Cognitive Dysfunction in Bipolar Disorder

A Guide for Clinicians

Edited by Joseph F. Goldberg, M.D. Katherine E. Burdick, Ph.D.

Washington, DC London, England Note: The authors have worked to ensure that all information in this book is accurate 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 errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. If you would like to buy between 25 and 99 copies of this or any other APPI title, you are eligible for a 20% discount; please contact APPI Customer Service at [email protected] or 800-368-5777. If you wish to buy 100 or more copies of the same title, please e-mail us at [email protected] for a price quote. Copyright © 2008 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 12 11 10 09 08 5 4 3 2 1 First Edition Typeset in Adobe Galliard and Optima American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Cognitive dysfunction in bipolar disorder : a guide for clinicians / edited by Joseph F. Goldberg, Katherine E. Burdick.—1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-58562-258-0 (alk. paper) 1. Manic-depressive illness. 2. Cognition disorders. I. Goldberg, Joseph F., 1963– II. Burdick, Katherine E., 1972– [DNLM: 1. Bipolar Disorder—complications. 2. Bipolar Disorder—physiopa- thology. 3. Cognition—physiology. 4. Cognition Disorders—etiology. WM 207 C6756 2008]

RC516.C62 2008 616.89’5—dc22 2008014109

British Library Cataloguing in Publication Data A CIP record is available from the British Library. Contents

Contributors ...... ix Foreword ...... xv Frederick K. Goodwin, M.D. Preface...... xix Joseph F. Goldberg, M.D., and Katherine E. Burdick, Ph.D.

1 Overview and Introduction: Dimensions of Cognition and Measures of Cognitive Function ...... 1 Katherine E. Burdick, Ph.D., and Terry E. Goldberg, Ph.D.

2 Attentional and Executive Functioning in Bipolar Disorder ...... 23 Luke Clark, D.Phil., and Guy Goodwin, M.D.

3 Memory Deficits Associated With Bipolar Disorder ...... 49 Safa Elgamal, M.D., M.Sc., Ph.D., Marta Sokolowska, Ph.D., and Glenda MacQueen, M.D., Ph.D.

4 The Endophenotype Concept: Examples From Neuropsychological and Neuroimaging Studies of Bipolar Disorder ...... 69 David C. Glahn, Ph.D., Katherine E. Burdick, Ph.D., and Carrie E. Bearden, Ph.D.

5 Impact of Mood, Anxiety, and Psychotic Symptoms on Cognition in Patients With Bipolar Disorder...... 89 Gin S. Malhi, M.B.Ch.B., B.Sc. (Hons), F.R.C.Psych., F.R.A.N.Z.C.P., M.D., Catherine M. Cahill, M.Sc., M.Psychol., and Philip Mitchell, M.B., B.S., M.D., F.R.A.N.Z.C.P., F.R.C.Psych. 6 Improving Psychotherapy Practice and Technique for Bipolar Disorder: Lessons From Cognitive Neuroscience ...... 113 Joseph F. Goldberg, M.D., Cory F. Newman, Ph.D., Gin S. Malhi, M.B.Ch.B., B.Sc. (Hons), F.R.C.Psych., F.R.A.N.Z.C.P., M.D., and David J. Miklowitz, Ph.D.

7 Adverse Cognitive Effects of Psychotropic Medications . . . . 137 Joseph F. Goldberg, M.D.

8 Pharmacologic Strategies to Enhance Neurocognitive Function ...... 159 Joseph F. Goldberg, M.D., and L. Trevor Young, M.D., Ph.D.

9 Cognitive Dysfunction in Children and Adolescents With Bipolar Disorder: Relative Contributions of Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder...... 195 Paula K. Shear, Ph.D., and Melissa P. DelBello, M.D.

10 Cognition and Functional Outcome in Bipolar Disorder...... 217 Ivan J. Torres, PhD., Colin M. DeFreitas, M.A., and Lakshmi N. Yatham, M.B.B.S., F.R.C.P.C., M.R.C.Psych.

11 Cognition Across the Life Span: Clinical Implications for Older Adults With Bipolar Disorder ...... 235 Eduard Vieta, M.D., Ph.D., Anabel Martinez-Aran, Ph.D., and Joseph F. Goldberg, M.D.

12 Summary and Assessment Recommendations for Practitioners...... 257 Joseph F. Goldberg, M.D., and Katherine E. Burdick, Ph.D.

Index ...... 273 Contributors

Carrie E. Bearden, Ph.D. Assistant Professor in Residence, Jane & Terry Semel Institute for Neuro- science and Human Behavior, Department of Psychiatry and Biobehav- ioral Sciences and Department of Psychology, University of California, Los Angeles, California

Katherine E. Burdick, Ph.D. Assistant Professor of Psychiatry, Albert Einstein College of Medicine, the Bronx, New York; Director, Neurocognitive Assessment Unit, Division of Psychiatry Research, The Zucker Hillside Hospital, North Shore Long Is- land Jewish Health System, Glen Oaks, New York

Catherine M. Cahill, M.Sc., M.Psychol. Clinical Psychologist, University of Sydney, Northern Clinical School, Royal North Shore Hospital; Clinical Psychologist, Traumatic Stress Clinic, Westmead Hospital, Sydney, Australia

Luke Clark, D.Phil. University Lecturer, Department of Experimental Psychology, University of Cambridge, Cambridge, England

Colin M. DeFreitas, M.A. Graduate Student, Department of Psychology, Simon Fraser University, Burnaby, British Columbia

Melissa P. DelBello, M.D. Vice-Chair for Clinical Research and Associate Professor of Psychiatry and Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

Safa Elgamal, M.D., M.Sc., Ph.D. Schlegel Research Chair in Aging and Assistant Professor of Cognitive Neuroscience, University of Waterloo, Waterloo, Ontario, Canada

ix x Cognitive Dysfunction in Bipolar Disorder

David C. Glahn, Ph.D. Director of Neuroimaging Core in Psychiatry and Associate Professor, De- partment of Psychiatry and Research Imaging Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Joseph F. Goldberg, M.D. Associate Clinical Professor of Psychiatry, Mount Sinai School of Medi- cine, New York, New York; Director, Affective Disorders Research Pro- gram, Silver Hill Hospital, New Canaan, Connecticut

Terry E. Goldberg, Ph.D. Professor of Psychiatry, Albert Einstein College of Medicine, Bronx, New York; Director of Research in Neurocognition, Division of Psychiatry Re- search, The Zucker Hillside Hospital, North Shore Long Island Jewish Health System, Glen Oaks, New York

Guy Goodwin, M.D. W.A. Handley Professor of Psychiatry, University of Oxford, Warneford Hospital, Oxford, England

Glenda MacQueen, M.D., Ph.D. Head, Mood Disorders Program; Associate Professor, Department of Psy- chiatry and Behavioral Neurosciences; Adjunct Member, Intestinal Dis- eases Research Program, McMaster University, Toronto, Ontario, Canada.

Gin S. Malhi, M.B.Ch.B., B.Sc. (Hons), M.R.C.Psych., F.R.A.N.Z.C.P., M.D. Professor and Head, Discipline of Psychological Medicine, University of Sydney, Sydney, Australia

Anabel Martinez-Aran, Ph.D. Head of the Neuropsychology Bipolar Disorders Program, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, University of Barce- lona, Barcelona, Spain

David J. Miklowitz, Ph.D. Professor of Psychology and Psychiatry, Department of Psychology, Uni- versity of Colorado, Boulder, Colorado Contributors xi

Philip Mitchell, M.B., B.S., M.D., F.R.A.N.Z.C.P., F.R.C.Psych. Professor and Head, School of Psychiatry, University of New South Wales, New South Wales, New Zealand

Cory F. Newman, Ph.D. Director, Center for Cognitive Therapy, Associate Professor of Psychol- ogy, Department of Psychiatry, University of Pennsylvania School of Med- icine, Philadelphia, Pennsylvania

Paula K. Shear, Ph.D. Professor of Psychology and Psychiatry, Director of Clinical Training, and Codirector of Graduate Studies, Department of Psychology, University of Cincinnati, Cincinnati, Ohio

Marta Sokolowska, Ph.D. Research Scientist, Department of Clinical Pharmacology, DecisionLine Clinical Research Corporation, Toronto, Ontario, Canada

Ivan J. Torres, Ph.D. Associate Professor L.T., Department of Psychology, Simon Fraser Uni- versity, Burnaby, British Columbia; Clinical Neuropsychologist, Riverview Hospital, Coquitlam, British Columbia; Research Scientist, BC Mental Health and Addiction Services; Research Consultant, Mood Disorders Centre, University of British Columbia, Vancouver, British Columbia, Canada

Eduard Vieta, M.D., Ph.D. Professor of Psychiatry, University of Barcelona; Director of the Bipolar Disorders Program, Clinical Institute of Neuroscience, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de In- vestigación Biomédica en Red de Salud Mental, University of Barcelona, Barcelona, Spain

Lakshmi N. Yatham, M.B.B.S., F.R.C.P.C., M.R.C.Psych. Professor of Psychiatry and Associate Head of Research and International Affairs, Department of Psychiatry, University of British Columbia, Van- couver, British Columbia, Canada

L. Trevor Young, M.D., Ph.D. Professor and Head, Department of Psychiatry, University of British Colum- bia, Vancouver, British Columbia, Canada xii Cognitive Dysfunction in Bipolar Disorder

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 or- ganization, and/or a government agency, as listed below:

Luke Clark, D.Phil.—Consultant: Cambridge Cognition, GlaxoSmith- Kline. Melissa P. DelBello, M.D.—Consulting/Advisory board: AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, France Foundation; Research support: AstraZeneca, Eli Lilly, Shire, Janssen, Pfizer, Somerset Pharmaceuti- cals; Speaker’s bureau: AstraZeneca, GlaxoSmithKline, Pfizer, France Foundation, Bristol Myers Squibb. Joseph F. Goldberg, M.D.—Consultant: AstraZeneca, Cephalon, Eli Lilly, GlaxoSmithKline; Speaker’s bureau: Abbott Laboratories, Astra- Zeneca, Eli Lilly, GlaxoSmithKline, Pfizer. Frederick K. Goodwin, M.D.—Consultant: GlaxoSmithKline, Lilly, Pfizer, Wyeth, AstraZeneca; Research support: GlaxoSmithKline; Speaker’s bureau: GlaxoSmithKline, Pfizer, Eli Lilly. Guy Goodwin, M.D.—Advisory board: AstraZeneca, BMS, Eli Lilly, Lun- dbeck, P1Vital, Sanofi-Aventis, Servier, Wyeth; Grant support: Sanofi- Aventis, Servier; Honoraria: AstraZeneca, BMS, Eisai, Lundbeck, Sanofi-Aventis, Servier. Philip Mitchell, M.D.—Consultant: Alphapharm; Honoraria: AstraZen- eca, Eli Lilly, Janssen-Cilag. Marta Sokolowska, Ph.D.—Employer: DecisionLine Clinical Research Corporation. Eduard Vieta, M.D., Ph.D.—Grant support: Instituto Carlos III, CIBER-SAM, Spain; Grant support/Consultant: AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Organon, Otsuka, Pfizer, Sanofi, Servier.

The following authors have no competing interests to report: Carrie E. Bearden, Ph.D. Katherine E. Burdick, Ph.D. Catherine M. Cahill, M.Sc., M.Psychol. Colin M. DeFreitas, M.A. Safa Elgamal, M.D., M.Sc., Ph.D. David C. Glahn, Ph.D. Terry E. Goldberg, Ph.D. Glenda MacQueen, M.D., Ph.D. Contributors xiii

Gin S. Malhi, M.B.Ch.B, B.Sc. (Hons), M.R.C.Psych., F.R.A.N.Z.C.P., M.D. Anabel Martinez-Aran, Ph.D. David J. Miklowitz, Ph.D. Cory F. Newman, Ph.D. Paula K. Shear, Ph.D. Ivan J. Torres, PhD. Lakshmi N. Yatham, M.B.B.S., F.R.C.P.C., M.R.C.Psych. L. Trevor Young, M.D., Ph.D. Foreword

This volume represents an ambitious, even bold, undertaking. The editors express it succinctly in the preface when they describe the book as both “timely” and “premature.” It is timely in that those of us who study and treat patients with bipolar disorder have only recently begun to appreciate that the symptoms, the functional deficits, and ultimately the pathophysi- ology of the major “mood” disorders involve a great deal more than mood. In contrast, neurologists and “schizophrenologists” have long appreciated the relevance of neuropsychology and the cognitive sciences. My personal experience reflects this recent awakening of bipolar experts to the cognitive dimensions of the illness. For example, in my own clinical practice, I am finding that my evaluation of patients’ progress has increasingly focused on where they are cognitively, particularly with respect to the so-called executive functions. For another personal window to the emer- gence of a neuropsychology of bipolar disorder, one has only to note that the neuropsychology chapter in the second edition of Manic-Depressive Ill- ness is twice as long as the equivalent chapter in the first edition (Goodwin and Jamison 1990, 2007). So this book is indeed timely—that is, it is time for all of us who treat bipolar patients to enlarge our focus and give the cognitive dimensions their due. But by pairing timely with premature in their preface, the editors give emphasis to the reality that, despite rapid progress, there are still many questions about cognitive function in bipolar disorder that remain unan- swered. This carefully edited, balanced, and comprehensive book is an important contribution to our field precisely because it plows new ground, carefully identifying the major gaps in knowledge while, nevertheless, outlining with clarity and readability the astounding amount of new information that con- tinues to accumulate at an accelerating pace from the increasingly inter- twined disciplines of neuropsychology, neuroimaging, neurogenetics, and the new field of functional outcomes research. This book is aimed at clinicians, and its aim is on target. Complex neuropsychological data and con- cepts are laid out in clear, largely jargon-free language, further enlightened by well-chosen examples and case histories. Equally important to its being on target is that the authors manage to achieve clarity without talking down

xv xvi Cognitive Dysfunction in Bipolar Disorder to clinicians. The introductory and summary chapters by Drs. Goldberg and Dr. Burdick are especially noteworthy examples of clarity undistorted by oversimplification. Given the relative youth of the research in this field, many readers will be surprised by the number of areas in which a consensus is already emerging. This is testimony to the vitality of this new field, which includes seasoned neuropsychologists who, having cut their teeth in schizophrenia, are ap- plying their experience and creativity to bipolar disorder. At the same time, developments in the neuropsychology of bipolar disorder have also been facilitated by the rapid development of increasingly sophisticated functional neuroimaging technologies. One area of consensus has to do with attention: it is disturbed in bipolar disorder across all phases, including remission. It is quite conceivable that many of the learning and memory problems experienced by patients with bipolar disorder may be secondary to this underlying deficit in attention. The importance of this deficit is highlighted in Chapter 6, “Improving Psy- chotherapy Practice and Technique for Bipolar Disorder: Lessons From Cognitive Neuroscience,” wherein Goldberg and colleagues cite therapeutic techniques for enhancing attention. That bipolar patients have apparently “state-independent” deficits in some executive functions represents another area of consensus. State-independent findings are intriguing because they may be markers of some pre- existing, underlying vulnerability, perhaps genetic. But to reemphasize and expand on a point made in this book, considerable caution must be exer- cised in the interpretation of state-independent (or so-called well-state) findings. For one thing, the ethics of clinical investigation requires that patients whose current well state has been achieved with the help of medications not be withdrawn from those medications for research purposes. On the other hand, when a patient is in an acute episode of mania or depression (the ill state), it is permissible to allow a brief drug-free washout period before a medication trial is initiated. Thus, state-independent findings almost invariably involve a treatment confound. A further problem is that most of the ill versus well comparisons are cross-sectional; there is a dearth of lon- gitudinal studies in which well and ill periods can be compared in the same patient. Likewise, there are very few data on individuals at high risk for bipolar disorder studied before the onset of their first episode. Finally, let me extract from this rich stew a few additional morsels that I found to be especially thought provoking:

• Poor adherence to treatment, which characterizes more than half of all bipolar patients and which is probably the largest single factor contrib- uting to poor response, in some cases derives from cognitive dysfunc- Foreword xvii

tion; that is, poor insight into the illness and failure to remember or appreciate the consequences of not treating it. • Following the lead of the schizophrenia field, cognitive function has recently been getting some attention at the U.S. Food and Drug Admin- istration (FDA), and some measures of cognition may be required for registration trials of new agents for bipolar disorder. • Specific cognitive functions are substantially heritable and are emerging as endophenotypes in the study of risk factors for bipolar disorder. • Anxiety symptoms in bipolar patients (which are common) can signifi- cantly impair cognitive function. Given that anxiety symptoms are treat- able, this association is of considerable clinical importance. • Assessment of functional outcomes in drug trials is now being required by the FDA, and it is clear that neurocognition is the major determinant of the extent of functional recovery. • The cognitive effects of the medications used in bipolar disorder may well go in either direction, even with the same drug. For example, lith- ium at higher doses can interfere with some cognitive functions, while at the same time its neuroprotective effects might well be expected to translate into some positive cognitive effects over time. • When comparing cognitive measures in bipolar and unipolar patients, it is critical to match both groups for total number of episodes; unfortu- nately, this is rarely done.

I predict that this book will have considerable impact, both on clinical research and on clinical care. It will be a shame if it does not. It may be both timely and premature, but for me, timely carries the day.

Frederick K. Goodwin, M.D.

References Goodwin FK, Jamison KR: Manic-Depressive Illness. New York, Oxford University Press, 1990 Goodwin FK, Jamison KR: Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd Edition. New York, Oxford University Press, 2007 This page intentionally left blank Preface

The presence of prominent affective symptoms has classically been viewed as the hallmark feature of bipolar disorder and as a fundamental character- istic that discriminates bipolar illness from primary psychotic disorders. Al- though mood disturbances are the sine qua non of bipolar disorder, contemporary research has pointed increasingly to nonaffective elements of psychopathology associated with the diagnosis. Problems with work and social functioning persist for lengthy periods in many individuals with bipolar disorder after the resolution of manic or depressive episodes, even in the absence of subsyndromal affective symptoms. These problems point to other factors that likely mediate functional recovery, including the ability to plan and think clearly, exercise reasonable judgment, solve problems with novelty and creativity, remember important information, recognize alternative points of view, and appreciate the ramifications of decisions made in everyday life—processes that lie at the heart of all functional human endeavors. Cognition spans a wide range of mental operations that bear on numer- ous aspects of bipolar disorder. For example, the loss of insight contributes to the ability to recognize signs of affective relapse, maintain treatment adherence, and exercise financial, medical, social, and professional decision making. Another example is executive function, which is a prerequisite for the capacity to understand and consent to treatment, whether routine or experimental. Confusion about the diagnosis of bipolar disorder itself stems in part from an overlap between symptoms of bipolar disorder and those of other conditions that involve problems with distractibility and sus- tained attention (e.g., attention-deficit/hyperactivity disorder) and disorders of planning and impulse control (e.g., impulse control disorders and Cluster B personality disorders). Cognitive problems may be misconstrued by patients or clinicians as signs of psychopathology, or vice versa. Prescrib- ers are often challenged when attempting to differentiate medication side effects from primary depressive or other illness symptoms, such as cognitive disorganization or trouble concentrating. Psychotherapists can be- come frustrated when patients with bipolar disorder have persistent trouble incorporating new insights and perspectives, or when they perseverate on distorted attitudes and beliefs and fail to change maladaptive behaviors,

xix