrated heritability of BD (then referred to as “manic-depressive dis­ order”) (Slater 1936). More recent studies (Bertelsen et al. 1977; Gershon et al. 1982) have anchored the early observations with studies that are more systematic and epidemiologically based. What was not determined was exactly what was inherited and how it caused disease. The next generation of genetic research moved beyond observations of pedigrees and epidemiology to more sophisticated analytic techniques. It was heralded by emerging genetic mapping technologies (Donis-Keller et al. 1987), including reports of successful identification of genetic link­ age in Huntington’s disease (Gusella et al. 1983) with subsequent charac­ terization of the underlying gene (MacDonald et al. 1993). Major efforts were focused on identification of families with evidence of BD segregat­ ing among members in order to conduct this research. Initial reports were encouraging (Egeland et al. 1987), albeit with evidence of genetic heterogeneity (Hodgkinson et al. 1987). Many challenges accompanied these early linkage studies, including the small sample size, need for rep­ lication, and changes in diagnosis over time (Kelsoe et al. 1989).

Genome-Wide Association Studies As the limitations of small sample sizes became apparent, association studies overtook genetic linkage analyses, and the genome-wide associ­ ation study (GWAS) quickly became the standard approach in genetic analyses (Burmeister et al. 2008). GWASs are essentially case-control design studies that compare the frequency of a specific allele in a group of individuals (cases) with the phenotype or disorder under study to its frequency in a control group that does not have the disorder (Cantor et al. 2010). The genetic measure is the genotype at a specific genetic loca­ tion along the genome that is known to vary, known as single nucleotide polymorphisms (SNPs). SNPs are variations in a single nucleotide within the genome. The human genome is composed of more than three billion nucleotides distributed over 23 pairs of chromosomes yielding an estimated 10 million SNPs. A typical GWAS study will use 200,000 to 2.4 million SNPs in the analysis. Because so many SNPs are tested in GWAS analy­

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ses, there are concerns about multiplicity and resultant need to correct for multiple testing. The overall accepted level of significance is 5×10 –8; the results are represented in a so-called Manhattan plot to demon­ strate the level of significance relative to other markers along the ge­ nome. Figure 6–1 shows a Manhattan plot from a GWAS study of more than 20,000 cases with bipolar disorder, compared with more than 30,000 without. Twenty-two individual loci that exceed threshold values for significance are identified (Stahl et al. 2017). Odds ratios of findings are typically low (