Medical Illness and Schizophrenia, Second Edition

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Medical Illness and

Schizophrenia Second Edition

This page intentionally left blank

Medical Illness and

Schizophrenia Second Edition

Edited by

Jonathan M. Meyer, M.D. Henry A. Nasrallah, M.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 © 2009 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 13 12 11 10 09 5 4 3 2 1 Second Edition Typeset in Adobe’s Book Antiqua and Albertus American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Medical illness and schizophrenia / edited by Jonathan M. Meyer, Henry A. Nasrallah. — 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-58562-346-4 (alk. paper) 1. Schizophrenics—Diseases. 2. Schizophrenics—Medical care. 3. Mentally ill—Diseases. 4. Mentally ill—Medical care. I. Meyer, Jonathan M., 1962– II. Nasrallah, Henry A. {DNLM: 1. Schizophrenia—complications. 2. Schizophrenia—epidemiology. 3. Comorbidity. 4. Patient Care. WM 203 M489 2009] RC514.M425 2009 616.89—dc22 2009005567 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

Contents Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix Disclosure of Interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

Part I Public Health Issues for Schizophrenia Patients

Chapter 1 Improving Physical Health Care for Patients With Serious Mental Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 David Folsom, M.D., M.P.H.

Chapter 2 Excessive Mortality and Morbidity Associated With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17 Daniel E. Casey, M.D. Thomas E. Hansen, M.D.

Chapter 3 Medical Outcomes From the CATIE Schizophrenia Study . . . . . . . . . . . . . . . . . . . . . 37 Henry A. Nasrallah, M.D.

Part II Metabolic Disease, Heart Disease, and Related Conditions

Chapter 4 Obesity and Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . .61 Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C.

Chapter 5 Glucose Intolerance and Diabetes in Patients With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91 David C. Henderson, M.D. Kathleen Miley, B.S.

Chapter 6 Effects of Antipsychotics on Serum Lipids . . . . . . . . . . . . . 117 Jonathan M. Meyer, M.D.

Chapter 7 The Spectrum of Cardiovascular Disease in Patients With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . .169 Jimmi Nielsen, M.D. Egon Toft, M.D., F.E.S.C.

Chapter 8 Behavioral Treatments for Weight Management of Patients With Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . 203 Rohan Ganguli, M.D., F.R.C.P.C. Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C. Guy Faulkner, B.Ed., M.Sc., Ph.D.

Chapter 9 Nicotine and Tobacco Use in Patients With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Andrea H. Weinberger, Ph.D. Tony P. George, M.D., F.R.C.P.C.

Part III Special Topics and Populations

Chapter 10 HIV and Hepatitis C in Patients With Schizophrenia . . . . . 247 Milton L. Wainberg, M.D. Francine Cournos, M.D. Karen McKinnon, M.A. Alan Berkman, M.D. Mark Drew Crosland Guimarães, M.D., D.Sc., M.P.H.

Chapter 11 Substance Abuse and Schizophrenia . . . . . . . . . . . . . . . . . 275 Peter F. Buckley, M.D. Jonathan M. Meyer, M.D.

Chapter 12 Sexual Dysfunction and Schizophrenia . . . . . . . . . . . . . . . . 303 Heidi J. Wehring, Pharm.D., B.C.P.P. Deanna L. Kelly, Pharm.D., B.C.P.P.

Chapter 13 Managing the Health Outcomes of Schizophrenia Treatment in Children and Adolescents . . . 343 Christoph U. Correll, M.D.

Chapter 14 Medical Health in Aging Persons With Schizophrenia . . . . 377 Samantha Brenner, M.P.H. Carl I. Cohen, M.D.

Chapter 15 Managing Health Outcomes of Women With Schizophrenia During Pregnancy and Breastfeeding . . . . . . .415 Adele C. Viguera, M.D., M.P.H. Mackenzie Varkula, D.O. Katherine Donovan, B.A. Ross J. Baldessarini, M.D.

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435

Contributors Ross J. Baldessarini, M.D. Professor of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts; Director, International Consortium for Psychotic Disorders Research, McLean Hospital, Belmont, Massachusetts Alan Berkman, M.D. Associate Professor of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York Samantha Brenner, M.P.H. Medical Student, Department of Psychiatry, State University of New York Health Science Center at Brooklyn, Brooklyn, New York Peter F. Buckley, M.D. Professor and Chairman, Department of Psychiatry, Medical College of Georgia, Augusta, Georgia Daniel E. Casey, M.D. Professor of Psychiatry and Neurology, Oregon Health and Science University, Portland, Oregon Carl I. Cohen, M.D. Professor and Director, Division of Geriatric Psychiatry, Department of Geriatric Psychiatry, State University of New York Health Science Center at Brooklyn, Brooklyn, New York Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C. Director, Mental Health and Metabolism Clinic, Centre for Addiction and Mental Health; Assistant Professor, Departments of Psychiatry and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada

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Medical Illness and Schizophrenia

Christoph U. Correll, M.D. Assistant Professor of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine; Medical Director, Director, Adverse Events Assessment and Prevention Unit, The Zucker Hillside Hospital North Shore, Long Island Jewish Health System, Glen Oaks, New York Francine Cournos, M.D. Professor of Clinical Psychiatry, Columbia College of Physicians and Surgeons; Director, Washington Heights Community Service, New York State Psychiatric Institute, New York, New York Mark Drew Crosland Guimarães, M.D., D.Sc., M.P.H. Professor of Epidemiology, Department of Preventive and Social Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Katherine Donovan, B.A. Clinical Research Coordinator, Massachusetts General Hospital Center for Women’s Health, Boston, Massachusetts Guy Faulkner, B.Ed., M.Sc., Ph.D. Professor, Faculty of Physical Education and Health, University of Toronto, Toronto, Ontario, Canada David Folsom, M.D., M.P.H. Assistant Professor of Psychiatry, University of California, San Diego, La Jolla, California Rohan Ganguli, M.D., F.R.C.P.C. Professor of Psychiatry and Executive Vice-President of Clinical Programs, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Tony P. George, M.D., F.R.C.P.C. Head, Addiction Psychiatry Program, Department of Psychiatry, University of Toronto, and Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Thomas E. Hansen, M.D. Associate Professor of Psychiatry, Oregon Health and Science University; Staff Psychiatrist, Portland Oregon State Hospital, Portland, Oregon

Contributors

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David C. Henderson, M.D. Director, Schizophrenia, Diabetes, and Weight Reduction Research Program, Massachusetts General Hospital; Associate Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts Deanna L. Kelly, Pharm.D., B.C.P.P. Associate Professor of Psychiatry and Acting Director, Treatment Research Program, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland Karen McKinnon, M.A. Research Scientist, New York State Psychiatric Institute; Project Director, Columbia University HIV Mental Health Training Project, Columbia University College of Physicians and Surgeons, New York, New York Jonathan M. Meyer, M.D. Assistant Professor of Psychiatry, University of California, San Diego; Staff Psychiatrist, San Diego VA Medical Center, La Jolla, California Kathleen Miley, B.S. Research Assistant, Massachusetts General Hospital, Boston, Massachusetts Henry A. Nasrallah, M.D. Professor of Psychiatry, Neurology and Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio Jimmi Nielsen, M.D. Research Psychiatrist, Unit for Psychiatric Research, Aarhus University Hospital and Aalborg Psychiatric Hospital, Aalborg, Denmark Egon Toft, M.D., F.E.S.C. Professor, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark Mackenzie Varkula, D.O. Resident Physician, Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland, Ohio Adele C. Viguera, M.D., M.P.H. Associate Professor of Psychiatry, Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland, Ohio

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Milton L. Wainberg, M.D. Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons; Director of Medical Education, Columbia University HIV Mental Health Training Project, New York, New York Heidi J. Wehring, Pharm.D., B.C.P.P. Fellow, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland Andrea H. Weinberger, Ph.D. Assistant Professor, Program for Research in Smokers with Mental Illness, Division of Substance Abuse, Department of Psychiatry, Yale University School of Medicine, The Connecticut Mental Health Center, New Haven, Connecticut

Disclosure of 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: Daniel E. Casey, M.D.—Consultant: Abbott Laboratories, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Janssen Pharmaceutica, NuPathe, Pfizer, Solvay Pharmaceuticals, and Wyeth Pharmaceuticals; Speaker’s bureau: Abbott Laboratories, Bristol-Myers Squibb, Janssen, and Pfizer. Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C.—Research grant funding: Pfizer Canada; Speaker’s fees: Pfizer Canada. Christoph U. Correll, M.D.—Grant support: Einstein Institute for Medical Research, National Institute of Mental Health (NIMH), and Stanley Foundation; Consultant: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Otsuka, Pfizer, Supernus, and Vanda; Speaker's bureau: AstraZeneca, Bristol-Myers Squibb, and Otsuka. Rohan Ganguli, M.D., F.R.C.P.C.—Consultant: Janssen; Speaker’s honoraria: Bristol-Myers Squibb. Tony P. George, M.D., F.R.C.P.C.—Grant support: Donaghue Medical Research Foundation, National Alliance for Research on Schizophrenia and Depression (NARSAD), National Institute on Drug Abuse (NIDA), Sanofi-Aventis, and Sepracor; Advisory board/consultant: Eli Lilly, Evotec, and Pfizer. David C. Henderson, M.D.—Research grants: NIMH, Solvay, and Takeda; Honoraria: Bristol-Myers Squibb, Covance, Janssen, Pfizer, Primedia, Reed Medical Education, and Solvay Pharmaceuticals. Deanna L. Kelly, Pharm.D., B.C.P.P.—Advisory board: Bristol-Myers Squibb and Solvay. Jonathan M. Meyer, M.D.—Research support: Bristol-Myers Squibb, NIMH, and Pfizer; Speaking/advising fees: AstraZeneca, Bristol-Myers Squibb, Organon, Pfizer, Vanda Pharmaceuticals, and Wyeth. Henry A. Nasrallah, M.D.—Research support: AstraZeneca, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, NIMH, Pfizer, Roche, and Sanofi; Consultant: AstraZeneca, Cephalon, Janssen, Pfizer, and Vanda; Speaker’s bureau: Abbott, AstraZeneca, Janssen, Pfizer, Solvay, and Vanda.

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Adele C. Viguera, M.D., M.P.H.—Grant/research support: AstraZeneca (Claffin Award), Berlex Laboratories, Eli Lilly, Epilepsy Foundation*, Forest, GlaxoSmithKline, Beecham Pharmaceuticals, Harvard Medical School's Scholars in Medicine Fellowship, Janssen, NARSAD, NIMH, Pfizer, Sepracor, Stanley Medical Research Institute, and Wyeth-Ayerst; Speaker's bureau/honoraria: AstraZeneca*, Eli Lilly, Forest*, GlaxoSmithKline, Novartis Pharmaceuticals, Wyeth-Ayerst; Advisory board: GlaxoSmithKline*, Novartis, and Wyeth-Ayerst*. *Funding in the last 12 months. Andrea H. Weinberger, Ph.D.—Grant support: NARSAD and Sepracor. The following authors affirmed that they have no competing interests: Alan Berkman, M.D. Samantha Brenner, M.P.H. Carl I. Cohen, M.D. Francine Cournos, M.D. Mark Drew Crosland Guimarães, M.D., D.Sc., M.P.H. Guy Faulkner, B.Ed., M.Sc., Ph.D. David Folsom, M.D., M.PH. Thomas E. Hansen, M.D. Karen McKinnon, M.A. Jimmi Nielsen, M.D. Egon Toft, M.D., F.E.S.C. Milton L. Wainberg, M.D. Heidi J. Wehring, Pharm.D., B.C.P.P.

American Psychiatric Publishing, Inc. (APPI)—Subsequent to peer review and acceptance for publication of this volume, APPI entered into an agreement for Dainippon Sumitomo Pharma America, Inc., to underwrite and distribute a separate printing of Medical Illness and Schizophrenia, 2nd Edition.

Preface Since the publication of the first edition of this volume in 2003, there has been a dramatic increase in the literature on optimizing medical outcomes for patients with schizophrenia. Sitting before me is the August 2008 issue of Psychiatric Services, which includes no less than eight research articles devoted to medical issues of relevance to those who care for individuals with severe mental illness. Despite the growing awareness of the unique medical needs in this patient population, natural causes of death remain the primary source of excess mortality, with recent data indicating a widening mortality gap between patients with schizophrenia and the general population (Saha et al. 2007). The recognition that antipsychotic treatment can be associated with deleterious metabolic and other health effects emphasizes the need to address medical aspects of schizophrenia treatment, yet the mental health community as a whole still has a great deal to accomplish toward achieving parity in physical health monitoring and treatment between the severely mentally ill and the rest of society. Barriers remain, but they are not insurmountable. We have expanded this second edition with the aim of providing a comprehensive resource for those who wish to be informed about the various medical issues that impinge on schizophrenia treatment. Our intent is to create a practical manual that can serve as a reference for the medical management of patients with severe mental illness across the age spectrum, with a focus on those areas of significant importance to schizophrenia patients, such as cardiometabolic disorders and their relationship to antipsychotic therapy, smoking, substance use, and infection with human immunodeficiency virus (HIV) and hepatitis C. We have also added a section on the important but neglected topic of sexual function in patients with schizophrenia and have devoted an entire chapter to the behavioral management of weight gain and obesity. The intent, as always, is to stimulate those who work in mental health settings to take a broader view of schizophrenia care, recognizing that this is a systemic disease with multiple manifestations that go beyond the obvious psychiatric symptoms. Jonathan M. Meyer, M.D. xv

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Reference Saha S, Chant D, McGrath J: A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 64:1123–1131, 2007

PART I Public Health Issues for Schizophrenia Patients


CHAPTER 1 Improving Physical Health Care for Patients With Serious Mental Illness David Folsom, M.D., M.P.H.

Much has been written about the need to integrate mental health care into the primary care setting. Psychiatrists and other mental health care providers have often criticized primary care physicians for underrecognizing and undertreating depression, substance abuse, and other common mental health conditions (Wells et al. 2000). Meanwhile, the challenge of providing quality medical care to patients with serious mental illnesses represents a similar challenge for psychiatrists. Atypical antipsychotic medications are the mainstay of contemporary pharmacological treatment for psychotic disorders (Harrington et al. 2000; IMS Health 2002; Jin et al. 2004). However, in the past decade, concern and awareness have been growing that these medications may cause or exacerbate medical conditions including weight gain and obesity (Daumit et al. 2003; Lieberman et al. 2005), elevated blood sugar and diabetes (Henderson et al. 2005; Leslie and Rosenheck 2004; Lieberman et al. 2005), and cerebrovascular events (Schneider et al. 2005). The U.S. Food and Drug Administration currently mandates that the package inserts for all six atypical antipsychotics—aripiprazole (Abilify 3

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2008), clozapine (Clozaril 2008), olanzapine (Zyprexa 2008), quetiapine (Seroquel 2008), risperidone (Risperdal 2008), and ziprasidone (Geodon 2008)—include black-box warnings regarding the increased risk of mortality in elderly patients with dementia and a warning about the risk of hyperglycemia and diabetes. These warnings and the emerging data on the medical side effects of antipsychotics have raised psychiatrists’ concern and awareness about comorbid medical conditions in their patients and have led to guidelines for the medical monitoring of patients taking these medications (American Diabetes Association et al. 2004; Marder et al. 2002). However, evidence that predates the atypical antipsychotics suggested that patients with severe mental illness (SMI) are at higher risk for several medical conditions and often receive inferior medical care, both of which likely contribute to their elevated mortality. In this chapter, I briefly review the data on the prevalence of comorbid medical conditions and the lack of quality medical care for patients with SMI, examine prior studies that attempt to improve the health status of these patients, and consider policies that might improve the integration of medical and mental health care for patients with SMI.

Medical Comorbidity and Access to Quality Medical Care for Patients With Serious Mental Illness Patients with schizophrenia and other serious mental illnesses constitute a particularly vulnerable group, for whom access to quality medical care is problematic (Druss et al. 2001a; Harvey et al. 2005). Druss et al. (2001a) reported that following myocardial infarction, patients with schizophrenia had a 30% greater 1-year mortality than patients who were not mentally ill. Approximately half of this increased mortality was due to a lack of quality medical treatment after the myocardial infarction. Folsom et al. (2002) found that in homeless patients with mental illness, those with schizophrenia were less likely to receive primary and preventive care than were patients with major depression. Furthermore, investigators have reported elevated cardiovascular risk (McCreadie 2003), as well as inferior medical care and elevated mortality in persons with schizophrenia compared with the general population (Koran et al. 1989; Phelan et al. 2001). For example, the rates of reported hypertension were 40% lower in persons with schizophrenia than in the general population, but the rates of admission for end-stage complications of hypertension, including cardiomyopathy and pulmonary

Improving Physical Health Care

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edema, were 1.8 and 1.5 times greater, respectively, in the patients with schizophrenia (Munk-Jørgensen et al. 2000). These findings suggest that patients with schizophrenia were less likely to receive treatment in the early phase of a disease and instead were receiving care later, when the disease became more severe and required hospitalization. Some encouraging data have also been published regarding health care for patients with schizophrenia. An investigation of patients treated in community-based settings found that, compared with the general population, a greater percentage of patients with schizophrenia had received primary care treatment in the prior year (Dickerson et al. 2003). At the same time, the growing concerns about the risk of diabetes, myocardial infarction, and stroke in patients taking atypical antipsychotics have increased the awareness of the importance of diagnosis and treatment of comorbid medical conditions in patients with schizophrenia (Folsom and Okereke 2005; Jin et al. 2004).

Models for Improving Medical Care for Patients With Serious Mental Illness Although the literature on interventions and service delivery models to improve the health outcomes of patients with SMI is not as extensive as that of treating depression in primary care, four basic approaches have been examined: 1) health care skills training for patients, 2) training of psychiatrists to directly provide primary care, 3) facilitated referral to primary care, and 4) co-location or integration of primary care with mental health care (Druss 2007).

Health Care Skills Training for Patients Several interventions that have been developed and tested focus on providing education and skills training for patients with chronic mental illnesses who also have a comorbid medical condition. Two skills training interventions specifically related to health care outcomes are particularly noteworthy. One intervention has been described by McKibbin et al. (2006), who enrolled 60 patients over age 40 with schizophrenia and comorbid diabetes into their diabetes awareness and rehabilitation training (DART) program. These authors tested whether patients who received an intervention based on social cognitive theory and incorporating standard diabetes self-management approaches experienced greater reductions in weight and hemoglobin A1c than did a comparison group that received only diabetes education. The intervention

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lasted 24 weeks, with patients randomly assigned to one of the two groups. At the end of the study, patients in the DART intervention lost an average of 2.3 kg, compared with a 2.7-kg weight gain in the comparison group; however, there were no significant differences in hemoglobin A1c between the two groups. The second skills training intervention is exemplified by Wu et al.’s (2008) study, which included patients who had experienced at least a 10% weight gain from atypical antipsychotics. A 2 ×2 factorial design was used to compare the effects of a lifestyle intervention, metformin (a diabetes medication that inhibits hepatic glucose production), both interventions, and placebo. This study, conducted in China, enrolled 128 patients and examined changes in weight after 12 weeks of treatment. Over the 12-week period, patients in the placebo group gained an average of 3.1 kg, whereas those receiving the lifestyle intervention lost 1.4 kg, those taking metformin lost 3.2 kg, and those in the combined lifestyle-metformin group lost 4.7 kg. Similar results were reported by Weber and Wyne (2006), who also tested a cognitive-behavioral intervention for overweight patients taking an atypical antipsychotic. The mean body mass index of patients enrolled in this study was 33, and at the end of the investigation, the mean weight loss for those in the intervention group was 2.4 kg, compared with 0.6 kg for those in the comparison group. These results demonstrate that lifestyle interventions modified for patients with schizophrenia and other serious mental illnesses can result in improved health outcomes. However, aside from weight gain and a single report on patients with diabetes, data are lacking on the effects of patient education interventions on other health outcomes for patients with SMI. Ongoing studies funded by the National Institute of Mental Health (NIMH) are examining health care outcomes, and in the coming years, information from these studies should help provide data on improving the health of patients with SMI and other health problems.

Training of Psychiatrists to Provide Primary Care A second approach to improving the health of patients with SMI is to have some aspects of primary health care provided by psychiatrists. McIntyre and Romano’s (1977) article “Is There a Stethoscope in the House (and Is It Used)?” highlighted the lack of practicing psychiatrists’ comfort with conducting physical examinations of their patients. Shore (1996) proposed that psychiatrists need to be able to provide


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basic primary care to their patients with SMI, arguing that psychiatrists are frequently the only physicians these patients see. Golomb et al. (2000) assembled a consensus panel of Veterans Affairs (VA) psychiatrists, internists, hospital administrators, and nurses to identify health conditions that would be appropriately treated by a psychiatrist who has primary care training and on-site supervision by an internist. All panel members agreed that a psychiatrist with primary care training could provide care for 17 of 38 preventive screening and counseling interventions but could perform only 10 of 157 evaluations of medical conditions and provide treatment for only 14 of 125 medical conditions. Examples of common medical conditions that the consensus panel thought primary care psychiatrists could treat included cough, headache, and nasal congestion. Examples of common conditions that the panel did not think that primary care psychiatrists could treat included chest pain and ear infection. A few psychiatry residencies have begun to train their residents to provide primary care to patients with serious mental illness. These programs include the University of California San Diego and the Oregon Health and Science University in Portland. In a series of reports, Dobscha and colleagues at the Portland VA describe the outcomes of providing this type of training in an integrated psychiatry primary medical care (PPMC) program (Dobscha and Ganzini 2001; Dobscha et al. 2005; Snyder et al. 2008). In one of these studies (Dobscha et al. 2005), nine graduates of the PPMC program and 34 other residency graduates were asked how comfortable they were with general medical conditions and how frequently they screened for or provided treatment for medical conditions. Responses indicated that, overall, the residents who worked in the PPMC program were more comfortable with general medical conditions than were their fellow residents who did not work in this program. However, few of the PPMC-trained residents provided direct medical care to their patients after graduation. In summary, despite some recommendations that training psychiatrists should provide a limited range of primary care to their patients with a serious mental illness, this model has been adopted in only a few residency training programs. In addition, although the data from these programs are limited, the psychiatrists whose training included providing primary care for some of their patients appeared to be more comfortable with the medical problems of their patients than were psychiatrists without such training, but the primary care–trained psychiatrists did not provide much direct medical care after leaving the training program.

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Facilitated Referral to Primary Care The third model for improving the health care of patients with SMI is to improve the ability of mental health centers to refer their patients to primary care providers and medical clinics. This can be done either by providing training, time, and resources to all of the mental health clinicians in a particular clinic or by having a specific care manager provide this linkage and care coordination. Some empirical evidence supports this model, and findings indicate that patients who receive specific help with accessing primary care treatment receive more primary and preventive health care than patients who do not receive such help. In a small pilot study, Bartels et al. (2004) compared the primary care received by 24 older patients with a serious mental illness who worked with a nurse care manager whose job was to help patients access primary and preventive health care. Using a chart review, the researchers found that, prior to the intervention, 17% of patients did not have a designated primary care provider and 29% had not received any preventive health care in the past year, whereas after working with the nurse case manager, all the patients had a designated primary care provider and had completed a preventive health care visit. In a larger study of 470 patients with a substance abuse disorder entering a detoxification program, Samet et al. (2003) randomly assigned half to a one-time comprehensive assessment plus working with a social worker to arrange for follow-up primary medical care at a clinic, and the other half of the patients received usual care. The patients in the clinic intervention group were more likely to have successfully seen a primary care physician at least once in the 12 months after completing the detoxification program than were patients who received usual care (69% vs. 53%). Currently, at least two ongoing NIMH-funded studies are examining whether this model would result in improved health outcomes for patients with serious mental illness (S. Bartels, personal communication, July 2008; Druss 2007).

Co-Location or Integration of Mental Health Treatment and Primary Care The fourth approach to improving the health care of patients with SMI is to co-locate primary care and mental health care within the same clinic, ideally in an integrated manner that has psychiatrists and primary care providers working together to care for patients with SMI and chronic medical conditions. These clinics would be staffed by a combination of psychiatry and primary care physicians, or by physicians du-


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ally trained in psychiatry and a primary care specialty (family medicine or internal medicine). Druss et al. (2001b) compared patient outcomes in a clinic that provided integrated medical and psychiatric care with those of a clinic providing a usual care model. In this VA-based study, 59 patients were randomly assigned to receive care in an integrated care clinic based in a VA mental health clinic that was also staffed by a full-time nurse practitioner, a part-time family physician, and a nurse case manager. The comparison group included 61 veterans who received their care in a typical VA outpatient medical clinic. Approximately three-fourths of the patients had a serious mental illness, with posttraumatic stress disorder, substance use disorders, and schizophrenia being the most common diagnoses. In addition, more than half of the patients had a previously unknown medical diagnosis. Compared to the patients receiving usual care, those in the integrated care clinic were more likely to use primary care services and less likely to use the emergency room. In addition, patients in the integrated clinic were more likely to receive preventive health care, including screening for colon cancer and diabetes, immunizations, and health education. Patients in the integrated clinic also rated their satisfaction with care more highly than did those in the comparison group, and demonstrated a small but significant improvement in their physical health-related quality of life. In an interesting qualitative assessment of this integrated clinic, Miller et al. (2003) used focus groups to identify three aspects of integrated care that were particularly important to people with a serious mental illness. First, patients reported that they had previously faced difficulty obtaining medical care in more traditional settings. For example, patients reported that in the past they had been turned away from medical clinics, were not treated with respect, or had their medical concerns dismissed. Second, the integrated clinic had greater flexibility and availability of resources, including a nurse case manager and a smaller patient panel size for the primary care providers. Finally, both patients and clinic staff noted that the communication between the patients’ psychiatrist and primary care provider was greater than what they had previously experienced, and primary care and mental health clinicians reported that they benefited from regular contact with each other. Another option for integrated care, training physicians in both psychiatry and a primary care specialty, has been less well studied. To date, two studies have been published describing the type of practice setting for dually trained physicians. A survey of physicians trained in both family medicine and psychiatry found that most (60%) practice both family medicine and psychiatry (McCahill and Palinkas 1997). In con-

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trast, psychiatrists also trained in internal medicine reported that only 15% practiced any type of medicine and 75% identified themselves as psychiatrists (Stiebel and Schwartz 2001). However, neither of these reports examined the patient outcomes of care provided by these dually trained physicians compared with usual care. Also, both of these studies are based on data that are more than a decade old, and more training programs are available now than when these data were published. Dual training programs in the United States are limited. Only seven training programs are offered in family medicine and psychiatry and 11 in internal medicine and psychiatry, and most of these programs take only two residents per year. In 2007, a total of 11 graduating medical students matched into family medicine and psychiatry residencies and 22 matched into internal medicine and psychiatry residencies (National Resident Matching Program 2008).Therefore, although this model of training physicians in both psychiatry and a primary care specialty offers the possibility of truly integrated medical and psychiatric care for patients with serious mental illness, the capacity of the current training programs is not large enough to provide this kind of care on a large scale. In summary, two models have been proposed for providing integrated medical and psychiatric care to people with serious mental illness: 1) co-locating primary care physicians in mental health clinics and 2) staffing these clinics with physicians trained in both psychiatry and a primary care specialty. Druss (2007) suggested that these types of clinics may be best suited for VA system and staff model health maintenance organizations, which use shared funding streams and medical records.

Challenges to Providing Medical Care for Patients With Serious Mental Illness Patient Level Researchers have offered several explanations as to why people with schizophrenia receive less health care than the general population. People with schizophrenia may have problems explaining their medical symptoms to primary care physicians. Physicians may be uncomfortable treating persons with schizophrenia (Lawrie et al. 1996), possibly reflecting a stigmatization of people with schizophrenia. Similarly, psychiatrists may not feel comfortable providing primary and preventive health care for their patients (McIntyre and Romano 1977). Fang and


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Rizzo (2007) used data from a national survey of physicians to examine whether psychiatrists had less access to medical services for their patients than did other medical specialists. This study compared psychiatrists’ reports of their ability to obtain medically necessary medical care for their patients with those of other specialist physicians. The study found that psychiatrists rated their ability to obtain most types of medical care “dramatically” lower than did other specialists, in part because many patients did not have insurance and those who did had barriers from their health plan.

Policy Level According to Horvitz-Lennon et al. (2006), challenges to integrating primary health care into specialty mental health treatment exist on three levels: clinical, organizational, and financial. Clinical challenges include the lack of training in physical health care by mental health clinicians. It is important to note that although most psychiatrists do not feel comfortable providing primary medical care, the knowledge of and comfort with medical problems is even lower among other mental health care providers, who rarely have formal medical training. Financial challenges include the high rates of uninsurance among persons with serious mental illness and the fact that financing for public mental health programs is typically separate from that of other public health programs. For example, in the San Diego County public mental health system, approximately 50% of patients with a serious mental illness are uninsured (Folsom et al. 2005). Furthermore, the application process for and financial restrictions of the public mental health system are separate and different from those of the safety-net health care program, resulting in a large number of patients receiving mental health treatment who do not have coverage for medical care.

Conclusion The growing recognition that people with schizophrenia and other serious mental illnesses have elevated rates of many medical conditions and often do not receive adequate medical care challenges psychiatrists and the mental health field to come up with practical approaches to improving their care. The four potential approaches examined in this chapter—health care skills training for patients, training psychiatrists to provide limited primary care, facilitated referral to primary care, and integration of primary care into mental health clinics—are all supported by some data. However, none of these approaches currently is


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widespread, and no single approach is likely to provide a solution. In an ideal world, psychiatrists would help ensure that their patients receive high-quality physical health care; staff at mental health clinics would help patients who need health care; mental health clinics would offer onsite primary care; and the financial barriers to providing integrated physical and mental health care would be removed.

Key Clinical Points ◗

Patients with schizophrenia and other serious mental illnesses receive less primary and preventive care than needed.

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Guidelines alone are unlikely to result in improved health care for patients with serious mental illness.

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Prior studies have examined four ways of improving health care for people with serious mental illness: health care skills training for patients, training psychiatrists to provide limited primary care, facilitated referral to primary care, and providing onsite primary care in mental health clinics.

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Integrating primary care into mental health clinics may require significant changes in how mental health care is funded and delivered.

References Abilify (package insert). Princeton, NJ, Bristol-Myers Squibb, 2008 American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al: Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care 27:596–601, 2004 Bartels SJ, Forester B, Mueser KT, et al: Enhanced skills training and health care management for older persons with severe mental illness. Community Ment Health J 40:75–90, 2004 Clozaril (package insert). East Hanover, NJ, Novartis Pharmaceuticals Corp., 2008 Daumit GL, Crum RM, Guallar E, et al: Outpatient prescriptions for atypical antipsychotics for African Americans, Hispanics, and whites in the United States. Arch Gen Psychiatry 60:121–128, 2003 Dickerson FB, McNary SW, Brown CH, et al: Somatic healthcare utilization among adults with serious mental illness who are receiving community psychiatric services. Med Care 41:560–570, 2003


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Dobscha SK, Ganzini L: A program for teaching psychiatric residents to provide integrated psychiatric and primary medical care. Psychiatr Serv 52:1651– 1653, 2001 Dobscha SK, Snyder KM, Corson K, et al: Psychiatry resident graduate comfort with general medical issues: impact of an integrated psychiatry-primary medical care training track. Acad Psychiatry 29:448–451, 2005 Druss BG: Improving medical care for persons with serious mental illness: challenges and solutions. J Clin Psychiatry 68:40–44, 2007 Druss BG, Bradford WB, Rosenheck RA, et al: Quality of medical care and excess mortality in older patients with mental disorders. Arch Gen Psychiatry 58:565–572, 2001a Druss BG, Rohrbaugh RM, Levinson CM, et al: Integrated medical care for patients with serious psychiatric illness. Arch Gen Psychiatry 58:861–868, 2001b Fang H, Rizzo JA: Do psychiatrists have less access to medical services for their patients? J Ment Health Policy Econ 10:63–71, 2007 Folsom DP, Okereke OI: Medical comorbidity in geriatric psychiatry. Am J Geriatr Psychiatry 13:1, 2005 Folsom D, McCahill M, Bartels S, et al: Medical comorbidity and receipt of medical care by older homeless people with schizophrenia or depression. Psychiatr Serv 53:1456–1460, 2002 Folsom DP, Hawthorne W, Lindamer L, et al: Prevalence and risk factors for homelessness and utilization of mental health services among 10,340 patients with serious mental illness in a large public mental health system. Am J Psychiatry 162:370–376, 2005 Geodon (package insert). New York, NY, Pfizer, Inc., 2008 Golomb BA, Pyne JM, Wright B, et al: The role of psychiatrists in primary care of patients with severe mental illness. Psychiatr Serv 51:766–773, 2000 Harrington C, Gregorian R, Gemmen E, et al; for The Lewin Group: Access and utilization of new antidepressant and antipsychotic medications. January 2000. Available at: http://aspe.hhs.gov/search/health/reports/Psychmedaccess/ index.htm#TOC. Accessed October 8, 2008. Harvey SB, Newton A, Moye GA: Physical health monitoring in schizophrenia: the use of an invitational letter in a primary care setting. Primary Care and Community Psychiatry 10:71–74, 2005 Henderson DC, Cagliero E, Copeland PM, et al: Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry 62:19–28, 2005 Horvitz-Lennon M, Kilbourne AM, Pincus HA: From silos to bridges: meeting the general health care needs of adults with severe mental illnesses. Health Aff (Millwood) 25:659–669, 2006 IMS Health: Atypical antipsychotics—generating evidence to inform policy and practice. 2002. Available at: http://research.imshealth.com/research/ research_schizophrenia.htm. Accessed May 15, 2006.

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Jin H, Meyer JM, Jeste DV: Atypical antipsychotics and glucose dysregulation: a systematic review. Schizophr Res 71:195–212, 2004 Koran LM, Sox HC, Marton KI, et al: Medical evaluation of psychiatric patients: results in a state mental health system. Arch Gen Psychiatry 46:733–740, 1989 Lawrie SM, Parsons C, Patrick J, et al: A controlled trial of general practitioners’ attitudes to patients with schizophrenia. Health Bull 54:201–203, 1996 Leslie DL, Rosenheck RA: Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 161:1709–1711, 2004 Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223, 2005 Marder SR, Essock SM, Miller AL, et al: The Mount Sinai Conference on the Pharmacotherapy of Schizophrenia. Schizophr Bull 28:5–16, 2002 McCahill ME, Palinkas LA: Physicians who are certified in family practice and psychiatry: who are they and how do they use their combined skills? J Am Board Fam Pract 10:111–115, 1997 McCreadie RG; Scottish Schizophrenia Lifestyle Group: Diet, smoking and cardiovascular risk in people with schizophrenia: descriptive study. Br J Psychiatry 183:534–539, 2003 McIntyre JS, Romano J: Is there a stethoscope in the house (and is it used)? Arch Gen Psychiatry 34:1147–1151, 1977 McKibbin CL, Patterson TL, Norman G, et al: A lifestyle intervention for older schizophrenia patients with diabetes mellitus: a randomized controlled trial. Schizophr Res 86:36–44, 2006 Miller CL, Druss BG, Rohrbaugh RM: Using qualitative methods to distill the active ingredients of a multifaceted intervention. Psychiatr Serv 54:568– 571, 2003 Munk-Jørgensen P, Mors O, Mortensen PB, et al: The schizophrenic patient in the somatic hospital. Acta Psychiatr Scand Suppl 407:96–99, 2000 National Resident Matching Program. Available at: http://www.nrmp.org/ data/resultsanddata2007.pdf. Accessed August 12, 2008. Phelan M, Stradins L, Morrison S: Physical health of people with severe mental illnesses. BMJ 322:443–444, 2001 Risperdal (package insert). Titusville, NJ, Janssen Pharmaceutica, Inc., 2008 Samet JH, Larson MJ, Horton NJ, et al: Linking alcohol- and drug-dependent adults to primary medical care: a randomized controlled trial of a multidisciplinary health intervention in a detoxification unit. Addiction 98:509– 516, 2003 Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebocontrolled trials. JAMA 294:1934–1943, 2005 Seroquel (package insert). Wilmington, DE, AstraZeneca Pharmaceuticals, LP, 2008 Shore JH: Psychiatry at a crossroad: our role in primary care. Am J Psychiatry 153:1398–1403, 1996


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Snyder K, Dobscha SK, Ganzini L, et al: Clinical outcomes of integrated psychiatric and general medical care. Community Ment Health J 44:147–154, 2008 Stiebel V, Schwartz CE: Physicians at the medicine/psychiatric interface: what do internist/psychiatrists do? Psychosomatics 42:377–381, 2001 Weber M, Wyne K: A cognitive/behavioral group intervention for weight loss in patients treated with atypical antipsychotics. Schizophr Res 83:95–101, 2006 Wells KB, Sherbourne C, Schoenbaum M, et al: Impacts of disseminating quality improvement programs for depression in managed primary care: a randomized controlled trial. JAMA 283:3204, 2000 Wu RR, Zhao JP, Jin H, et al: Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 299:185–193, 2008 Zyprexa (package insert). Indianapolis, IN, Eli Lilly, Inc., 2008


CHAPTER 2 Excessive Mortality and Morbidity Associated With Schizophrenia Daniel E. Casey, M.D. Thomas E. Hansen, M.D.

Psychiatric conditions have long been recognized to be associated with premature mortality. In his review, Brown (1997) noted that “lunatics” (perhaps 25% having schizophrenia) in a study from 1841 experienced mortality at three to 14 times the rate seen in the general population. According to Brown, Eugen Bleuler reported that mortality in patients with schizophrenia was 1.4 times the expected rate, caused by accidents, suicide, refusing food, infectious disease, and other diseases from poor sanitation. Brown stated that although Emil Kraepelin considered mortality to be only slightly increased in dementia praecox, he reported that suicide, negativism, diet, and poor cooperation with medical care contributed to increased mortality. Studies from the first half of the twentieth century found mortality rates in psychiatric patients to be two and four times higher than in age- and gender-matched populations (Brown 1997). Hazards of institutional care (such as tuberculosis and gastrointestinal disease) added to risks associated with the underlying psychiatric illness. Unnatural causes (suicide and accidental 17

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death) became an increasingly important cause of premature death with the shift from inpatient to outpatient care for patients with schizophrenia (Black et al. 1985). More recently, cardiovascular disease and diabetes may be increasing in importance as causes of death and morbidity in these patients (Jeste et al. 1996). This chapter updates our earlier review (Casey and Hansen 2003) of mortality and morbidity associated with schizophrenia. Data clearly demonstrate that the life span for patients with schizophrenia is shortened. Many conditions leading to premature death are evident during patients’ lifetimes and account for the majority of the excess morbidity seen in patients with schizophrenia. Both patient behaviors and societal aspects of care for schizophrenia can contribute to this increase in morbidity.

Life Span and Mortality in Patients With Schizophrenia Mortality Rates Reports on mortality rates commonly use record linkage methodology: databases of all deaths in a region are linked with population registers of psychiatric patients (community or hospital derived) so that the number of deaths in a group of patients with a specific diagnosis can be determined. This observed number is contrasted to the number expected based on life expectancy data for people of the same age and gender applied to the time period studied. The ratio of observed to expected cases is the standardized mortality ratio (SMR), sometimes reported as the ratio multiplied by 100. The 95% confidence interval (CI) values indicate statistical significance, with lower CI values above 1.0 (or 100, when the SMR is multiplied by 100) supporting significance for elevated SMR, and upper CI values below 1.0 (or 100) supporting significance for decreased SMR (Harris and Barraclough 1998). In this chapter, for ease of comparison, we report SMR and CI data without multiplying by 100, even if so reported in cited references. Reviews of mortality rates consistently find increased death rates in patients with schizophrenia. This consistency is remarkable when one considers variation in methods across individual studies and reviews. For instance, individual studies from earlier periods may be overly influenced by inclusion of hospitalized patients (lower risk of suicide, higher risk of diseases related to institutionalization), whereas later studies are likely to include outpatients (greater risk of suicide) and to be more precise in diagnosis.

Excessive Mortality and Morbidity

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Three reviews that summarized results from studies conducted between 1942 and 1996 found the mortality rate in patients with schizophrenia to be between 1.5 and 2 times the expected rate. Allebeck (1989) reviewed nine studies published between 1942 and 1985 in which patients had been followed at least 5 years and found mortality about twice the expected rate. He noted difficulty in ascertaining whether rates had changed because diagnostic and study criteria had varied over time. Brown (1997) examined studies published between 1986 and 1996 with schizophrenia patient populations of at least 100 individuals recruited after 1952 that included observed and expected death rates and that had follow-up periods of at least 2 years, with losses to followup of less than 15%. He found an aggregate SMR of 1.51 (95% CI 1.48– 1.54). The SMR for suicide was elevated (8.38, 95% CI 7.84–8.94), as were the SMR for accidents (2.16, 95% CI 1.96–2.36) and the SMR for natural causes of death (1.1, 95% CI 1.05–1.15). Brown interpreted data about specific natural causes of death conservatively, stating that patients with schizophrenia die from the same diseases as the rest of the population. He noted that peptic ulcer (perhaps related to alcohol use) and pneumonia (probably associated with elderly institutionalized patients) caused deaths at higher than expected rates. Harris and Barraclough (1998) reviewed mortality rates in cohorts of patients with various mental disorders between 1966 and 1995 (20 studies, nine countries, almost 36,000 patients) and found a death risk in patients with schizophrenia that was 1.6 times expected. The death risk from unnatural causes (suicide and violence) was 4.3 times that expected, whereas death from natural causes was 1.4 times that expected, but natural causes accounted for 68% of the excess in expected deaths. In our earlier review (Casey and Hansen 2003), we described three studies published in 2000–2001, with data on patients studied between 1973 and 1995, in which mortality rates were reported to be somewhat higher than in the earlier reviews (significantly increased relative risk or SMR of 2.4–3.8, depending on patient gender). A meta-analysis by Saha et al. (2007) confirms that SMRs for schizophrenia are increasing; the analysis reviewed 37 articles published between 1980 and 2006 from 25 countries and found the overall SMR to be 2.58. When studies were grouped by midpoint of the follow-up period, SMR increased from 1.84 in the 1970s, to 2.98 in the 1980s, and to 3.2 in the 1990s. A study not included in the meta-analysis from rural China (Ran et al. 2007) followed 510 patients with schizophrenia for the 10-year period of 1994–2004 and further demonstrated higher mortality in more recent studies (overall SMR of 4.0, 95% CI 2.4–5.8).

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Life expectancy and survival curve data offer further confirmation of increased mortality associated with schizophrenia. In our earlier review (Casey and Hansen 2003), we noted that in three studies based on 5- to 10-year follow-up of patients, authors projected decreased life expectancy of 8–16 years in general and of 3–4 years for patients ages 60 years and older. Three more recent studies also utilize survival data. Patients with first admissions for psychosis in Suffolk County, New York, between 1989 and 1995 were evaluated for survival rates at 5 and 10 years using survival curves; survival rates were 96.9% at 5 years and 94.5% at 10 years for the 235 patients with schizophrenia or schizoaffective disorder, with 60% of deaths resulting from unnatural causes (Craig et al. 2006). In a 10-year (1981–1991) mortality study of 255 patients with schizophrenia from Uppsala, Sweden, 23% of patients died compared with 11% of the 1,275 controls (P=0.003) (Fors et al. 2007). Patients with schizophrenia (n =319) seen at the Mayo Clinic from 1950–1980 were followed up to 2005 (mean 23.5 years); 44% died during this time, a rate higher (P 7%) in phase 1. Only those randomized to ziprasidone lost much of the weight they had gained from the phase 1 antipsychotic. Differences did emerge between the phase 1 results and those seen in the phase 2 efficacy and tolerability pathways, but a consistent pattern remains: olanzapine is associated with the greatest deleterious changes in metabolic parameters, whereas ziprasidone is associated with the most benign changes.

Phase 3 Findings The open-label phase 3 included subjects who had discontinued phases 1 and 2. They were given a wide range of FGAs and/or SGAs. Aripiprazole, the only atypical antipsychotic that was not included in the first two phases of the CATIE because the drug was launched too late, was used in some patients in phase 3. The only surprising data regarding the metabolic changes in phase 3 were that glucose levels increased by 13 mg/dL in patients taking aripiprazole, which was a larger increase than with any other antipsychotic in this phase (Stroup et al., in press). This finding was unexpected, because aripiprazole has demonstrated a benign metabolic profile in FDA trials and in previous published studies. All other metabolic findings were consistent with phase 1 and phase 2 profiles.

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4

Ziprasidone

Risperidone

Quetiapine

Olanzapine

0 –2 –4 –6 –8 –10 –12

FIGURE 3–8.

Phase 2 tolerability arm weight change in CATIE subjects with weight gain >7% in phase 1.


Mean change from baseline (lbs)

2

Medical Outcomes From the CATIE Study

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Conclusion The 5-year, double-blind, NIMH-sponsored effectiveness study known as the CATIE schizophrenia trial provided highly informative data about the comparative metabolic profiles of various antipsychotics and revealed the high risk for metabolic syndrome and CHD in a large sample (N= 1,460) of patients with chronic schizophrenia in the United States. These metabolic findings are likely to influence clinical practice research studies, prevention initiatives, and public policy in the foreseeable future. Although the primary measure outcome of the CATIE schizophrenia trial was effectiveness (i.e., all-cause discontinuation), a valuable body of metabolic data was obtained from the study sample, one that points to significant health problems seen in patients with schizophrenia.


The prevalence of metabolic syndrome in the CATIE schizophrenia subjects at the time of enrollment was 43%, about twice the prevalence in the general population.

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Olanzapine was associated with a fourfold higher monthly weight gain in phase 1 compared to the other antipsychotics.

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Fasting blood glucose, cholesterol, and triglyceride levels were most elevated with olanzapine and were not changed or declined with ziprasidone.

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Quetiapine resulted in higher lipid increases than risperidone, which had no deleterious effect on lipids.

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The overall metabolic profile of second-generation antipsychotics in phase 2 (both the efficacy and tolerability pathways) were the same as seen in phase 1 for olanzapine (highest increases) and ziprasidone (lowest increases or actual decreases), but were somewhat variable for quetiapine and risperidone.

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Subjects with >7% body weight increase in phase 1 lost weight only if they were assigned to ziprasidone in phase 2.

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QTc was minimally affected by all second-generation antipsychotics used in the CATIE study.

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Levels of the inflammatory marker C-reactive protein were increased with olanzapine or quetiapine but not with other antipsychotics.


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Aripiprazole was associated with the highest mean increase in fasting glucose among first-generation or second-generation antipsychotics in phase 3, the opposite of what was expected.

References Allison DB, Mentore JL, Heo M, et al: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696, 1999 American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al: Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care 27:596–601, 2004 Colton CW, Manderscheid RW: Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis 3:1–14, 2006 Goff DC, Sullivan L, McEvoy JP, et al: A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 80:45–53, 2005 Grundy SM, Brewer B, Cleeman JI, et al: Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109:433–438, 2004 Kasper S, Winkler D: Addressing the limitations of the CATIE study. World J Biol Psychiatry 7:126–127, 2006 Koller EA, Doraiswamy PM: Olanzapine-associated diabetes mellitus. Pharmacotherapy 22:841–852, 2002 Koller EA, Cross JT, Doraiswamy PM, et al: Risperidone-associated diabetes mellitus: a pharmacovigilance study. Pharmacotherapy 23:735–744, 2003 Koller EA, Weber J, Doraiswamy PM, et al: A survey of reports of quetiapineassociated hyperglycemia and diabetes mellitus. J Clin Psychiatry 65:857– 863, 2004 Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223, 2005 McEvoy JP, Meyer JM, Goff DC, et al: Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 80:19–32, 2005 Meyer JM: Strategies for the long-term treatment of schizophrenia: real-world lessons from the CATIE trial. J Clin Psychiatry 68 (suppl 1):28–33, 2007

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Meyer JM, Nasrallah HA, McEvoy JP, et al: The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial: clinical comparison of subgroups with and without the metabolic syndrome. Schizophr Res 80:9–18, 2005 Meyer JM, Davis VG, Goff DC, et al: Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1. Schizophr Res 101:273–286, 2008a Meyer JM, Davis VG, McEvoy JP, et al: Impact of antipsychotic treatment on nonfasting triglycerides in the CATIE schizophrenia trial. Schizophr Res 103:104–109, 2008b Miller BJ, Paschall CB, Svendsen DP: Mortality and medical comorbidity among patients with serious mental illness. Psychiatr Serv 57:1482–1487, 2006 Miller DD, McEvoy JP, Davis SM, et al: Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res 80:33–43, 2005 Nasrallah H: A review of the effect of atypical antipsychotics on weight. Psychopharmacology 28:83–96, 2003 Nasrallah HA, Meyer JM, Goff DC, et al: Low rates of treatment for hypertension, dyslipidemia, and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res 86:15–22, 2006 Newcomer JW: Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19 (suppl 1):1–93, 2005 Newcomer JW, Nasrallah HA, Loebel AD: The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol 5 (suppl 1):S1–S6, 2004 Stroup TS, Lieberman JA, McEvoy JP, et al: Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 163:611–622, 2006 Stroup TS, Lieberman JA, McEvoy JP, et al: Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res (in press) Swartz MS, Wagner HR, Swanson JW, et al: The effectiveness of antipsychotic medications in patients who use or avoid illicit substances: results from the CATIE study. Schizophr Res 100:39–52, 2008 Umbricht DS, Pollack S, Kane JM: Clozapine and weight gain. J Clin Psychiatry 55 (suppl B):157–160, 1994


PART II Metabolic Disease, Heart Disease, and Related Conditions


CHAPTER 4 Obesity and Schizophrenia Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C.

Obesity is a common and burgeoning health problem that has an impact on both life expectancy and quality of life. Epidemic proportions of individuals are overweight and obese worldwide (James et al. 2001; Ogden et al. 2007). The prevalence of obesity is even greater among individuals with schizophrenia, who are known to have increased morbidity and mortality from obesity-related diseases (McEvoy et al. 2005; Osby et al. 2000), as well as poor access to primary and preventive health care (Druss et al. 2001; Meyer 2007). Individuals with schizophrenia may be predisposed to obesity because of biological and lifestyle factors but also require long-term treatment with antipsychotic medications that can promote weight gain (Green et al. 2000; Newcomer 2005). With the growth in prescription of second-generation antipsychotic (SGA) medications over the past 10 years, antipsychoticassociated weight gain has emerged as an iatrogenic issue of major public health concern. The problem is compounded further by the fact that commonly coprescribed psychiatric medications, antidepressants, and mood stabilizers also contribute to weight gain (Aronne and Segal 2003; Fava 2000). In addition, patients with schizophrenia are challenged by cognitive and functional deficits that need to be considered in clinical evaluation and in the delivery of obesity interventions. Although obesity medicine is now being recognized as a subspecialty in its own right, 61

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its application for individuals with serious mental illness, such as schizophrenia, is in its infancy. The onus for management is falling to mental health professionals. Clinicians of today who treat patients with schizophrenia are challenged to become knowledgeable in the assessment, prevention, and treatment of obesity and its complications. In this chapter, I review the clinical definition of obesity and its medical consequences; the epidemiology and determinants of obesity in the general population and in individuals with schizophrenia; and the assessment, monitoring, and management of obesity for patients with schizophrenia within a mental health context.

Definition and Measurement Obesity is considered a disease by the World Health Organization (2004), which defines obesity as a condition of excess body fat to the extent that health is impaired. However, measuring body fat accurately is difficult and requires highly specialized procedures (Pi-Sunyer 2000). For clinical purposes, obesity is usually defined by the body mass index (BMI), a measure of weight that takes height into account. In addition to BMI, a measure of the distribution of body fat is important, because the central accumulation of fat within the abdominal region (central, visceral, or abdominal adiposity) is a major factor that influences the effect of increasing weight on health. Central adipose tissue is now seen as an endocrine organ that releases substances (adipokines) that have systemic effects. Adipokines include leptin, tumor necrosis factor-alpha, adiponectin, C-reactive protein, interleukin-6, and plasminogen activator inhibitor type 1. Central adiposity is most accurately measured by computer-assisted tomography or magnetic resonance imaging, which enable a distinction to be made between subcutaneous and intra-abdominal fat. However, for practical purposes, the simple waist circumference is the common clinical proxy for central adiposity (Lemieux et al. 1996). Waist-to-hip ratio has also been used for this purpose, but this measure is less favored because racial and ethnic differences in hip size complicate interpretation (Ogden et al. 2007). Both BMI and waist circumference are independently correlated with health outcomes, but waist circumference has been shown to be an even better predictor of obesity-related disease. BMI and waist circumference measures have limitations. Although body fat is a continuous variable with an incremental health risk, BMI and waist circumference are often used as categorical variables with cutoff values that reflect risk. Also, these measures do not adequately take

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into account individual, gender, and racial or ethnic differences in body type and body composition. BMI is calculated by dividing weight (measured in kilograms) by height (measured in meters) squared (i.e., BMI=kg/m2). Consensus exists among international health agencies, including the National Heart, Lung, and Blood Institute and the World Heath Organization, regarding BMI cutoffs. A BMI of 25–29.9 kg/m2 is considered overweight, and a BMI of ≥30 kg/m 2 is deemed obese. Obesity is further classified as class 1 (BMI 30–34.9 kg/m2), class 2 (BMI 35–39.9 kg/m2), and class 3 or severe obesity (BMI ≥40 kg/m2). BMI is a less accurate correlate for body fat when used for muscular individuals, who may have a high BMI and normal or low body fat, and for very short individuals (Pi-Sunyer 2000). In addition, because of differences in body composition, for a given BMI, women tend to have a higher percentage of body fat than men, and older individuals have a higher percentage of body fat than younger individuals (Ogden et al. 2007). Waist circumference is measured in the standing position with a simple tape measure placed around the waist. The waist is defined as midway between the top of the pelvis and the lowest rib. Measurement is taken after a modest expiration. For individuals with a pendulous abdomen, the waist circumference can be measured using the maximum girth, with the patient lying on his or her side on an examination table. Cutoff points are 88 cm for women and 102 cm for men. Racial or ethnic differences in body habitus can also influence the interpretation of waist circumference; therefore, the International Diabetes Federation has defined ethnic-specific cutoffs for waist circumference for the metabolic syndrome (Alberti et al. 2006). Metabolic syndrome, also known as syndrome X and insulin-resistance syndrome, is a clustering of risk markers reflecting a state of insulin resistance and compensatory hyperinsulinemia that has wide-ranging medical consequences. According to the revised Adult Treatment Panel III/American Heart Association definition, three out of the five following component criteria are required to diagnose metabolic syndrome (Grundy et al. 2005): 1. Abdominal obesity (waist circumference) ≥88 cm in women and ≥ 102 cm in men 2. Blood pressure ≥130/85 mmHg or antihypertensive treatment 3. Fasting glucose ≥5.6 mmol/L (100 mg/dL) or antidiabetic treatment 4. Fasting triglycerides ≥1.8 mmol/L (150 mg/dL) or treatment 5. Fasting high-density lipoprotein (HDL) 80 cm • South Asian, Chinese: men > 90 cm; women >80 cm • Japanese: men >85 cm; women > 90 cm

Health Consequences of Obesity Central adiposity is specifically associated with the development of insulin resistance and, consequently, type 2 diabetes, hyperlipidemia (especially raised triglycerides and low HDL), coronary heart disease, hypertension, and polycystic ovarian disease. With obesity in general, rates of gallbladder disease; respiratory disease, including obstructive sleep apnea; certain cancers (colorectal, prostate, endometrial, gallbladder, cervical, ovarian, and breast); gout; and arthritis are also increased (Pi-Sunyer 1993). Obesity reduces life expectancy. In examining deaths attributable to being overweight and obese, investigators found that more than 80% of these deaths occurred in individuals with BMIs of at least 30 kg/m2 (Allison et al. 1999b). Years of life are lost primarily because of coronary heart disease (Dorn et al. 1997). Shortened life span has been specifically noted in patients with serious mental illness, such as schizophrenia (Osby et al. 2000), with a recent report indicating as much as 25–30 years of potential life lost (Colton and Manderscheid 2006). Obesity also has a negative impact on the quality of life, and this has also been explored in samples of schizophrenia patients. Based on results from the Psychological Well-Being Index, Allison et al. (2003) reported that weight gain with antipsychotic treatment was related to poorer quality of life as well as reduced well-being and vitality. Strassnig et al. (2003a) found that the physical component score of the Medical Outcomes Study 36-Item Short-Form Health Status Survey, a measure of quality of life that assesses both physical and mental health, was inversely correlated with the physical component score of patients with schizophrenia, suggesting that the burden from obesity is primarily experienced as a physical problem, a finding that was confirmed by Faulkner et al. (2007a) who found that, in addition, waist circumference was a better predictor of reduced quality of life than BMI. Those with

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obesity describe also being stigmatized. In the general population it has been demonstrated that this phenomenon also occurs with health services, causing obese individuals to avoid visiting health care providers (Drury and Louis 2002). Patients with schizophrenia face the additional stigma of having a mental illness. The economic burden of obesity is immense (Thompson and Wolf 2001). Direct health care costs are estimated to account for 5.5%–7.0% of national health expenditure in the United States and 2.0%–3.5% in other countries. When considering comorbidities, the three largest contributors to cost are hypertension, type 2 diabetes, and coronary artery disease. The cost of lost productivity due to obesity is almost as great as the direct medical costs. In the treatment of patients with schizophrenia, lipid lowering, antihypertensive, and antidiabetic medications are now commonly coprescribed with antipsychotic medications, adding considerable costs to health care budgets.

Epidemiology of Obesity In the general population, rates of overweight and obesity are rising at an alarming rate, with no plateau in sight. In the United States, almost two-thirds of adults (66%) were overweight or obese in 2004; 32% were obese and 5% had class 3 obesity (Wang and Beydoun 2007). The prevalence of obesity has more than doubled since 1980 (Ogden et al. 2007). In Canada in 2004, 65% of the adult population was overweight or obese, but the overall rate of obesity (23%) was lower than in the United States (Tjepkema 2006). Using linear regression, Wang and Beydoun (2007) predicted that 75% of the U.S. adult population will be overweight or obese and 41% will be obese by 2015. Studies have demonstrated that the distribution of obesity varies by gender, racial and ethnic group, and socioeconomic status, with minority and low-socioeconomic-status groups having higher prevalence. In 2004, more men than women were overweight and obese, but women had higher rates of obesity, especially in non-Hispanic black and Mexican American communities, where rates of obesity in women were as high as 49% and 38%, respectively (Wang and Beydoun 2007). Weight appears to vary more by socioeconomic status, race and ethnicity, and nationality for women than for men, and some authors have suggested that weight may be associated more closely with social and cultural roles for women than for men (Ogden et al. 2007). In patients with schizophrenia, rates of obesity are even higher than in the general population and are estimated to fall between 40% and

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60% (Catapano and Castle 2004). The average BMI in recent schizophrenia trials has often approximated or been in the obese range, as illustrated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, where the recruitment strategy was designed to be broadly representative of patients with schizophrenia. In the sample of patients (n =1,460) recruited between January 2001 and December 2004 (Lieberman et al. 2005), the mean BMI at baseline was 29.7 kg/m2 (men 28.5 kg/m 2; women 33.0 kg/m2) (McEvoy et al. 2005). In a Canadian study of 240 adult patients with schizophrenia recruited in 2003 and 2004 and treated with antipsychotic medication, Cohn et al. (2004b) found that the mean BMI was 28.7 kg/m2 (men 28.0 kg/m 2; women 30.1 kg/m2) and the rate of obesity was 31% in men and 43% in women. In the same study, the rate of metabolic syndrome was two times higher in patients with schizophrenia than in age- and gender-matched general population controls. Similarly, baseline CATIE data revealed that men and women with schizophrenia were 138% and 251% more likely, respectively, to have metabolic syndrome than a National Health and Nutrition Examination Survey matched sample (McEvoy et al. 2005). To compare rates of obesity in schizophrenia patients with the general population prior to the widespread use of atypical antipsychotics, Allison et al. (1999a) investigated BMI in patients with and without schizophrenia using data from the mental health supplement of the 1989 National Health Interview Schedule. Men with schizophrenia had a BMI similar to that of men without schizophrenia (26.14 vs. 25.63), but women with schizophrenia had a higher BMI than women without schizophrenia (27.36 vs. 24.50, P< 0.001). A consistent finding in these various studies has been that women with schizophrenia have a differentially higher rate of obesity and metabolic syndrome relative to the general population than do men with schizophrenia. Although this finding is similar to what has been found in various minority and lowincome groups, the reasons have yet to be fully explored.

Determinants and Mechanisms of Obesity General and Evolutionary Factors Weight maintenance is governed by a formula that is deceptively simple: energy input must equal energy output. Energy input is essentially food consumed, whereas energy output comprises a number of elements of which physical activity is the main modifiable factor and accounts for about 30% of energy output. Other energy output factors include basal metabolism (60% of energy output), diet-induced thermo-

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genesis (10% of energy output), and adaptive thermogenesis or alteration in metabolism related to environmental, psychological, or other influences, such as habitual body movement (Groff and Gropper 1999). (Subtle akathisia, which was a common side effect with classic antipsychotics, probably accounted for significant energy expenditure.) Energy balance is tightly controlled but tilted toward weight gain because of physiological adaptations that defend against weight loss, so that a very small positive energy balance of 100 calories a day (the equivalent of one slice of bread) results in a gain of 4.5 kg in 1 year. Evolutionary concepts best explain the evolving epidemic of obesity in developed and developing countries (Ogden et al. 2007; Pi-Sunyer 2003). The human body has evolved to survive the threat of famine from a time when food was scarce and a great deal of effort and energy was required to procure food. In contrast, many people now have an abundant supply of cheap, easily obtainable, and palatable food, and at the same time less requirement and opportunity for exercise. What was an advantage in times of food scarcity becomes a liability when the food supply is abundant or when there is change from a traditional diet to a more westernized diet. When food is scarce and weight is lost, the body has a powerful biological drive to regain weight: basal metabolic rate drops, and hunger signals increase. In contrast, when excessive weight is gained, biological signals are muted; there is no great increase in basal metabolism, and individuals tend to become less rather than more active. The thrifty phenotype hypothesis, as proposed by Hales and Barker (2001), is an extension of this view: With poor intrauterine nutritional conditions, the child efficiently conserves energy and is prepared for survival in an environment where food resources will be scarce. Then, when exposed to an environment of food excess, such an individual who is efficient at conserving energy would be predisposed to obesity. This hypothesis has gained considerable favor in explaining susceptibility to metabolic disturbance, particularly type 2 diabetes. The thrifty phenotype hypothesis also suggests a mechanism whereby patients with schizophrenia may be predisposed to obesity and associated metabolic disturbance. Epidemiological research has shown an association between intrauterine and childhood undernutrition and the lifetime risk of schizophrenia. For example, there was a doubling of the rate of schizophrenia following both the Dutch winter famine (1945) and the Chinese famine (1959–1961) (Hoek et al. 1998; St Clair et al. 2005). In addition, studies have demonstrated a relationship between schizophrenia and small size at birth, thinness in childhood, and short stature (Gunnell et al. 2003; Wahlbeck et al. 2001).

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Genetics and Neurophysiology Estimates of the heritability of obesity range from 30% to 70% (Martínez-Hernández et al. 2007). Different sets of monozygotic twins that are overfed differ in the degree to which excess calories are stored as fat, but within each set of twins the susceptibility to gain weight in a given environment is similar. Although a number of rare syndromes associated with obesity have been found to be caused by discrete genetic defects or chromosomal abnormalities (e.g., Prader-Willi syndrome), the more common forms of obesity likely involve more complex interactions between the environment and a multitude of polymorphisms located in genes and candidate regions throughout the genome. Genetic investigation has focused on genes that encode and regulate food intake, energy expenditure, and adipogenesis. Food intake is regulated by peptides such as leptin and neuropeptide Y that bind with receptors in the hypothalamus, as well as by a range of peptides synthesized along the gastrointestinal tract, such as ghrelin and cholecystokinin (Schwartz et al. 2000). Research on energy expenditure has focused on the sympathetic nervous system, in particular the β-adrenergic receptor gene family, and on uncoupling proteins at the mitochondrial level (Martínez-Hernández et al. 2007). In adipogenesis, peroxisome proliferator–activated receptor-γ (PPAR-γ) has become a focus of investigation (Marti et al. 2002).

Lifestyle Habitual diet and level of physical activity are important factors that contribute to energy balance and the development of obesity. Dietary intake has been studied in schizophrenia samples, but results have been conflicting. In a cohort of 102 middle-aged patients with schizophrenia living in the community, English researchers reported that patients had a diet higher in fat and lower in fiber than the general population (Brown et al. 1999). Using a 24-hour diet recall in 146 outpatients with schizophrenia living in Pittsburgh, Strassnig et al. (2003b) reported that patients consumed more food than matched control subjects, but the macronutrient composition (percentage of calories from fat, protein, and carbohydrate) was similar in both groups. In contrast, Henderson et al. (2006) used 4-day food diaries—a more rigorous sampling strategy—to evaluate the diet of 88 patients with schizophrenia attending a community mental health clinic in Boston and made comparisons with general population controls matched by age, gender, and ethnicity. The patients consumed significantly fewer calories and less carbohydrate, protein, total fat, and saturated fat than the general population controls.

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Habitual diet is notoriously difficult to measure and is prone to various degrees of underreporting (O’Neil 2001), which may help explain these discrepant findings. Patients with schizophrenia are often financially disadvantaged, and diet can vary based on the local availability of low-cost foods. Patients are often housed in group homes and boarding houses, where food, if it is provided, is cost-based and tends to be high in starch and sugar. In a Toronto study, Cohn et al. (2004a) found that the diet of 162 outpatients with schizophrenia was similar in calorie count to that of individuals in the general population but was high in simple carbohydrates, particularly easily available chips and soda—a diet that has been implicated in development of metabolic syndrome (McKeown et al. 2004). Findings regarding physical inactivity in samples of patients with schizophrenia have been more consistent. Multiple investigators have reported low levels of physical activity in patients compared with the general population (Brown et al. 1999; Cohn et al. 2004a; Daumit et al. 2005; Ussher et al. 2007). Daumit et al. (2005) pointed out that walking tended to be the only form of physical activity and that women and those without regular social contact were more inactive. Ussher et al. (2007) indicated that patients reported low levels of social support for exercising and that fatigue and illness were the most common barriers to activity.

Obesogenic Environment An important consideration is how the environment influences lifestyle and the development of obesity. The “obesogenicity” of an environment is the sum of influences that the surroundings, opportunities, or conditions of life have on promoting obesity in individuals or populations (Swinburn et al. 1999). The concept of the obesogenic environment has been applied to the built environment, particularly in cities and suburbs (Papas et al. 2007). Attempts have been made to analyze obesogenic factors in school systems and to promote healthier environments with access to nutritious foods and the promotion of physical activity (Nollen et al. 2007). However, little attention has been paid to the obesogenic environment in mental health settings. How environments are structured in psychiatric group homes, inpatient units, and community clinics, with provision of opportunities for physical exercise and healthy eating, is an important focus for future research.

Antipsychotic-Induced Weight Gain Antipsychotic medications are a mainstay in the treatment of schizophrenia, and in most cases long-term maintenance treatment is advised.

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Significant weight gain has been recognized as a common side effect, particularly with low-potency classic antipsychotics and certain second-generation antipsychotics. This issue, which is now recognized as a public health concern (Green et al. 2000), has garnered much attention, particularly over the past 10 years. In a comprehensive review of the published literature, including randomized clinical trials, Newcomer (2005) identified clozapine and olanzapine as being associated with the greatest risk of clinically significant weight gain; risperidone, quetiapine, amisulpride, and zotepine as having intermediate risk; and ziprasidone and aripiprazole as having the lowest risk. This view is consistent with the findings of a consensus development conference among the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity. The report, published simultaneously in two journals in 2004, similarly assigned antipsychotics to high, intermediate, and low risk for weight gain and attributed the associated risk for type 2 diabetes and dyslipidemia in the same rank order (American Diabetes Association et al. 2004). Antipsychotics are associated with both short-term (10–12 weeks) and long-term weight gain. Allison et al. (1999c) conducted a metaanalysis to compare the weight-gain liability of antipsychotics over the short term (10 weeks). Using a random-effects model, average weight gain was 4.5 kg with clozapine, 4.1 kg with olanzapine, 2.5 kg with chlorpromazine, 2.1 kg with risperidone, 1.1 kg with haloperidol, and 0.05 kg with ziprasidone (Allison et al. 1999c). Other investigators have reported the short-term weight gain to be 2.3 kg with quetiapine (Jones et al. 1999) and 0.6 kg with aripiprazole (Marder et al. 2003). Weight gain tends to be rapid, particularly during the first 3 months of treatment, with significant weight increases often noted within a few weeks of treatment (Newcomer 2005). Weight gain generally plateaus within 9 months or 1 year, although clozapine tends to have a longer weight-gain trajectory, with patients continuing to gain weight for up to 5 years (Henderson et al. 2000). Considerable interindividual variability in weight gain occurs, and average weight gain belies the fact that individual patients can gain a very large amount of weight (sometimes in excess of 45 kg) on a particular medication. Susceptibility to weight gain may be genetically determined, and at a future time genetic testing might be used for predicting which patients are prone to excessive weight gain (Müller and Kennedy 2006). Clinical experience has shown that the following variables predict weight gain:

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1. Type of antipsychotic: Antipsychotics differ considerably in weightgain liability. 2. Previous antipsychotic exposure: Patients who are antipsychotic naive or switched from a classic antipsychotic or an SGA with low weight-gain risk to an antipsychotic with high weight-gain risk are more susceptible to weight gain. In contrast, those switched from an antipsychotic with high to one with low weight-gain liability tend to lose weight. 3. Age: Children, adolescents, or young adults are more likely to gain weight; older patients are less susceptible to weight gain. 4. Baseline weight: Patients with a low baseline weight tend to gain more weight. 5. Race and ethnicity: Certain groups, including those of African, South Asian, Hispanic, and Native American descent, have higher baseline rates of metabolic disturbance and may also be more susceptible to weight gain. 6. Clinical response: Although controversial, a number of investigators have found an association between weight gain and antipsychotic response. 7. Antipsychotic dose and plasma level: These are generally not correlated with weight gain when prescribed within the recommended dose range, although clozapine may be an exception. Longer-term weight gain is difficult to compare across antipsychotics because of patient attrition and the difficulties adjusting for variables such as prior antipsychotic exposure. In a randomized, controlled trial of 263 first-episode patients with no or limited prior exposure to antipsychotics that compared olanzapine (mean modal dose 9.1 mg/day) and haloperidol (mean modal dose 4.4 mg/day), the weight gain after 2 years of treatment for olanzapine was 10.2 kg using a last-observationcarried-forward analysis and 14 kg for observed cases. For haloperidol, weight gain was 4 kg using a last-observation-carried-forward analysis and 7.5 kg for observed cases (Zipursky et al. 2005). The neuroendocrine mechanisms that underlie antipsychoticinduced weight gain are not fully understood. However, the relationship between neurotransmitter-binding profiles of different antipsychotics and their propensity to induce weight gain has been explored (Nasrallah 2008). Wirshing et al. (1999) astutely observed a correlation between weight gain and antipsychotic binding affinity for the histamine-1 (H1) receptor. Kroeze et al. (2003) more recently concluded that H 1 receptor affinity is positively correlated with weight gain among both typical and atypical antipsychotics. Others have confirmed this

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(S.F. Kim et al. 2007; Matsui-Sakata et al. 2005). S.F. Kim et al. (2007), using a mouse model, found that antipsychotics that induce weight gain selectively activate hypothalamic AMP-kinase via the H1 receptors. H1 activity is involved in appetite regulation and sedation, both relevant to weight gain. These findings may guide antipsychotic drug development toward drugs less implicit in weight gain. Other targets for investigation include the 5-HT2C gene (De Luca et al. 2007; Reynolds et al. 2002) and the SNAP-25, α-2a, leptin, and GNB3 genes (Müller and Kennedy 2006).

Managing Obesity in Schizophrenia The management of obesity includes an understanding and evaluation of risk factors, prevention of weight gain, metabolic assessment, and ongoing monitoring of the patient, as well as the application of pharmacological and nonpharmacological strategies of prevention and treatment. Clearly, psychiatrists cannot do this work alone. What is required is to develop a system of assessment and management in which roles and tasks are clearly defined and often delegated.

Tooling the Office or Clinic Clinicians should think through how to set up the environment, equipment, systems, and personnel within the office or clinic to facilitate care of patients who are obese (Kushner 2007). The clinic or office should be accessible for these patients. Hallways and doors should not be too narrow, washrooms need to be large enough, and the waiting area and examination or interview room should have a number of sturdy, armless chairs. Posters, artwork, and magazines should not overly promote “thinness.” However, posters promoting balanced healthy eating and physical activity are appropriate, as is information about weight-loss programs and services. The examination area should be equipped with appropriate equipment for assessing obese patients. Most office or hospital scales do not measure above 300–350 lb (135–160 kg). Clinics should obtain a scale with greater capacity and position it so the patient can be weighed privately and away from public view. A wall-mounted measure or an extendable height meter attached to the scale should be available for measuring the patient’s height. Also, a variety of cuff sizes should be provided for measuring blood pressure. “Miscuffing” is the most common error in measuring blood pressure, and undercuffing accounts for the majority of errors (Manning et al. 1983). Tape measures should be

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available for measuring waist circumference, and a calculator or chart is needed for determining BMI. Each office or clinic needs to establish a procedure for metabolic monitoring. The paper or electronic health record should allow for the recording and tracking of screening medical history questions, clinical measures, and laboratory tests used in metabolic monitoring. Commercial tracking sheets, usually sponsored by pharmaceutical companies, are available. The clinic where I work has developed an electronic tool that is integrated into the medical record and the patient care plan that allows for the tracking of metabolic parameters and performs calculations such as whether the patient has metabolic syndrome, Framingham risk score, target lipid values, and so forth (Khoury et al. 2008). Forms or computer systems should be readily available to order needed laboratory tests. Systems need to be in place for referring patients for primary care or specialist consultation and for referring patients for nutrition counseling and to professionals who promote physical activity. Larger clinics or programs should develop group-based interventions to promote healthy lifestyle changes. The roles and tasks of personnel should be clearly defined. Registered nurses can obtain the vital measurements, including weight, height, waist circumference, and blood pressure, and provide health teaching. Nurse practitioners can provide most components of primary health care. Co-location of primary health care (primary care physician or nurse practitioner) within psychiatric services is an excellent model for integrating health care (Druss et al. 2001). Office secretaries and assistants can facilitate referrals, remind patients of appointments, and distribute written material. Although the exact role and function of each team member varies from one setting to another, what is most important is that care is coordinated and that individuals work together as a team.

Assessment and Metabolic Monitoring of the Patient Patients can be assessed at various points—as a new antipsychotic medication is prescribed, after substantial weight has been gained, upon admission to hospital, at annual examinations, at each visit, and so on. Ideally, to inform care, these various assessments should be recorded and tracked, along with prescribed medications and intervention efforts. Electronic record systems are particularly helpful in this regard and can also provide reminders when assessments are due. We (Cohn and Sernyak 2006) have reviewed recommendations regarding metabolic monitoring published in various countries. Table 4–1

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provides a structure informed by these guidelines and used in our clinic for assessment of patients who are overweight or obese and are being treated with psychiatric medications associated with weight gain (antipsychotics, mood stabilizers, and antidepressants). Monitoring, which consists of medical history, measurements, and laboratory tests, is conducted at the first opportunity—when the patient first presents at the office of clinic or at the time of hospital admission. Monitoring is then repeated annually. A new baseline is established when a new antipsychotic (or mood medication) is started, with a follow-up evaluation 3 months later. Weight is measured at every visit and graphed over time across encounters (inpatient and outpatient). Diet, activity, motivation, and environmental factors (see “General and Lifestyle” column in Table 4–1) are evaluated during clinic visits. To evaluate diet and physical activity, we have found it useful in our clinic to have the patient, with the support of family or caregivers, complete 3 days of food records, a standard food frequency questionnaire, and a physical activity questionnaire prior to the initial appointment. We have been able to validate the reliability of the International Physical Activity Questionnaire (Craig et al. 2003) in a sample of patients with schizophrenia (Faulkner et al. 2006). These assessments are mailed to the patient before the appointment, reviewed during the initial consultation, and used to inform the development of a treatment plan. We have also found it useful to get a baseline measure of fitness by using the 6-minute walking test (ATS Committee on Proficiency Standards 2002), a simple structured assessment of the distance an individual walks over 6 minutes.

Strategies for the Prevention and Management of Obesity Behavioral lifestyle interventions focused on diet and physical activity should be combined with biological (mostly pharmacological) strategies to benefit patients who are obese (Faulkner and Cohn 2006). Figure 4–1 provides a recommended outline for the sequencing of interventions. Behavioral interventions are discussed in detail in Chapter 8, “Behavioral Treatments for Weight Management of Patients With Schizophrenia.” This section focuses on biological strategies. Medication Choice. Weight-gain liability should be factored in when choosing psychotropic medications. The choice of psychotropic medication may have the greatest influence on weight gain and associated metabolic disturbance. Good evidence exists for a range of weight-gain liability for antipsychotic medications (Allison et al. 1999c; Newcomer

TABLE 4–1.

Metabolic assessment of patients treated using antipsychotic medications Medical history

•

Medications • Current antipsychotic medication(s) • Previous antipsychotic trials • Newly prescribed antipsychotic (date) • Coprescribed mood stabilizers • Coprescribed antidepressants • Coprescribed lipid medication(s) • Coprescribed diabetes medication(s) • Coprescribed antihypertensive medication(s)

• •

•

Current psychiatric and medical contacts Income and source Living situation: Are meals provided? Who does the shopping and cooking? Recreational opportunities? Self-report of weight change over time

Physical activity • Premailed International Physical Activity Questionnaire 1 • Interest in and barriers to increasing physical activity • 6-Minute walking test 2 Diet • Premailed food frequency questionnaire and 3-day food diary • Interest in and feasibility of making dietary changes

Examination (measurement) Laboratory tests • • • •

Height Weight Waist circumference Blood pressure

For nondiabetic patients (No known diagnosis of diabetes) • Fasting glucosea Measuring guide • Fasting insulin Height: No shoes • Fasting lipid Weight: No shoes; single layer profile of clothing (Total, HDL, and Waist circumference: Standing LDL cholesterol position and triglycerides) Blood pressure: Average of two measures. Patient seated For diabetic patients Risk factors and resting for at least 5 • Race/ethnicity • Fasting glucose minutes, >30 minutes from • Family history of diabetes • Fasting lipid last cigarette or coffee. Arm • History of gestational diabetes profile relaxed and supported at • History of coronary vascular disease • HBA1C heart level. Choose (angina, myocardial infarction, or • Random urine appropriate cuff size as stroke) microalbuminb indicated by cuff markers. • Cigarette smoking

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a Patients with impaired fasting glucose (5.6–6.9 mmol or 100–125 mg/dL) have follow-up glucose tolerance test (fasting glucose and 2-hour glucose after 75-g oral glucose drink). bIf elevated, urine albumin/creatinine ratio. 1 Craig et al. 2003; Faulkner et al. 2006. 2ATS Committee on Proficiency Standards 2002. Source. Adapted from Cohn and Sernyak 2006.

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2005). Antidepressant and mood-stabilizing medications also contribute to weight gain (Aronne and Segal 2003; Fava 2000) because these medications are commonly coprescribed with antipsychotics. Lithium carbonate, valproic acid, selective serotonin reuptake inhibitors, and mirtazapine have all been implicated in weight gain. Young, first-episode patients are more susceptible to antipsychoticinduced weight gain (Zipursky et al. 2005) and also tend to have a robust response to antipsychotic medications (Perkins et al. 2004). Initial treatment with antipsychotic medications known to induce significant weight gain should be avoided. Care should also be taken in the choice of concomitant psychiatric medications. In patients who have gained significant weight or developed metabolic complications, all medications should be reviewed from both metabolic and psychiatric perspectives (Faulkner and Cohn 2006). Medication Switching. Switching from one antipsychotic medication to another can have significant effects on body weight and metabolic parameters. Reviews (Weiden 2007; Weiden and Buckley 2007) suggest that switching to low-liability antipsychotics (ziprasidone or aripiprazole) can have a more substantial impact on reversing weight gain and lipid disturbance than other intervention strategies, particularly if the weight gain and metabolic derangement clearly occurred during the course of prior treatment with an antipsychotic medication with greater metabolic liability. The metabolic benefit from switching is therefore dependent on the prior treatment. Outpatients, predominantly with schizophrenia, were switched from a previous antipsychotic—olanzapine (n = 104), risperidone (n = 58), or conventional antipsychotic (n =108)—to ziprasidone (mean dose 91 mg/day) and reevaluated after 6 weeks (Weiden et al. 2003a). Weight and metabolic benefit depended on which drug the patients were originally taking. Those switched from olanzapine experienced the greatest metabolic benefit, with significant reductions in body weight (1.76 kg), nonfasting total cholesterol, and triglycerides. Those switched from risperidone experienced less weight loss (0.86 kg) but similar reductions in nonfasting total cholesterol and triglycerides. However, those switched from conventional antipsychotics had no change in weight or lipid measures. A companion paper from the same data set (Weiden et al. 2003b) supported the view that stable but symptomatic patients can safely be switched from a previous antipsychotic using a variety of switching strategies (e.g., abrupt discontinuation of previous antipsychotic or gradual cross-titration), often with benefit to psychiatric symptomatology. An extension of this study provided long-

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Consider metabolic risk in choice of antipsychotic

Provide patient, family, and caregiver education about potential metabolic side effects

Conduct baseline screening and regular metabolic monitoring

Provide lifestyle counseling

With significant weight gain/ metabolic disturbance: Review all medications from a metabolic and psychiatric perspective; consider risk/benefit of switch

Provide referral to structured lifestyle intervention focused on diet, physical activity, and behavior change

If lifestyle intervention is unsuccessful, consider adjunctive pharmacotherapy; for severe obesity and significant disability, consider evaluation and workup for obesity surgery

FIGURE 4–1. Prevention and management of antipsychotic-related metabolic disturbance. Source.

Adapted from Faulkner and Cohn 2006.

term data for 153 patients followed for 58 weeks (Weiden et al. 2008). Average weight loss from baseline was 10.3% (9.8 kg) and 7.8% (6.9 kg) if the previous antipsychotic was olanzapine or risperidone, respectively. Those patients switched from olanzapine and risperidone also sustained significant reductions in nonfasting cholesterol and triglycerides, with maximum reductions occurring rapidly at 6 weeks after the switch. Those switched from conventional antipsychotics to ziprasidone did not change in body weight or lipid measures. Data from the CATIE study (Lieberman et al. 2005) also provide evidence in a randomized trial of differential effects on body weight

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when antipsychotics are switched. Patients switched to olanzapine gained 0.9 kg per month. Patients switched to quetiapine and risperidone also gained weight, but less (0.23 kg per month on quetiapine and 0.18 kg per month on risperidone). Those switched to ziprasidone and perphenazine lost 0.13 and 0.09 kg per month, respectively. Patients switched to aripiprazole (Casey et al. 2003) experience weight changes very similar to patients who are switched to ziprasidone. Again, weight change depended on the previous antipsychotic. Taken together, data from these studies indicate that weight loss and metabolic benefit can be achieved by switching medication, particularly if these problems clearly developed while a patient was taking the prior medication. However, switching is always hazardous because patients can decompensate. The biggest challenge is the patient who has been doing well psychiatrically while taking an antipsychotic but has gained weight or developed metabolic complications. In such a case, the risks of switching may be greater, and the patient and family need to be informed of the potential risks and benefits and then carefully consider whether to switch medication. Discontinuing or switching antipsychotics becomes a critical issue when diabetes or diabetic ketoacidosis can be clearly linked to an antipsychotic prescription, because resolution of diabetes can occur (Jin et al. 2004). Medication Addition. One strategy to prevent weight gain or to promote weight loss is to add a medication associated with weight loss to the antipsychotic medication regimen. In the general population, controlled clinical trials have established modest efficacy for obesity drugs in combination with lifestyle therapy (Li et al. 2005). Orlistat (lipase inhibitor) and sibutramine (serotonin/dopamine/norepinephrine reuptake inhibitor) are the only drugs currently approved for long-term weight loss. Average weight loss in the general population (psychiatric patients were excluded) at 12 months was 2.7 kg (95% CI 2.3–3.1) for individuals taking orlistat and 4.3 kg (95% CI 3.6–4.9) for those taking sibutramine (Padwal et al. 2003). In the context of antipsychoticinduced weight gain, brief (6–16 weeks) randomized controlled trials have been conducted in patients with schizophrenia using a number of compounds, as summarized in Table 4–2. In a Cochrane review, Faulkner et al. (2007b) focused on weight change to compare efficacy reported in studies identified using a systematic search and retrieval protocol. Unfortunately, no long-term studies have been published. In these studies, the weight loss medication is either added when the antipsychotic is first prescribed to prevent weight gain (e.g., reboxetine in first-episode psychosis being treated with olanzapine) (Poyurovsky

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et al. 2003, 2007) or added later when patients have already gained substantial weight (e.g., the use of metformin in children and adolescents whose weight had increased by more than 10% in less than 1 year while taking atypical antipsychotics) (Klein et al. 2006). Many of these studies have been conducted in patients taking clozapine and olanzapine. The studies have been heterogeneous, and results have been mixed. When there is a weight benefit, it tends to be modest (approximately 2–4 kg over 3 months). Negative results have been seen with fluoxetine and reboxetine addition. Sibutramine was found effective with patients on olanzapine (Henderson et al. 2005) (but the benefits were reversed when patients stopped taking sibutramine). Sibutramine was ineffective in clozapine-treated patients (Henderson et al. 2007). Topiramate has been more consistently effective for weight loss in open-label as well as double-blind studies (J.H. Kim et al. 2006; Ko et al. 2005), and doses of 200 mg/day have been more effective than 100 mg/day (Ko et al. 2005). However, topiramate has many side effects, both common (paresthesia) and potentially serious (cognitive impairment, narrowangle glaucoma, and metabolic acidosis). Metformin may be more helpful in reducing or preventing weight gain during the early stages of treatment for psychosis or in younger individuals. Metformin was found to be effective in reducing weight gain when coprescribed with olanzapine in patients treated for a first psychotic episode (Wu et al. 2008) and in reversing weight gain and improving insulin sensitivity in children and adolescents who had recently gained weight during treatment with atypical antipsychotics (Klein et al. 2006). However, metformin addition was not able to prevent weight gain in an adult sample of schizophrenia patients with a more chronic course who were switched to olanzapine (Baptista et al. 2006). The release of rimonabant, a selective cannabinoid CB1 receptor antagonist, was highly anticipated because of promising phase 3 results in weight loss, smoking cessation, and improvement of metabolic profiles in patients with metabolic syndrome, all of which would benefit patients with schizophrenia (Cox 2005). Rimonabant is currently approved in Europe but not in the United States or Canada. Because recent data indicate significant psychiatric adverse effects, primarily depression and anxiety, there was a recommendation against rimonabant approval in 2007 by the FDA (Rumsfeld and Nallamothu 2008). Given that H1 receptor affinity appears to be implicated in antipsychotic-associated weight gain, interest has been shown in the use of betahistine, an H1 receptor agonist and H3 antagonist, to prevent weight gain. Promising results were reported in a small open-label study (Poyurovsky et al. 2005). Placebo-controlled studies are still needed.

Antipsychotic × trial duration

Amantadine (antiparkinsonian) Famotidine (H2 receptor antagonist) D-Fenfluramine (removed from market) Fluoxetine (SSRI)

Olanzapine × 16 weeks (Deberdt et al. 2005) Olanzapine × 6 weeks (Poyurovsky et al. 2004) Typical depots × 12 weeks (Goodall et al. 1988) Olanzapine × 8 weeks (Poyurovsky et al. 2002) Olanzapine × 16 weeks (Bustillo et al. 2003) Olanzapine × 12 weeks (Wu et al. 2008) Atypical AP × 16 weeks (Klein et al. 2006) Olanzapine × 14 weeks (Baptista et al. 2006) Olanzapine × 8 weeks (Atmaca et al. 2003) Olanzapine × 16 weeks (Cavazzoni et al. 2003)

Metformin (antidiabetic)

Nizatidine (H2 receptor antagonist)

Agent dose: n for intervention group: outcome, expressed as weight change relative to placebo [95% CI] 100–300 mg: n= 35: −1.7 [−3.9, 0.5] kg 40 mg OD: n= 7: no effect 30 mg OD: n= 9: −2.6 [−5.5, −0.1] kg 20 mg OD: n= 15: no effect 60 mg OD: n= 15: no effect 250 mg tid: n= 18: −5.0 [−7.3, −2.7] kg 500 mg OD: n= 9 (ages 10–17): −4.1 [−7.3, −1.0] kg 850–1,750 mg: n= 20: no effect 150 mg bid: n =18: −6.8 [−7.9, −5.7] kg 300 mg bid: n =58: less wt gain, 3 and 4 wk; effect lost, 16 wk 150 mg bid: n =57: no effect


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TABLE 4–2. Randomized, controlled trials of medication addition for weight gain in schizophrenia

TABLE 4–2. Randomized, controlled trials of medication addition for weight gain in schizophrenia (continued) Antipsychotic × trial duration

Phenylpropanolamine (removed from market) Reboxetine (SNRI)

Clozapine × 12 weeks (Borovicka et al. 2002) Olanzapine × 6 weeks (Poyurovsky et al. 2003) Olanzapine × 6 weeks (Poyurovsky et al. 2007) Clozapine × 12 weeks (Henderson et al. 2007) Mixed × 16 weeks (Weiden et al. 2003c) Olanzapine × 12 weeks (Henderson et al. 2005) Atypical AP × 12 weeks (Ko et al. 2005)

Sibutramine (serotonin/ dopamine RI)

Topiramate (anticonvulsant)

Agent dose: n for intervention group: outcome, expressed as weight change relative to placebo [95% CI] 75 mg: n =8: no effect 4 mg/d: n =13: −3.0 [−5.6, −0.5] kg 4 mg/d: n =31: −1.5 [−2.9, −0.1] kg 15 mg: n =11: no effect 15 mg: n =29: no effect

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15 mg: n =19: −4.6 [−5.2, −4.0] kg 200 mg/d: n =17: −5.1 [−7.4, −2.7] kg 100 mg/d: n =16: −1.4 [−4.2, 1.5] kg

Note. RI= reuptake inhibitor; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI= selective serotonin reuptake inhibitor. Source.

Adapted from Faulkner and Cohn 2006.

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Insufficient data are available to suggest the routine use of medication additions (Faulkner and Cohn 2006). Each medication brings the potential of additional side effects, effect sizes are small, and accessing and covering the costs of these drugs are often problematic. Medication additions should, however, be contemplated when other approaches such as behavioral interventions have been exhausted and switching to a different antipsychotic has been ruled out. Obesity Surgery. Surgery is an effective intervention for treating severe obesity (Schneider and Mun 2005; Sharma and Iacobellis 2006), resulting in more significant and longer-lasting loss of weight than other treatments. Criteria for selecting patients for bariatric surgery include the following: 1) BMI > 40 kg/m2 or BMI > 35 kg/m 2 with significant obesity-related comorbidities; 2) repeated failure of other nonsurgical interventions; 3) psychologically stable patient with realistic expectations; and 4) absence of alcoholism, other addictions, or major psychopathology (NIH Conference 1991). These criteria make it difficult for patients with schizophrenia and other forms of severe mental illness to access surgical intervention. Surgical procedures can involve gastric restriction using vertical or adjustable bands to create a small neogastric pouch, or shortening the functional length of the intestinal surface for nutrient absorption, as in gastric bypass or biliopancreatic diversion. The current gold standard for bariatric surgery is the Roux-en-Y gastric bypass, which is a combination of the restrictive and bypass procedures (Sharma and Iacobellis 2006). Patients with schizophrenia require advocacy and very close medical follow-up and support to access and derive maximum benefit from any of these effective interventions.

Conclusion Although obesity is endemic in the general population, its prevalence and consequences are amplified for patients with schizophrenia. Responsibility for organizing health promotion and obesity interventions lies with the providers of psychiatric care, because these services are often not otherwise accessible and because medications used to treat schizophrenia contribute to the development of obesity. Genetic, medication, lifestyle, and environmental factors are determinants of obesity in patients with schizophrenia, but genetic prediction of an individual’s susceptibility to gain weight taking a particular medication is not yet a reality, and practitioners have to rely on clinical evaluation and

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ongoing monitoring. Clinicians and mental health services are challenged to set up systems for the assessment, monitoring, prevention, and treatment of obesity.


Obesity affects life expectancy and quality of life and is more common in patients with schizophrenia than in the general population.

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Genetics, psychotropic medications, lifestyle, and the environment are contributing factors.

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Clinical assessment of the patient includes a review of medical history, diet, and level of physical activity; physical measurements (weight, height, waist circumference, and blood pressure); and laboratory tests. These parameters should be tracked in an organized manner along with prescribed psychotropic medication (metabolic monitoring).

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The clinic or office should be set up to facilitate care of obese patients. Considerations include the environment, equipment, systems, and use of personnel.

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Prevention and management of obesity in schizophrenia require consideration of choice of psychotropic medication, health counseling and behavioral interventions, medication switching, medication addition, and obesity surgery.

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CHAPTER 5 Glucose Intolerance and Diabetes in Patients With Schizophrenia David C. Henderson, M.D. Kathleen Miley, B.S.

In recent years, tremendous progress has been made in the treatment of schizophrenia and other psychotic disorders. In particular, the introduction of atypical antipsychotic agents has helped numerous patients gain control of both positive and negative symptoms of schizophrenia. Studies also suggest that the newer antipsychotic agents increase compliance, prevent relapse (Csernansky et al. 2002), and may offer improvement in the treatment of cognitive dysfunction (Meltzer 2001). These treatment successes, combined with a lower risk of extrapyramidal symptoms (e.g., parkinsonism) and improved control of positive and negative symptoms, have led many psychiatrists to favor the newer, atypical antipsychotic medications over the older, typical agents. Furthermore, the atypical antipsychotic agent clozapine has been found to be a highly effective agent in improving symptoms for those patients who have had treatment resistance to other antipsychotic medications (Lewis et al. 2006). 91

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The use of atypical antipsychotic medications, however, has not proven to be trouble free. Numerous reports in the psychiatric and medical literature have suggested an association between atypical antipsychotic agents and impaired glucose metabolism, diabetes mellitus, and diabetic ketoacidosis (Elias and Hofflich 2008; Henderson 2002; Henderson et al. 2007; Perez-Iglesias et al. 2007; Saddichha et al. 2008). After a brief review of diabetes pathophysiology, especially type 2 diabetes mellitus, and its short- and long-term medical consequences, we examine glucose intolerance and diabetes in individuals with schizophrenia before and following the introduction of typical and atypical antipsychotic medications. Finally, we make recommendations for monitoring and screening for glucose intolerance and diabetes in patients with schizophrenia.

Diagnostic Criteria and Pathophysiology of Diabetes Mellitus Both diabetes and glucose intolerance are characterized by problems in glucose-insulin regulation. According to the American Diabetes Association (ADA), if an individual has the typical symptoms of diabetes, such as polyuria, polydipsia, and unexplained weight loss, plus a casual plasma glucose level ≥200 mg/dL (11.1 mmol/L), a fasting plasma glucose level ≥126 mg/dL (7.0 mmol/L), or a 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L) post 75-g oral glucose load, then he or she has diabetes mellitus (American Diabetes Association 2008). Similarly, if an individual has a 2-hour plasma glucose level ≥140 mg/dL and

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