Medical-Schizophr

Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

Disclosure of Interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

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

Part IPublic Health Issues for Schizophrenia Patients

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

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

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

Part IIMetabolic Disease, Heart Disease,

and Related Conditions

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

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

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

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

Chapter 8Behavioral Treatments for Weight Management of Patients With Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . 203Rohan 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 9Nicotine and Tobacco Use in Patients With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Andrea H. Weinberger, Ph.D.Tony P. George, M.D., F.R.C.P.C.

Part IIISpecial Topics and Populations

Chapter 10HIV and Hepatitis C in Patients With Schizophrenia . . . . . 247Milton 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 11Substance Abuse and Schizophrenia . . . . . . . . . . . . . . . . . 275Peter F. Buckley, M.D.Jonathan M. Meyer, M.D.

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

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

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

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

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

ix

Contributors

Ross J. Baldessarini, M.D.

Professor of Psychiatry, Harvard Medical School and MassachusettsGeneral Hospital, Boston, Massachusetts; Director, International Con-sortium 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 NewYork Health Science Center at Brooklyn, Brooklyn, New York

Peter F. Buckley, M.D.Professor and Chairman, Department of Psychiatry, Medical College ofGeorgia, Augusta, Georgia

Daniel E. Casey, M.D.

Professor of Psychiatry and Neurology, Oregon Health and ScienceUniversity, Portland, Oregon

Carl I. Cohen, M.D.Professor and Director, Division of Geriatric Psychiatry, Departmentof Geriatric Psychiatry, State University of New York Health ScienceCenter 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 Addictionand Mental Health; Assistant Professor, Departments of Psychiatryand Nutritional Sciences, University of Toronto, Toronto, Ontario,Canada

x Medical Illness and Schizophrenia

Christoph U. Correll, M.D.

Assistant Professor of Psychiatry and Behavioral Sciences, Albert Ein-stein College of Medicine; Medical Director, Director, Adverse EventsAssessment and Prevention Unit, The Zucker Hillside Hospital NorthShore, Long Island Jewish Health System, Glen Oaks, New York

Francine Cournos, M.D.Professor of Clinical Psychiatry, Columbia College of Physicians andSurgeons; Director, Washington Heights Community Service, NewYork 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 Med-icine, Faculty of Medicine, Federal University of Minas Gerais, BeloHorizonte, Minas Gerais, Brazil

Katherine Donovan, B.A.

Clinical Research Coordinator, Massachusetts General Hospital Centerfor Women’s Health, Boston, Massachusetts

Guy Faulkner, B.Ed., M.Sc., Ph.D.Professor, Faculty of Physical Education and Health, University ofToronto, 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 ClinicalPrograms, 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, Uni-versity of Toronto, and Schizophrenia Program, Centre for Addictionand Mental Health, Toronto, Ontario, Canada

Thomas E. Hansen, M.D.Associate Professor of Psychiatry, Oregon Health and Science Uni-versity; Staff Psychiatrist, Portland Oregon State Hospital, Portland,Oregon

Contributors xi

David C. Henderson, M.D.

Director, Schizophrenia, Diabetes, and Weight Reduction Research Pro-gram, Massachusetts General Hospital; Associate Professor of Psychia-try, Harvard Medical School, Boston, Massachusetts

Deanna L. Kelly, Pharm.D., B.C.P.P.Associate Professor of Psychiatry and Acting Director, Treatment Re-search Program, Maryland Psychiatric Research Center, University ofMaryland 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, ColumbiaUniversity 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, Massa-chusetts

Henry A. Nasrallah, M.D.

Professor of Psychiatry, Neurology and Neuroscience, University ofCincinnati College of Medicine, Cincinnati, Ohio

Jimmi Nielsen, M.D.Research Psychiatrist, Unit for Psychiatric Research, Aarhus UniversityHospital and Aalborg Psychiatric Hospital, Aalborg, Denmark

Egon Toft, M.D., F.E.S.C.Professor, Department of Health Science and Technology, Aalborg Uni-versity, Aalborg, Denmark

Mackenzie Varkula, D.O.

Resident Physician, Department of Psychiatry and Psychology, Cleve-land Clinic Foundation, Cleveland, Ohio

Adele C. Viguera, M.D., M.P.H.Associate Professor of Psychiatry, Department of Psychiatry and Psy-chology, Cleveland Clinic Foundation, Cleveland, Ohio

xii Medical Illness and Schizophrenia

Milton L. Wainberg, M.D.

Associate Clinical Professor of Psychiatry, Columbia UniversityCollege 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 MarylandSchool of Medicine, Baltimore, Maryland

Andrea H. Weinberger, Ph.D.Assistant Professor, Program for Research in Smokers with MentalIllness, Division of Substance Abuse, Department of Psychiatry, YaleUniversity School of Medicine, The Connecticut Mental Health Center,New Haven, Connecticut

xiii

Disclosure of Interests

The following contributors to this book have indicated a financial interest in or otheraffiliation with a commercial supporter, a manufacturer of a commercial product, a pro-vider of a commercial service, a nongovernmental organization, and/or a governmentagency, 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: Ab-bott Laboratories, Bristol-Myers Squibb, Janssen, and Pfizer.

Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C.—Research grant funding: PfizerCanada; Speaker’s fees: Pfizer Canada.

Christoph U. Correll, M.D.—Grant support: Einstein Institute for Medical Re-search, National Institute of Mental Health (NIMH), and Stanley Founda-tion; Consultant: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen,Otsuka, Pfizer, Supernus, and Vanda; Speaker's bureau: AstraZeneca, Bris-tol-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 ResearchFoundation, National Alliance for Research on Schizophrenia and Depres-sion (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; Hon-oraria: Bristol-Myers Squibb, Covance, Janssen, Pfizer, Primedia, ReedMedical Education, and Solvay Pharmaceuticals.

Deanna L. Kelly, Pharm.D., B.C.P.P.—Advisory board: Bristol-Myers Squibband Solvay.

Jonathan M. Meyer, M.D.—Research support: Bristol-Myers Squibb, NIMH, andPfizer; Speaking/advising fees: AstraZeneca, Bristol-Myers Squibb, Organon,Pfizer, Vanda Pharmaceuticals, and Wyeth.

Henry A. Nasrallah, M.D.—Research support: AstraZeneca, Forest Pharmaceu-ticals, GlaxoSmithKline, Janssen, NIMH, Pfizer, Roche, and Sanofi; Con-sultant: AstraZeneca, Cephalon, Janssen, Pfizer, and Vanda; Speaker’sbureau: Abbott, AstraZeneca, Janssen, Pfizer, Solvay, and Vanda.

xiv Medical Illness and Schizophrenia

Adele C. Viguera, M.D., M.P.H.—Grant/research support: AstraZeneca (ClaffinAward), Berlex Laboratories, Eli Lilly, Epilepsy Foundation*, Forest,GlaxoSmithKline, Beecham Pharmaceuticals, Harvard Medical School'sScholars in Medicine Fellowship, Janssen, NARSAD, NIMH, Pfizer, Sep-racor, Stanley Medical Research Institute, and Wyeth-Ayerst; Speaker'sbureau/honoraria: AstraZeneca*, Eli Lilly, Forest*, GlaxoSmithKline, Novar-tis 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 andacceptance for publication of this volume, APPI entered into an agreement forDainippon Sumitomo Pharma America, Inc., to underwrite and distribute aseparate printing of Medical Illness and Schizophrenia, 2nd Edition.

xv

Preface

Since the publication of the first edition of this volume in 2003,there has been a dramatic increase in the literature on optimizing med-ical outcomes for patients with schizophrenia. Sitting before me is theAugust 2008 issue of Psychiatric Services, which includes no less thaneight research articles devoted to medical issues of relevance to thosewho care for individuals with severe mental illness. Despite the grow-ing 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 patientswith schizophrenia and the general population (Saha et al. 2007). Therecognition that antipsychotic treatment can be associated with delete-rious metabolic and other health effects emphasizes the need to addressmedical aspects of schizophrenia treatment, yet the mental health com-munity as a whole still has a great deal to accomplish toward achievingparity in physical health monitoring and treatment between the se-verely mentally ill and the rest of society. Barriers remain, but they arenot insurmountable.

We have expanded this second edition with the aim of providing acomprehensive resource for those who wish to be informed about thevarious medical issues that impinge on schizophrenia treatment. Ourintent is to create a practical manual that can serve as a reference for themedical management of patients with severe mental illness across theage spectrum, with a focus on those areas of significant importance toschizophrenia patients, such as cardiometabolic disorders and their re-lationship to antipsychotic therapy, smoking, substance use, and infec-tion with human immunodeficiency virus (HIV) and hepatitis C. Wehave also added a section on the important but neglected topic of sexualfunction in patients with schizophrenia and have devoted an entirechapter to the behavioral management of weight gain and obesity. Theintent, as always, is to stimulate those who work in mental health set-tings to take a broader view of schizophrenia care, recognizing that thisis a systemic disease with multiple manifestations that go beyond theobvious psychiatric symptoms.


xvi Medical Illness and Schizophrenia

ReferenceSaha S, Chant D, McGrath J: A systematic review of mortality in schizophrenia:

is the differential mortality gap worsening over time? Arch Gen Psychiatry64:1123–1131, 2007

PART I

Public HealthIssues for

SchizophreniaPatients

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3

CHAPTER 1

Improving PhysicalHealth Care for

Patients With SeriousMental Illness

David Folsom, M.D., M.P.H.

Much has been written about the need to integrate mentalhealth care into the primary care setting. Psychiatrists and other mentalhealth care providers have often criticized primary care physicians forunderrecognizing and undertreating depression, substance abuse, andother common mental health conditions (Wells et al. 2000). Meanwhile,the challenge of providing quality medical care to patients with seriousmental illnesses represents a similar challenge for psychiatrists.

Atypical antipsychotic medications are the mainstay of contempo-rary pharmacological treatment for psychotic disorders (Harrington etal. 2000; IMS Health 2002; Jin et al. 2004). However, in the past decade,concern and awareness have been growing that these medications maycause or exacerbate medical conditions including weight gain and obe-sity (Daumit et al. 2003; Lieberman et al. 2005), elevated blood sugarand diabetes (Henderson et al. 2005; Leslie and Rosenheck 2004; Lieber-man et al. 2005), and cerebrovascular events (Schneider et al. 2005). TheU.S. Food and Drug Administration currently mandates that the pack-age inserts for all six atypical antipsychotics—aripiprazole (Abilify

4 Medical Illness and Schizophrenia

2008), clozapine (Clozaril 2008), olanzapine (Zyprexa 2008), quetiapine(Seroquel 2008), risperidone (Risperdal 2008), and ziprasidone (Geodon2008)—include black-box warnings regarding the increased risk ofmortality in elderly patients with dementia and a warning about therisk of hyperglycemia and diabetes. These warnings and the emergingdata on the medical side effects of antipsychotics have raised psychia-trists’ concern and awareness about comorbid medical conditions intheir patients and have led to guidelines for the medical monitoring ofpatients taking these medications (American Diabetes Association et al.2004; Marder et al. 2002). However, evidence that predates the atypicalantipsychotics suggested that patients with severe mental illness (SMI)are at higher risk for several medical conditions and often receive infe-rior medical care, both of which likely contribute to their elevated mor-tality. In this chapter, I briefly review the data on the prevalence ofcomorbid medical conditions and the lack of quality medical care forpatients with SMI, examine prior studies that attempt to improve thehealth status of these patients, and consider policies that might improvethe integration of medical and mental health care for patients with SMI.

Medical Comorbidity and Access to Quality Medical Care for Patients With Serious Mental IllnessPatients with schizophrenia and other serious mental illnesses consti-tute a particularly vulnerable group, for whom access to quality medi-cal care is problematic (Druss et al. 2001a; Harvey et al. 2005). Druss etal. (2001a) reported that following myocardial infarction, patients withschizophrenia had a 30% greater 1-year mortality than patients whowere not mentally ill. Approximately half of this increased mortalitywas due to a lack of quality medical treatment after the myocardial in-farction. Folsom et al. (2002) found that in homeless patients with men-tal illness, those with schizophrenia were less likely to receive primaryand preventive care than were patients with major depression. Further-more, investigators have reported elevated cardiovascular risk (Mc-Creadie 2003), as well as inferior medical care and elevated mortality inpersons with schizophrenia compared with the general population (Ko-ran et al. 1989; Phelan et al. 2001). For example, the rates of reported hy-pertension were 40% lower in persons with schizophrenia than in thegeneral population, but the rates of admission for end-stage complica-tions of hypertension, including cardiomyopathy and pulmonary

Improving Physical Health Care 5

edema, were 1.8 and 1.5 times greater, respectively, in the patients withschizophrenia (Munk-Jørgensen et al. 2000). These findings suggestthat patients with schizophrenia were less likely to receive treatment inthe early phase of a disease and instead were receiving care later, whenthe disease became more severe and required hospitalization.

Some encouraging data have also been published regarding healthcare for patients with schizophrenia. An investigation of patientstreated in community-based settings found that, compared with thegeneral population, a greater percentage of patients with schizophreniahad received primary care treatment in the prior year (Dickerson et al.2003). At the same time, the growing concerns about the risk of diabe-tes, myocardial infarction, and stroke in patients taking atypical anti-psychotics have increased the awareness of the importance of diagnosisand treatment of comorbid medical conditions in patients with schizo-phrenia (Folsom and Okereke 2005; Jin et al. 2004).

Models for Improving Medical Care for Patients With Serious Mental IllnessAlthough the literature on interventions and service delivery models toimprove the health outcomes of patients with SMI is not as extensive asthat of treating depression in primary care, four basic approaches havebeen examined: 1) health care skills training for patients, 2) training ofpsychiatrists to directly provide primary care, 3) facilitated referral toprimary care, and 4) co-location or integration of primary care withmental health care (Druss 2007).

Health Care Skills Training for PatientsSeveral interventions that have been developed and tested focus onproviding education and skills training for patients with chronic mentalillnesses who also have a comorbid medical condition. Two skills train-ing interventions specifically related to health care outcomes are partic-ularly noteworthy. One intervention has been described by McKibbinet al. (2006), who enrolled 60 patients over age 40 with schizophreniaand comorbid diabetes into their diabetes awareness and rehabilitationtraining (DART) program. These authors tested whether patients whoreceived an intervention based on social cognitive theory and incorpo-rating standard diabetes self-management approaches experiencedgreater reductions in weight and hemoglobin A1c than did a compari-son group that received only diabetes education. The intervention


lasted 24 weeks, with patients randomly assigned to one of the twogroups. At the end of the study, patients in the DART intervention lostan average of 2.3 kg, compared with a 2.7-kg weight gain in the compar-ison group; however, there were no significant differences in hemoglo-bin 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 a10% weight gain from atypical antipsychotics. A 2×2 factorial designwas used to compare the effects of a lifestyle intervention, metformin (adiabetes medication that inhibits hepatic glucose production), both in-terventions, and placebo. This study, conducted in China, enrolled 128patients and examined changes in weight after 12 weeks of treatment.Over the 12-week period, patients in the placebo group gained an aver-age of 3.1 kg, whereas those receiving the lifestyle intervention lost1.4 kg, those taking metformin lost 3.2 kg, and those in the combinedlifestyle-metformin group lost 4.7 kg. Similar results were reported byWeber and Wyne (2006), who also tested a cognitive-behavioral inter-vention for overweight patients taking an atypical antipsychotic. Themean body mass index of patients enrolled in this study was 33, and atthe end of the investigation, the mean weight loss for those in the inter-vention group was 2.4 kg, compared with 0.6 kg for those in the com-parison group.

These results demonstrate that lifestyle interventions modified forpatients with schizophrenia and other serious mental illnesses can re-sult in improved health outcomes. However, aside from weight gainand a single report on patients with diabetes, data are lacking on the ef-fects of patient education interventions on other health outcomes forpatients with SMI. Ongoing studies funded by the National Institute ofMental Health (NIMH) are examining health care outcomes, and in thecoming years, information from these studies should help provide dataon improving the health of patients with SMI and other health prob-lems.

Training of Psychiatrists to Provide Primary Care

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


basic primary care to their patients with SMI, arguing that psychiatristsare frequently the only physicians these patients see. Golomb et al.(2000) assembled a consensus panel of Veterans Affairs (VA) psychia-trists, internists, hospital administrators, and nurses to identify healthconditions that would be appropriately treated by a psychiatrist whohas primary care training and on-site supervision by an internist. Allpanel members agreed that a psychiatrist with primary care trainingcould provide care for 17 of 38 preventive screening and counseling in-terventions but could perform only 10 of 157 evaluations of medicalconditions and provide treatment for only 14 of 125 medical conditions.Examples of common medical conditions that the consensus panelthought primary care psychiatrists could treat included cough, head-ache, and nasal congestion. Examples of common conditions that thepanel did not think that primary care psychiatrists could treat includedchest pain and ear infection.

A few psychiatry residencies have begun to train their residents toprovide primary care to patients with serious mental illness. These pro-grams include the University of California San Diego and the OregonHealth and Science University in Portland. In a series of reports, Dob-scha and colleagues at the Portland VA describe the outcomes of pro-viding this type of training in an integrated psychiatry primary medicalcare (PPMC) program (Dobscha and Ganzini 2001; Dobscha et al. 2005;Snyder et al. 2008). In one of these studies (Dobscha et al. 2005), ninegraduates of the PPMC program and 34 other residency graduates wereasked how comfortable they were with general medical conditions andhow frequently they screened for or provided treatment for medicalconditions. Responses indicated that, overall, the residents whoworked in the PPMC program were more comfortable with generalmedical conditions than were their fellow residents who did not workin this program. However, few of the PPMC-trained residents provideddirect medical care to their patients after graduation.

In summary, despite some recommendations that training psychia-trists should provide a limited range of primary care to their patientswith a serious mental illness, this model has been adopted in only a fewresidency training programs. In addition, although the data from theseprograms are limited, the psychiatrists whose training included provid-ing primary care for some of their patients appeared to be more com-fortable with the medical problems of their patients than werepsychiatrists without such training, but the primary care–trained psy-chiatrists did not provide much direct medical care after leaving thetraining program.


Facilitated Referral to Primary CareThe third model for improving the health care of patients with SMI is toimprove the ability of mental health centers to refer their patients to pri-mary care providers and medical clinics. This can be done either by pro-viding training, time, and resources to all of the mental health cliniciansin a particular clinic or by having a specific care manager provide thislinkage and care coordination. Some empirical evidence supports thismodel, and findings indicate that patients who receive specific helpwith accessing primary care treatment receive more primary and pre-ventive health care than patients who do not receive such help.

In a small pilot study, Bartels et al. (2004) compared the primary carereceived by 24 older patients with a serious mental illness who workedwith a nurse care manager whose job was to help patients access pri-mary and preventive health care. Using a chart review, the researchersfound that, prior to the intervention, 17% of patients did not have a des-ignated primary care provider and 29% had not received any preven-tive health care in the past year, whereas after working with the nursecase manager, all the patients had a designated primary care providerand had completed a preventive health care visit.

In a larger study of 470 patients with a substance abuse disorder en-tering a detoxification program, Samet et al. (2003) randomly assignedhalf to a one-time comprehensive assessment plus working with a so-cial 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 theclinic intervention group were more likely to have successfully seen aprimary care physician at least once in the 12 months after completingthe detoxification program than were patients who received usual care(69% vs. 53%).

Currently, at least two ongoing NIMH-funded studies are examiningwhether this model would result in improved health outcomes for pa-tients with serious mental illness (S. Bartels, personal communication,July 2008; Druss 2007).

Co-Location or Integration of Mental Health Treatment and Primary CareThe fourth approach to improving the health care of patients with SMIis to co-locate primary care and mental health care within the sameclinic, ideally in an integrated manner that has psychiatrists and pri-mary care providers working together to care for patients with SMI andchronic medical conditions. These clinics would be staffed by a combi-nation of psychiatry and primary care physicians, or by physicians du-


ally trained in psychiatry and a primary care specialty (family medicineor internal medicine).

Druss et al. (2001b) compared patient outcomes in a clinic that pro-vided integrated medical and psychiatric care with those of a clinic pro-viding a usual care model. In this VA-based study, 59 patients wererandomly assigned to receive care in an integrated care clinic based ina VA mental health clinic that was also staffed by a full-time nurse prac-titioner, a part-time family physician, and a nurse case manager. Thecomparison group included 61 veterans who received their care in atypical VA outpatient medical clinic. Approximately three-fourths ofthe patients had a serious mental illness, with posttraumatic stress dis-order, substance use disorders, and schizophrenia being the most com-mon diagnoses. In addition, more than half of the patients had apreviously unknown medical diagnosis. Compared to the patients re-ceiving usual care, those in the integrated care clinic were more likelyto use primary care services and less likely to use the emergency room.In addition, patients in the integrated clinic were more likely to receivepreventive health care, including screening for colon cancer and diabe-tes, immunizations, and health education. Patients in the integratedclinic also rated their satisfaction with care more highly than did thosein the comparison group, and demonstrated a small but significant im-provement 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 inte-grated care that were particularly important to people with a seriousmental illness. First, patients reported that they had previously faceddifficulty obtaining medical care in more traditional settings. For exam-ple, patients reported that in the past they had been turned away frommedical clinics, were not treated with respect, or had their medical con-cerns dismissed. Second, the integrated clinic had greater flexibility andavailability of resources, including a nurse case manager and a smallerpatient panel size for the primary care providers. Finally, both patientsand clinic staff noted that the communication between the patients’psychiatrist and primary care provider was greater than what they hadpreviously experienced, and primary care and mental health cliniciansreported that they benefited from regular contact with each other.

Another option for integrated care, training physicians in both psy-chiatry and a primary care specialty, has been less well studied. To date,two studies have been published describing the type of practice settingfor dually trained physicians. A survey of physicians trained in bothfamily medicine and psychiatry found that most (60%) practice bothfamily medicine and psychiatry (McCahill and Palinkas 1997). In con-


trast, psychiatrists also trained in internal medicine reported that only15% practiced any type of medicine and 75% identified themselves aspsychiatrists (Stiebel and Schwartz 2001). However, neither of these re-ports examined the patient outcomes of care provided by these duallytrained physicians compared with usual care. Also, both of these stud-ies are based on data that are more than a decade old, and more trainingprograms are available now than when these data were published.

Dual training programs in the United States are limited. Only seventraining programs are offered in family medicine and psychiatry and 11in internal medicine and psychiatry, and most of these programs takeonly two residents per year. In 2007, a total of 11 graduating medicalstudents matched into family medicine and psychiatry residencies and22 matched into internal medicine and psychiatry residencies (NationalResident Matching Program 2008).Therefore, although this model oftraining physicians in both psychiatry and a primary care specialty of-fers the possibility of truly integrated medical and psychiatric care forpatients with serious mental illness, the capacity of the current trainingprograms is not large enough to provide this kind of care on a largescale.

In summary, two models have been proposed for providing inte-grated medical and psychiatric care to people with serious mental ill-ness: 1) co-locating primary care physicians in mental health clinics and2) staffing these clinics with physicians trained in both psychiatry anda primary care specialty. Druss (2007) suggested that these types of clin-ics may be best suited for VA system and staff model health mainte-nance organizations, which use shared funding streams and medicalrecords.

Challenges to Providing Medical Care for Patients With Serious Mental IllnessPatient LevelResearchers have offered several explanations as to why people withschizophrenia receive less health care than the general population. Peo-ple with schizophrenia may have problems explaining their medicalsymptoms to primary care physicians. Physicians may be uncomfort-able treating persons with schizophrenia (Lawrie et al. 1996), possiblyreflecting a stigmatization of people with schizophrenia. Similarly, psy-chiatrists may not feel comfortable providing primary and preventivehealth care for their patients (McIntyre and Romano 1977). Fang and


Rizzo (2007) used data from a national survey of physicians to examinewhether psychiatrists had less access to medical services for their pa-tients than did other medical specialists. This study compared psychia-trists’ reports of their ability to obtain medically necessary medical carefor their patients with those of other specialist physicians. The studyfound that psychiatrists rated their ability to obtain most types of med-ical care “dramatically” lower than did other specialists, in part becausemany patients did not have insurance and those who did had barriersfrom their health plan.

Policy LevelAccording to Horvitz-Lennon et al. (2006), challenges to integrating pri-mary health care into specialty mental health treatment exist on threelevels: clinical, organizational, and financial. Clinical challenges includethe lack of training in physical health care by mental health clinicians.It is important to note that although most psychiatrists do not feel com-fortable providing primary medical care, the knowledge of and comfortwith medical problems is even lower among other mental health careproviders, who rarely have formal medical training. Financial chal-lenges include the high rates of uninsurance among persons with seri-ous mental illness and the fact that financing for public mental healthprograms is typically separate from that of other public health pro-grams. For example, in the San Diego County public mental health sys-tem, approximately 50% of patients with a serious mental illness areuninsured (Folsom et al. 2005). Furthermore, the application process forand financial restrictions of the public mental health system are sepa-rate and different from those of the safety-net health care program, re-sulting in a large number of patients receiving mental health treatmentwho do not have coverage for medical care.

ConclusionThe growing recognition that people with schizophrenia and other se-rious mental illnesses have elevated rates of many medical conditionsand often do not receive adequate medical care challenges psychiatristsand the mental health field to come up with practical approaches to im-proving their care. The four potential approaches examined in thischapter—health care skills training for patients, training psychiatriststo provide limited primary care, facilitated referral to primary care, andintegration of primary care into mental health clinics—are all sup-ported by some data. However, none of these approaches currently is


widespread, and no single approach is likely to provide a solution. Inan ideal world, psychiatrists would help ensure that their patients re-ceive high-quality physical health care; staff at mental health clinicswould help patients who need health care; mental health clinics wouldoffer onsite primary care; and the financial barriers to providing inte-grated physical and mental health care would be removed.

Key Clinical Points

◗ Patients with schizophrenia and other serious mental illnesses receiveless primary and preventive care than needed.

◗ Guidelines alone are unlikely to result in improved health care for pa-tients with serious mental illness.

◗ Prior studies have examined four ways of improving health care forpeople with serious mental illness: health care skills training for pa-tients, training psychiatrists to provide limited primary care, facilitatedreferral to primary care, and providing onsite primary care in mentalhealth clinics.

◗ Integrating primary care into mental health clinics may require signif-icant changes in how mental health care is funded and delivered.

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17

CHAPTER 2

Excessive Mortalityand Morbidity

Associated WithSchizophrenia

Daniel E. Casey, M.D.Thomas E. Hansen, M.D.

Psychiatric conditions have long been recognized to be associ-ated with premature mortality. In his review, Brown (1997) noted that“lunatics” (perhaps 25% having schizophrenia) in a study from 1841 ex-perienced mortality at three to 14 times the rate seen in the general pop-ulation. According to Brown, Eugen Bleuler reported that mortality inpatients with schizophrenia was 1.4 times the expected rate, caused byaccidents, suicide, refusing food, infectious disease, and other diseasesfrom poor sanitation. Brown stated that although Emil Kraepelin con-sidered mortality to be only slightly increased in dementia praecox, hereported that suicide, negativism, diet, and poor cooperation with med-ical care contributed to increased mortality. Studies from the first halfof the twentieth century found mortality rates in psychiatric patients tobe two and four times higher than in age- and gender-matched popula-tions (Brown 1997). Hazards of institutional care (such as tuberculosisand gastrointestinal disease) added to risks associated with the under-lying psychiatric illness. Unnatural causes (suicide and accidental


death) became an increasingly important cause of premature deathwith the shift from inpatient to outpatient care for patients with schizo-phrenia (Black et al. 1985). More recently, cardiovascular disease anddiabetes may be increasing in importance as causes of death and mor-bidity in these patients (Jeste et al. 1996).

This chapter updates our earlier review (Casey and Hansen 2003) ofmortality and morbidity associated with schizophrenia. Data clearly dem-onstrate 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 pa-tients with schizophrenia. Both patient behaviors and societal aspects ofcare for schizophrenia can contribute to this increase in morbidity.

Life Span and Mortality in Patients With SchizophreniaMortality RatesReports on mortality rates commonly use record linkage methodology:databases of all deaths in a region are linked with population registersof psychiatric patients (community or hospital derived) so that thenumber of deaths in a group of patients with a specific diagnosis can bedetermined. This observed number is contrasted to the number ex-pected based on life expectancy data for people of the same age andgender applied to the time period studied. The ratio of observed to ex-pected cases is the standardized mortality ratio (SMR), sometimes re-ported 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 forelevated SMR, and upper CI values below 1.0 (or 100) supporting sig-nificance for decreased SMR (Harris and Barraclough 1998). In thischapter, for ease of comparison, we report SMR and CI data withoutmultiplying by 100, even if so reported in cited references.

Reviews of mortality rates consistently find increased death rates inpatients with schizophrenia. This consistency is remarkable when oneconsiders variation in methods across individual studies and reviews.For instance, individual studies from earlier periods may be overly in-fluenced by inclusion of hospitalized patients (lower risk of suicide,higher risk of diseases related to institutionalization), whereas laterstudies are likely to include outpatients (greater risk of suicide) and tobe more precise in diagnosis.

Excessive Mortality and Morbidity 19

Three reviews that summarized results from studies conducted be-tween 1942 and 1996 found the mortality rate in patients with schizo-phrenia to be between 1.5 and 2 times the expected rate. Allebeck (1989)reviewed nine studies published between 1942 and 1985 in which pa-tients had been followed at least 5 years and found mortality abouttwice the expected rate. He noted difficulty in ascertaining whetherrates had changed because diagnostic and study criteria had variedover time. Brown (1997) examined studies published between 1986 and1996 with schizophrenia patient populations of at least 100 individualsrecruited after 1952 that included observed and expected death ratesand that had follow-up periods of at least 2 years, with losses to follow-up 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 werethe SMR for accidents (2.16, 95% CI 1.96–2.36) and the SMR for naturalcauses of death (1.1, 95% CI 1.05–1.15). Brown interpreted data aboutspecific natural causes of death conservatively, stating that patientswith schizophrenia die from the same diseases as the rest of the popu-lation. He noted that peptic ulcer (perhaps related to alcohol use) andpneumonia (probably associated with elderly institutionalized pa-tients) caused deaths at higher than expected rates. Harris and Barra-clough (1998) reviewed mortality rates in cohorts of patients withvarious mental disorders between 1966 and 1995 (20 studies, nine coun-tries, almost 36,000 patients) and found a death risk in patients withschizophrenia that was 1.6 times expected. The death risk from unnat-ural causes (suicide and violence) was 4.3 times that expected, whereasdeath from natural causes was 1.4 times that expected, but naturalcauses accounted for 68% of the excess in expected deaths.

In our earlier review (Casey and Hansen 2003), we described threestudies published in 2000–2001, with data on patients studied between1973 and 1995, in which mortality rates were reported to be somewhathigher than in the earlier reviews (significantly increased relative riskor SMR of 2.4–3.8, depending on patient gender). A meta-analysis bySaha et al. (2007) confirms that SMRs for schizophrenia are increasing;the analysis reviewed 37 articles published between 1980 and 2006 from25 countries and found the overall SMR to be 2.58. When studies weregrouped by midpoint of the follow-up period, SMR increased from 1.84in the 1970s, to 2.98 in the 1980s, and to 3.2 in the 1990s. A study not in-cluded in the meta-analysis from rural China (Ran et al. 2007) followed510 patients with schizophrenia for the 10-year period of 1994–2004 andfurther demonstrated higher mortality in more recent studies (overallSMR of 4.0, 95% CI 2.4–5.8).


Life expectancy and survival curve data offer further confirmation ofincreased mortality associated with schizophrenia. In our earlier review(Casey and Hansen 2003), we noted that in three studies based on 5- to10-year follow-up of patients, authors projected decreased life expect-ancy of 8–16 years in general and of 3–4 years for patients ages 60 yearsand older. Three more recent studies also utilize survival data. Patientswith first admissions for psychosis in Suffolk County, New York, be-tween 1989 and 1995 were evaluated for survival rates at 5 and 10 yearsusing survival curves; survival rates were 96.9% at 5 years and 94.5% at10 years for the 235 patients with schizophrenia or schizoaffective dis-order, with 60% of deaths resulting from unnatural causes (Craig et al.2006). In a 10-year (1981–1991) mortality study of 255 patients withschizophrenia from Uppsala, Sweden, 23% of patients died comparedwith 11% of the 1,275 controls (P=0.003) (Fors et al. 2007). Patients withschizophrenia (n=319) seen at the Mayo Clinic from 1950–1980 were fol-lowed up to 2005 (mean 23.5 years); 44% died during this time, a ratehigher (P<0.001) than for a comparable U.S. population (the specificrate was not reported, but appears to be 34% from the survival curvecomparison) (Capasso et al. 2008).

Thus, data from the last 50 years demonstrate that the increase inmortality seen for patients with schizophrenia in earlier time periodspersists. Furthermore, the disparity in death rates between patientswith schizophrenia and the general population appears to be widening.

Suicide and Other Unnatural Causes of MortalityReviews consistently find that patients with schizophrenia die fromsuicide at increased rates compared with the general population (Alle-beck 1989; Harris and Barraclough 1998), although underreporting is apossibility because suicides can be incorrectly reported as resultingfrom accidents or undetermined causes (Allebeck 1989). In this section,we focus on suicide as an unnatural cause of death given the lower mor-tality rates from accidents. For instance, one review reported SMRs of8.38 for suicide and 2.16 for accidents (Brown 1997). In a Danish registerstudy of patients admitted between 1973 and 1993 who died by 1993,Hiroeh et al. (2001) reported for males an SMR of 10.7 for suicide com-pared with 2.1 for accidents, and for females an SMR of 10.8 for suicidecompared with 2.9 for accidents.

In our earlier review (Casey and Hansen 2003), we summarized datafrom multiple studies; SMR values generally ranged from 12 to 20, exceptSMR of 1.32 in one study (Mortensen and Juel 1990) that included mostlyelderly institutionalized patients from 1957 to 1986. Several recent stud-


ies have found suicide SMRs in the higher range. The rate of suicide inthe general population and in patients with schizophrenia in Denmarkdeclined between 1981 and 1997, but the incidence ratio remained 20times higher for patients with schizophrenia (Nordentoft et al. 2004).Even correcting for social and demographic differences, the rate re-mained high at 12.26. A French 10-year follow-up study starting in 1993(Limosin et al. 2007) found the suicide SMR for males to be 15.8 (95% CI13.7–18.2) and for females to be 17.7 (95% CI 13.6–23.1). In both of thesestudies, suicide rates were highest within the first year of follow-up.

The suicide mortality data support several observations. The in-crease in risk from suicide for patients with schizophrenia was muchlower many years ago when patients were commonly kept in hospitalsfor long time periods. The risk is greatest early in the course of illnessand close to the hospital discharge, so that mortality rates vary betweenstudies depending in part on study inclusion criteria. Finally, the risk ofsuicide appears to be increasing, perhaps related to greater reliance onless intensive treatment emphasizing outpatient care.

A national psychological autopsy study from Finland provides im-portant details about the nature of suicide by patients with schizophre-nia (Heila et al. 1997). All suicides occurring during a 1-year periodduring 1987 and 1988 were identified. Providers and next of kin wereinterviewed, and adequacy of medication was examined. This samplehad a somewhat older age of suicide (mean 40 years old) than hospital-treated or initially treated patient groups. The mean illness durationwas 15.5 years, and 75% of patients had active symptoms. About 9%had current suicide-command hallucinations. Twenty-five (27%) werehospitalized at the time of suicide, and 29 (32%) had been dischargedwithin 3 months. A depressive syndrome had been present during ei-ther a residual or an active phase of psychosis in 61 patients (66%), withdepressive symptoms at the time of suicide in 59 (64%). Drug overdosewas the most common single cause of death (34 patients, 37%), al-though various violent means were used in 37 cases (40%). Of 34 drugoverdoses, 27 (79%) were with neuroleptic medication and 25 (74%)specifically involved low-potency neuroleptics. The authors suspectedthat with the shift toward outpatient management, the availability ofdrugs to use in overdoses has increased. Additional data on risk factorsand adequacy of treatment were reviewed for the 88 patients who werein treatment at the time of suicide (Heila et al. 1999). Data on compli-ance and treatment responsiveness were available for about 72 patients.For the entire group of patients who committed suicide (either with ac-tive psychotic symptoms or during a residual phase of illness), only 34(47%) appeared to be compliant and to be receiving an adequate dosage


of antipsychotic medication. Data were similar when the patients in ac-tive phase of illness were examined separately. Only 26 (46%) of the 57patients experiencing active symptoms at the time of suicide were re-ceiving an adequate dosage (defined as 700 mg daily in chlorpromazineequivalents) and were compliant in taking medication. These two stud-ies suggest the importance of effective medication management andprovision of appropriate intensity of treatment (if not inpatient, thenclose outpatient observation) in this era of managed care. The Frenchstudy cited above also notes the importance of substance abuse (Li-mosin et al. 2007).

Estimates of the lifetime risk of suicide, defined as the proportion ofall deaths to which suicide contributes, provide an additional perspec-tive on the importance of suicide in schizophrenia-associated mortality.Data from a large meta-analysis (Harris and Barraclough 1998) were an-alyzed by plotting the percentage of patients who had died against thepercentage of patients who had died by suicide. The curve that bestmodeled the data was extrapolated to the point at which all members ofthe cohort would be deceased; the percentage of deaths by suicide wasestimated to be 4% of all deaths, which is lower than the frequentlycited value of 10% lifetime risk for suicide in patients with schizophre-nia (Inskip et al. 1998). This finding was confirmed in a more recentmeta-analysis (Palmer et al. 2005). Using both proportionate mortalityand case fatality statistics from 61 studies to maximize accuracy in esti-mating suicide risk, the authors concluded that 4.9% of patients withschizophrenia will commit suicide, usually near the onset of illness.

An emphasis on suicide rates may be misleading in terms of absoluterisk, because suicide is rare and natural causes of death are far morecommon in the general population. Roughly two-thirds of excessdeaths in patients with schizophrenia are by causes other than suicide,illustrating that although many patients with schizophrenia die fromsuicide, far more die from other causes. For example, suicide accountedfor only 38% of the excess mortality in one review (Harris and Barra-clough 1998) and 35% of excess mortality in another (Brown 1997). In aSouthampton, England, cohort treated in 1981–1982 with 13 years offollow-up, suicide and other unnatural causes accounted for 33% of thedeaths (Brown et al. 2000). Another way to understand this issue is tonote that although the relative risk for suicide in patients with schizo-phrenia compared with the general population is higher than the rela-tive risk for natural causes of death, the absolute risk for natural causesof death is far higher than for suicide in patients with schizophrenia.Thus, excess mortality in schizophrenia derives primarily from naturalcauses rather than from suicide. (See Table 2–1.)


Natural Causes of Death in Patients With SchizophreniaAn autopsy study from the time when phenothiazine medications werenew, roughly 50 years ago, provided a view of death by natural causes(Hussar 1966). Autopsy data from 1,275 chronically hospitalized pa-tients with schizophrenia who died at age 40 or older found that heartdisease and cancer were the most common causes of death (similar tofindings in the general population age 40+ years of that time). Pneumo-nia was somewhat overrepresented as a cause of death. Undeterminedcauses and aspiration of food were in the top eight causes of death inthe patients with schizophrenia but not in the general population. Theauthors speculated that phenothiazines could be responsible, althoughthey noted that other investigators at the time found no association be-tween the new medications and death rates.

More recent studies quantify increased mortality for various naturalcauses in patients with schizophrenia. Harris and Barraclough (1998)reviewed mortality rates in cohorts of patients with various mental dis-orders between 1966 and 1995. Cohorts of patients with schizophreniahad an SMR of 1.37 for natural causes, with significant increases in ex-pected deaths from a variety of medical conditions (infectious, endo-crine, circulatory, respiratory, digestive, and genitourinary disorders).In our previous review (Casey and Hansen 2003), we discussed severalsubsequent studies that reported somewhat higher values for disease-specific SMR (1.9–2.3).

Reviewing individual studies for increased risk of specific disorderspresents challenges. Many studies report categories of diseases fromthe International Classification of Diseases (ICD) rather than specific disor-ders, not all studies report on the same categories of illness, and someillnesses could fall into more than one category. Also, findings vary be-tween studies, perhaps because the SMR is greatly influenced by a

TABLE 2–1. Evidence for increased mortality associated with schizophrenia

• Increased overall mortality rates in patients with schizophrenia: 1.5–4 times expected

• Decrease in longevity from survival curves: 8–16 years• Increased mortality rates for suicide: 12 to more than 20 times

expected• Lifetime death from suicide: about 5%• Increased standardized mortality ratio from natural causes: at least

2 times expected (varies by disorder)


small number of observed cases when the expected rate is low. Still, ex-amining individual studies may be helpful in understanding risks formore recent periods, because reviews are likely to include older studiesthat reflect risks that are no longer as common (e.g., institutionalizationand infectious diseases). Two recent Danish register studies of patientswith schizophrenia covering overlapping time periods between 1973and 2001 found significant increases in SMR (with some variation bygender) on the order of 1.44–2.98 for cardiovascular disease, cancer, res-piratory diseases, endocrine conditions, gastrointestinal and genitouri-nary diseases, nervous system illnesses, and infectious diseases (Hiroehet al. 2008; Laursen et al. 2007). (See Table 2–2.)

Cancer, cardiovascular disease, and diabetes warrant additional dis-cussion. The failure to demonstrate increased risk of cancer in patientswith schizophrenia when all causes of cancer are aggregated has led tomuch speculation, including the possibility that having schizophreniamay convey protection from cancer. Consistent and increasing findingsof both numbers of deaths from, and risk for, disorders such as cardio-vascular disease and diabetes are of current interest.

Cancer incidence and mortality rates reported for patients withschizophrenia range from decreased to increased, varying by typeof cancer, gender, and country, as well as across studies. In a U.S. pop-ulation report (Cohen et al. 2002) using a mortality follow-back data-base that sampled 1% of all deaths from 1986, cancer was the cause of25 of the 130 deaths in patients with schizophrenia. The unadjustedodds ratio indicated a decreased risk for cancer (0.62, 95% CI 0.4–0.96).Overall, the patients with schizophrenia died at a younger age (55.6 vs.63.7 years, P<0.001); adjusting for age and other factors yielded an oddsratio of 0.59 (95% CI 0.38–0.93). A Danish register study (Dalton et al.2005) of patients admitted with schizophrenia between 1969 and 1995and followed through 1995 found no difference in overall cancer risk,but differences were seen based on gender and location of cancer. Menhad decreased risks of prostate, rectal, and nonmelanoma skin cancer,and a nonsignificant decrease in lung cancer, whereas women had anincreased risk of breast cancer. Other authors have noted offsets in mor-tality risk by location. A decreased rate of lung cancer in males wasnoted to offset an increased rate of breast cancer in females (Mortensenand Juel 1990) and digestive cancers (Newman and Bland 1991). In thelatter study, the SMR for digestive disorders was 1.7 (P<0.05) and forlung cancer was 0.7 (NS). Limited access to cigarettes for institutional-ized patients has been raised as a possible explanation for reduced ratesof lung cancer (Harris and Barraclough 1998).


Two incidence studies on cancer in patients with schizophrenia illus-trate varying results between geographic locations for different types ofcancer. The authors of the World Health Organization’s three-cohortstudy (Gulbinat et al. 1992) concluded that patients with schizophreniado not demonstrate any consistent increase or decrease in risk for can-cer. In contrast, the authors of a records linkage study using the Finnishcancer and psychiatric illness registries found a modest but signif-icantly elevated standardized incidence ratio (SIR) for cancer (1.17,95% CI 1.09–1.25) in patients with schizophrenia (Lichtermann et al.2001), with the incidence of lung cancer twice as high in patients withschizophrenia (SIR 2.17, 95% CI 1.78–2.60). They also noted that the in-cidence of gallbladder cancer was elevated (SIR 2.07, 95% CI 1.03–3.70)and wondered about the role of obesity and poor diet in patients withschizophrenia, given that these are risk factors for gallstones, and hencepossibly for gallbladder cancer.

An investigation of possible lower rates of lung cancer death in patientswith schizophrenia (Masterson and O’Shea 1984) led to speculation thatphenothiazine medication might have antitumor activity. However, an al-ternative explanation may be that patients with schizophrenia die fromother causes, such as cardiovascular disease, before they reach the ex-pected age of death from lung cancer. Arguing against the hypothesis thatphenothiazines have antitumor activity, the authors found that breastcancer caused proportionately more deaths in the patients with schizo-phrenia (8.3% vs. 3.4% in the general population, P<0.04). The authorsalso speculated that being nulliparous and having elevated prolactin,both associated with schizophrenia illness and treatment, while practic-ing inadequate breast care (insufficient self-examinations and incompletereporting of lumps) could have caused the increase in breast cancer.

TABLE 2–2. Conditions associated with increased mortality from schizophrenia

• Cardiovascular disease• Diabetes• Respiratory disorders• Gastrointestinal diseases• Central nervous system disorders• Genitourinary diseases• Infectious diseases• Cancer (controversial; breast cancer may be increased and lung

cancer decreased)


Whether patients with schizophrenia have an increased risk of breastcancer remains unresolved. Two reports using similar Danish registerdata analysis methods and time periods came to different conclusionsabout breast cancer risk (Dalton et al. 2003, 2005). As part of a largerstudy of all types of cancer in men and women, female patients(N=9,743) admitted for schizophrenia between 1969 and 1993 had abreast cancer SIR of 1.2 (95% CI 1.05–1.38) (Dalton et al. 2005). In an-other study of women who developed breast cancer between 1970 and1997, patients with schizophrenia were identified (N=7,541) and foundto have decreased risk (relative risk 0.97, 95% CI 0.76–1.20). When con-trolled for fertility issues, the relative risk fell to 0.90 (95% CI 0.71–1.12).The authors noted that this finding is not surprising because womenwith schizophrenia are more likely to be nulliparous, a risk factor forbreast cancer. They also speculated that alcohol use, another risk factorfor breast cancer (not controlled for in their study), may contribute tothe apparent increase in risk for breast cancer reported in other studies(Dalton et al. 2003).

Researchers who study disease-related mortality rates often reporton endocrine and metabolic conditions without specifically mentioningdiabetes, although one might expect it to be the most common endo-crine condition. For instance, in a British study of patients followedfrom 1981 to 1994 (Brown et al. 2000), the SMR for all endocrine disor-ders was elevated at 11.66 (95% CI 3.79–27.21) and the diabetes SMRwas 9.96 (95% CI 2.05–29.11), indicating that most of the endocrine mor-tality was accounted for by diabetes. Two recent studies found lowerbut significant elevations in mortality from all endocrine disorders. In aDanish register study of patients between 1973 and 1993 (Hiroeh et al.2008), the endocrine SMR was 1.99 (95% CI 1.37–2.91) for females and2.29 (95% CI 1.58–3.32) for males. In another Danish study (Laursen etal. 2007) covering 1973–2001, the rate was higher for males (SMR 3.56,95% CI 2.68–4.73) and lower for females (SMR 1.69, 95% CI 1.14–2.5).Given the accepted increased risk of diabetes associated with someatypical antipsychotic medications (American Diabetes Association etal. 2004), one should expect increasing mortality from diabetes in the fu-ture. However, some of the increase may instead appear as increasedcardiovascular mortality.

Cardiovascular disease causes a large number of deaths in both thegeneral population and patients with schizophrenia. In the review byHarris and Barraclough (1998), circulatory diseases caused 2,313 deathsout of the 5,591 deaths from natural causes, leading to an SMR in malesof 1.1 (95% CI 1.04–1.16) and in females of 1.02 (NS, 95% CI 0.96–1.08).Although the increase in risk is relatively small, the number of excess


deaths is substantial (230 more than expected compared with a total ofexcess deaths from natural causes of 1,250). Subsequent studies foundhigher cardiovascular mortality rates. In one study (Brown et al. 2000),circulatory disease had an SMR of 2.49 (95% CI 1.64–3.63); more specif-ically, cardiovascular disease had an SMR of 1.87 (95% CI 1.02–2.98).The Danish register studies noted comparable rates of 1.6–2.1. In theirstudy involving patients from 1973 to 1993, Hiroeh et al. (2008) foundthe circulatory disorder SMR in females to be 1.61 (95% CI 1.47–1.76)and in males to be 1.91 (95% CI 1.75–2.08), whereas Laursen et al. (2007),in their 1973–2001 study, found the cardiovascular disease SMR infemales to be 1.72 (95% CI 1.53–1.93) and in males to be 2.07 (95% CI1.85–2.32).

With rising mortality rates related to natural causes, especially dia-betes and cardiovascular disease, increased attention to morbidity andhealth behaviors in patients with schizophrenia is warranted. In thischapter, we touch on these topics only briefly because they are coveredin detail in subsequent chapters of this volume (Chapter 4, “Obesityand Schizophrenia”; Chapter 5, “Glucose Intolerance and Diabetes inPatients With Schizophrenia”; Chapter 7, “The Spectrum of Cardiovas-cular Disease in Patients With Schizophrenia”; and Chapter 9, “Nico-tine and Tobacco Use in Patients With Schizophrenia”).

Morbidity in SchizophreniaMedical ConditionsThe increased rate of mortality from natural causes associated withschizophrenia should be reflected in higher rates of morbidity. In ourchapter (Casey and Hansen 2003) in the previous edition of this book,we discussed reviews and studies that found medical conditions in35%–70% of patients with schizophrenia. The disorders included diabe-tes, hyponatremia, thyroid disorder, urinary tract infection, bladderdysfunction, hypertension, liver disease, seizures, and visual problems,among others.

Results from the interview survey study of patients with schizophre-nia from the Patient Outcomes Research Team program (Dixon et al.1999) illustrate increased medical morbidity. Of 719 patients, 469 (65%)reported having at least one lifetime medical condition, 256 (36%) hadmore than one condition, and 343 (48%) said the medical condition wasactive. The authors did not have a comparison control group but notedthat the rates for diabetes, hypertension, and cardiac diseases were allhigher than rates reported for these conditions in the National Health


Interview Survey. Not surprisingly, the number of medical comorbidi-ties correlated significantly with patient self-rating of physical health.

Jeste et al. (1996) reviewed reports on medical comorbidity in schizo-phrenia; for unclear reasons, rheumatoid arthritis seems to occur onlyrarely in patients with schizophrenia, whereas rates of cardiovasculardisease and diabetes mellitus appear to be increased. The authors re-ported that studies vary in finding increased rates of other specific ill-nesses and that the impression of decreased risk of cancer does notappear to be valid. In the first of two morbidity studies of middle-agedto elderly patients, the authors compared patients with schizophreniawith a group of patients with depression and another group withAlzheimer’s disease; lower rates of physical illnesses were found in thepatients with schizophrenia. In the second study, 45 patients withschizophrenia were compared with 38 normal control subjects; patientsin both groups were older than age 45 years. Indications of morbiditywere comparable, but the control group was about 10 years older thanthe patients with schizophrenia, suggesting that the schizophreniagroup’s rate of morbidity was comparable to that of an older popula-tion. The authors noted that patients with schizophrenia endorsedmore medical concerns when questioned in a structured manner.

The expected increase in morbidity in patients with schizophreniawas also seen in a case-control study of hospitalizations in Stockholm,Sweden (Dalmau et al. 1997). The authors gathered data regardingtreatment of somatic conditions in 775 schizophrenia patients and 775case-matched control subjects regardless of whether the treatment oc-curred in a psychiatric or a general medical ward. The schizophreniagroup had 523 (67%) admissions compared with 373 (48%) for the con-trol group over the 15-year study period (McNemar test, P=0.000). Anincreased odds ratio was found for almost all medical disorders occur-ring in patients with schizophrenia, with the exception of genitouri-nary, musculoskeletal, and sensory organ diseases. Tumors (combinedmalignant and benign) were found twice as often in patients withschizophrenia.

In summary, data demonstrate increased morbidity from medicalconditions in patients with schizophrenia. Although almost all disor-ders can occur at higher than expected rates, cardiovascular disease anddiabetes are particular concerns.

Substance AbusePatients with schizophrenia have increased rates of all types ofsubstance abuse (Dixon 1999), as is covered in detail in Chapter 11,


“Substance Abuse and Schizophrenia.” The adverse psychiatric effects(Dixon 1999) combined with medical problems caused by substanceabuse lead to the expectation of increased morbidity and mortality inpatients with schizophrenia who abuse drugs or alcohol. Not surpris-ingly, Dalmau et al. (1997) found that inclusion of schizophrenia pa-tients with substance abuse in their study cohort increased the numberof somatic conditions that occurred more frequently in schizophreniapatients than in a nonpsychiatric control population. Also, results froma study of diabetes mortality in patients with co-occurring psychoticand substance use disorders suggested that diabetes may be increasedin this group and be associated with a high mortality rate (Jackson et al.2007).

Health Maintenance in Patients With SchizophreniaTreatment ConcernsTreatment during the first half of the twentieth century undoubtedlycontributed to morbidity and mortality in schizophrenia. Physical in-terventions such as leucotomy, insulin coma therapy, and cardiazol-induced convulsive therapy all carried substantial risk (Brown 1997).In the past 50 years, morbidity and mortality concerns related to treat-ment have shifted to medications, with recent attention focused onextrapyramidal side effects, cardiac conduction, and metabolic side ef-fects (American Diabetes Association et al. 2004; Fontaine et al. 2001). Ina 10-year follow-up study of mortality and medication use in patientswith schizophrenia, Waddington et al. (1998) found that antipsychoticpolypharmacy and absence of cotreatment with anticholinergic medi-cation significantly increased mortality. No clear explanation related toother factors that might covary with polypharmacy seemed plausible,leaving the authors to wonder whether concurrent use of multiple an-tipsychotic medications causes some adverse biological consequence,or whether unrecognized subclinical drug-induced parkinsonism couldcontribute to mortality. A 1978–1980 Finnish study also found thatincreased mortality correlated with the number of prescribed typicalantipsychotic medications (Joukamaa et al. 2006). Certainly, extrapyra-midal side effects, including tardive dyskinesia, cause substantial mor-bidity in patients with schizophrenia (Casey 1993; Hansen et al. 1997).For further reading on the contribution of atypical antipsychotic medi-cations to various metabolic problems, please see other chapters in this


volume: Chapter 4, “Obesity and Schizophrenia”; Chapter 5, “GlucoseIntolerance and Diabetes in Patients With Schizophrenia”; Chapter 7,“The Spectrum of Cardiovascular Disease in Patients With Schizophre-nia”; and Chapter 9, “Nicotine and Tobacco Use in Patients WithSchizophrenia.”

Patient Health Habits and Related ConcernsBehaviors such as abuse of drugs and alcohol, smoking, lack of exercise,and dietary indiscretion appear to contribute to mortality in the generalpopulation, and thus are likely to do so in patients with schizophrenia(Brown et al. 1999). Brown et al. (2000) noted that the SMR related tonatural causes of death was significantly elevated in smokers (3.6, 95%CI 2.7–4.71) but not in nonsmokers (1.78, 95% CI 0.85–3.28). The authorsreviewed apparently avoidable natural causes of death in these pa-tients; causes included failure to recognize medical disease by the pa-tient or care provider (3–8 cases), missed diagnoses (3 cases), poortreatment compliance (unable to quantify), treatment refusal (2 cases),and inadequate social support (1 case).

Brown et al. (1999) directly investigated lifestyle concerns in 102 pa-tients with schizophrenia. Patients with schizophrenia ate a diet signif-icantly higher in fat and lower in fiber (significant for males, trend forfemales) than the reference population. Roughly one-third of the pa-tients with schizophrenia reported doing no exercise, and no patient re-ported doing strenuous exercise (comparison rates not provided). Intheir sample, female patients demonstrated a trend toward obesity(P=0.09). The rate of smoking was higher in patients with schizophre-nia than in the comparison sample (68% vs. 28% in males, 57% vs. 25%in females); alcohol consumption was decreased in males and unexcep-tional in females.

A study of 22 outpatients with schizophrenia conducted in 1992–1993 found similar results (Holmberg and Kane 1999): patients withschizophrenia were less likely to practice health-promoting behaviorsthan were nonpsychiatric populations. In a study of smoking in Irish in-patients with schizophrenia (Masterson and O’Shea 1984), the rate ofsmoking was higher than for the general population (males 84% vs.41%, females 82% vs. 36%), as were daily consumption of cigarettes,preference for medium- to high-tar cigarettes (59% vs. 1%), and dura-tion of smoking (longer than 16 years, 80% vs. 56%).

The sum of the evidence indicates clearly that patients with schizo-phrenia engage in behaviors that can be expected to increase morbidityand mortality.


Access to Health CareOne can easily imagine that decreased access to either medical or psy-chiatric care could exacerbate morbidity and contribute to increasedmortality in patients with schizophrenia, and a number of reportssuggest that access to medical care may be limited for patients withschizophrenia. Multiple factors could contribute to decreased access, in-cluding limitations in the communication of symptoms by patients,poor cooperation by psychotic patients, stigma toward patients withschizophrenia, and insufficient attention to medical problems by mentalhealth providers (Druss and Rosenheck 1997; Goldman 1999). Dixon etal. (1999) found that less than 70% of the patients with medical problemswere receiving treatment for their medical conditions in a study of 719patients with schizophrenia from the Patient Outcomes Research Teamproject. Masterson and O’Shea (1984) speculated that inadequate breastexaminations and incomplete reporting of breast lumps could have con-tributed to the increased rate of death from breast cancer in their study.The diagnosis of schizophrenia was significantly negatively associatedwith timeliness, access, and intensity of postdischarge medical care in astudy of U.S. veterans (Druss and Rosenheck 1997). Finally, two relatedstudies have demonstrated disparity in care for patients with schizo-phrenia following myocardial infarction. Patients with schizophreniawere less likely to have cardiac catheterization, more likely to die in theyear after discharge, and less likely to receive interventions that repre-sent quality of care following acute myocardial infarction (i.e., reperfu-sion therapy, or at discharge, aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors) (Druss et al. 2000, 2001).

Among the homeless, having a diagnosis of schizophrenia may beassociated with better care and reduced mortality compared with thegeneral homeless population. The age-adjusted mortality rate for aNew York City homeless sample (follow-up period 1987–1994) wasabout four times that in a comparable reference group (Barrow et al.1999). Having a mental illness had a significant protective effect, possi-bly explained by provision of relatively greater services and betterhousing for homeless people who were mentally ill than for otherhomeless people. Likewise, having schizophrenia appeared to conveyprotection from mortality in a Boston homeless population (Hwang etal. 1998). The benefit of additional care most likely creates only an im-pression of protection, however, considering that the comparisongroups are highly ill and impoverished. For example, mortality wasstudied in homeless individuals who had been referred to a clinic inSydney, Australia, between 1988 and 1991 (Babidge et al. 2001). The


SMR for the nonschizophrenia group was 4.41 (95% CI 2.02–6.19) com-pared with 2.52 (95% CI 1.8–3.43) for the schizophrenia group. Thus, al-though the SMR was much lower in the schizophrenia group, it stillrepresented a mortality rate more than twice that expected in the gen-eral population.

ConclusionThe literature conclusively establishes that patients with schizophreniadie at higher rates and earlier than other people. The causes of this ex-cess mortality have varied over time, reflecting issues related tochanges in the care of patients with schizophrenia and the unhealthylifestyles that result from a combination of their illness and the type ofcare available. At this time, interventions must address risks from sui-cide and from medical illnesses. Effective medications with side-effectprofiles that promote adherence to treatment plans must be provided.Avoiding adverse metabolic side effects, or at least monitoring and at-tempting to correct them as they occur, is also critical in reversing thetrend toward higher mortality in patients with schizophrenia. Finally,the mental health system must work to ensure that adequate social ser-vices, medical treatment, and psychiatric care are provided despite so-ciety’s drive to reduce health care costs.

Key Clinical Points

◗ Schizophrenia carries increased mortality, as demonstrated by in-creased mortality rates and shortened life span.

◗ Differences in mortality rates between patients with schizophrenia andthe general population are increasing.

◗ Suicide rates are very high for patients with schizophrenia, especiallyearly in the course of illness.

◗ Increased rates of death from natural causes account for many of theexcess deaths seen in patients with schizophrenia, although the increasesin mortality rates associated with natural causes are not as great asthose associated with suicide.

◗ The natural causes of death for patients with schizophrenia are similarto those that occur in the general population, with cardiovascular dis-ease and diabetes being notably problematic.


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37

CHAPTER 3

Medical OutcomesFrom the CATIE

Schizophrenia Study

Henry A. Nasrallah, M.D.

When the Clinical Antipsychotic Trials for Intervention Effective-ness (CATIE) schizophrenia study was designed and submitted to theNational Institute of Mental Health (NIMH) for funding in 1999, themain purpose of the study was to establish whether second-generationantipsychotics (SGAs) were more effective than first-generation anti-psychotics (FGAs). Specifically, effectiveness was defined as discontin-uation due to any of four reasons: lack of efficacy, lack of tolerability,emergence of safety problems (i.e., potential medical health threat), andpatient decision (i.e., nonadherence and dropping out of the study).Measures related to physical health were considered a secondary out-come of this large study.

By the time the initial findings of the CATIE trial were published in2005 (Lieberman et al. 2005), the predominant focus in the field ofschizophrenia pharmacotherapy had shifted from claims over relativeefficacy of various SGAs to the medical complications of the SGA class,specifically metabolic disorders such as obesity, diabetes, hyperlipi-demia, and hypertension (Nasrallah et al. 2006; Newcomer 2005). For-tunately, the CATIE study included several laboratory measures ofmetabolic function, including all five metabolic syndrome criteria:


waist circumference, fasting triglycerides, fasting high-density lipopro-tein, blood pressure, and fasting serum glucose (Grundy et al. 2004). Atotal of 1,460 persons with schizophrenia consented to participate in theCATIE study, and several analyses of metabolic parameters at CATIEbaseline and again after administration of the SGA and FGA medica-tions used in phases 1 and 2 have been published and are discussed inthis review. Interestingly, although the effectiveness results of CATIE(i.e., the differential discontinuation of the four SGA agents and oneFGA agent during phase 1) were subjected to intense critiques due tomethodological issues, the metabolic data were widely accepted andwere regarded as objectively valid and uninfluenced by design stipula-tions (Kasper and Winkler 2006; Meyer 2007).

In addition to analyzing the CATIE metabolic data (with pre hochypotheses based on the totality of the literature and evidence thatemerged while CATIE was being conducted 1999–2004), the research-ers involved in the CATIE study also accumulated data on other health-related issues such as substance abuse and neurological movementdisorders, both of which are discussed in this overview of the medicalfindings of the CATIE study.

The Buildup to the CATIEAwareness of the adverse metabolic effects from certain SGAs acceler-ated during the 5 years that it took to conduct the CATIE study (Nasral-lah 2003; Newcomer et al. 2004). A key review by Allison et al. (1999)raised awareness of the seriousness of weight gain secondary to anti-psychotic treatment, whether from FGAs or SGAs. Allison et al.’s liter-ature review of comparative weight gain across old and newantipsychotics was a turning point in that it reframed the discussionabout weight gain and its serious metabolic consequences as an impor-tant threat to the health of patients receiving antipsychotics. Awarenessof the serious (and occasionally fatal) metabolic effects posed by someSGAs essentially replaced concerns over tardive dyskinesia, which hadreigned supreme as the greatest health issue related to FGA exposure.Interestingly, Allison et al.’s review also implied that weight gain wasa major problem with certain low-potency FGA agents (thioridazineand chlorpromazine), a fact that was often overlooked due to the preoc-cupation with tardive dyskinesia and the increasing use of high-potency FGAs in the years prior to widespread SGA use. Allison et al.’sanalysis influenced the CATIE study design to the extent that on the ba-sis of Allison et al.’s data, a weight-neutral SGA, ziprasidone, wasplanned as a treatment arm more than 2 years before final U.S. Food

Medical Outcomes From the CATIE Study 39

and Drug Administration (FDA) approval in 2001. Because of its benignmetabolic profile, ziprasidone was included not only as one of the SGAoptions in phase 1 but also as a key element of the tolerability pathwayin phase 2 of the CATIE study (Stroup et al. 2006). Aripiprazole, anothermetabolically benign SGA, came too late to be included in phase 1 or 2but was included in phase 3, the open-label phase of CATIE in whichinvestigators could choose any approved antipsychotic for subjectswho had dropped out of phase 2 (Stroup et al., in press).

Although weight gain secondary to clozapine was widely recog-nized in the 1990s, prior to the CATIE study (Umbricht et al. 1994), itwas regarded as the unavoidable cost for treating refractory schizo-phrenia patients for whom there were no options; however, after sev-eral first-line SGA drugs were introduced (risperidone in 1993,olanzapine in 1996, quetiapine in 1997), the incidence of weight gainand diabetes increased markedly due to the drugs’ widespread use. Bythe turn of the millennium, while patients were being actively recruitedfor the CATIE study, metabolic disorders related to SGA use movedinto the spotlight for both clinicians and researchers. From 2002through 2004, the FDA MedWatch data from cases of diabetes and dia-betic ketoacidosis (including deaths) were published in a series of pa-pers (Koller and Doraiswamy 2002; Koller et al. 2003, 2004). TheEuropean Union and Japan subsequently added a diabetes warning toolanzapine’s product label in 2002, and in August 2003, the FDA im-posed a class warning for diabetes on all SGA drugs, despite the ab-sence of data implicating ziprasidone and aripiprazole.

Three months after the FDA class warning, the American DiabetesAssociation, along with the American Psychiatric Association, Ameri-can Association of Clinical Endocrinologists, and North American As-sociation for the Study of Obesity, held a meeting in Philadelphia onNovember 19, 2003. The purpose of this joint conference was to gener-ate a consensus statement (American Diabetes Association et al. 2004)on the association between SGA exposure and weight gain, lipidchanges, and diabetes (predominantly level 2, 3, and 4 evidence) afterreviewing the pre-CATIE world literature. The consensus statement,which was published jointly in the February 2004 issues of Diabetes Careand the Journal of Clinical Psychiatry, concluded that the members of theSGA class were associated with differential risks of weight gain, diabe-tes, and hyperlipidemia. Clozapine and olanzapine were found to havethe highest risk, risperidone and quetiapine to have intermediate risk,and aripiprazole and ziprasidone to have the lowest risk. As will be dis-cussed in the next section, the prospective, randomized, double-blindCATIE trial generated level 1 evidence about metabolic complications


of SGAs that professionals were waiting for, and confirmed the conclu-sions of the consensus statement regarding obesity and diabetes. More-over, the CATIE data refined the knowledge of the relative metaboliceffects of quetiapine and indicated that risperidone might be somewhatless of a metabolic offender than quetiapine, particularly with regard toeffects on serum triglyceride levels (Meyer et al. 2008a, 2008b).

CATIE Baseline Data on Medical Illness in SchizophreniaDemographicsSeveral health-related findings were reported in the CATIE schizophre-nia sample, which comprised 1,460 outpatients from 57 public, aca-demic, and private settings around the United States. The sample was75% male, with a mean age of 41 years and a mean duration of illness ofover 14 years. About 60% of the sample was white, 35% black, and 5%other races. Twelve percent of the sample was of Hispanic or Latino eth-nicity. The mean educational level was 12.2 years, about 60% had nevermarried, and 85% were unemployed. CATIE employed a broad enroll-ment strategy in an attempt to replicate the patient population seen inreal-world clinical settings, as opposed to the type of patient often re-cruited for pharmaceutical trials, which excluded patients with medicalcomorbidities or substance use. As a result, the data provide a represen-tative, cross-sectional view of the health of chronic schizophrenia pa-tients in the United States.

Diabetes and Metabolic SyndromeAt CATIE study baseline, 11% of enrolled subjects had diabetes type 1or 2, 14% had hyperlipidemia, and 20% had hypertension. Table 3–1shows the mean number of metabolic syndrome criteria met at CATIEstudy baseline in subjects with fasting blood samples available, alongwith overall metabolic syndrome prevalence (McEvoy et al. 2005).Metabolic syndrome prevalence in the CATIE sample, in both malesand females, was twice the rate seen in a sample from the general pop-ulation that was matched for age, gender, race, and ethnicity (using theNational Health and Nutrition Examination Survey [NHANES] IIIstudy population as the source for comparator matching) (Figure 3–1).These were the first detailed data documenting an unusually high prev-alence of metabolic syndrome in the schizophrenia outpatient popula-tion in the United States during the period when subjects were beingrecruited into the CATIE study.


Cardiovascular RiskA comparison of 10-year cardiac risk estimates in the CATIE schizo-phrenia sample compared to matched controls from the NHANES IIIwas also conducted using the baseline CATIE data (Goff et al. 2005).This analysis showed that the 10-year coronary heart disease (CHD)risk (using the Framingham CHD risk algorithm) was significantly ele-vated in the CATIE sample versus the matched general population(P=0.0001) in males (9.4% vs. 7.0%) and females (6.3% vs. 4.2%). The pa-tients with schizophrenia also had significantly higher rates of smoking(68% vs. 35%), diabetes (13% vs. 3%), and hypertension (27% vs. 17%),and lower HDL cholesterol (43.7 vs. 49.3 mg/dL) compared to theNHANES III control group. Goff et al. concluded that the CATIE datashowing greater 10-year CHD risk are consistent with the publishedstudies of increased cardiac mortality in schizophrenia.

Lack of Medical TreatmentIn light of the high prevalence of metabolic syndrome in the CATIEschizophrenia sample, one would expect that the subjects with meta-bolic disorders such as diabetes, hyperlipidemia, and hypertensionwould be receiving the appropriate standard medical treatments for

FIGURE 3–1. Prevalence of metabolic syndrome in CATIE schizophreniastudy participants at baseline versus the general adult population (NationalHealth and Nutrition Examination Survey [NHANES] III data).*P= 0.0001 CATIE versus NHANES.

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edical Illness and SchizophreniaTABLE 3–1. Metabolic syndrome and criteria prevalences among CATIE fasting subjects

Subject cohort

Syndrome/criteria White male Black male Hispanic male White female Black female Hispanic female

Mean age (years) 39.8±11.2 38.5±11.6 38.0±12.3 44.2±10.7 44.0±9.8 44.5±10.2

Mean BMI (kg/m2) 28.9±6.3 27.7±5.8 29.0±6.6 32.5±8.2 33.8±8.1 31.7±6.5MS prevalence,

ATPIII criteria40.9% (n=342) 22.7% (n=141) 31.8% (n=66) 56.5% (n=92) 43.1% (n=72) 73.3% (n=15)

Criteria met (n=343) (n=141) (n=67) (n=93) (n=73) (n=15)0 12.2% 23.4% 13.4% 8.6% 5.5% 6.7%1 23.9% 31.9% 19.4% 12.6% 23.3% 6.7%2 23.0% 22.0% 35.8% 22.6% 28.8% 13.3%3 24.2% 10.6% 14.9% 26.9% 27.4% 46.7%4 14.3% 9.2% 13.4% 24.7% 12.3% 20.0%5 2.3% 2.8% 3.0% 4.3% 2.7% 6.7%

Mean number of criteria met

2.11±1.32 1.59±1.35 2.05±1.31 2.59±1.34 2.26±1.19 2.87±1.25

MS prevalence, AHA criteria

44.4% (n=342) 23.4% (n=141) 40.9% (n=66) 58.1% (n=93) 47.2% (n=72) 73.3% (n=15)

Criteria met (n=343) (n=141) (n=67) (n=93) (n=73) (n=15)0 12.0% 22.7% 13.4% 8.6% 5.5% 6.7%1 21.0% 31.2% 16.4% 11.8% 20.6% 6.7%2 22.7% 22.7% 29.9% 21.5% 27.4% 13.3%

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3 22.3% 11.4% 20.9% 26.9% 28.8% 40.0%4 16.9% 9.2% 14.9% 25.8% 13.7% 26.7%5 4.1% 2.8% 4.5% 5.4% 4.1% 6.7%

Mean number of criteria met

2.25±1.38 1.62±1.35 2.21±1.38 2.66±1.36 2.37±1.23 2.93±1.28

Criteria prevalence: all subjectsWaist circumference 41.2% (n=663) 28.5% (n=351) 37.8% (n=127) 70.8% (n=195) 76.5% (n=153) 77.0% (n=40)Blood pressure 46.9% (n=674) 55.3% (n=358) 38.8% (n=129) 38.4% (n=198) 48.1% (n=154) 47.5% (n=40)HDL 54.3% (n=671) 35.6% (n=357) 55.0% (n=129) 69.1% (n=194) 52.6% (n=154) 64.1% (n=39)

Criteria prevalence: fasting subjectsWaist circumference 39.0% (n=341) 26.2% (n=141) 38.5% (n=65) 76.1% (n=92) 74.7% (n=71) 86.7% (n=15)Blood pressure 45.9% (n=342) 57.1% (n=141) 40.9% (n=66) 41.9% (n=93) 50.0% (n=72) 60.0% (n=15)Triglycerides 58.3% (n=343) 31.9% (n=141) 61.2% (n=67) 53.8% (n=93) 28.8% (n=73) 46.7% (n=15)HDL 55.1% (n=343) 34.8% (n=141) 53.7% (n=66) 72.0% (n=93) 52.1% (n=73) 66.7% (n=15)Glucose≥100 26.5% (n=343) 17.7% (n=141) 28.4% (n=67) 22.6% (n=93) 34.3% (n=73) 33.3% (n=15)Glucose≥110 13.4% (n=343) 14.9% (n=141) 11.9% (n=67) 16.1% (n=93) 23.3% (n=73) 26.7% (n=15)

Note. AHA=American Heart Association; ATPIII=National Cholesterol Education Program Adult Treatment Panel III;BMI=body mass index; HDL=high-density lipoprotein; MS=metabolic syndrome.

TABLE 3–1. Metabolic syndrome and criteria prevalences among CATIE fasting subjects (continued)

Subject cohort

Syndrome/criteria White male Black male Hispanic male White female Black female Hispanic female


these serious medical disorders. However, Nasrallah et al. (2006) foundthat a high proportion of subjects were not receiving treatment for theirserious medical diseases at the time of their enrollment into the CATIEtrial. This serious lack of care means that persons with schizophreniaface a double jeopardy for early cardiovascular mortality: high rate ofmetabolic disorders and diminished quality of medical treatment. Thiscombination of high medical risk and poor medical care may be one ofthe reasons that persons with schizophrenia lose an average of morethan 25 potential years of life, according to research from several U.S.states (Colton and Manderscheid 2006; B.J. Miller et al. 2006). Metabolicdisorders are also highly associated with depression; when CATIE sub-jects with metabolic syndrome were compared to CATIE subjects with-out metabolic syndrome, the only significant difference found was ahigher rate of depression and somatic concern among the group withmetabolic syndrome (Meyer et al. 2005).

Other Medical Risk FactorsOf the CATIE subjects, 37% met criteria for substance abuse or depen-dence, 23% met criteria specifically for substance use, and 40% were ab-stinent (Swartz et al. 2008). Given the health risks of oral andintravenous substance use, abuse, and dependence, this is an additionalmedical risk factor for individuals with schizophrenia, a fact discussedat length in Chapter 11, “Substance Abuse and Schizophrenia.” An-other medical risk factor in the CATIE sample was tardive dyskinesia,a serious form of neurotoxicity. Of the 1,460 subjects, 231 (15.8%) hadtardive dyskinesia at the time of enrollment in CATIE (D.D. Miller et al.2005). Of interest are the findings that the tardive dyskinesia subgrouphad 1.5 times higher prevalence of substance abuse and 4.5 times higherodds of more severe psychopathology compared to those without tar-dive dyskinesia.

CATIE Phase 1 Medical FindingsSeveral metabolic parameters were differentially influenced by the fiveantipsychotic agents—perphenazine (an FGA), risperidone, quetiapine,olanzapine, and ziprasidone (added after 40% of the sample had beenrecruited)—selected for phase 1 of the CATIE trial (Lieberman et al.2005). Figure 3–2 shows the mean monthly weight change, with theolanzapine group showing over fourfold greater weight gain comparedwith the other antipsychotics during phase 1, and subjects randomized


to ziprasidone showing a mean decrease in weight. Figure 3–3 showsthe percentage of subjects who gained a significant amount of weight(>7%) with each of the five antipsychotics. Again, the olanzapine cohorthad the greatest problems with weight gain, with 30% gaining morethan 7% of their baseline weight, and ziprasidone was the least offend-ing medication, causing weight gain in only 6% of subjects. No statisti-cally significant between-group changes in mean fasting glucose levelsoccurred across the various antipsychotics, although olanzapine hadthe highest numeric increase and ziprasidone the lowest. However, re-sults indicated significant between-drug differences for change in gly-cosylated hemoglobin, a long-term measure of glycemic control thatreflects values over the prior 2 months. As seen in Figure 3–4, the great-est increase in glycosylated hemoglobin was in the olanzapine group,and the ziprasidone group had an overall decrease. Similar divergenceswere seen with cholesterol and triglycerides (Figures 3–5 and 3–6) andare discussed in detail in Chapter 6, “Effects of Antipsychotics on Se-rum Lipids” (see Tables 6–2 and 6–3).

Each patient’s corrected QT interval on the electrocardiogram (QTc)was measured every 3 months while participating in the CATIE study.Figure 3–7 shows that the QTc was minimally increased in all antipsy-chotic groups during CATIE phase 1. These negligible increases suggestthat, contrary to the perception at the launch of the CATIE study, anti-psychotic-related QTc changes are not a major medical threat to per-sons receiving atypical antipsychotics. The effects of antipsychotics onQTc are discussed at length in Chapter 7, “The Spectrum of Cardiovas-cular Disease in Patients With Schizophrenia,” but data from CATIEphase 1 revealed that in routine clinical practice, there are not worri-some QT changes with any SGA, including ziprasidone, which hadbeen a source of concern. The past several years of clinical experiencewith millions of patients confirms the CATIE data in that unlike meta-bolic complications (e.g., metabolic syndrome and diabetes), whichhave increased markedly in populations receiving SGAs, morbidity ormortality from QTc changes is relatively minuscule.

The development of cataracts was a concern only for patients takingquetiapine, based on preclinical findings from animal models. In phase1, no difference was found among the antipsychotics, with quetiapinein particular showing minimal risk for cataracts, confirming that cata-ract development is a phenomenon encountered for the preclinical spe-cies studied (beagle dogs) but not humans.

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FIGURE 3–2. Monthly weight gain (pounds/month) by subjects during CATIE phase 1, phase 2 tolerability arm (2T), and phase2 efficacy arm (2E).

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Change in Metabolic Syndrome Status With TreatmentDetailed analysis of changes in metabolic syndrome criteria in CATIEphase 1 were published in 2008 (Meyer et al. 2008a) and showed that after3 months of exposure, the prevalence of metabolic syndrome increased inthe olanzapine group from 34.8% to 43.9%, but decreased in the ziprasi-done group from 37.7% to 29.9% (olanzapine vs. ziprasidone P=0.001)(Table 3–2). Subjects in the olanzapine and quetiapine groups also had anaverage waist circumference increase of 1.8 cm, compared with a 1-cmincrease in the risperidone group and no change in the ziprasidonegroup, whereas subjects in the perphenazine group experienced a loss of1 cm. The greatest increase in triglycerides occurred with olanzapine(+21.5 mg/dL). Although these findings are consistent with metabolicstudies published before release of the CATIE results, they indicatedgreater effects of quetiapine on adiposity than previously indicated bythe American Diabetes Association et al. (2004) consensus paper.

Nonfasting Triglyceride LevelsAlthough the metabolic syndrome criterion for triglycerides is a fastinglevel of 150 mg/dL or greater, recent studies indicate that nonfasting

FIGURE 3–4. Phase 1 changes in glycosylated hemoglobin.

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triglyceride levels may have a stronger association with cardiovascularrisk than do fasting triglycerides. An analysis of the phase 1 CATIE dataafter 3 months of exposure (Meyer et al. 2008b) showed that the highestmean and median increases were in subjects randomly assigned to que-tiapine (mean +54.7 mg/dL, median +26 mg/dL) and olanzapine (mean+54.7 mg/dL, median +26.5 mg/dL), whereas ziprasidone was neutral(mean +0.0 mg/dL, median +8 mg/dL) and decreases were seen in bothrisperidone (mean −18.4 mg/dL, median −6.5 mg/dL) and perphena-zine (mean −1.3 mg/dL, median −22 mg/dL). Pairwise comparison in-dicated a significant between-group difference for perphenazine versusolanzapine and a trend for perphenazine versus quetiapine.

Inflammatory MarkersSeveral biomarkers of cardiometabolic risk were collected in phase 1of the CATIE trial and are still being analyzed at the time of writingof this chapter. However, data for one important inflammatory marker,C-reactive protein (CRP) have been analyzed (J.M. Meyer et al., in prep-aration) to examine the comparative effects of various antipsychotics af-ter 3 months of exposure. Olanzapine and quetiapine had the greatestnumerical increases, and significant treatment differences were ob-served between olanzapine versus perphenazine (P<0.001) and risperi-done (P=0.001) in subjects with lower baseline cardiovascular risk(defined as CRP <1 mg/L). After 12 months of exposure, the difference

TABLE 3–2. Proportion of subjects at baseline and 3 months meeting the criteria for metabolic syndrome in phase 1 of the CATIE schizophrenia trial—all classifiable subjects

Metabolic syndrome

Agent n Baseline 3 months

Olanzapine 164 34.8% 43.9%a

Perphenazine 129 37.2% 38.0%Quetiapine 143 37.8% 37.1%Risperidone 147 30.6% 30.6%Ziprasidone 77 37.7% 29.9%a

Overall treatment difference 0.015aChange from baseline to 3 months in proportion of subjects meetingcriteria for metabolic syndrome is greater for olanzapine than forziprasidone (P=0.001) among all classifiable subjects.

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FIGURE 3–5. Changes in serum triglycerides across CATIE phase 1, phase 2 tolerability arm (2T), and phase 2 efficacy arm (2E).

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FIGURE 3–6. Changes in total cholesterol across CATIE phase 1, phase 2 tolerability arm (2T), and phase 2 efficacy arm (2E).

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FIGURE 3–7. Mean changes in QT interval in CATIE phase 1 and phase 2 tolerability arm (2T).

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between olanzapine and perphenazine groups remained significant,and a significant difference (P=0.003) was observed between olanzapineand ziprasidone. These data confirm that agents associated with greatercardiometabolic risk are associated with adverse changes in other mea-sures that correlate with deleterious cardiovascular outcomes.

Phase 2 FindingsSubjects who discontinued their antipsychotics in phase 1 of the CATIEstudy due to lack of efficacy were randomized either to clozapine or toone of three atypical antipsychotics: olanzapine, quetiapine, or risperi-done. Those who discontinued due to tolerability or safety reasons (orwho refused participation in the efficacy arm) were randomized to eitherziprasidone or to one of the three atypical antipsychotics. In both arms ofphase 2, the tolerability arm and the efficacy arm, all subjects were ran-domly assigned to receive agents that they did not take in phase 1. Meta-bolic parameters (weight, waist circumference, glucose, triglycerides,and cholesterol) were measured as in phase 1. (See Figures 3–5 and 3–6.)

Figure 3–2 shows the mean weight gain per month in both pathwaysof phase 2 compared to phase 1, and Figure 3–3 shows the percentage ofsubjects with weight gain >7% for both phase 2 pathways. Figure 3–8also shows the weight changes in phase 2 in subjects who had a signifi-cant amount of weight gain (>7%) in phase 1. Only those randomized toziprasidone lost much of the weight they had gained from the phase 1antipsychotic. Differences did emerge between the phase 1 results andthose seen in the phase 2 efficacy and tolerability pathways, but a con-sistent pattern remains: olanzapine is associated with the greatest dele-terious changes in metabolic parameters, whereas ziprasidone isassociated with the most benign changes.

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

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FIGURE 3–8. Phase 2 tolerability arm weight change in CATIE subjects with weight gain >7% in phase 1.

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ConclusionThe 5-year, double-blind, NIMH-sponsored effectiveness study knownas the CATIE schizophrenia trial provided highly informative dataabout the comparative metabolic profiles of various antipsychotics andrevealed the high risk for metabolic syndrome and CHD in a large sam-ple (N=1,460) of patients with chronic schizophrenia in the UnitedStates. These metabolic findings are likely to influence clinical practiceresearch studies, prevention initiatives, and public policy in the foresee-able future. Although the primary measure outcome of the CATIEschizophrenia trial was effectiveness (i.e., all-cause discontinuation), avaluable body of metabolic data was obtained from the study sample,one that points to significant health problems seen in patients withschizophrenia.

Key Clinical Points

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

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

◗ Fasting blood glucose, cholesterol, and triglyceride levels were most el-evated with olanzapine and were not changed or declined with ziprasi-done.

◗ Quetiapine resulted in higher lipid increases than risperidone, whichhad no deleterious effect on lipids.

◗ The overall metabolic profile of second-generation antipsychotics inphase 2 (both the efficacy and tolerability pathways) were the same asseen in phase 1 for olanzapine (highest increases) and ziprasidone (low-est increases or actual decreases), but were somewhat variable for que-tiapine and risperidone.

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

◗ QTc was minimally affected by all second-generation antipsychoticsused in the CATIE study.

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


◗ Aripiprazole was associated with the highest mean increase in fastingglucose among first-generation or second-generation antipsychotics inphase 3, the opposite of what was expected.

ReferencesAllison DB, Mentore JL, Heo M, et al: Antipsychotic-induced weight gain: a

comprehensive research synthesis. Am J Psychiatry 156:1686–1696, 1999American Diabetes Association, American Psychiatric Association, American


Colton CW, Manderscheid RW: Congruencies in increased mortality rates,years of potential life lost, and causes of death among public mental healthclients 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 es-timates in schizophrenia patients from the CATIE study and matched con-trols. Schizophr Res 80:45–53, 2005

Grundy SM, Brewer B, Cleeman JI, et al: Definition of metabolic syndrome: re-port of the National Heart, Lung, and Blood Institute/American Heart As-sociation conference on scientific issues related to definition. Circulation109:433–438, 2004

Kasper S, Winkler D: Addressing the limitations of the CATIE study. World JBiol Psychiatry 7:126–127, 2006

Koller EA, Doraiswamy PM: Olanzapine-associated diabetes mellitus. Pharma-cotherapy 22:841–852, 2002

Koller EA, Cross JT, Doraiswamy PM, et al: Risperidone-associated diabetesmellitus: a pharmacovigilance study. Pharmacotherapy 23:735–744, 2003

Koller EA, Weber J, Doraiswamy PM, et al: A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. J Clin Psychiatry 65:857–863, 2004


McEvoy JP, Meyer JM, Goff DC, et al: Prevalence of the metabolic syndrome inpatients with schizophrenia: baseline results from the Clinical Antipsy-chotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial andcomparison with national estimates from NHANES III. Schizophr Res80:19–32, 2005

Meyer JM: Strategies for the long-term treatment of schizophrenia: real-worldlessons from the CATIE trial. J Clin Psychiatry 68 (suppl 1):28–33, 2007


Meyer JM, Nasrallah HA, McEvoy JP, et al: The Clinical Antipsychotic Trials ofIntervention Effectiveness (CATIE) schizophrenia trial: clinical compari-son of subgroups with and without the metabolic syndrome. Schizophr Res80:9–18, 2005

Meyer JM, Davis VG, Goff DC, et al: Change in metabolic syndrome parameterswith antipsychotic treatment in the CATIE schizophrenia trial: prospectivedata from phase 1. Schizophr Res 101:273–286, 2008a

Meyer JM, Davis VG, McEvoy JP, et al: Impact of antipsychotic treatment onnonfasting triglycerides in the CATIE schizophrenia trial. Schizophr Res103:104–109, 2008b

Miller BJ, Paschall CB, Svendsen DP: Mortality and medical comorbidityamong patients with serious mental illness. Psychiatr Serv 57:1482–1487,2006

Miller DD, McEvoy JP, Davis SM, et al: Clinical correlates of tardive dyskinesiain 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. Psy-chopharmacology 28:83–96, 2003

Nasrallah HA, Meyer JM, Goff DC, et al: Low rates of treatment for hyperten-sion, dyslipidemia, and diabetes in schizophrenia: data from the CATIEschizophrenia trial sample at baseline. Schizophr Res 86:15–22, 2006

Newcomer JW: Second-generation (atypical) antipsychotics and metabolic ef-fects: a comprehensive literature review. CNS Drugs 19 (suppl 1):1–93,2005

Newcomer JW, Nasrallah HA, Loebel AD: The Atypical Antipsychotic Therapyand Metabolic Issues National Survey: practice patterns and knowledge ofpsychiatrists. J Clin Psychopharmacol 5 (suppl 1):S1–S6, 2004

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Stroup TS, Lieberman JA, McEvoy JP, et al: Results of phase 3 of the CATIEschizophrenia trial. Schizophr Res (in press)

Swartz MS, Wagner HR, Swanson JW, et al: The effectiveness of antipsychoticmedications in patients who use or avoid illicit substances: results from theCATIE study. Schizophr Res 100:39–52, 2008

Umbricht DS, Pollack S, Kane JM: Clozapine and weight gain. J Clin Psychiatry55 (suppl B):157–160, 1994


PART II

Metabolic Disease, Heart Disease,

and RelatedConditions


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CHAPTER 4

Obesity andSchizophrenia

Tony Cohn, M.B.Ch.B., M.Sc., F.R.C.P.C.

Obesity is a common and burgeoning health problem that hasan impact on both life expectancy and quality of life. Epidemic propor-tions of individuals are overweight and obese worldwide (James et al.2001; Ogden et al. 2007). The prevalence of obesity is even greateramong individuals with schizophrenia, who are known to have in-creased morbidity and mortality from obesity-related diseases (Mc-Evoy et al. 2005; Osby et al. 2000), as well as poor access to primary andpreventive health care (Druss et al. 2001; Meyer 2007). Individuals withschizophrenia may be predisposed to obesity because of biological andlifestyle factors but also require long-term treatment with antipsychoticmedications that can promote weight gain (Green et al. 2000; New-comer 2005). With the growth in prescription of second-generation an-tipsychotic (SGA) medications over the past 10 years, antipsychotic-associated weight gain has emerged as an iatrogenic issue of major pub-lic health concern. The problem is compounded further by the fact thatcommonly coprescribed psychiatric medications, antidepressants, andmood stabilizers also contribute to weight gain (Aronne and Segal 2003;Fava 2000). In addition, patients with schizophrenia are challenged bycognitive and functional deficits that need to be considered in clinicalevaluation and in the delivery of obesity interventions. Although obe-sity medicine is now being recognized as a subspecialty in its own right,


its application for individuals with serious mental illness, such asschizophrenia, is in its infancy. The onus for management is falling tomental health professionals. Clinicians of today who treat patients withschizophrenia are challenged to become knowledgeable in the assess-ment, prevention, and treatment of obesity and its complications.

In this chapter, I review the clinical definition of obesity and its med-ical consequences; the epidemiology and determinants of obesity in thegeneral population and in individuals with schizophrenia; and the as-sessment, monitoring, and management of obesity for patients withschizophrenia within a mental health context.

Definition and MeasurementObesity is considered a disease by the World Health Organization(2004), which defines obesity as a condition of excess body fat to the ex-tent that health is impaired. However, measuring body fat accurately isdifficult 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 impor-tant, because the central accumulation of fat within the abdominal re-gion (central, visceral, or abdominal adiposity) is a major factor thatinfluences the effect of increasing weight on health. Central adipose tis-sue is now seen as an endocrine organ that releases substances (adipo-kines) that have systemic effects. Adipokines include leptin, tumornecrosis factor-alpha, adiponectin, C-reactive protein, interleukin-6,and plasminogen activator inhibitor type 1.

Central adiposity is most accurately measured by computer-assistedtomography or magnetic resonance imaging, which enable a distinctionto be made between subcutaneous and intra-abdominal fat. However, forpractical purposes, the simple waist circumference is the common clinicalproxy for central adiposity (Lemieux et al. 1996). Waist-to-hip ratio hasalso been used for this purpose, but this measure is less favored becauseracial and ethnic differences in hip size complicate interpretation (Ogdenet al. 2007). Both BMI and waist circumference are independently corre-lated with health outcomes, but waist circumference has been shown tobe an even better predictor of obesity-related disease.

BMI and waist circumference measures have limitations. Althoughbody fat is a continuous variable with an incremental health risk, BMIand waist circumference are often used as categorical variables with cut-off values that reflect risk. Also, these measures do not adequately take

Obesity 63

into account individual, gender, and racial or ethnic differences in bodytype and body composition. BMI is calculated by dividing weight (mea-sured in kilograms) by height (measured in meters) squared (i.e.,BMI=kg/m2). Consensus exists among international health agencies, in-cluding the National Heart, Lung, and Blood Institute and the WorldHeath Organization, regarding BMI cutoffs. A BMI of 25–29.9 kg/m2

is considered overweight, and a BMI of ≥30 kg/m2 is deemed obese.Obesity is further classified as class 1 (BMI 30–34.9 kg/m2), class 2 (BMI35–39.9 kg/m2), and class 3 or severe obesity (BMI ≥40 kg/m2). BMI is aless accurate correlate for body fat when used for muscular individuals,who may have a high BMI and normal or low body fat, and for veryshort individuals (Pi-Sunyer 2000). In addition, because of differences inbody composition, for a given BMI, women tend to have a higher per-centage of body fat than men, and older individuals have a higher per-centage of body fat than younger individuals (Ogden et al. 2007).

Waist circumference is measured in the standing position with a sim-ple tape measure placed around the waist. The waist is defined as mid-way between the top of the pelvis and the lowest rib. Measurement istaken after a modest expiration. For individuals with a pendulous ab-domen, the waist circumference can be measured using the maximumgirth, 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 ethnicdifferences in body habitus can also influence the interpretation ofwaist circumference; therefore, the International Diabetes Federationhas defined ethnic-specific cutoffs for waist circumference for the met-abolic syndrome (Alberti et al. 2006).

Metabolic syndrome, also known as syndrome X and insulin-resistancesyndrome, is a clustering of risk markers reflecting a state of insulin re-sistance and compensatory hyperinsulinemia that has wide-rangingmedical consequences. According to the revised Adult Treatment PanelIII/American Heart Association definition, three out of the five follow-ing 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 treatment3. Fasting glucose ≥5.6 mmol/L (100 mg/dL) or antidiabetic treat-

ment4. Fasting triglycerides ≥1.8 mmol/L (150 mg/dL) or treatment5. Fasting high-density lipoprotein (HDL) <1.03 mmol/L (40 mg/dL)

in men and <1.29 mmol/L (50 mg/dL) in women


By the International Diabetes Federation definition of metabolic syn-drome (Alberti et al. 2006), abdominal obesity is a necessary criterion,and two additional criteria (as listed above) are required for the diag-nosis. Waist circumference cutoffs vary by racial or ethnic group asfollows:

• Europids or Middle Eastern: men >94 cm; women >80 cm• South Asian, Chinese: men >90 cm; women >80 cm• Japanese: men >85 cm; women >90 cm

Health Consequences of ObesityCentral adiposity is specifically associated with the development of in-sulin resistance and, consequently, type 2 diabetes, hyperlipidemia (es-pecially raised triglycerides and low HDL), coronary heart disease,hypertension, and polycystic ovarian disease. With obesity in general,rates of gallbladder disease; respiratory disease, including obstructivesleep apnea; certain cancers (colorectal, prostate, endometrial, gallblad-der, cervical, ovarian, and breast); gout; and arthritis are also increased(Pi-Sunyer 1993).

Obesity reduces life expectancy. In examining deaths attributable tobeing overweight and obese, investigators found that more than 80% ofthese deaths occurred in individuals with BMIs of at least 30 kg/m2 (Al-lison et al. 1999b). Years of life are lost primarily because of coronaryheart disease (Dorn et al. 1997). Shortened life span has been specificallynoted in patients with serious mental illness, such as schizophrenia(Osby et al. 2000), with a recent report indicating as much as 25–30 yearsof potential life lost (Colton and Manderscheid 2006).

Obesity also has a negative impact on the quality of life, and this hasalso been explored in samples of schizophrenia patients. Based on re-sults from the Psychological Well-Being Index, Allison et al. (2003) re-ported that weight gain with antipsychotic treatment was related topoorer quality of life as well as reduced well-being and vitality. Strass-nig et al. (2003a) found that the physical component score of the Medi-cal Outcomes Study 36-Item Short-Form Health Status Survey, ameasure of quality of life that assesses both physical and mental health,was inversely correlated with the physical component score of patientswith schizophrenia, suggesting that the burden from obesity is prima-rily experienced as a physical problem, a finding that was confirmed byFaulkner et al. (2007a) who found that, in addition, waist circumferencewas a better predictor of reduced quality of life than BMI. Those with

Obesity 65

obesity describe also being stigmatized. In the general population it hasbeen demonstrated that this phenomenon also occurs with health ser-vices, causing obese individuals to avoid visiting health care providers(Drury and Louis 2002). Patients with schizophrenia face the additionalstigma of having a mental illness.

The economic burden of obesity is immense (Thompson and Wolf2001). Direct health care costs are estimated to account for 5.5%–7.0% ofnational health expenditure in the United States and 2.0%–3.5% in othercountries. When considering comorbidities, the three largest contribu-tors to cost are hypertension, type 2 diabetes, and coronary artery dis-ease. The cost of lost productivity due to obesity is almost as great as thedirect medical costs. In the treatment of patients with schizophrenia,lipid lowering, antihypertensive, and antidiabetic medications are nowcommonly coprescribed with antipsychotic medications, adding con-siderable costs to health care budgets.

Epidemiology of ObesityIn the general population, rates of overweight and obesity are rising atan alarming rate, with no plateau in sight. In the United States, almosttwo-thirds of adults (66%) were overweight or obese in 2004; 32% wereobese and 5% had class 3 obesity (Wang and Beydoun 2007). The prev-alence of obesity has more than doubled since 1980 (Ogden et al. 2007).In Canada in 2004, 65% of the adult population was overweight orobese, but the overall rate of obesity (23%) was lower than in the UnitedStates (Tjepkema 2006). Using linear regression, Wang and Beydoun(2007) predicted that 75% of the U.S. adult population will be over-weight or obese and 41% will be obese by 2015.

Studies have demonstrated that the distribution of obesity varies bygender, racial and ethnic group, and socioeconomic status, with minor-ity and low-socioeconomic-status groups having higher prevalence. In2004, more men than women were overweight and obese, but womenhad higher rates of obesity, especially in non-Hispanic black and Mexi-can American communities, where rates of obesity in women were ashigh as 49% and 38%, respectively (Wang and Beydoun 2007). Weightappears to vary more by socioeconomic status, race and ethnicity, andnationality for women than for men, and some authors have suggestedthat weight may be associated more closely with social and culturalroles for women than for men (Ogden et al. 2007).

In patients with schizophrenia, rates of obesity are even higher thanin the general population and are estimated to fall between 40% and


60% (Catapano and Castle 2004). The average BMI in recent schizophre-nia trials has often approximated or been in the obese range, as illus-trated in the Clinical Antipsychotic Trials of Intervention Effectiveness(CATIE) study, where the recruitment strategy was designed to bebroadly representative of patients with schizophrenia. In the sample ofpatients (n=1,460) recruited between January 2001 and December 2004(Lieberman et al. 2005), the mean BMI at baseline was 29.7 kg/m2 (men28.5 kg/m2; women 33.0 kg/m2) (McEvoy et al. 2005). In a Canadianstudy of 240 adult patients with schizophrenia recruited in 2003 and2004 and treated with antipsychotic medication, Cohn et al. (2004b)found that the mean BMI was 28.7 kg/m2 (men 28.0 kg/m2; women30.1 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 higherin patients with schizophrenia than in age- and gender-matched gen-eral population controls. Similarly, baseline CATIE data revealed thatmen and women with schizophrenia were 138% and 251% more likely,respectively, to have metabolic syndrome than a National Health andNutrition Examination Survey matched sample (McEvoy et al. 2005).

To compare rates of obesity in schizophrenia patients with the gen-eral population prior to the widespread use of atypical antipsychotics,Allison et al. (1999a) investigated BMI in patients with and withoutschizophrenia using data from the mental health supplement of the1989 National Health Interview Schedule. Men with schizophrenia hada BMI similar to that of men without schizophrenia (26.14 vs. 25.63), butwomen with schizophrenia had a higher BMI than women withoutschizophrenia (27.36 vs. 24.50, P<0.001). A consistent finding in thesevarious studies has been that women with schizophrenia have a differ-entially higher rate of obesity and metabolic syndrome relative to thegeneral population than do men with schizophrenia. Although thisfinding is similar to what has been found in various minority and low-income groups, the reasons have yet to be fully explored.

Determinants and Mechanisms of ObesityGeneral and Evolutionary FactorsWeight maintenance is governed by a formula that is deceptively sim-ple: energy input must equal energy output. Energy input is essentiallyfood consumed, whereas energy output comprises a number of ele-ments of which physical activity is the main modifiable factor and ac-counts for about 30% of energy output. Other energy output factorsinclude basal metabolism (60% of energy output), diet-induced thermo-

Obesity 67

genesis (10% of energy output), and adaptive thermogenesis or alter-ation in metabolism related to environmental, psychological, or otherinfluences, such as habitual body movement (Groff and Gropper 1999).(Subtle akathisia, which was a common side effect with classic antipsy-chotics, probably accounted for significant energy expenditure.) Energybalance is tightly controlled but tilted toward weight gain because ofphysiological adaptations that defend against weight loss, so that a verysmall positive energy balance of 100 calories a day (the equivalent ofone slice of bread) results in a gain of 4.5 kg in 1 year.

Evolutionary concepts best explain the evolving epidemic of obesityin developed and developing countries (Ogden et al. 2007; Pi-Sunyer2003). The human body has evolved to survive the threat of faminefrom a time when food was scarce and a great deal of effort and energywas required to procure food. In contrast, many people now have anabundant supply of cheap, easily obtainable, and palatable food, and atthe same time less requirement and opportunity for exercise. What wasan advantage in times of food scarcity becomes a liability when the foodsupply is abundant or when there is change from a traditional diet to amore westernized diet. When food is scarce and weight is lost, the bodyhas a powerful biological drive to regain weight: basal metabolic ratedrops, and hunger signals increase. In contrast, when excessive weightis gained, biological signals are muted; there is no great increase inbasal metabolism, and individuals tend to become less rather than moreactive. The thrifty phenotype hypothesis, as proposed by Hales andBarker (2001), is an extension of this view: With poor intrauterine nutri-tional conditions, the child efficiently conserves energy and is preparedfor survival in an environment where food resources will be scarce.Then, when exposed to an environment of food excess, such an individ-ual who is efficient at conserving energy would be predisposed toobesity. This hypothesis has gained considerable favor in explainingsusceptibility to metabolic disturbance, particularly type 2 diabetes.

The thrifty phenotype hypothesis also suggests a mechanismwhereby patients with schizophrenia may be predisposed to obesityand associated metabolic disturbance. Epidemiological research hasshown an association between intrauterine and childhood undernutri-tion and the lifetime risk of schizophrenia. For example, there was adoubling of the rate of schizophrenia following both the Dutch winterfamine (1945) and the Chinese famine (1959–1961) (Hoek et al. 1998; StClair et al. 2005). In addition, studies have demonstrated a relationshipbetween schizophrenia and small size at birth, thinness in childhood,and short stature (Gunnell et al. 2003; Wahlbeck et al. 2001).


Genetics and NeurophysiologyEstimates of the heritability of obesity range from 30% to 70% (Mar-tínez-Hernández et al. 2007). Different sets of monozygotic twins thatare 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 givenenvironment is similar. Although a number of rare syndromes associ-ated with obesity have been found to be caused by discrete genetic de-fects or chromosomal abnormalities (e.g., Prader-Willi syndrome), themore common forms of obesity likely involve more complex interac-tions between the environment and a multitude of polymorphisms lo-cated in genes and candidate regions throughout the genome.

Genetic investigation has focused on genes that encode and regulatefood intake, energy expenditure, and adipogenesis. Food intake is reg-ulated by peptides such as leptin and neuropeptide Y that bind withreceptors in the hypothalamus, as well as by a range of peptides synthe-sized along the gastrointestinal tract, such as ghrelin and cholecystoki-nin (Schwartz et al. 2000).

Research on energy expenditure has focused on the sympathetic ner-vous system, in particular the β-adrenergic receptor gene family, and onuncoupling proteins at the mitochondrial level (Martínez-Hernández etal. 2007). In adipogenesis, peroxisome proliferator–activated receptor-γ(PPAR-γ) has become a focus of investigation (Marti et al. 2002).

LifestyleHabitual diet and level of physical activity are important factors thatcontribute to energy balance and the development of obesity. Dietaryintake has been studied in schizophrenia samples, but results have beenconflicting. In a cohort of 102 middle-aged patients with schizophrenialiving in the community, English researchers reported that patients hada 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 withschizophrenia living in Pittsburgh, Strassnig et al. (2003b) reported thatpatients consumed more food than matched control subjects, but themacronutrient composition (percentage of calories from fat, protein,and carbohydrate) was similar in both groups. In contrast, Hendersonet al. (2006) used 4-day food diaries—a more rigorous sampling strat-egy—to evaluate the diet of 88 patients with schizophrenia attending acommunity mental health clinic in Boston and made comparisons withgeneral population controls matched by age, gender, and ethnicity. Thepatients consumed significantly fewer calories and less carbohydrate,protein, total fat, and saturated fat than the general population controls.

Obesity 69

Habitual diet is notoriously difficult to measure and is prone to variousdegrees of underreporting (O’Neil 2001), which may help explain thesediscrepant findings.

Patients with schizophrenia are often financially disadvantaged, anddiet can vary based on the local availability of low-cost foods. Patientsare often housed in group homes and boarding houses, where food, ifit is provided, is cost-based and tends to be high in starch and sugar. Ina Toronto study, Cohn et al. (2004a) found that the diet of 162 outpa-tients with schizophrenia was similar in calorie count to that of individ-uals in the general population but was high in simple carbohydrates,particularly easily available chips and soda—a diet that has been impli-cated in development of metabolic syndrome (McKeown et al. 2004).

Findings regarding physical inactivity in samples of patients withschizophrenia have been more consistent. Multiple investigators have re-ported low levels of physical activity in patients compared with the gen-eral 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 tendedto be the only form of physical activity and that women and those with-out regular social contact were more inactive. Ussher et al. (2007) indi-cated that patients reported low levels of social support for exercisingand that fatigue and illness were the most common barriers to activity.

Obesogenic EnvironmentAn important consideration is how the environment influences lifestyleand the development of obesity. The “obesogenicity” of an environ-ment is the sum of influences that the surroundings, opportunities, orconditions of life have on promoting obesity in individuals or popula-tions (Swinburn et al. 1999). The concept of the obesogenic environmenthas been applied to the built environment, particularly in cities andsuburbs (Papas et al. 2007). Attempts have been made to analyze obe-sogenic factors in school systems and to promote healthier environ-ments with access to nutritious foods and the promotion of physicalactivity (Nollen et al. 2007). However, little attention has been paid tothe obesogenic environment in mental health settings. How environ-ments are structured in psychiatric group homes, inpatient units, andcommunity clinics, with provision of opportunities for physical exer-cise and healthy eating, is an important focus for future research.

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


Significant weight gain has been recognized as a common side effect,particularly with low-potency classic antipsychotics and certain sec-ond-generation antipsychotics. This issue, which is now recognized asa public health concern (Green et al. 2000), has garnered much atten-tion, particularly over the past 10 years.

In a comprehensive review of the published literature, including ran-domized clinical trials, Newcomer (2005) identified clozapine and olanza-pine as being associated with the greatest risk of clinically significantweight gain; risperidone, quetiapine, amisulpride, and zotepine as hav-ing intermediate risk; and ziprasidone and aripiprazole as having thelowest risk. This view is consistent with the findings of a consensus devel-opment conference among the American Diabetes Association, AmericanPsychiatric Association, American Association of Clinical Endocrinolo-gists, and the North American Association for the Study of Obesity. Thereport, published simultaneously in two journals in 2004, similarly as-signed antipsychotics to high, intermediate, and low risk for weight gainand attributed the associated risk for type 2 diabetes and dyslipidemia inthe 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 meta-analysis to compare the weight-gain liability of antipsychotics over theshort term (10 weeks). Using a random-effects model, average weightgain was 4.5 kg with clozapine, 4.1 kg with olanzapine, 2.5 kg withchlorpromazine, 2.1 kg with risperidone, 1.1 kg with haloperidol, and0.05 kg with ziprasidone (Allison et al. 1999c). Other investigators havereported the short-term weight gain to be 2.3 kg with quetiapine (Joneset al. 1999) and 0.6 kg with aripiprazole (Marder et al. 2003).

Weight gain tends to be rapid, particularly during the first 3 monthsof treatment, with significant weight increases often noted within a fewweeks of treatment (Newcomer 2005). Weight gain generally plateauswithin 9 months or 1 year, although clozapine tends to have a longerweight-gain trajectory, with patients continuing to gain weight for upto 5 years (Henderson et al. 2000).

Considerable interindividual variability in weight gain occurs, andaverage weight gain belies the fact that individual patients can gain avery large amount of weight (sometimes in excess of 45 kg) on a partic-ular medication. Susceptibility to weight gain may be genetically deter-mined, and at a future time genetic testing might be used for predictingwhich patients are prone to excessive weight gain (Müller and Kennedy2006).

Clinical experience has shown that the following variables predictweight gain:

Obesity 71

1. Type of antipsychotic: Antipsychotics differ considerably in weight-gain liability.

2. Previous antipsychotic exposure: Patients who are antipsychotic naiveor switched from a classic antipsychotic or an SGA with lowweight-gain risk to an antipsychotic with high weight-gain risk aremore susceptible to weight gain. In contrast, those switched from anantipsychotic with high to one with low weight-gain liability tendto lose weight.

3. Age: Children, adolescents, or young adults are more likely to gainweight; older patients are less susceptible to weight gain.

4. Baseline weight: Patients with a low baseline weight tend to gainmore weight.

5. Race and ethnicity: Certain groups, including those of African, SouthAsian, Hispanic, and Native American descent, have higher base-line rates of metabolic disturbance and may also be more suscepti-ble to weight gain.

6. Clinical response: Although controversial, a number of investigatorshave found an association between weight gain and antipsychoticresponse.

7. Antipsychotic dose and plasma level: These are generally not correlatedwith weight gain when prescribed within the recommended doserange, although clozapine may be an exception.

Longer-term weight gain is difficult to compare across antipsychoticsbecause of patient attrition and the difficulties adjusting for variablessuch as prior antipsychotic exposure. In a randomized, controlled trialof 263 first-episode patients with no or limited prior exposure to anti-psychotics that compared olanzapine (mean modal dose 9.1 mg/day)and haloperidol (mean modal dose 4.4 mg/day), the weight gain after2 years of treatment for olanzapine was 10.2 kg using a last-observation-carried-forward analysis and 14 kg for observed cases. For haloperidol,weight gain was 4 kg using a last-observation-carried-forward analysisand 7.5 kg for observed cases (Zipursky et al. 2005).

The neuroendocrine mechanisms that underlie antipsychotic-induced weight gain are not fully understood. However, the relation-ship between neurotransmitter-binding profiles of different antipsy-chotics and their propensity to induce weight gain has been explored(Nasrallah 2008). Wirshing et al. (1999) astutely observed a correlationbetween weight gain and antipsychotic binding affinity for the hista-mine-1 (H1) receptor. Kroeze et al. (2003) more recently concluded thatH1 receptor affinity is positively correlated with weight gain amongboth typical and atypical antipsychotics. Others have confirmed this


(S.F. Kim et al. 2007; Matsui-Sakata et al. 2005). S.F. Kim et al. (2007), us-ing a mouse model, found that antipsychotics that induce weight gainselectively activate hypothalamic AMP-kinase via the H1 receptors. H1

activity is involved in appetite regulation and sedation, both relevant toweight gain. These findings may guide antipsychotic drug develop-ment toward drugs less implicit in weight gain. Other targets for inves-tigation 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 andKennedy 2006).

Managing Obesity in SchizophreniaThe management of obesity includes an understanding and evaluationof risk factors, prevention of weight gain, metabolic assessment, andongoing monitoring of the patient, as well as the application of pharma-cological and nonpharmacological strategies of prevention and treat-ment. Clearly, psychiatrists cannot do this work alone. What is requiredis to develop a system of assessment and management in which rolesand tasks are clearly defined and often delegated.

Tooling the Office or ClinicClinicians should think through how to set up the environment, equip-ment, systems, and personnel within the office or clinic to facilitate careof patients who are obese (Kushner 2007). The clinic or office should beaccessible for these patients. Hallways and doors should not be too nar-row, washrooms need to be large enough, and the waiting area and ex-amination or interview room should have a number of sturdy, armlesschairs. Posters, artwork, and magazines should not overly promote“thinness.” However, posters promoting balanced healthy eating andphysical activity are appropriate, as is information about weight-lossprograms and services.

The examination area should be equipped with appropriate equip-ment for assessing obese patients. Most office or hospital scales do notmeasure above 300–350 lb (135–160 kg). Clinics should obtain a scalewith greater capacity and position it so the patient can be weighed pri-vately and away from public view. A wall-mounted measure or an ex-tendable height meter attached to the scale should be available formeasuring the patient’s height. Also, a variety of cuff sizes should beprovided for measuring blood pressure. “Miscuffing” is the most com-mon error in measuring blood pressure, and undercuffing accounts forthe majority of errors (Manning et al. 1983). Tape measures should be

Obesity 73

available for measuring waist circumference, and a calculator or chartis needed for determining BMI.

Each office or clinic needs to establish a procedure for metabolicmonitoring. The paper or electronic health record should allow for therecording and tracking of screening medical history questions, clinicalmeasures, and laboratory tests used in metabolic monitoring. Commer-cial tracking sheets, usually sponsored by pharmaceutical companies,are available. The clinic where I work has developed an electronic toolthat is integrated into the medical record and the patient care plan thatallows for the tracking of metabolic parameters and performs calcula-tions such as whether the patient has metabolic syndrome, Framing-ham risk score, target lipid values, and so forth (Khoury et al. 2008).Forms or computer systems should be readily available to order neededlaboratory tests. Systems need to be in place for referring patients forprimary care or specialist consultation and for referring patients for nu-trition counseling and to professionals who promote physical activity.Larger clinics or programs should develop group-based interventionsto promote healthy lifestyle changes.

The roles and tasks of personnel should be clearly defined. Regis-tered nurses can obtain the vital measurements, including weight,height, waist circumference, and blood pressure, and provide healthteaching. Nurse practitioners can provide most components of primaryhealth care. Co-location of primary health care (primary care physicianor nurse practitioner) within psychiatric services is an excellent modelfor integrating health care (Druss et al. 2001). Office secretaries and as-sistants can facilitate referrals, remind patients of appointments, anddistribute written material. Although the exact role and function ofeach team member varies from one setting to another, what is most im-portant is that care is coordinated and that individuals work together asa team.

Assessment and Metabolic Monitoring of the Patient Patients can be assessed at various points—as a new antipsychotic med-ication is prescribed, after substantial weight has been gained, upon ad-mission to hospital, at annual examinations, at each visit, and so on.Ideally, to inform care, these various assessments should be recordedand tracked, along with prescribed medications and intervention ef-forts. Electronic record systems are particularly helpful in this regardand can also provide reminders when assessments are due.

We (Cohn and Sernyak 2006) have reviewed recommendations re-garding metabolic monitoring published in various countries. Table 4–1


provides a structure informed by these guidelines and used in our clinicfor assessment of patients who are overweight or obese and are beingtreated with psychiatric medications associated with weight gain (anti-psychotics, mood stabilizers, and antidepressants).

Monitoring, which consists of medical history, measurements, andlaboratory tests, is conducted at the first opportunity—when the patientfirst presents at the office of clinic or at the time of hospital admission.Monitoring is then repeated annually. A new baseline is establishedwhen a new antipsychotic (or mood medication) is started, with a fol-low-up evaluation 3 months later. Weight is measured at every visitand graphed over time across encounters (inpatient and outpatient).Diet, activity, motivation, and environmental factors (see “General andLifestyle” column in Table 4–1) are evaluated during clinic visits.

To evaluate diet and physical activity, we have found it useful in ourclinic to have the patient, with the support of family or caregivers, com-plete 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 Physi-cal Activity Questionnaire (Craig et al. 2003) in a sample of patientswith schizophrenia (Faulkner et al. 2006). These assessments are mailedto the patient before the appointment, reviewed during the initial con-sultation, and used to inform the development of a treatment plan. Wehave also found it useful to get a baseline measure of fitness by usingthe 6-minute walking test (ATS Committee on Proficiency Standards2002), a simple structured assessment of the distance an individualwalks over 6 minutes.

Strategies for the Prevention and Management of ObesityBehavioral lifestyle interventions focused on diet and physical activityshould be combined with biological (mostly pharmacological) strate-gies to benefit patients who are obese (Faulkner and Cohn 2006). Figure4–1 provides a recommended outline for the sequencing of interven-tions. Behavioral interventions are discussed in detail in Chapter 8,“Behavioral Treatments for Weight Management of Patients WithSchizophrenia.” This section focuses on biological strategies.

Medication Choice. Weight-gain liability should be factored in whenchoosing psychotropic medications. The choice of psychotropic medi-cation may have the greatest influence on weight gain and associatedmetabolic disturbance. Good evidence exists for a range of weight-gainliability for antipsychotic medications (Allison et al. 1999c; Newcomer

Obesity

75TABLE 4–1. Metabolic assessment of patients treated using antipsychotic medications

General and lifestyle Medical history Examination (measurement) Laboratory tests

• 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 Questionnaire1

• Interest in and barriers to increasing physical activity

• 6-Minute walking test2

Diet• Premailed food frequency

questionnaire and 3-day food diary• Interest in and feasibility of making

dietary changes

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)

Risk factors• Race/ethnicity• Family history of diabetes• History of gestational diabetes• History of coronary vascular disease

(angina, myocardial infarction, or stroke)

• Cigarette smoking

• Height• Weight• Waist circumference• Blood pressure

Measuring guideHeight: No shoesWeight: No shoes; single layer

of clothingWaist circumference: Standing

positionBlood pressure: Average of

two measures. Patient seated and resting for at least 5 minutes, >30 minutes from last cigarette or coffee. Arm relaxed and supported at heart level. Choose appropriate cuff size as indicated by cuff markers.

For nondiabetic patients(No known diagnosis

of diabetes)• Fasting glucosea

• Fasting insulin• Fasting lipid

profile(Total, HDL, and

LDL cholesterol and triglycerides)

For diabetic patients• Fasting glucose• Fasting lipid

profile• HBA1C• Random urine

microalbuminb

aPatients 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 after75-g oral glucose drink). bIf elevated, urine albumin/creatinine ratio.1Craig et al. 2003; Faulkner et al. 2006. 2ATS Committee on Proficiency Standards 2002.Source. Adapted from Cohn and Sernyak 2006.


2005). Antidepressant and mood-stabilizing medications also contrib-ute to weight gain (Aronne and Segal 2003; Fava 2000) because thesemedications are commonly coprescribed with antipsychotics. Lithiumcarbonate, valproic acid, selective serotonin reuptake inhibitors, andmirtazapine have all been implicated in weight gain.

Young, first-episode patients are more susceptible to antipsychotic-induced weight gain (Zipursky et al. 2005) and also tend to have a ro-bust response to antipsychotic medications (Perkins et al. 2004). Initialtreatment with antipsychotic medications known to induce significantweight gain should be avoided. Care should also be taken in the choiceof concomitant psychiatric medications. In patients who have gainedsignificant weight or developed metabolic complications, all medica-tions should be reviewed from both metabolic and psychiatric perspec-tives (Faulkner and Cohn 2006).

Medication Switching. Switching from one antipsychotic medicationto another can have significant effects on body weight and metabolicparameters. Reviews (Weiden 2007; Weiden and Buckley 2007) suggestthat switching to low-liability antipsychotics (ziprasidone or aripipra-zole) can have a more substantial impact on reversing weight gain andlipid disturbance than other intervention strategies, particularly if theweight gain and metabolic derangement clearly occurred during thecourse of prior treatment with an antipsychotic medication with greatermetabolic liability. The metabolic benefit from switching is thereforedependent on the prior treatment.

Outpatients, predominantly with schizophrenia, were switchedfrom a previous antipsychotic—olanzapine (n = 104), risperidone(n=58), or conventional antipsychotic (n=108)—to ziprasidone (meandose 91 mg/day) and reevaluated after 6 weeks (Weiden et al. 2003a).Weight and metabolic benefit depended on which drug the patientswere originally taking. Those switched from olanzapine experiencedthe greatest metabolic benefit, with significant reductions in bodyweight (1.76 kg), nonfasting total cholesterol, and triglycerides. Thoseswitched from risperidone experienced less weight loss (0.86 kg) butsimilar reductions in nonfasting total cholesterol and triglycerides.However, those switched from conventional antipsychotics had nochange in weight or lipid measures. A companion paper from the samedata set (Weiden et al. 2003b) supported the view that stable but symp-tomatic patients can safely be switched from a previous antipsychoticusing a variety of switching strategies (e.g., abrupt discontinuation ofprevious antipsychotic or gradual cross-titration), often with benefit topsychiatric symptomatology. An extension of this study provided long-

Obesity 77

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, respec-tively. Those patients switched from olanzapine and risperidone alsosustained significant reductions in nonfasting cholesterol and triglycer-ides, with maximum reductions occurring rapidly at 6 weeks after theswitch. Those switched from conventional antipsychotics to ziprasi-done did not change in body weight or lipid measures.

Data from the CATIE study (Lieberman et al. 2005) also provideevidence in a randomized trial of differential effects on body weight

FIGURE 4–1. Prevention and management of antipsychotic-related metabolic disturbance.Source. Adapted from Faulkner and Cohn 2006.

Consider metabolic risk inchoice of antipsychotic

Provide patient, family, andcaregiver education about

potential metabolic side effects

Conduct baseline screening and regularmetabolic monitoring

With significant weight gain/metabolic disturbance: Review

all medications from a metabolicand psychiatric perspective;

consider risk/benefit of switch

Provide referral to structuredlifestyle intervention focused

on diet, physical activity,and behavior change

If lifestyle intervention is unsuccessful,consider adjunctive pharmacotherapy;

for severe obesity and significantdisability, consider evaluation

and workup for obesity surgery

Provide lifestylecounseling


when antipsychotics are switched. Patients switched to olanzapinegained 0.9 kg per month. Patients switched to quetiapine and risperi-done also gained weight, but less (0.23 kg per month on quetiapine and0.18 kg per month on risperidone). Those switched to ziprasidone andperphenazine lost 0.13 and 0.09 kg per month, respectively. Patientsswitched to aripiprazole (Casey et al. 2003) experience weight changesvery similar to patients who are switched to ziprasidone. Again, weightchange depended on the previous antipsychotic.

Taken together, data from these studies indicate that weight loss andmetabolic benefit can be achieved by switching medication, particularlyif these problems clearly developed while a patient was taking the priormedication. However, switching is always hazardous because patientscan decompensate. The biggest challenge is the patient who has beendoing well psychiatrically while taking an antipsychotic but has gainedweight or developed metabolic complications. In such a case, the risksof switching may be greater, and the patient and family need to be in-formed of the potential risks and benefits and then carefully considerwhether to switch medication. Discontinuing or switching antipsychot-ics becomes a critical issue when diabetes or diabetic ketoacidosis canbe clearly linked to an antipsychotic prescription, because resolution ofdiabetes can occur (Jin et al. 2004).

Medication Addition. One strategy to prevent weight gain or to pro-mote weight loss is to add a medication associated with weight loss tothe antipsychotic medication regimen. In the general population, con-trolled clinical trials have established modest efficacy for obesity drugsin combination with lifestyle therapy (Li et al. 2005). Orlistat (lipase in-hibitor) and sibutramine (serotonin/dopamine/norepinephrine re-uptake inhibitor) are the only drugs currently approved for long-termweight loss. Average weight loss in the general population (psychiatricpatients were excluded) at 12 months was 2.7 kg (95% CI 2.3–3.1) for in-dividuals taking orlistat and 4.3 kg (95% CI 3.6–4.9) for those takingsibutramine (Padwal et al. 2003). In the context of antipsychotic-induced weight gain, brief (6–16 weeks) randomized controlled trialshave been conducted in patients with schizophrenia using a number ofcompounds, as summarized in Table 4–2. In a Cochrane review,Faulkner et al. (2007b) focused on weight change to compare efficacy re-ported in studies identified using a systematic search and retrieval pro-tocol. Unfortunately, no long-term studies have been published.

In these studies, the weight loss medication is either added when theantipsychotic is first prescribed to prevent weight gain (e.g., reboxetinein first-episode psychosis being treated with olanzapine) (Poyurovsky

Obesity 79

et al. 2003, 2007) or added later when patients have already gained sub-stantial weight (e.g., the use of metformin in children and adolescentswhose weight had increased by more than 10% in less than 1 year whiletaking atypical antipsychotics) (Klein et al. 2006). Many of these studieshave 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 (approximately2–4 kg over 3 months). Negative results have been seen with fluoxetineand reboxetine addition. Sibutramine was found effective with patientson olanzapine (Henderson et al. 2005) (but the benefits were reversedwhen patients stopped taking sibutramine). Sibutramine was ineffec-tive in clozapine-treated patients (Henderson et al. 2007). Topiramatehas been more consistently effective for weight loss in open-label aswell as double-blind studies (J.H. Kim et al. 2006; Ko et al. 2005), anddoses of 200 mg/day have been more effective than 100 mg/day (Ko etal. 2005). However, topiramate has many side effects, both common(paresthesia) and potentially serious (cognitive impairment, narrow-angle glaucoma, and metabolic acidosis).

Metformin may be more helpful in reducing or preventing weightgain during the early stages of treatment for psychosis or in younger in-dividuals. Metformin was found to be effective in reducing weight gainwhen coprescribed with olanzapine in patients treated for a first psy-chotic episode (Wu et al. 2008) and in reversing weight gain and im-proving insulin sensitivity in children and adolescents who had recentlygained weight during treatment with atypical antipsychotics (Klein etal. 2006). However, metformin addition was not able to prevent weightgain in an adult sample of schizophrenia patients with a more chroniccourse who were switched to olanzapine (Baptista et al. 2006).

The release of rimonabant, a selective cannabinoid CB1 receptor an-tagonist, was highly anticipated because of promising phase 3 results inweight loss, smoking cessation, and improvement of metabolic profilesin patients with metabolic syndrome, all of which would benefit pa-tients with schizophrenia (Cox 2005). Rimonabant is currently ap-proved in Europe but not in the United States or Canada. Becauserecent data indicate significant psychiatric adverse effects, primarilydepression and anxiety, there was a recommendation against rimona-bant approval in 2007 by the FDA (Rumsfeld and Nallamothu 2008).

Given that H1 receptor affinity appears to be implicated in antipsy-chotic-associated weight gain, interest has been shown in the use of beta-histine, an H1 receptor agonist and H3 antagonist, to prevent weightgain. Promising results were reported in a small open-label study(Poyurovsky et al. 2005). Placebo-controlled studies are still needed.

80M

edical Illness and SchizophreniaTABLE 4–2. Randomized, controlled trials of medication addition for weight gain in schizophrenia

Added agent Antipsychotic × trial durationAgent dose: n for intervention group: outcome, expressed as weight change relative to placebo [95% CI]

Amantadine(antiparkinsonian)

Olanzapine × 16 weeks (Deberdt et al. 2005)

100–300 mg: n=35: −1.7 [−3.9, 0.5] kg

Famotidine(H2 receptor antagonist)

Olanzapine × 6 weeks (Poyurovsky et al. 2004)

40 mg OD: n=7: no effect

D-Fenfluramine(removed from market)

Typical depots × 12 weeks (Goodall et al. 1988)

30 mg OD: n= 9: −2.6 [−5.5, −0.1] kg

Fluoxetine(SSRI)



Olanzapine × 16 weeks (Bustillo et al. 2003)


Metformin(antidiabetic)

Olanzapine × 12 weeks (Wu et al. 2008)

250 mg tid: n=18: −5.0 [−7.3, −2.7] kg

Atypical AP × 16 weeks (Klein et al. 2006)

500 mg OD: n=9 (ages 10–17): −4.1 [−7.3, −1.0] kg

Olanzapine × 14 weeks (Baptista et al. 2006)

850–1,750 mg: n=20: no effect

Nizatidine(H2 receptor antagonist)

Olanzapine × 8 weeks (Atmaca et al. 2003)

150 mg bid: n=18: −6.8 [−7.9, −5.7] kg300 mg bid: n=58: less wt gain, 3 and 4 wk; effect lost, 16 wk

Olanzapine × 16 weeks (Cavazzoni et al. 2003)

150 mg bid: n=57: no effect

Obesity

81

Phenylpropanolamine(removed from market)

Clozapine × 12 weeks (Borovicka et al. 2002)

75 mg: n=8: no effect

Reboxetine(SNRI)


4 mg/d: n=13: −3.0 [−5.6, −0.5] kg


4 mg/d: n=31: −1.5 [−2.9, −0.1] kg

Sibutramine (serotonin/ dopamine RI)

Clozapine × 12 weeks (Henderson et al. 2007)


Mixed × 16 weeks (Weiden et al. 2003c)


Olanzapine × 12 weeks (Henderson et al. 2005)

15 mg: n=19: −4.6 [−5.2, −4.0] kg

Topiramate(anticonvulsant)

Atypical AP × 12 weeks (Ko et al. 2005)

200 mg/d: n=17: −5.1 [−7.4, −2.7] kg100 mg/d: n=16: −1.4 [−4.2, 1.5] kg

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

Source. Adapted from Faulkner and Cohn 2006.

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

Added agent Antipsychotic × trial durationAgent dose: n for intervention group: outcome, expressed as weight change relative to placebo [95% CI]


Insufficient data are available to suggest the routine use of medica-tion additions (Faulkner and Cohn 2006). Each medication brings thepotential of additional side effects, effect sizes are small, and accessingand covering the costs of these drugs are often problematic. Medicationadditions should, however, be contemplated when other approachessuch as behavioral interventions have been exhausted and switching toa different antipsychotic has been ruled out.

Obesity Surgery. Surgery is an effective intervention for treating severeobesity (Schneider and Mun 2005; Sharma and Iacobellis 2006), result-ing in more significant and longer-lasting loss of weight than othertreatments. Criteria for selecting patients for bariatric surgery includethe following: 1) BMI>40 kg/m2 or BMI>35 kg/m2 with significantobesity-related comorbidities; 2) repeated failure of other nonsurgicalinterventions; 3) psychologically stable patient with realistic expecta-tions; and 4) absence of alcoholism, other addictions, or major psycho-pathology (NIH Conference 1991). These criteria make it difficult forpatients with schizophrenia and other forms of severe mental illness toaccess surgical intervention.

Surgical procedures can involve gastric restriction using vertical oradjustable bands to create a small neogastric pouch, or shortening thefunctional length of the intestinal surface for nutrient absorption, as ingastric bypass or biliopancreatic diversion. The current gold standardfor bariatric surgery is the Roux-en-Y gastric bypass, which is a combi-nation of the restrictive and bypass procedures (Sharma and Iacobellis2006). Patients with schizophrenia require advocacy and very closemedical follow-up and support to access and derive maximum benefitfrom any of these effective interventions.

ConclusionAlthough obesity is endemic in the general population, its prevalenceand consequences are amplified for patients with schizophrenia. Re-sponsibility for organizing health promotion and obesity interventionslies with the providers of psychiatric care, because these services are of-ten not otherwise accessible and because medications used to treatschizophrenia contribute to the development of obesity. Genetic, med-ication, lifestyle, and environmental factors are determinants of obesityin patients with schizophrenia, but genetic prediction of an individual’ssusceptibility to gain weight taking a particular medication is not yeta reality, and practitioners have to rely on clinical evaluation and

Obesity 83

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

Key Clinical Points

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

◗ Genetics, psychotropic medications, lifestyle, and the environment arecontributing factors.

◗ 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 withprescribed psychotropic medication (metabolic monitoring).

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

◗ Prevention and management of obesity in schizophrenia require con-sideration of choice of psychotropic medication, health counseling andbehavioral interventions, medication switching, medication addition,and obesity surgery.

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CHAPTER 5

Glucose Intoleranceand Diabetes in

Patients WithSchizophrenia

David C. Henderson, M.D.Kathleen Miley, B.S.

In recent years, tremendous progress has been made in the treat-ment of schizophrenia and other psychotic disorders. In particular, theintroduction of atypical antipsychotic agents has helped numerous pa-tients gain control of both positive and negative symptoms of schizo-phrenia. Studies also suggest that the newer antipsychotic agentsincrease compliance, prevent relapse (Csernansky et al. 2002), and mayoffer improvement in the treatment of cognitive dysfunction (Meltzer2001). These treatment successes, combined with a lower risk of ex-trapyramidal symptoms (e.g., parkinsonism) and improved control ofpositive and negative symptoms, have led many psychiatrists to favorthe newer, atypical antipsychotic medications over the older, typicalagents. Furthermore, the atypical antipsychotic agent clozapine hasbeen found to be a highly effective agent in improving symptoms forthose patients who have had treatment resistance to other antipsychoticmedications (Lewis et al. 2006).


The use of atypical antipsychotic medications, however, has notproven to be trouble free. Numerous reports in the psychiatric andmedical literature have suggested an association between atypical an-tipsychotic 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 dia-betes mellitus, and its short- and long-term medical consequences, weexamine glucose intolerance and diabetes in individuals with schizo-phrenia before and following the introduction of typical and atypicalantipsychotic medications. Finally, we make recommendations formonitoring and screening for glucose intolerance and diabetes in pa-tients with schizophrenia.

Diagnostic Criteria and Pathophysiology of Diabetes MellitusBoth diabetes and glucose intolerance are characterized by problems inglucose-insulin regulation. According to the American Diabetes Asso-ciation (ADA), if an individual has the typical symptoms of diabetes,such as polyuria, polydipsia, and unexplained weight loss, plus a ca-sual plasma glucose level ≥200 mg/dL (11.1 mmol/L), a fasting plasmaglucose level ≥126 mg/dL (7.0 mmol/L), or a 2-hour plasma glucoselevel ≥200 mg/dL (11.1 mmol/L) post 75-g oral glucose load, then he orshe has diabetes mellitus (American Diabetes Association 2008). Simi-larly, if an individual has a 2-hour plasma glucose level ≥140 mg/dLand <200 mg/dL post 75-g oral glucose load, he or she is said to have im-paired glucose tolerance. Impaired fasting glucose is defined as a levelfrom 100 to 125 mg/dL, whereas fasting glucose values <100 mg/dL areconsidered to be in the normal range (American Diabetes Association2008).

Two pathophysiological processes can lead to the development ofglucose intolerance and diabetes mellitus, the first being a problemwith insulin secretion, as in type 1 and the later stages of type 2 diabetesmellitus, and the second being a problem with insulin action, otherwiseknown as insulin resistance, as seen in type 2 diabetes mellitus (Lebo-vitz 2001). In the first case, the beta cells of the pancreas have been de-stroyed by an autoimmune process, and hyperglycemia occurs becausenot enough insulin is secreted to facilitate glucose uptake in skeletalmuscle tissue, inhibit glucose production in hepatic tissue, and sup-press lipolysis in adipose tissue. In type 2 diabetes mellitus, although

Glucose Intolerance and Diabetes 93

enough insulin may be secreted, insulin resistance prevents the insulinfrom working at the sites of skeletal muscle, hepatic, and adipose tis-sues. Indeed, a reactive hyperinsulinemia may occur, which may helpcontrol plasma glucose levels initially, but eventually the beta cells inthe pancreas begin to deteriorate at a genetically determined rate, andthe compensatory hyperinsulinemia decreases (Lebovitz 2001). As thisoccurs, the postprandial plasma glucose levels increase progressively,and the individual progresses from normal glucose tolerance to im-paired glucose tolerance to type 2 diabetes mellitus. Thus, patients withtype 2 diabetes mellitus have both insulin resistance and an insulinsecretory deficit due to decreased beta cell function.

Both type 1 and type 2 diabetes mellitus are diseases with multifac-torial inheritance. Researchers are confident that no single gene causestype 1 or type 2 diabetes mellitus, and that development of this hetero-geneous group of disorders is likely the result of multiple genes and en-vironmental factors. For example, the interaction of genetic factors suchas beta cell abnormalities and a predisposition for central obesity withexcess caloric intake, high fat ingestion, and decreased physical activitycan lead to type 2 diabetes mellitus in some individuals (Lebovitz 2001).

Drugs are another environmental factor that can cause diabetes mel-litus by either destroying the beta cells in the pancreas or by causing in-sulin resistance by one of the following mechanisms: 1) increasingappetite and caloric intake, leading to obesity; 2) altering fat distribu-tion (central obesity is a risk factor for diabetes mellitus); 3) decreasingphysical activity because of increased sedation; 4) decreasing oxidativemetabolism in tissues; 5) interfering with the insulin action cascade; 6)increasing counterregulatory hormones; or 7) increasing free fatty acidrelease from adipose tissue (Lebovitz 2001). Later in this chapter, wediscuss the possible mechanisms by which atypical antipsychotic med-ications may cause glucose intolerance or diabetes mellitus, exacerbateexisting diabetes, or induce diabetic ketoacidosis in patients withschizophrenia.

Medical Complications of Glucose Intolerance and Diabetes MellitusHyperglycemia and diabetes mellitus are associated with acute andchronic complications associated with significant morbidity and mor-tality. Diabetic ketoacidosis, an acute complication of diabetes mellitus,is seen more often in patients with type 1 than in patients with type 2diabetes mellitus and is a serious and potentially fatal complication.


Ketoacidosis is defined by low serum pH (≤7.35), low serum bicarbon-ate levels (≤15), and an anion gap in the presence of ketonemia (West-phal 1996). The diabetic patient is also susceptible to a variety of chroniccomplications that affect the cardiovascular system, nervous system,eyes, kidneys, and wound-healing capabilities. Most of these complica-tions are a result of microvascular and macrovascular disease that ismore extensive and appears much earlier in the diabetic patient than inthe general population (Newcomer 2001).

Macrovascular disease in the form of atherosclerosis increases therisk of cardiovascular and cerebrovascular events such as myocardialinfarction and stroke, thus accounting for much of the disability anddeath among diabetic patients (Haupt and Newcomer 2001; Henderson2001). Results from studies conducted with large samples of patientswithout diabetes show that even modest increases in fasting plasmaglucose levels that do not meet the diagnostic criteria for diabetes mel-litus put patients at increased risk for cardiovascular disease and com-plications, including coronary artery disease, myocardial infarction,and other vascular problems, as well as increased risk for cardiovascu-lar death (Gerstein et al. 1999). In peripheral sites, atherosclerosis cancause claudication and “diabetic foot,” a condition in which patientsdevelop nonhealing ulcers that are prone to infection on their lower ex-tremities and feet as a result of vascular insufficiency and sensory defi-cits from impairments in the peripheral nervous system. Diabeticneuropathy is a complication that contributes significantly to morbidityin diabetic patients because it not only contributes to diabetic foot butalso can affect any part of the nervous system, resulting in sensory def-icits, paresthesias, motor abnormalities, or autonomic dysfunction(Henderson 2001). A large percentage of diabetic patients also experi-ence ophthalmic complications such as diabetic retinopathy and dis-eases of the anterior chamber that affect vision (e.g., cataracts), leadingto blindness and significant disability.

Finally, many diabetic patients suffer a great deal from microvascu-lar- and macrovascular-induced nephropathy, which can cause hyper-tension, proteinuria, and a decrease in the glomerular filtration rate,leading to renal failure. Indeed, diabetic nephropathy is the most prev-alent cause of end-stage renal failure (Schernthaner 2008) and is a lead-ing cause of morbidity and mortality in diabetic patients.

Metabolic SyndromeObesity (especially visceral), insulin resistance, and dyslipidemia,along with hypertension (Henderson et al. 2004), are major, modifiable


cardiovascular risk factors associated with macrovascular complica-tions. These metabolic abnormalities and hypertension are key compo-nents of metabolic syndrome, which is highly predictive of overt type 2diabetes mellitus and cardiovascular disease (Wannamethee et al.2005). The prevalence of metabolic syndrome and cardiovascular dis-ease in the schizophrenia population taking atypical antipsychotics ismuch higher than in the general population (Bobes et al. 2007; Casey etal. 2004; Newcomer 2004, 2007a, 2007b; Newcomer and Haupt 2006;Osby et al. 2000). McEvoy et al. (2005) found that the age-adjusted prev-alence rates of metabolic syndrome in patients in the Clinical Antipsy-chotic Trials of Intervention Effectiveness (CATIE) schizophrenia trialwere 40.9% based on criteria from the third report of the National Cho-lesterol Education Program Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults and 42.7% based on cri-teria from the American Heart Association.

Lifestyle FactorsAllison et al. (2003) reported that patients treated with antipsychoticmedications who have experienced weight gain have a reduced qualityof life, poorer self-reported general health, and decreased vitality. Byincreasing a patient’s risk of obesity, antipsychotic agents may be plac-ing patients at risk for associated morbidity and mortality (Pi-Sunyer2002). Patients who gain greater than 7% of their total body weight areat risk for developing hypertension and type 2 diabetes mellitus. Therisk for diabetes mellitus is increased approximately twofold in mildlyobese, fivefold in moderately obese, and 10-fold in severely obese per-sons (Pi-Sunyer 1993).

Although patients with schizophrenia tend to consume fewer calo-ries, their food choices differ from those of the general population andthey are less likely to make healthy dietary choices (Brown et al. 1999;Henderson et al. 2006a; McCreadie et al. 1998; Pereira et al. 1997; Strass-nig et al. 2003). Studies suggest that high dietary saturated fat and lowomega-3 polyunsaturated fatty acid play a key role in the developmentof type 2 diabetes mellitus (Peet 2004a) and contribute to a poor clinicaloutcome for people with schizophrenia (Christensen and Christensen1988; Peet 2003, 2004b). No studies have reported on whether atypicalantipsychotic-induced insulin resistance has any relationship to poor di-etary profile in this population. However, one study showed that cloza-pine-treated patients with schizophrenia consumed almost twice asmuch sugar as those taking other antipsychotic agents (Stokes and Peet2004). Coccurello et al. (2006) and Fell et al. (2007) observed that olanza-


pine treatment in mice altered dietary macronutrient selection such thatthey preferred a diet high in fat and sugar. Identification of any link be-tween poor dietary profile and glucose metabolism abnormalities in-duced by atypical antipsychotic drugs in the schizophrenia populationwould be helpful to emphasize preventive measures through dietarymodification prior to taking aggressive therapeutic approaches.

Central obesity is a significant risk factor for the development of type2 diabetes mellitus in patients with schizophrenia as well as in the gen-eral population. The prevalence of obesity and overweight in peoplewith type 2 diabetes mellitus is as high as 80%–90% (Carolino et al.2008). Apparently, however, the duration of obesity is a greater deter-minant of risk than that conferred by simply being obese. That is, if a pa-tient gains a considerable amount of weight and maintains this weight,his or her risk of developing hyperglycemia or type 2 diabetes mellitusappears to be increased (Henderson 2001).

Glucose Intolerance and Diabetes Mellitus in Patients With SchizophreniaFindings From the Pre-Antipsychotic EraEarly reports dating back to the 1920s, before the use of antipsychoticagents, suggest that individuals with schizophrenia and other psychoticdisorders exhibited an elevated risk for developing glucose intoleranceor diabetes mellitus (Braceland et al. 1945; Haupt and Newcomer 2001;Marinow 1971; Saddichha et al. 2008; Waitzkin 1966). Specifically, thereports indicate a pattern of insulin resistance in patients with schizo-phrenia independent of adverse medication effects. These studies, how-ever, suffered from several methodological problems: flaws in thediagnostic criteria for schizophrenia, and lack of control for age, weight,fat distribution, ethnicity, diet, or exercise, all of which are variablesnow known to play a role in an individual’s risk for developing gluco-regulatory disturbances (Haupt and Newcomer 2001). Thus, because nowell-controlled studies exist, the debate continues as to whether indi-viduals with schizophrenia, when unmedicated, are at increased riskfor developing diabetes compared with the general population.

Conventional Antipsychotic Agents, Diabetes, and Glucose IntoleranceConventional antipsychotic agents, which have primarily antidopa-minergic activity, may alter glucose-insulin homeostasis (Hägg et al. 1998).


In particular, the low-potency phenothiazines may induce diabetes melli-tus or aggravate existing diabetes mellitus (Hägg et al. 1998; Haupt andNewcomer 2001). Because of this finding, chlorpromazine has been used toprevent hypoglycemia in patients with malignant insulinoma. Further-more, chlorpromazine has been shown to induce hyperglycemia in healthyvolunteers as well as in patients with latent diabetes (Hägg et al. 1998).

Other conventional antipsychotic agents, such as the high-potencyagent haloperidol, are associated with a decrease in the prevalence rateof diabetes in the schizophrenia population. For example, Mukherjee etal. (1996) found an overall diabetes prevalence rate of 15% in 95 patientswith schizophrenia. In patients younger than age 50 years, there wereno cases of diabetes mellitus. For patients ages 50–59 years, however,the prevalence rate was 12.9%, and for patients ages 60–69 years, theprevalence rate was 18.9%. Finally, for those ages 70–74 years, the prev-alence rate was 16.7%. After controlling for age, gender, and cumulativeduration of antipsychotic treatment, Mukherjee et al. (1996) found thatmedication-free patients were more likely to develop diabetes mellitusthan were those receiving treatment with conventional agents. Of note,the prevalence rates quoted in this study exceeded those expected fortype 2 diabetes mellitus in the general population, lending further evi-dence to the argument that schizophrenia may indeed be an indepen-dent risk factor for the development of diabetes mellitus (Henderson2002; Henderson et al. 2005a).

Several other reports have suggested higher rates of type 2 diabetesmellitus in patients with schizophrenia than in the general population,even before widespread use of atypical antipsychotics (Dixon et al.2000). In a sample of 26 medication-naive first-episode schizophreniapatients, Ryan et al. (2003) found evidence of insulin resistance and im-paired glucose tolerance, with 15% of subjects exhibiting abnormal glu-cose metabolism on an oral glucose tolerance test. Several more recentstudies of neuroleptic-naive first-episode schizophrenia patients havealso confirmed the presence of glucose-insulin homeostasis dysfunc-tion in this patient population (Cohn et al. 2006; Spelman et al. 2007; vanNimwegen et al. 2008; Venkatasubramanian et al. 2007).

In summary, examination of reports discussing the prevalence ratesof diabetes mellitus or impaired glucose tolerance in patients withschizophrenia shows that among the conventional antipsychoticagents, the effects of glucose regulation may vary in magnitude acrossindividual agents. Specifically, the phenothiazines may increase a pa-tient’s susceptibility for developing diabetes mellitus, but no significantassociation has been found between diabetes mellitus and the use ofother conventional antipsychotic medications.


Atypical Antipsychotic Medications, Diabetes, and Glucose Intolerance

The greatest benefits of the introduction of the atypical antipsychoticmedications as a group—clozapine, olanzapine, quetiapine, risperi-done, and ziprasidone—have been improvements in the treatment ofnegative symptoms and concomitant improvements in cognitive func-tion (Lewis et al. 2006; Meltzer 2001). The improvements in cognitivefunction, which include the aspects of executive function, verbal flu-ency, attention, and memory and learning, can lead to improved func-tioning in both home and work environments (Meltzer 2001). However,these benefits have not come without a cost, because many atypical an-tipsychotic agents are associated with significant weight gain, whichhas an adverse effect on health and medication compliance.

In the Clinical Antipsychotic Trials for Intervention Effectiveness(CATIE) schizophrenia study, funded by the National Institute of Men-tal Health, 74% of patients discontinued their study medication (eitherperphenazine, olanzapine, quetiapine, risperidone, or ziprasidone) be-fore 18 months in phase 1 (Lieberman et al. 2005). The time to discontin-uation of treatment for any cause was significantly longer in the grouptaking olanzapine. Although symptom outcomes were similar in phase 1for all groups, as indicated by total scores on the Positive and NegativeSyndrome Scale for Schizophrenia, the groups demonstrated signifi-cant differences in weight gain and significant glucose metabolismchanges (with olanzapine resulting in the greatest negative effect). Inthe phase 2 tolerability arm, the time to treatment discontinuation waslonger for both olanzapine (6.3 months) and risperidone (7 months)than for quetiapine (4 months). In subjects who had discontinued theirprevious phase 1 drug because of side effects and were switched to an-other drug, olanzapine was more effective than quetiapine and zipra-sidone, and risperidone was more effective than quetiapine (Stroup etal. 2006). However, olanzapine, compared with the other agents, wasagain associated with greater and more significant weight gain and in-creases in lipids and glucose (Nasrallah 2006). The CATIE trial alsofound that at baseline, the subjects with schizophrenia had elevatedrates of metabolic syndrome and its individual components comparedwith matched controls from the general population (McEvoy et al.2005). Additionally, elevated risk for cardiovascular disease was ob-served at baseline compared with this same pool of matched controls(Goff et al. 2005). (For more discussion of the CATIE trial findings, seeChapter 3, “Medical Outcomes From the CATIE SchizophreniaStudy.”)


Although CATIE has been the largest randomized, double-blind,non-industry sponsored trial to report metabolic data, numerous earlierreports in the medical and psychiatric literature have linked the use ofatypical antipsychotic agents to the development of glucose intoler-ance, new-onset diabetes mellitus, diabetic ketoacidosis, and exacerba-tion of existing type 1 or type 2 diabetes mellitus, even in patients whoare not obese (Henderson 2002; Henderson et al. 2007). Koller and col-leagues from the U.S. Food and Drug Administration research programconducted a MedWatch surveillance program analysis and reported384 cases of clozapine-related diabetes (Koller et al. 2001), of which 242were new-onset diabetes cases and 54 were cases of exacerbation in pa-tients with preexisting diabetes. Their report also identified 80 cases ofclozapine-induced probable diabetic ketoacidosis and 25 deaths. Ofnote, the majority of diabetic ketoacidosis episodes occurred within thefirst 6 months of clozapine treatment, and one patient developed diabe-tes mellitus immediately after he accidentally took a 500-mg dose ofclozapine. In another study, Koller and Doraiswamy (2002) found a to-tal of 289 cases of olanzapine-related diabetes, of which 225 were new-onset diabetes, with 100 cases of diabetic ketoacidosis and 25 deaths.Given that the MedWatch surveillance program is able to identify onlya small percentage of cases, the incidence of clozapine- and olanzapine-induced diabetes mellitus and diabetic ketoacidosis is likely muchgreater than reported.

Hägg et al. (1998), using an oral glucose tolerance test, found that12% of patients treated with clozapine developed type 2 diabetes and10% developed impaired glucose tolerance compared to 6% and 3%, re-spectively, of patients treated with conventional depot antipsychoticmedications. In an analysis of 45 published cases of new-onset diabetesmellitus or diabetic ketoacidosis following treatment with atypicalantipsychotic agents, Jin et al. (2002) reported that 20 patients hadreceived clozapine, 19 olanzapine, 3 quetiapine, and 3 risperidone. Ina study of the association between the atypical antipsychotic agents anddiabetes mellitus in patients with schizophrenia or related psychoses,Melkersson et al. (1999) found elevated fasting insulin levels andreduced growth hormone–dependent insulin-like growth factor I in28 patients taking conventional antipsychotic agents compared with13 patients taking clozapine, thus suggesting insulin resistance withsecondary increased hyperinsulinemia related to clozapine therapy.

Our group conducted a 5-year naturalistic study examining, in 96 pa-tients with schizophrenia treated with clozapine, the incidence of treat-ment-emergent diabetes in relation to other factors such as weight gain,lipid level abnormalities, age, clozapine dose, and concomitant treat-


ment with valproic acid (Henderson et al. 2000). Patients with diabetesprior to clozapine initiation experienced a twofold increase in insulin re-quirements or required a switch to insulin from an oral hypoglycemicagent. At baseline, the patients’ mean weight was 79.6 kg and mean bodymass index was 26.9 kg/m2. Their mean age at the time of clozapine ini-tiation was 36.4 years. The sample was 26.8% female and 91% Caucasian.During the 5-year follow-up, 30 patients (36%) were diagnosed with di-abetes. Patients experienced significant weight gain, which continueduntil approximately month 46 from the beginning of clozapine treat-ment, but weight gain was not a significant risk factor for the develop-ment of diabetes in this study. After the conclusion of the 5-year study,this cohort was followed for an additional 5 years, resulting in a 10-yearnaturalistic study that examined the metabolic and cardiovascular sideeffects of clozapine treatment. At the end of the 10-year study, Hender-son et al. (2005c) reported a mean weight gain of approximately 13.6 kgand an estimated 10-year cardiovascular disease mortality rate of 9%.Over the same period, 33 (34%) of the 96 patients developed diabetes, togenerate a 43% estimated 10-year incidence rate of new-onset diabetes.

In another study, we examined data for patients with schizophreniatreated at our hospital during a 7-year period and found that 18.4%of patients with schizophrenia were diagnosed with diabetes mellituscompared to 6.6% in the general hospital population (P<0.001) (Hen-derson et al. 2007). Twenty-three patients with schizophrenia wereidentified with diabetic ketoacidosis; of these, 11 had new-onset dia-betes presenting as diabetic ketoacidosis, 8 had diabetic ketoacidosiswith known diabetes mellitus, 2 had new-onset diabetes mellitus–hyperosmolar hyperglycemic syndrome, and 2 had hyperosmolarhyperglycemic syndrome with known diabetes mellitus. The incidenceof diabetes presenting as diabetic ketoacidosis in patients with schizo-phrenia was more than 10-fold higher than that reported in the generalpopulation: 14.93 per 10,000 patient years in patients with schizo-phrenia versus 1.4 per 10,000 patient years in the general population(P<0.000001) and versus 1.98 per 10,000 patient years in the generalhospital population (P<0.000001). The incidence of diabetic ketoacido-sis in patients taking each of the atypical antipsychotic drugs over the7-year period was as follows: clozapine, 2.2%; olanzapine, 0.8%; andrisperidone, 0.2% (no incidence with ziprasidone or quetiapine). Of the11 patients with diabetes presenting as diabetic ketoacidosis, the meanhemoglobin A1c level at admission was 13.3%±1.9% (10.4%–16.9%).The elevated hemoglobin A1c levels observed suggest that patients hadundiagnosed diabetes mellitus for at least several weeks before their di-abetic ketoacidosis episode.


A few reports have linked the atypical antipsychotic agents risperi-done and quetiapine to new-onset diabetes mellitus and glucose intol-erance, but not nearly as many as those described for clozapine andolanzapine (Henderson 2001; Henderson et al. 2005a; Perez-Iglesias etal. 2007). Griffiths and Springuel (2001), using the Canadian AdverseDrug Reaction Monitoring Program, reported 37 cases of suspected glu-cose metabolism disorders associated with atypical antipsychoticagents. With clozapine there were 8 cases of diabetes mellitus, 5 casesof diabetic ketoacidosis, and 4 cases of hyperglycemia. For olanzapine2 cases of diabetes mellitus were reported, along with 3 cases of diabeticketoacidosis, 2 cases of diabetic coma, and 3 cases of hyperglycemia.For quetiapine, 1 case of diabetes mellitus and 2 cases of diabetic ketoac-idosis were reported. Finally, for risperidone 1 case of diabetes mellitus,1 case of labile blood glucose levels, 3 cases of hyperglycemia, and2 cases of hypoglycemia in patients with a previous history of diabetesmellitus were reported. Of note, there were 3 deaths from the 10 casesof diabetic ketoacidosis.

Wirshing et al. (2001) reported two cases of new-onset diabetes in ris-peridone-treated patients. Both subjects were African American, wereoverweight or obese prior to risperidone initiation, and gained signifi-cant weight while receiving treatment with risperidone. These caseshighlight the importance of understanding risk factors for diabetes inpatients receiving treatment with atypical antipsychotic agents.

Finally, Fryburg et al. (2001) reported a double-blind controlled trialcomparing olanzapine and ziprasidone therapy on the basis of meta-bolic indices. In a comparison of baseline to 6-week follow-up, olanza-pine subjects showed a significant increase in body weight, fastingserum insulin, cholesterol, triglycerides and a parameter for insulin re-sistance, suggesting increased insulin resistance in the olanzapinegroup but not the ziprasidone group. Similarly, Perez-Iglesias et al.(2007) conducted a 12-week study in which 128 patients taking eitherhaloperidol, olanzapine, or risperidone were assessed. Although alltreatment groups showed a worsening lipid profile, increases in triglyc-eride levels were observed only in the olanzapine group.

All of the reports indicate that the strength of the association be-tween the atypical antipsychotic medications and disturbances in glu-cose regulation can vary across the different medications, with manymore cases of medication-induced hyperglycemia, diabetes mellitus,and diabetic ketoacidosis occurring with clozapine and olanzapinetreatment than with treatment with the atypical agents risperidone,quetiapine, and ziprasidone (Haupt and Newcomer 2001). Also, it isimportant to recognize that the reports of diabetic ketoacidosis associ-


ated with clozapine and olanzapine treatments and the increased inci-dence of new-onset type 2 diabetes may represent two distinctpopulations with varying risks for developing the diseases (Henderson2002; Henderson et al. 2007).

Causative Mechanisms With Atypical Antipsychotic AgentsThe atypical antipsychotic medications could lead to hyperglycemiaand diabetes mellitus in a number of ways. As discussed earlier in thischapter, decreased sensitivity (increased resistance) to insulin and de-creased insulin secretion as a result of decreased beta cell function areinvolved in the development of type 2 diabetes. A few controlled stud-ies suggest that the atypical antipsychotic medications affect insulin re-sistance rather than causing a primary defect in insulin secretion(Henderson 2007; Henderson et al. 2005a). The insulin resistance seenduring atypical antipsychotic treatment may be a result of increasedcentral adiposity or may arise from the direct effect of the medication’saction on the glucose transporter function (Haupt and Newcomer2001). Dwyer et al. (1999) studied the effects of atypical antipsychoticagents on glucose transporter function. They suggested that a structure-function relationship exists in which similar drugs, such as clozapineand olanzapine, achieve relatively higher intracellular concentrationsand bind to, and thus interfere with, the function of the glucose trans-porter proteins.

Another mechanism by which the atypical antipsychotic agents maylead to hyperglycemia and diabetes mellitus is by antagonism of the se-rotonin 5-HT1A receptors. Antagonism of these receptors may decreasepancreatic beta cell responsiveness to blood sugar levels, thus resultingin disturbances in glucose metabolism secondary to decreased insulinsecretion (Gilles et al. 2005). Melkersson et al. (2000), however, foundthat patients treated with olanzapine had higher fasting insulin levelson comparison of baseline to 5-month follow-up, suggesting that im-paired beta cell function is an unlikely cause for olanzapine-associateddiabetes mellitus. Their group found that although 11 of 14 (79%) olan-zapine-treated patients were normoglycemic and only three showed in-creased blood glucose values, the majority of patients (10 of 14, or 71%)had insulin levels above the normal limit. The report also notedincreased rates of hyperleptinemia, hypertriglyceridemia, and hyper-cholesterolemia. In short, Melkersson et al. found that olanzapine treat-ment was associated with weight gain and elevated levels of insulin,leptin, and blood levels as well as insulin resistance, with three patients


diagnosed with diabetes mellitus. The elevated insulin values argueagainst the theory that antagonism of the serotonin receptors by someatypical antipsychotic agents, a property that could theoretically lead todecreased beta cell insulin production, causes hyperglycemia and dia-betes mellitus. It is also worth noting that olanzapine has little affinityfor 5-HT1A receptors.

Notably, in several of the case studies and research studies men-tioned in this chapter, weight gain was not associated with the develop-ment of diabetes mellitus or diabetic ketoacidosis during atypicalantipsychotic therapy. Indeed, many of the individuals who developeddiabetes mellitus or diabetic ketoacidosis were of normal weight. Thus,although all obese individuals are at increased risk for the developmentof type 2 diabetes, the added obesity caused by the atypical antipsy-chotic medications does not appear to be the sole reason for the devel-opment of diabetes mellitus or diabetic ketoacidosis in patients withschizophrenia. Nevertheless, if patients with schizophrenia gain con-siderable amounts of weight and maintain that weight, their risk of de-veloping type 2 diabetes is significantly increased.

InterventionsThe potential benefit of improving health behavior was demonstrated ina longitudinal study of 85,000 nurses. Results indicated that 83% of coro-nary heart disease events were avoided by 3% of individuals who main-tained a desirable weight, ate a healthy diet, exercised regularly, drankalcoholic beverages moderately, and did not smoke (Stampfer et al. 2000).In nurses who achieved three of the above components, 51% of coronaryevents were avoided. Although achieving a healthy lifestyle may be moredifficult for patients with schizophrenia, the potential benefits warrantintensive efforts toward this goal on the part of patients and caregivers.

Switching to a more weight-neutral atypical antipsychotic agent of-fers promise in halting or reversing weight gain and improving glucosemetabolism, but many patients and their clinicians are reluctant to riska worsening or return of psychotic symptoms and risk relapse (Casey etal. 2003; Luebbe et al. 2006; Spurling et al. 2007; Weiden et al. 2003).Menza et al. (2004) reported on a 52-week multimodal weight controlprogram using nutrition, exercise, and behavioral interventions in31 patients with schizophrenia or schizoaffective disorder and found,using a last observation carried forward (LOCF) analysis, a significantreduction in weight, body mass index (BMI), hemoglobin A1c, and sys-tolic and diastolic blood pressure, with 20 of 31 completing the program.


A number of pharmacological interventions have been evaluated toimprove glucose metabolism. One study randomized 26 first-episodeschizophrenia patients to either olanzapine 10 mg or olanzapine 10 mgplus reboxetine 4 mg (Poyurovsky et al. 2003). Patients receiving thecombination had less weight gain (2.5±2.7 kg) than patients receivingolanzapine alone (5.5±3.1 kg). In another study, fluoxetine was ineffec-tive in diminishing olanzapine-induced weight gain in first-episodeschizophrenia patients (Poyurovsky et al. 2002). In a 16-week double-blind trial, Radulovic et al. (2002) evaluated the addition of sibutraminewith behavioral weight counseling to an ongoing antipsychotic regimenin stable, overweight, or obese outpatients with schizophrenia. Twenty-one patients were assigned to either sibutramine (up to 15 mg/day) orplacebo in a 2:1 ratio. Nineteen completed at least 4 weeks of double-blind treatment (sibutramine: 14; placebo: 5), with 11 completing thefull 16 weeks. There were no significant differences between groups onweight loss (placebo group −4.2 kg; sibutramine group −3.7 kg) or BMI(−1.46 kg/m2 in the placebo group; −1.32 kg/m2 in the sibutraminegroup) in an LOCF analysis. The small sample size and high dropoutrate may have limited the opportunity to detect differences betweengroups. In a placebo-controlled trial of sibutramine with a behavioralnutrition program in olanzapine-treated subjects (Henderson et al.2005b), the mean weight loss was 3.8±1.1 kg in the sibutramine groupand 0.8±0.7 kg in the placebo group (P<0.05). However, no improve-ments in lipids were detected in this study. Another study examinedthe effect of amantadine for weight loss in olanzapine-treated patients(Deberdt et al. 2005). An LOCF analysis indicated a modest but signifi-cant difference in change in weight comparing amantadine to placebogroup at weeks 8, 12, and 16. At week 16 the result was −0.19±4.58 kgfor amantadine versus 1.28±4.26 kg for placebo (P=0.045).

In a study of 24 patients with treatment-resistant schizophreniawho began taking aripiprazole with decreased doses of clozapine,Karunakaren et al. (2006) reported an average weight loss of 5.1 kg over34 weeks. Mitsonis et al. (2007) reported on 27 patients for whom ari-piprazole was added to stable doses of clozapine. Although no signifi-cant weight loss was noted, patients’ total scores on the Positive andNegative Syndrome Scale for Schizophrenia improved significantly. Ina 6-week open-label trial to examine the effects of adjunctive aripipra-zole in 10 clozapine-treated subjects, patients decreased in weight (from99.5±18.1 kg to 96.9±17.4 kg) (P=0.003) from baseline to study end-point (Henderson et al. 2006b). Significant decreases were also seen infasting total serum cholesterol (from 211±27 mg/dL to 184±27 mg/dL)(P=0.002) and triglycerides (from 274±229 to 176±106 mg/dL) (P=0.04).


Morrison et al. (2002) openly treated 19 adolescents taking olanza-pine, risperidone, quetiapine, or valproate, with metformin 500 mgthree times a day. The mean weight loss at 12 weeks was 2.93±3.13 kg,with 15 of 19 patients losing some weight. In a 12-week study compar-ing the addition of fluvoxamine to low-dose clozapine (≤250 mg/day)with high-dose clozapine monotherapy (≤600 mg/day), Lu et al. (2004)found that subjects on monotherapy had significantly greater increasesin weight, BMI, serum glucose, and triglyceride levels. Wu et al. (2008)randomized 40 first-episode schizophrenia patients to treatment witheither olanzapine 15 mg/day plus metformin 750 mg/day or olanza-pine plus placebo for 12 weeks. They found that weight, BMI, waist cir-cumference, insulin, and insulin resistance increased less with thecombination. Baptista et al. (2008) reported on a 12-week study withmetformin (850–1,700 mg) plus sibutramine (10–20 mg, n=13) or pla-cebo (n=15) in olanzapine-treated patients with chronic schizophrenia.Weight loss was similar in both groups, although the combination didprevent a triglyceride increase.

Monitoring and Screening RecommendationsThe development of glucose intolerance and diabetes mellitus may be avery serious comorbid complication of treatment with antipsychoticagents, thus contributing to morbidity and mortality in patients withschizophrenia. The development of hyperglycemia in patients withschizophrenia often goes unrecognized, as it does in approximately50% of the general population. Because patients taking antipsychoticmedications may be at increased risk for developing diabetes, closemonitoring and screening for obesity and hyperglycemia are impera-tive for individualizing treatment decisions and reducing the risks ofmorbidity and mortality. Before starting treatment with an atypicalantipsychotic, the clinician should perform a risk factor assessment fordiabetes mellitus and other metabolic disorders. This risk assessmentshould include baseline serum lipid and glucose values (preferablyfasting), weight, BMI, age, ethnicity, family history of diabetes in a first-degree relative, level of physical activity, and diet (American DiabetesAssociation et al. 2004).

The American Diabetes Association (2008) recommends that routinescreening for diabetes begin at age 45 in whites with no other riskfactors for diabetes, and further recommends repeat testing for thisgroup every 3 years thereafter if the results are within normal range.


The association recommends beginning surveillance at an earlier ageand more frequent monitoring for individuals with any of the followingrisk factors for diabetes and cardiovascular disease: obesity, a first-degree relative with diabetes, membership in a high-risk ethnic popu-lation (African Americans; Hispanic Americans; Asian Americans, in-cluding Indian Asians; Pacific Islanders; and Native Americans),previous diagnosis of gestational diabetes or delivery of a baby largerthan 4.4 kg, hypertension (>130/85 mmHg), a high-density lipoproteinlevel ≤40 mg/dL in men and ≤50 mg/dL in women, a triglyceride level≥150 mg/dL, or previous diagnosis of impaired fasting glucose (fastingplasma glucose level ≥100 mg/dL but <126 mg/dL) or impaired glu-cose tolerance (oral glucose tolerance test revealing 2-hour postloadglucose level of ≥140 mg/dL but <200 mg/dL).

Because schizophrenia is associated with increased rates of diabetesmellitus or impaired glucose regulation, and because the newer, atypi-cal antipsychotic agents appear to increase this risk even further, itseems reasonable that patients with schizophrenia, and especially pa-tients taking atypical antipsychotic medications, should be screened forhyperglycemia before age 45 and monitored more frequently than ev-ery 3 years. This is especially appropriate in light of case reports of new-onset diabetes mellitus associated with atypical antipsychotic therapyin patients under age 20. Additionally, patients with higher risk factorsshould be examined more closely. African American, Asian, and Latinopatients should be monitored closely, particularly if they have otherrisk factors for diabetes independent of ethnicity. If factors such asweight gain, elevated lipids, or hypertension develop, early interven-tions are necessary to prevent the onset of diabetes. Although very littleis known about the underlying reasons that some patients treated withatypical antipsychotic agents experience diabetic ketoacidosis, under-taking a risk assessment with each patient may help in choosing saferagents for each individual. We recommend monitoring weight changesand blood pressure at each office visit, as well as fasting glucose and lip-ids at baseline and every 3 months. Also, patients must be instructed tonotify the treatment team if they experience any physical symptoms ormedical disorders, because a number of diabetic ketoacidosis episodeshave occurred in conjunction with other acute medical disorders suchas infections and pancreatitis. A recent study found that hemoglobinA1c levels were significantly elevated in patients with schizophreniawith new-onset diabetes mellitus presenting as diabetic ketoacidosis(Henderson et al. 2007). Therefore, more frequent monitoring of hemo-globin A1c levels may aid in forewarning physicians of a patient’s riskfor developing diabetes mellitus or diabetic ketoacidosis. Finally, pa-


tients treated with atypical antipsychotic agents, particularly clozapineand olanzapine, should be screened more frequently.

In contrast to use of some of the atypical antipsychotic agents, treat-ment with ziprasidone and aripiprazole are associated with minimalimpact on metabolic parameters. Ziprasidone may offer significant ad-vantages because it appears to be weight neutral (Allison et al. 1999;Gardner et al. 2005; Henderson 2007); however, additional clinical ex-perience is necessary with this agent before definitive conclusions canbe reached. Aripiprazole also appears to be associated with minimalweight gain and little or no negative impact on serum lipids or glucosemetabolism (Melkersson and Dahl 2004).

Therefore, a reasonable approach would be to take baseline mea-sures (fasting blood glucose, lipids, weight, waist measurements, bloodpressure) for all patients and to repeat fasting glucose and lipids every6 months if possible. Weight and blood pressure can be monitored morefrequently in the office. Monitoring of glycohemoglobin may be usefulin this population if fasting glucose is difficult to obtain. However, gly-cohemoglobin may not be sensitive enough to detect lower levels of hy-perglycemia, glycohemoglobin changes will lag 2–3 months behindchanges in glucose homeostasis, and criteria for diagnosing diabeteswith glycohemoglobin do not exist. Education and referral to weight re-duction and exercise programs may play a significant preventive role.In addition, weight gain should initiate meaningful dietary interven-tion. Finally, the clinician should be alert to the possibility of diabeticketoacidosis.

If a patient develops diabetes while receiving treatment with anatypical antipsychotic agent, consideration should be given to switch-ing to another antipsychotic agent. Although diabetic ketoacidosis ap-pears to be uncommon, it is of great concern because it increases the riskof death. Patients who experience an episode of diabetic ketoacidosisshould be switched to a different antipsychotic agent that has a lowerimpact on glucose metabolism. Reports and clinical experience suggestthat in a case of atypical antipsychotic agent–associated diabetes or di-abetic ketoacidosis, discontinuation of the antipsychotic agent may re-sult in a complete resolution of the hyperglycemia and diabetes.Clozapine-treated patients have few options. Clozapine remains themost effective agent for the treatment-resistant schizophrenia popula-tion, and patients often have failed to benefit from several other anti-psychotic agents. Interventions to reduce the factors that contribute toimpaired glucose tolerance, such as weight loss programs, encouragingexercise, and lowering the clozapine dose, may lead to improvement.Other approaches, including augmentation with a more neutral anti-


psychotic agent such as aripiprazole, may result in improvements inpatients’ weight and metabolic parameters (Henderson et al. 2006b).For patients treated with other atypical agents, switching to anotheragent should be considered in addition to the preceding interventions.Finally, diabetic patients who are placed on these agents must be mon-itored more closely to prevent a worsening of glycemic control.

The widely distributed guidelines published by the American Diabe-tes Association et al. (2004) recommend monitoring of all patients whoare taking atypical antipsychotic agents by performing a baseline as-sessment, including fasting glucose and lipids, waist and weight mea-surements, and blood pressure. They recommend repeating themeasures 3 months later and then annually. Regardless of whetherthese specific guidelines are followed, individual clinicians and pro-grams should develop and adhere to a monitoring system to improvethe safety of patients taking these medications.

ConclusionAtypical antipsychotic medications have helped to improve the lives ofpatients with schizophrenia by alleviating positive and negative symp-toms and bringing some improvement in cognitive function. This im-provement is helping patients to function in the home and in theworkplace, thus improving the patients’ quality of life. At the sametime, however, the atypical antipsychotics appear to be associated withthe development of glucose intolerance, new-onset diabetes mellitus,diabetic ketoacidosis, and exacerbation of existing diabetes mellitus.These disturbances in glucose metabolism have their own medical con-sequences, including cardiovascular disease, cerebrovascular disease,diabetic retinopathy, neuropathy, and diabetic nephropathy, all ofwhich can lead to considerable morbidity and mortality. Thus, to mini-mize morbidity and mortality associated with the use of atypical anti-psychotic medications, close screening and monitoring for diabetesmellitus should become a priority for all clinicians treating patientswith schizophrenia who are receiving atypical antipsychotic therapy.

Key Clinical Points

◗ Many clinicians choose to prescribe atypical antipsychotic medications,such as clozapine, olanzapine, quetiapine, risperidone, ziprasidone, andaripiprazole, instead of the older agents, because the newer agentshave fewer extrapyramidal symptoms and may increase adherence and


prevent relapse. However, these medications may also increase the riskof metabolic disorders, such as impaired glucose metabolism, diabetesmellitus, and diabetic ketoacidosis.

◗ The choice of antipsychotic medications should be based on perceivedefficacy and knowledge of short- and long-term side effects. A generallyreasonable approach is to choose the safest medications available firstand, if the patient has no response, work the way up the risk ladder. Formetabolic problems, prevention is preferable over intervention.

◗ Diabetes mellitus and glucose intolerance are characterized by problemsin glucose-insulin regulation. The symptoms that warrant a diabetesdiagnosis include polyuria, polydipsia, unexplained weight loss, a casualplasma glucose level ≥200 mg/dL, a fasting plasma glucose ≥ 126 mg/dL,or a 2-hour plasma glucose level ≥ 200 mg/dL post 75-g oral glucoseload. Glucose intolerance is characterized by a 2-hour plasma glucoselevel ≥ 140 mg/dL and <200 mg/dL post 75-g oral glucose load.

◗ Glucose metabolism abnormalities, including onset of diabetes mellitus,diabetic ketoacidosis, cerebrovascular disease, cardiovascular disease,myocardial infarction and stroke, diabetic retinopathy, and neuropa-thy, are associated with considerable medical morbidity and mortality.

◗ Atypical antipsychotic agents have been associated with significant weightgain, particularly the development of central obesity, which can lead toseveral comorbid cardiovascular conditions as well as type 2 diabetes.

◗ The incidence of disturbances in glucose regulation varies across antipsy-chotics; many more cases of medication-induced hyperglycemia, diabe-tes mellitus, or diabetic ketoacidosis occur with clozapine and olanzapinethan with risperidone, quetiapine, ziprasidone, and aripiprazole.

◗ Mechanisms by which atypical antipsychotic agents could lead to glu-cose abnormalities and diabetes mellitus include causing insulin resis-tance by either increasing central or visceral adiposity or affecting theglucose transporter function antagonism of serotonin 5-HT1A, whichmay decrease pancreatic beta cell responsiveness to blood sugar levelsand treatment-induced weight gain.

◗ Close and frequent monitoring and screening for obesity and hyper-glycemia is imperative for individualizing treatment decisions and re-ducing the risks for morbidity and mortality for patients withschizophrenia taking antipsychotic mediations.

◗ Lifestyle interventions and recommendations should be given at thestart of the medications and reinforced at every visit.



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CHAPTER 6

Effects ofAntipsychotics on

Serum Lipids


Patients with severe mental illnesses, such as schizophrenia or bi-polar disorder, are a medically vulnerable population at high risk forcardiovascular mortality (Newcomer and Hennekens 2007), with stan-dardized mortality ratios from cardiovascular disease that are twotimes greater than in the general population (Osby et al. 2000, 2001).Although much of psychiatric care for individuals with schizophreniais focused on suicide prevention, cardiovascular disease remains thesingle largest cause of death among males and females with schizo-phrenia.

Given this sobering data, it is imperative that those who care for pa-tients with severe mental illness have a working knowledge of the risksassociated with cardiovascular disease and the patterns of risk factorsseen in this patient population. Recognition and treatment of diabetesmellitus is covered in Chapter 5, “Glucose Intolerance and Diabetes inPatients With Schizophrenia,” but the importance of diabetes relatesnot only to the adverse effects of hyperglycemia but also to its impacton cardiovascular risk. Diabetes mellitus is considered equivalent tohaving established coronary heart disease (CHD) for future risk of ma-jor cardiovascular events (e.g., myocardial infarction, sudden death)


(Expert Panel on Detection, Evaluation and Treatment of High BloodCholesterol in Adults 2001). This view of diabetes-related CHD risk isbased on indications that patients with established diabetes have thesame future myocardial infarction incidence as nondiabetics who havealready experienced a myocardial infarction (Haffner et al. 1998).

For nondiabetics, the focus for preventing cardiovascular disease re-mains on modification of the traditional risk factors of hypertension,hyperlipidemia, and smoking. Baseline data from the Clinical Antipsy-chotic Trials of Intervention Effectiveness (CATIE), sponsored by theNational Institute of Mental Health, provide the most timely and com-plete picture of the risk patterns in patients with chronic schizophreniaresiding in the United States (Goff et al. 2005). Among the 1,460 schizo-phrenia patients assessed at study entry, 10-year CHD risk, calculatedusing Framingham scores, was significantly elevated compared withage-, gender-, and race- and ethnicity-matched controls from a generalpopulation database in both males (9.4% vs. 7.0%) and females (6.3% vs.4.2%) (P=0.0001). In particular, schizophrenia patients compared withcontrols had significantly higher rates of smoking (68% vs. 35%), dia-betes (13% vs. 3%), and hypertension (27% vs. 17%) and lower high-density lipoprotein (HDL) cholesterol levels (43.7 vs. 49.3 mg/dL)(P<0.001). Moreover, CATIE subjects also had greater prevalence ofcentral adiposity and elevated serum triglycerides, both of which arecomponents of the metabolic syndrome and are associated with insulinresistance and future diabetes risk (McEvoy et al. 2005). The importanceof monitoring serum triglyceride values during antipsychotic treatmentwill become readily apparent, because this is the lipid parameter mostgreatly affected by offending medications. Another concerning findingfrom CATIE (covered in Chapter 3, “Medical Outcomes From theCATIE Schizophrenia Study”) was the significant undertreatment ofhypertension and dyslipidemia, reinforcing the idea that cliniciansmust redouble efforts to both monitor and treat the basic cardiovascularrisks in patients with schizophrenia (Nasrallah et al. 2006).

The induction of hyperlipidemia during antipsychotic therapy thusrepresents a serious condition, not only because of its inherent impacton cardiovascular risk but also because of its occurrence in a group thatalready possesses considerable risk (Saari et al. 2004). What has becomeevident in recent years is that the atypical antipsychotics have a de-creased liability for neurological side effects, but certain agents in thisclass have a marked propensity for adverse metabolic outcomes, espe-cially hyperlipidemia (Meyer and Koro 2004). One is tempted to hy-pothesize that the widespread use of atypical antipsychotics withmetabolic liabilities may be responsible for the widening mortality gap

Effects of Antipsychotics on Serum Lipids 119

between schizophrenia patients and the general population (Saha et al.2007), but the fact remains that more must be done to prevent morbidityand early mortality from CHD. This chapter is intended to guide the cli-nician in selecting medications and appropriate monitoring strategiesfor hyperlipidemia based on the best available data. This discussion isbolstered by the publication of the double-blind, controlled data fromphases 1 and 2 of the CATIE schizophrenia trial (Daumit et al. 2008; Lie-berman et al. 2005; Meyer et al. 2008a, 2008b; Stroup et al. 2006). Thelarge population under study in CATIE is one of the best sources of pro-spective information regarding certain compounds, especially per-phenazine and quetiapine, for which prospective data were previouslysorely lacking.

Due to increased interest in improving medical outcomes for pa-tients with severe mental illness (Marder et al. 2004), minimization ofiatrogenically induced lipid problems and appropriate monitoring ofthose at risk are increasingly becoming the standards of care for this pa-tient population. Recognizing which antipsychotics impose the greatestrisk for hyperlipidemia and understanding the common dyslipidemiapatterns seen during use of these antipsychotics are necessary for pro-viding high-quality care to antipsychotic-treated patients.

Hyperlipidemia and Coronary Heart DiseaseA complete review of lipid physiology is beyond the scope of this chap-ter; however, some information is worth noting herein. The majorclasses of lipoproteins are divided on the basis of their weight undercentrifugation (Kwiterovich 2000). The lightest are chylomicrons de-rived from dietary triglycerides and very-low-density lipoproteins(VLDL) that are endogenously produced triglyceride-rich particles. Thenext heavier particles are low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Total cholesterol, as obtained on a lipidpanel, reflects the combination of serum concentrations of VLDL (calcu-lated as serum triglyceride levels divided by 5), LDL, and HDL. Normalserum total cholesterol concentration is defined as a fasting level under200 mg/dL, normal HDL is ≥40 mg/dL, and the ideal serum LDL con-centration is determined by cardiovascular risk factors as noted below.The rate-limiting step in cholesterol synthesis is a reaction catalyzed bythe enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, thetarget for a class of lipid-lowering agents called statins. The MultipleRisk Factor Intervention Trial clearly established the linear association


between CHD and serum cholesterol, but further research clarified thatrisk is more properly associated with abnormalities involving the LDLand HDL cholesterol fractions and separately by serum triglycerides(Stamler et al. 1986).

A series of landmark studies published in the mid-1990s demon-strated the significant association between reduction in LDL levels andreduced cardiovascular events and mortality. The Scandinavian Sim-vastatin Survival Study was a randomized, double-blind, placebo-controlled trial of cholesterol lowering in 4,444 patients with coronaryheart disease who were already following a lipid-lowering diet andwere followed for a median of 5.4 years (“Randomised Trial of Choles-terol Lowering” 1994). This secondary prevention study found that sta-tin therapy reduced total cholesterol by 28% and LDL by 38%, and ledto a 42% reduction in coronary deaths and a 30% decrease in all-causemortality compared to the placebo cohort. A randomized, double-blind,placebo-controlled secondary prevention trial of pravastatin in 9,014patients (ages 31–75) with ischemic heart disease followed for 6.1 yearson average showed a 24% reduction in nonfatal myocardial infarctionor death due to CHD (“Prevention of Cardiovascular Events andDeath” 1998). A similar 24% reduction in nonfatal myocardial infarc-tion or death due to CHD was seen in a randomized, double-blind,placebo-controlled secondary prevention trial of pravastatin after myo-cardial infarction in 4,159 patients who had normal cholesterol levels(Sacks et al. 1996).

Moreover, two primary prevention studies of patients without CHDbut with either hypercholesterolemia or low HDL levels and averagetotal cholesterol identified profound benefits from statin therapy.The West of Scotland Coronary Prevention Study was a randomized,double-blind, placebo-controlled trial of pravastatin in 6,595 men, ages45–64 years, with mean total cholesterol of 272 mg/dL and no historyof myocardial infarction, followed for a mean of 4.9 years (Shepherd etal. 1995). A 32% reduction in the development of CHD and a 22% reduc-tion in total mortality were found in this trial (Shepherd et al. 1995). TheAir Force/Texas Coronary Atherosclerosis Prevention Study was a pri-mary prevention trial of lovastatin versus placebo in men and womenwith no clinical evidence of cardiovascular disease and average totalcholesterol and LDL levels, but low HDL (Downs et al. 1998). Over the5.2 years of this study, a 37% reduction in risk of major coronary eventswas seen in the lovastatin group compared to the placebo group.

To establish the 2001 National Cholesterol Education Programguidelines, the Expert Panel on Detection, Evaluation and Treatmentof High Blood Cholesterol in Adults (2001) used the results of these


and other studies to establish LDL goals based on the number of under-lying major cardiovascular risk factors: smoking, hypertension (havingblood pressure ≥140/90 mmHg or taking antihypertensive medication),low HDL cholesterol (<40 mg/dL), family history of premature CHD(CHD in male first-degree relative <55 years or female first-degreerelative <65 years), and age (men ≥45 years or women ≥55 years). Thefasting LDL goal is <160 mg/dL for those with zero or one risk factor,<130 mg/dL for those with two or more risk factors, and <100 mg/dLfor those with CHD or CHD-equivalent disorders (e.g., diabetes melli-tus). Recent updates to the 2001 guidelines suggest even lower LDLgoals (<70 mg/dL) are appropriate for those who are at very high riskby virtue of having diabetes mellitus, multiple metabolic syndrome riskfactors, and persistent risk factors such as smoking in conjunction withestablished CHD or acute coronary syndrome (Stone et al. 2005).

Although LDL continues to be the main focus of lipid-lowering ther-apy due to evidence from multiple large studies, other lipid parametersmust be addressed and are secondary targets for therapy. Significantdata from the Framingham Heart Study show a 2%–4% increase in riskof CHD-related death for each 1-mg/dL decrease in HDL, with over30% of deaths occurring in those with normal total cholesterol values(Wilson et al. 1988). Because low HDL is one of the metabolic syndromecriteria, the 2005 National Cholesterol Education Program update sug-gests targeting low HDL in those who have already met LDL goals butcontinue to manifest the characteristic dyslipidemia associated withmetabolic syndrome (i.e., low HDL, elevated fasting triglycerides)(Stone et al. 2005). Elevated fasting triglycerides occur as a direct resultof insulin resistance, because insulin-dependent lipases in fat cells arenormally inhibited by insulin. As insulin resistance worsens, inappro-priately high levels of lipolysis lead to the release of excess amounts offree fatty acids that are hepatically transformed into triglycerides(Smith 2007). Elevated fasting triglyceride levels thus become a sen-sitive marker of insulin resistance, and therefore are included as ametabolic syndrome criterion. Moreover, a fasting triglyceride:HDLcholesterol ratio ≥3.0 performs better than fasting glucose in predictinginsulin resistance among prediabetic individuals (McLaughlin et al.2003).

The sensitivity of the triglyceride:HDL ratio to insulin resistance de-rives from the fact that increased triglyceride levels interfere with an im-portant regulatory function governing the production of apolipoproteinB100, a core lipoprotein in very-low-density, intermediate-density, andlow-density lipoprotein particles (Smith 2007). The overproduction ofapolipoprotein B100 results in more of these triglyceride-rich particles,


with resultant hypertriglyceridemia. In addition, the greater presence ofthese light triglyceride-rich lipoproteins causes the transfer of triglycer-ides to HDL at the expense of HDL cholesterol content. After passagethrough the liver, where triglyceride is cleaved by enzymatic processes,the remaining HDL particle is smaller than normal and more readilycleared in the kidney, resulting in the characteristic low serum HDL lev-els seen with insulin-resistant states (Smith 2007). The triglyceride:HDLratio thus reflects the combined effects of low HDL and elevated triglyc-erides seen in insulin-resistant patients.

Although serum triglyceride concentrations are considered a sec-ondary focus of lipid-lowering treatment, evidence from several stud-ies link elevated triglycerides (i.e., ≥200 mg/dL) to increased CHD risk(Cullen 2000; Jeppesen et al. 1998; Rubins 2000), an increased risk thatis independent of HDL levels (Jeppesen et al. 1998). Evidence also hasbeen reported that supports monitoring of nonfasting triglycerides, be-cause atherosclerosis may be a postprandial phenomenon in whichatherogenic remnant lipoproteins (chylomicrons and VLDL) play a crit-ical role (Eberly et al. 2003). These triglyceride-rich particles are smallerthan other lipid components and more readily penetrate arterial intimalcells. Individuals are in a nonfasting state most of the day with respectto serum triglycerides, with triglyceride levels peaking 4 hours after anoral fat load and returning to baseline values only after 8 hours (Nor-destgaard et al. 2007).

Large population studies indicate a significant linear correlation be-tween nonfasting triglyceride values and directly measured remnant li-poproteins (Nordestgaard et al. 2007). Data from a prospectiveCopenhagen, Denmark, study (N=13,981, mean follow-up 26 years) so-lidified the link between nonfasting triglycerides and cardiovascularevents by identifying the significant relationship between nonfastingtriglyceride levels in men and women and risk of major cardiovascular-related events, including CHD, myocardial infarction, and mortality(Nordestgaard et al. 2007). Compared with individuals with nonfastingtriglyceride levels <88.5 mg/dL, women and men with levels of 177.0–264.6 mg/dL had adjusted hazard ratios for myocardial infarction of 2.5and 1.6, respectively. The superiority of nonfasting triglycerides overfasting triglycerides is also seen in prospective data from the Women’sHealth Study (N=26,509, median follow-up 11.4 years) (Bansal etal. 2007). Although no relationship was found between increasing ter-tiles of fasting triglyceride values and risk of cardiovascular events infully adjusted models, nonfasting triglyceride tertiles were significantlyassociated with cardiovascular risk, with triglyceride levels measured2–4 hours postprandially showing the strongest association. The impor-


tance of fasting and nonfasting hypertriglyceridemia is of further con-cern for those who care for schizophrenia patients, given the associationbetween elevated triglycerides and therapy with low-potency phe-nothiazines and the dibenzodiazepine-derived compounds clozapine,olanzapine, and quetiapine (a dibenzothiazepine).

Hyperlipidemia and Typical AntipsychoticsAlthough typical antipsychotics are used in less than 10% of patientswith schizophrenia in the United States, they are commonly availablethroughout the world and represent an important class of psychotropicmedications. Moreover, a review of the lipid effects of typical antipsy-chotics illustrates an important concept seen in the atypical antipsy-chotic data: medications with similar modes of therapeutic action canhave disparate metabolic profiles. Within a decade after the widespreaduse of chlorpromazine and other low-potency phenothiazines, severalstudies emerged examining the metabolic profiles of this class of anti-psychotics (Clark and Johnson 1960; Clark et al. 1967; Mefferd et al.1958). In general, these compounds were found to elevate serum trig-lycerides and total cholesterol but with greater effects on triglycerideconcentrations. Subsequent studies of the phenothiazine chlorprom-azine and related compounds (Clark et al. 1970, 1972) confirmed thesefindings that high serum triglycerides seemed to be the primary signif-icant lipid abnormality, but elevated total cholesterol could also befound. What also emerged from this early literature was the fact thatcertain D2 antagonists did not exert the same changes on serum lipidsas seen with the lower-potency phenothiazines.

The lipid neutrality of high-potency typical antipsychotics was seenin the early uncontrolled studies of butyrophenone derivatives pub-lished in the mid-1960s (Braun and Paulonis 1967; Clark et al. 1968;Simpson and Cooper 1966; Simpson et al. 1967) and a placebo-controlledtrial in 1971 (Serafetinides et al. 1971). Comparative trials of low-potencyphenothiazines and butyrophenones (primarily haloperidol) publishedin the 1970s confirmed the lipid neutrality of high-potency agents,whereas low-potency phenothiazine treatment was associated withhyperlipidemia, primarily in the form of hypertriglyceridemia (Serafe-tinides et al. 1972; Vaisanen et al. 1979).

Surprisingly, only a limited amount of subsequent work has beenpublished in the past two decades covering lipid changes during typi-cal antipsychotic therapy. Table 6–1, which is a summary of studies,


case reports, and case series related to lipids and antipsychotics thathave been published since 1980, demonstrates the paucity of controlleddata on typical antipsychotics after 1980. Two papers were publishedby a Japanese group in 1984 and 1985 that analyzed serum total choles-terol and triglycerides in male chronic schizophrenia inpatients takingphenothiazines or butyrophenones compared with age- and sex-matched controls (Sasaki et al. 1984, 1985). The cohort exposed to phe-nothiazines had mean serum triglycerides of 163 mg/dL, comparedwith 104 mg/dL for the butyrophenone group and 127 mg/dL for thecontrol group, with no significant differences in total cholesterol acrossthe three groups. The phenothiazine cohort also had higher serum LDLcholesterol and decreased HDL cholesterol concentrations comparedwith the other study arms. Cross-sectional studies from Pakistan(Shafique et al. 1988) and a psychiatric hospital in Spain (Martínez et al.1994) substantiated earlier findings, although specific analysis on thebasis of type of neuroleptic prescribed was not performed in the Span-ish study.

Lastly, the CATIE schizophrenia trial employed a medium-potencyphenothiazine, perphenazine, as one of its treatment arms in phase 1,thus providing controlled comparative data versus atypical antipsy-chotics in a randomized, double-blind study (Lieberman et al. 2005). Asshown in Table 6–2, use of perphenazine was associated with modestincreases in serum triglycerides and total cholesterol, with a greater ef-fect on triglycerides. The extent of lipid changes related to perphena-zine use in neuroleptic-naive patients might actually be greater thanseen in CATIE phase 1, because 22% of the CATIE sample at baselinewas taking olanzapine. Given olanzapine’s known effects on serum lip-ids, olanzapine-exposed patients switched to perphenazine in phase 1would likely have minimal further increases in serum triglycerides.Further analysis of CATIE data at the end of phase 1 (Table 6–3), ob-tained after approximately 9 months of exposure, revealed that per-phenazine exposure was associated with favorable effects on serumHDL in whites (+2.7 mg/dL) in a manner that was significantly differ-ent from olanzapine (−1.7 mg/dL); however, perphenazine induced amean decrease of 1.3 mg/dL in nonwhites, and this was significantlydifferent from that seen for ziprasidone (+4.3 mg/dL) (Meyer et al.2008a). Whether this represents a specific moderating effect of race andethnicity on perphenazine’s metabolic effects or merely the results ofan unusual cohort remains to be seen. The effect of perphenazineon fasting triglycerides depended on the subject’s baseline triglyceridevalues—those with low fasting triglycerides experienced a mean in-crease of 28.7 mg/dL, comparable to most of the other agents studied,


whereas those with high baseline triglycerides (>148 mg/dL) experi-enced a mean decrease of 27.5 mg/dL. With the increasing use of atyp-ical antipsychotics throughout the world, these may be the lastrandomized, controlled data published on the lipid effects of a typicalantipsychotic.

Hyperlipidemia and Atypical AntipsychoticsAtypical antipsychotics have been designed primarily to mimic theidentifiable features of clozapine’s pharmacology: weaker D2 an-tagonism than typical antipsychotics, combined with potent serotonin5-HT2A antagonism (Meyer and Simpson 1997). A recurring theme, re-lated to the metabolic effects of this antipsychotic class, echoes the ear-lier findings for typical agents, namely that drugs with similarmechanisms of action may have disparate metabolic adverse effects.This analogy is more than superficial, because the structurally relateddibenzodiazepine-derived atypical antipsychotics—olanzapine, cloza-pine, and quetiapine—all appear to have significantly greater effects onserum triglycerides than total cholesterol, much like the low-potencyphenothiazines, whereas other atypical antipsychotics—ziprasidone,risperidone, and aripiprazole—have minimal lipid effects, as did thehigh-potency typical antipsychotics.

ClozapineThrough 2002 virtually no randomized, prospective, controlled datahad been published on the lipid effects of the atypical antipsychotics,but the early literature is replete with case reports and retrospectivestudies, primarily focused on clozapine, the only atypical antipsychoticavailable until 1994. The first reports of hyperlipidemia with atypicalantipsychotics were small studies of fluperlapine, a dibenzodiazepine-derived compound never marketed. Two trial reports published in themid-1980s documented elevated triglycerides, in one case as high as 900mg/dL (Fleischhacker et al. 1986; Müller-Oerlinghausen 1984). Despiteclozapine’s use from the 1960s onward, the first case report of hyper-lipidemia (presenting as hypertriglyceridemia) occurred in 1994(Vampini et al. 1994) and was followed in 1995 by a report of four cloz-apine-treated patients with hypertriglyceridemia whose triglyceridesnormalized upon switching to risperidone (Ghaeli and Dufresne 1995).The following year (1996), the authors of that case series published


a chart review comparing serum lipids in patients exposed to clozapineor typical antipsychotics (primarily butyrophenones) for at least 1 yearwith no prior history of hyperlipidemia or use of lipid-lowering agents(Ghaeli and Dufresne 1996). This retrospective study found serum tri-glycerides 114 mg/dL higher in the clozapine cohort (P<0.001) butnearly identical total cholesterol levels (clozapine 217.0±52.9 mg/dLvs. typical antipsychotics 215.0±43.2 mg/dL). A 1998 study comparing30 patients taking clozapine to 30 patients taking typical antipsychoticsfor at least 1 year also found higher triglycerides in the clozapine group(202.9±131.1 mg/dL) compared with the typical group (134.4±51.9mg/dL), but again without significant differences in total cholesterol(clozapine 197.1±46.4 mg/dL vs. typical antipsychotics 194.9±51.5 mg/dL)(Spivak et al. 1998). A small prospective study (Dursun et al. 1999) andtwo subsequent chart reviews of long-term clozapine-treated patients,one with 70 patients (Spivak et al. 1999) and the other with 222 patients(Gaulin et al. 1999), demonstrated that the mean increase in serum trig-lycerides ranged from 41% to 45%.

More recent cross-sectional and short- and long-term prospectiveclozapine studies have noted the same pattern of marked elevations ofserum triglycerides with modest increases in total cholesterol (Atmacaet al. 2003b; Baymiller et al. 2003; Henderson et al. 2000; Leonard et al.2002; Wirshing et al. 2002) compared with baseline and with typicalantipsychotics (Lund et al. 2001). A 1-year prospective study of 50 cloz-apine-treated patients (Baymiller et al. 2003) found mean increases of41.7% in serum triglycerides, exactly in the range predicted by prior ret-rospective data, and only a 7.5% increase in total cholesterol. The au-thors also noted that no significant changes occurred in HDL and LDLand that triglyceride elevations peaked between days 41 and 120 andthen declined, but still remained elevated at the 1-year interval. As partof a 5-year naturalistic study of 82 clozapine-treated patients withschizophrenia, Henderson et al. (2000) found ongoing increases in se-rum triglycerides (linear coefficient 2.75 mg/dL per month, P=0.04). Asubsequent 10-year follow-up study of clozapine-treated patientsfound that triglycerides had plateaued significantly, with a linear coef-ficient over that time frame of 0.5 mg/dL/month (P=0.04) (Hendersonet al. 2005). In neither study were total cholesterol changes significant.Other cross-sectional, retrospective and other nonprospective cloza-pine studies are noted in Table 6–1, but the “efficacy” arm of CATIEphase 2 (hereafter referred to as phase 2b) generated prospective ran-domized data on a sample of 49 schizophrenia patients compared with50 subjects assigned to other agents (McEvoy et al. 2006). As seen inTable 6–2, the exposure-adjusted mean increases in serum lipids for


clozapine-treated subjects were greatest for triglycerides and substan-tially less for total cholesterol. The samples for each of the other phase2b drug arms are extremely small (<15), so the findings for the otheratypical antipsychotics in phase 2b are of limited reliability.

OlanzapineThe first published studies of olanzapine-associated hypertriglyceri-demia appeared in 1999 and revealed patterns of dyslipidemia similarto those reported for clozapine. A study of nine patients followed for anaverage of 16 months while taking olanzapine (mean age 41 years,mean olanzapine dose 19 mg/day) showed a mean increase in serumtriglycerides of 41%, with no significant changes in total cholesterol lev-els and a mean weight gain of 10 kg (Sheitman et al. 1999). A subsequentreport on 25 inpatients followed prospectively for 12 weeks found amean fasting triglyceride increase of 37%. Both weight and triglycerideincreases were significant (P<0.05), and a significant association wasfound between weight gain and triglyceride change (P<0.02); however,after controlling for baseline weight, analysis of covariance showed noindependent increase in triglycerides (Osser et al. 1999).

Subsequent work involving olanzapine illustrates not only its muchgreater effect on serum triglycerides than on total cholesterol, but alsothe risk of severe hypertriglyceridemia. Melkersson et al. (2000) followeda group of 14 patients with schizophrenia taking olanzapine for an aver-age of 5 months and noted that 62% had elevated fasting triglycerides(mean 273.45 mg/dL) and 85% exhibited hypercholesterolemia (mean257.14 mg/dL). Although these lipid changes were comparable to thosereported for clozapine, the issue of severe hypertriglyceridemia wasnoted in Meyer’s (2001) case series of 12 olanzapine and two quetiapinepatients with fasting triglyceride levels exceeding 500 mg/dL, includingone patient taking olanzapine whose fasting serum triglyceride levelswere measured at 7,688 mg/dL, and a subsequent case of olanzapine-associated severe hypertriglyceridemia (triglycerides 5,093 mg/dL) re-ported by Stoner et al. (2002) in a patient who also developed new-onsettype 2 diabetes mellitus. As discussed later in the section “MonitoringRecommendations for Hyperlipidemia During Antipsychotic Therapy,”one concern with serum triglyceride levels of 1,000 mg/dL or greater isthe development of acute pancreatitis, and the majority of cases that areassociated with atypical antipsychotic treatment are related to olanza-pine or clozapine exposure (Koller et al. 2003).

The cases of severe hypertriglyceridemia are extreme findings, butthe majority of studies published since 2001 have confirmed the greater


effects of olanzapine on serum lipids, primarily on triglycerides, com-pared to more lipid-neutral medications such as high-potency typicalantipsychotics or risperidone, ziprasidone, and aripiprazole. The ear-lier comparative literature comprised retrospective, cross-sectional, orsmall prospective studies, but confirmed the greater effects of olanza-pine on serum lipids than other atypical antipsychotic medications(with the exception of clozapine) (Atmaca et al. 2003a, 2003b; Bouchardet al. 2001; Garyfallos et al. 2003; Kinon et al. 2001, 2004; Meyer 2002;Wirshing et al. 2002). Also, two retrospective large database studieswere performed using data from a Great Britain General Practice Re-search Practice Database (Koro et al. 2002) and the state of CaliforniaMediCal claims system (Lambert et al. 2005). Koro et al.’s (2002) case-control study of 18,309 schizophrenia patients, which included 1,268 in-cident cases of hyperlipidemia, compared typical antipsychotics, ris-peridone, and olanzapine to no antipsychotic usage, and found thatrisperidone use was not associated with increased odds of hyperlipi-demia compared to typical antipsychotic use or no antipsychotic expo-sure, whereas olanzapine use was associated with a nearly fivefoldincrease in the odds of developing hyperlipidemia compared with noantipsychotic exposure and more than a threefold increase comparedwith typical antipsychotic use. Lambert et al.’s (2005) case-control studyof MediCal claims after schizophrenia diagnosis, in patients with anti-psychotic monotherapy within 12 weeks prior to hyperlipidemia claim,found greater risk of hyperlipidemia for olanzapine compared to typi-cal antipsychotics or risperidone. Increasing the exposure window to 24or 52 weeks did not affect the results.

A cross-sectional study by Alméras et al. (2004) is noteworthy in thatother lipid parameters were studied in addition to triglycerides and to-tal cholesterol. In Quebec, Canada, the researchers examined only maleschizophrenia patients treated with olanzapine (n=42) or risperidone(n=45) for >6 months and compared the results of a comprehensivelipid panel with those from a reference group of nondiabetic males(mean ages: 28.4 risperidone; 31.7 olanzapine; 32.8 controls). The olan-zapine-treated cohort had significantly higher serum cholesterol, LDL,triglycerides, cholesterol:HDL ratio, and apolipoprotein B, and sig-nificantly lower HDL, smaller LDL peak particle size, and lower apo-lipoprotein A1. Interestingly, compared to the control group, theolanzapine subjects had no significant differences on total cholesterol,triglycerides, or LDL, but they did have lower HDL levels and a highercholesterol:HDL ratio. Additionally, the risperidone cohort had lowertotal cholesterol and LDL levels but lower HDL levels than the refer-ence group.


Given the modest size of the early prospective literature and the un-controlled nature of many retrospective studies, questions were raisedabout the extent to which olanzapine induces greater dyslipidemia thanrisperidone. Phases 1 and 2a of the CATIE schizophrenia trial providedan answer (Lieberman et al. 2005; Meyer et al. 2008a; Stroup et al. 2006),as shown in Tables 6–2 and 6–3. This large, randomized study demon-strated convincingly that olanzapine is one of the greatest offendingagents with respect to its effects on serum lipids, again mostly on serumtriglycerides, whereas both risperidone and ziprasidone appear neu-tral. Phase 2a is likely more reflective of the true extent of olanzapine’seffects, as the CATIE trial design mandated that those who entered thatarm of the trial not be exposed to an agent to which they had been ran-domized in phase 1. Thus, all of the subjects in the olanzapine arm ofphase 2a were new starts to that medication. This fact explains why thetriglyceride increase in phase 2a olanzapine subjects was 94.1 mg/dL,compared with only a 40.5-mg/dL increase seen in the phase 1 olanza-pine cohort, 22% of whom were taking olanzapine at study baseline.The analysis of nonfasting triglycerides also revealed the greater dele-terious impact of olanzapine compared with other agents, particularlywhen nonswitchers were removed from the analysis (Meyer et al.2008b).

The differential impact of olanzapine compared with other agentscan also be seen in switch studies (Casey et al. 2003; Meyer et al. 2005;Spurling et al. 2007; Su et al. 2005; Weiden et al. 2003, 2007). Institution-alized populations may experience less adverse metabolic effects, asseen in a switch study of developmentally disabled adults (McKee et al.2005) and two studies of olanzapine in elderly inpatient populations,one including patients with schizophrenia or schizoaffective disorder(Barak and Aizenberg 2003) and the other including patients with de-mentia of the Alzheimer type with behavioral disturbances or psycho-sis (De Deyn et al. 2004). For the latter two studies in particular, what isnot known is whether it is subject age or the fact of being confined witha fixed dietary regimen that mitigates the development of dyslipi-demia.

QuetiapineQuetiapine and zotepine are structurally related to the other dibenzo-diazepine-derived antipsychotics clozapine and olanzapine, but lim-ited information has been published regarding their metabolic effects.The extent of available information was so sparse that the American Di-abetes Association et al.’s (2004) consensus paper on metabolic effects


of atypical antipsychotics was unclear whether quetiapine could be dif-ferentiated from risperidone in its effects on serum lipids. Comparedwith clozapine and olanzapine, quetiapine generally has a lower risk ofcausing significant weight gain (Lieberman et al. 2005; Wetterling 2001).Nonetheless, the available data suggest that quetiapine shares the pro-pensity with other benzodiazepine-derived atypical antipsychotics toelevate serum triglyceride levels, as illustrated by case reports byDomon and Cargile (2002) and Meyer (2001), two 6-week prospectivecomparative studies by Atmaca et al. (2003a, 2003b), and an 8-weekstudy by Shaw et al. (2001). As with other dibenzodiazepine-derivedatypical antipsychotics, there were lesser effects on total cholesterolthan on triglycerides (Shaw et al. 2001). The extent of the lipid effectswas best seen in the CATIE trials (Lieberman et al. 2005; Meyer et al.2008a, 2008b; Stroup et al. 2006), especially phase 2a, in which quetia-pine’s nearly 40-mg/dL elevation in serum triglycerides was secondonly to that of olanzapine and more than that for risperidone or ziprasi-done, despite weight gain only marginally greater than for risperidone.Analysis of 3-month changes in nonfasting lipids during CATIE phase1 also found that quetiapine was associated with a mean increase (+59.8mg/dL) that was nearly identical to that of olanzapine (+61.5 mg/dL)when nonswitchers were removed from the analysis (Meyer et al.2008b).

Zotepine is associated with weight gain similar to that experiencedwith olanzapine and clozapine (Wetterling 2001), but the sum total ofthe published literature on lipid changes during zotepine therapy is onecase report in which serum triglycerides peaked at 1,247 mg/dL andnormalized upon switch to a high-potency typical agent (Wetterling2002).

Nonbenzodiazepine Agents: Risperidone, Ziprasidone, and AripiprazoleThe limited effects of the nonbenzodiazepine agents—risperidone,ziprasidone, and aripiprazole—on serum lipids has been demonstratedin large prospective trials, because the pharmaceutical industry rou-tinely includes multiple lipid measures as part of study protocols. Themore benign effects of risperidone were largely known from compara-tive trials versus olanzapine, as confirmed by the results from CATIEphases 1 and 2a (Lieberman et al. 2005; Meyer et al. 2008a, 2008b; Stroupet al. 2006). Although doubts about the differential effects of quetiapineand risperidone on serum lipids were expressed several years ago in theconsensus paper by the American Diabetes Association et al. (2004),


when quetiapine is prescribed in full therapeutic doses for schizophre-nia, it appears to elevate serum triglycerides in a manner not typicallyseen with risperidone.

Ziprasidone appears to have even less adverse effect on serum lipidsthan risperidone, as evidenced by the statistically significant improve-ment in serum triglycerides and total cholesterol over 6 weeks when pa-tients were switched to ziprasidone from risperidone (Kingsbury et al.2001). The lipid neutrality of ziprasidone has been subsequently con-firmed in a retrospective chart review (Brown and Estoup 2005) and inmultiple prospective trials of short duration (6 weeks) (Simpson et al.2004; Weiden et al. 2003) and longer duration (≥26 weeks) (Breier et al.2005; Cohen et al. 2004; Simpson et al. 2005; Weiden et al. 2007), includ-ing CATIE phases 1 and 2a (Lieberman et al. 2005; Meyer et al. 2008a,2008b; Stroup et al. 2006) in which the net impact of ziprasidone treat-ment was to lower serum lipid levels.

Early clinical trials data suggested that aripiprazole also had nomi-nal effects on serum lipids (Goodnick and Jerry 2002), a finding con-firmed in large prospective trials. In a 26-week trial versus olanzapine(McQuade et al. 2004), the mean change in fasting triglycerides was+79.4 mg/dL with olanzapine but only +6.5 mg/dL with aripiprazole(P<0.05), whereas HDL decreased by 3.39 mg/dL with olanzapine andincreased 3.61 mg/dL with aripiprazole (P<0.05). Changes in serumLDL for the drug cohorts were not significantly different, but the inci-dence of new dyslipidemias was significantly greater for olanzapine onthe basis of the proportion of new subjects with endpoint serumLDL>130 mg/dL (38% olanzapine vs. 19% aripiprazole, P<0.05). Re-cent switch studies confirm that patients switched to aripiprazole frommetabolically more offending medications experience improvements inserum lipids, again primarily triglycerides, but with measurablechanges for other parameters (Spurling et al. 2007).

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edical Illness and SchizophreniaTABLE 6–1. Lipid changes during antipsychotic therapy: 1984–2008

Reference Study design Findings

Müller-Oerlinghausen 1984

Multicenter fluperlapine trial in43 schizophrenia and depression

patients

In 16 of 28 patients, TG increased significantly and serum TC increased notably.

Sasaki et al. 1984

Chart review of chronic phenothia-zine users (mean exposure 8 years);

10-week prospective data in 8 new phenothiazine-treated patients

Patients chronically treated with phenothiazines (chlorpromazine, levomepromazine, perphenazine) had significantly higher HDL (P<0.001) and higher TG (P<0.05) than normal controls. HDL decreased 24% within 1 week of new phenothiazine exposure, with no significant changes in TC and TG levels after 10 weeks.

Sasaki et al. 1985

Chart review of males with chronic schizophrenia; excluded patients with DM or taking lipid-lowering medication

17 phenothiazine14 haloperidol14 healthy controls

After mean 8 years of antipsychotic exposure, no effect of butyrophenones on lipids, but significantly elevated mean fasting TG levels for the phenothiazine group (163 mg/dL) compared to the butyrophenone group (104 mg/dL) and controls (127 mg/dL). No significant differences in TC, LDL, or HDL values across the three groups.

Fleischhacker et al. 1986

Double-blind, prospective 6-week study

6 haloperidol6 fluperlapine

No significant differences in mean HDL or TC between groups or compared to baseline by day 28. One fluperlapine subject developed serum TG level of 900 mg/dL on day 7 and required treatment on day 28.

Effects of A

ntipsychotics on Serum L

ipids133

Shafique et al. 1988

Chart review of males with chronic schizophrenia treated for 6–12 months

35 phenothiazine30 butyrophenone22 combined drug classes

Significant elevations of TC, VLDL, and LDL levels in patients taking phenothiazines and LDL in patients taking butyrophenone. VLDL and LDL levels significantly higher and HDL levels lower in patients taking combined therapy.

Martínez et al. 1994

Chart review of 311 chronically hospitalized schizophrenia patients

225 neuroleptic exposed (mostly haloperidol, thioridazine, or fluphenazine) for prior 2 years

86 no psychotropic medications

Neuroleptic administration was associated with changes in HDL and TG in males but not in females.

Vampini et al. 1994

Case report: 1 taking clozapine 400 mg/day

Increased TG levels after 15 months.

Ghaeli and Dufresne 1995

Case series:4 clozapine-treated patients

(doses 600–900 mg/day) switched to risperidone

Increased serum TG levels in patients taking clozapine decreased upon switching to risperidone, and increased upon clozapine rechallenge.

TABLE 6–1. Lipid changes during antipsychotic therapy: 1984–2008 (continued)


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Ghaeli and Dufresne 1996

Chart review of 67 schizophrenia patients

39 clozapine21 high-potency typical

antipsychotics2 medium-potency typical

antipsychotics5 low-potency typical

antipsychotics

Mean TG significantly higher in clozapine vs. typical groups (264.6 mg/dL vs. 149.8 mg/dL, P<0.001). Difference was not explained

by concomitant illness or medication, age, or gender. No significant difference in TC.

Spivak et al. 1998

Chart review of schizophrenia patients

30 clozapine (mean 295.0±165 mg/day)

30 typical antipsychotics (mean 348.9±298.8 mg/day in CPZ equivalents)

Mean TG significantly higher in clozapine vs. typical group after 1 year of treatment (202.9 mg/dL vs. 134.4 mg/dL, P<0.01). No significant difference in serum TC.

Dursun et al. 1999

Prospective 12-week study8 clozapine

(mean 352±73 mg/day)

Small increase in TG levels (11%) but no significant changes in other lipid levels after 12 weeks.



Effects of A


ipids135

Gaulin et al. 1999


222 treated with clozapine or haloperidol

After a mean treatment period of 590 days for clozapine and 455 days for haloperidol, 45% increase in serum TG in clozapine-treated patients (P<0.01) and insignificant decrease in serum TG in haloperidol-treated patients.

Osser et al. 1999

Prospective study in schizophrenia patients

25 olanzapine (mean 13.8±4.4 mg/day)

37% (60 mg/dL) increase in fasting TG from baseline (P<0.05). Fasting TC did not increase.

Sheitman et al. 1999

Prospective study in schizophrenia patients

9 olanzapine (mean 19 mg/day)

After 16 months, mean increase in serum TG was 70 mg/dL (5 patients had >50% increase in TG). No significant change in TC, HDL, or LDL.

Spivak et al. 1999


70 clozapine (mean 332.9±168.1 mg/day)

30 typical antipsychotics (mean 347.3±247.3 mg/day in CPZ equivalents)

Mean TG increased in the clozapine group and decreased in the typical antipsychotic group after 6 months of treatment (P<0.005).

Henderson et al. 2000

5-year naturalistic study82 clozapine

Significant changes in serum TG (P=0.04) (linear coefficient=2.75 mg/dL per month, SE=1.28).



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Melkersson et al. 2000

Prospective cohort study14 olanzapine

(median 12.5 mg/day)

62% prevalence of hypertriglyceridemia (mean 273.45 mg/dL) and 85% prevalence of hypercholesterolemia (mean 257.14 mg/dL) after a median exposure of 5 months (range 2.4–16.8 months).

Wu et al. 2000 Case report:1 Chinese male, age 25, taking

clozapine

Dose-dependent increases in fasting serum TG and glucose.

Baptista et al. 2001

Cross-sectional cohort study of women matched for age, BMI, and day of menses

26 typical antipsychotics (>6 consecutive months of treatment)

26 controls

Antipsychotic-treated subjects had a trend for lower HDL and increased insulin resistance.

Bouchard et al. 2001

Retrospective study22 olanzapine

(mean 12.8±4.4 mg/day)22 risperidone

(mean 2.8±1.8 mg/day)

After mean exposure of 17.9 months (olanzapine) and 17.4 months (risperidone), olanzapine patients compared to risperidone patients had significantly higher TG (185 mg/dL vs. 115 mg/dL, P<0.01), significantly higher VLDL (0.9 mol/L vs. 0.5 mol/L, P<0.03), and a trend for a higher cholesterol/HDL ratio (5.3 vs. 4.3, P=0.06) and lower HDL (P=0.08). No significant differences in TC, fasting glucose, or insulin.



Effects of A


ipids137

Domon and Webber 2001

Case report:1 African American male, age 15,

taking olanzapine 20 mg/day

After 3 months, weight 91 kg, fasting glucose 90 mg/dL, fasting TG 155 mg/dL, fasting TC 131 mg/dL; 5 months later, weight peaked at 108 kg, then declined with onset of type 2 DM. Maximum TG 298 mg/dL with olanzapine. Both DM and hyperlipidemia resolved over 8 weeks after olanzapine was discontinued.

Kingsbury et al. 2001

Prospective 6-week switch study37 ziprasidone

(mean 124.3 mg/day)Prior meds:15 from olanzapine12 from risperidone10 from typical antipsychotics

Significant decreases in serum TC (−17.57 mg/dL, P<0.001) and serum TG (−62.38 mg/dL, P=0.018). Change in TG correlated with weight change (r=0.409, P=0.018, r2=0.167). Change in TC did not correlate with weight change.

Kinon et al. 2001

Retrospective cohort573 olanzapine (5–20 mg/day)103 haloperidol (5–20 mg/day)

Median nonfasting endpoint serum TC was significantly higher for olanzapine-treated than for haloperidol-treated patients (205.7 mg/dL vs. 189.9 mg/dL, P=0.002).

Lund et al. 2001

Retrospective cohort study2,461 typical antipsychotics552 clozapine

Clozapine significantly increased relative risk of hyperlipidemia in patients ages 20–34 years (RR 2.4; 95% CI 1.1–5.2) but not in older patients.

Meyer 2001 Case series12 olanzapine (5–20 mg/day)2 quetiapine (200–250 mg/day)

Hypertriglyceridemia reported up to 7,668 mg/dL with olanzapine and 1,932 mg/dL with quetiapine. Time to peak TG ranged from 1 to 23.5 months.



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Nguyen and Murphy 2001

Case report:1 boy, age 10, taking olanzapine

5 mg/day for ADHD

Over 3 months, experienced 9-kg weight gain with resulting TC of 193 mg/dL and TG of 183 mg/dL. 5 weeks after olanzapine was discontinued, TC 151 mg/dL, TG 61 mg/dL, and over 9-kg weight loss.

Shaw et al. 2001

8-week open trial in adolescents with psychosis

15 quetiapine (300–800 mg/day)

TC remained unchanged.

Domon and Cargile 2002

Case report:1 African American female,

age 17, taking quetiapine 600 mg/day and metformin1,000 mg po bid for type 2 DM

On admission, TC 235 mg/dL, TG 456 mg/dL. Quetiapine discontinued with complete resolution of DM and hyperlipidemia. At 6 weeks postquetiapine (and 4 weeks without metformin), TC 226 mg/dL and TG 163 mg/dL.

Goodnick and Jerry 2002

Meta-analysis of trial data of 1,919 patients treated with one of the following: aripiprazole, olanzapine, risperidone, haloperidol, or placebo

Meta-analysis of short-term trial data showed that increases in TC following aripiprazole administration were lower than for haloperidol, risperidone, or placebo. A 26-week trial comparing aripiprazole to olanzapine found significant differences after 4 weeks: olanzapine increased TC, whereas aripiprazole decreased TC. Data from a 1-year study found that aripiprazole produced less of an increase in TC than haloperidol.



Effects of A


ipids139

Koro et al. 2002

Case-control database study of 18,309 schizophrenia patients, with 1,268 incident cases of hyperlipidemia; typical or atypical antipsychotic use analyzed

Olanzapine use was associated with nearly a fivefold increase in the odds of developing hyperlipidemia compared with no antipsychotic exposure and more than a threefold increase compared with those receiving typical antipsychotics.

Leonard et al. 2002

Chart review, 13 males, 8 females21 clozapine

(mean 485 mg/day)

11 patients (52%) had hypertriglyceridemia, 3 (14%) had hypercholesterolemia. Mean TC 193±46 mg/dL (range 131–309 mg/dL), mean TG 196±142 mg/dL (range 39–665 mg/dL).

Martin and L’Ecuyer 2002

Retrospective chart review of child and adolescent inpatients, mean age 12.8 years

22 risperidone (mean 2.7±2.2 mg/day)

After mean exposure of 4.9±1.0 months, no significant changes in serum TG or TC levels were seen in the group as a whole.

Meyer 2002 Retrospective chart review of 1-year exposure

47 risperidone47 olanzapine

After 52 weeks, TC increased 24 mg/dL with olanzapine vs. 7 mg/dL with risperidone (P=0.029), and fasting TG increased by 88 mg/dL with olanzapine vs. 30 mg/dL with risperidone (P=0.042). In the nongeriatric cohort, TC increased 31 mg/dL with olanzapine vs. 7 mg/dL with risperidone (P=0.004), and fasting TG increased 105 mg/dL with olanzapine vs. 32 mg/dL with risperidone (P=0.037).



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Stoner et al. 2002

Case report:1 African American male, age 42,

with treated hyperlipidemia taking olanzapine 15 mg/day

Baseline lipid panel: TC 227 mg/dL, TG 134 mg/dL, HDL 38 mg/dL. After 8 weeks of olanzapine serum: TG 5,093 mg/dL, TC 375 mg/dL, with evidence of new-onset type 2 DM (fasting glucose 395 mg/dL, hemoglobin A1c 11.9%).

Virkkunen et al. 2002

Case report: 1 male, age 48, taking

olanzapine 10–15 mg/day for 1 month

6-kg weight gain; 3.6% decrease in basal and 11.4% decrease in 3-hour energy expenditure; decrease in HDL; increase in TG and LDL. No change in insulin sensitivity using euglycemic hyperinsulinemic clamp.

Wetterling 2002

Case report:1 patient taking zotepine

Maximum TG of 1,247 mg/dL, which normalized upon switch to high-potency typical antipsychotic.

Wirshing et al. 2002

Chart review39 clozapine42 olanzapine49 risperidone13 quetiapine41 haloperidol41 fluphenazine

Clozapine was associated with greatest increase in TC, whereas risperidone and fluphenazine were associated with decreases. Clozapine and olanzapine were associated with greatest increase in TG levels.



Effects of A


ipids141

Atmaca et al. 2003a

6-week prospective schizophrenia study

14 quetiapine (mean 535.7 mg/day)

14 olanzapine (mean 15.7 mg/day)

14 risperidone (mean 6.7 mg/day)

14 clozapine (mean 207.1 mg/day)

11 controls (no psychotropic medication)

Compared to controls, significant increases in fasting TG seen for olanzapine (+31.23 mg/dL, P<0.001), clozapine (+36.28 mg/dL, P<0.001), and quetiapine (+11.64 mg/dL, P<0.05), but not risperidone (+3.87 mg/dL, P<0.76).

Atmaca et al. 2003b

6-week prospective schizophrenia study

15 haloperidol15 olanzapine15 quetiapine

Serum TG increases were much greater for olanzapine compared to quetiapine or haloperidol, and for quetiapine compared to haloperidol.



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Barak and Aizenberg 2003

Prospective 6-month study of elderly inpatients (mean age 71.7) with schizophrenia or schizoaffec-tive disorder (16 female, 5 male)


After a mean duration of 289 days of olanzapine treatment, no significant change from baseline serum lipid levels was found for TG or TC.

Baymiller et al. 2003

Prospective 1-year open-label study50 clozapine

(mean 454±109 mg/day)

From baseline, 54.7 mg/dL (41.7%) increase in serum TG (P=0.001) and 14.4 mg/dL (7.5%) increase in TC (P<0.001). No significant changes in HDL or LDL. Serum TG peaked between days 41 and 120 and then declined, but still remained elevated. Use of propranolol exacerbated increases in TC and TG.

Garyfallos et al. 2003

8-week prospective randomized study of acute schizophrenia spectrum inpatients



Compared to baseline, significant increases in fasting TG (+43.5 mg/dL, P<0.001) for olanzapine but not risperidone (+7.5 mg/dL, P>0.05). Nonsignificant increases in TC: +10.2 mg/dL for olanzapine, +0.7 mg/dL for risperidone. Between-group difference in change was significant for both TG and cholesterol parameters (P<0.001 for each).



Effects of A


ipids143

Melkersson and Dahl 2003

Cross-sectional study of lipids and insulin parameters in long-term treatment (mean 8.2 years for clozapine, 1.2 years for olanzapine)

18 clozapine (median 400 mg/day)

16 olanzapine (median 10 mg/day)

TG elevated in 44% of clozapine group and 56% of olanzapine group. Cholesterol elevated in 39% of clozapine group and 63% of olanzapine group. High LDL in 17% of clozapine- and 38% of olanzapine-treated patients. Normal HDL in all but one of each drug group. No significant between-group differences in hyperlipidemia rates or median lipid levels.

Weiden et al. 2003

6-week ziprasidone switch study; all labs were nonfasting; mean ziprasidone dose 91 mgPrior medications:

104 from olanzapine58 from risperidone108 from typical antipsychotics

Median changes from baseline for TG: −50 mg/dL in those switched from olanzapine (P<0.0001) and −29 mg/dL in those switched from risperidone (P<0.01). Median changes in cholesterol: −17 mg/dL (P<0.0001) in those switched from olanzapine and −12 mg/dL (P<0.005) for those switched from risperidone. Cholesterol levels declined in 76% of patients switched from olanzapine and 72% switched from risperidone. Reductions in lipid levels in patients switched from typical antipsychotics were nonsignificant.



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Alméras et al. 2004

Cross-sectional study of male schizophrenia patients in Canada; all subjects taking drug >6 months; results compared with reference group of nondiabetic males (mean ages: 28.4 risperidone, 31.7 olanzapine, 32.8 controls)



Risperidone subjects had significantly lower serum cholesterol, LDL, TG, cholesterol:HDL ratio, and apolipoprotein B. Risperidone cohort had significantly higher HDL, larger LDL peak particle size, and greater apolipoprotein A1. Compared to reference group, no differences for olanzapine group for cholesterol, TG, or LDL, but lower HDL and higher cholesterol:HDL ratio. Risperidone cohort had lower cholesterol and LDL but also lower HDL than the reference group.

Cohen et al. 2004

Chart review of 10 autistic adults (mean age 43) switched to ziprasidone and followed >6 months

10 ziprasidone (mean 128 mg/day)

Data on lipids available for only 5 subjects; 4 of 5 had a decrease in TC, but mean decrease (−2.6 mg/dL) was not significant; 3 of 5 had a decrease in serum TG, but mean decrease (−21.8 mg/dL) was not significant.



Effects of A


ipids145

De Deyn et al. 2004

Randomized, fixed-dose, 10-week trial of olanzapine (1.0, 2.5, 5.0, 7.5 mg/day) vs. placebo for psychosis/behavioral disturbance in patients with Alzheimer’s disease; mean age 76.6 years

520 olanzapine129 placebo

Serum values not provided, but report states that cholesterol and TG levels were not significantly different among or between treatment groups.

Kinon et al. 2004

Randomized, prospective 4-month study comparing those who switched to olanzapine with those who continued prior medication

27 olanzapine27 risperidone/typical

antipsychotics

After 4 months, no significant within-group change in mean TC (−4.7 mg/dL, P=0.69) or TG (−6.6 mg/dL, P=0.81) in patients switched to olanzapine, or in those who continued taking typical antipsychotics/risperidone (TC: −0.6 mg/dL, P=0.69; TG: +13.6 mg/dL, P=0.28). Elevations in lipids noted prior to month 4 in olanzapine cohort, but declined over time.



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McQuade et al. 2004

26-week double-blind, randomized trial in acutely relapsed schizophrenia patients

156 aripiprazole (mean 25.1 mg/day)


At week 26, mean change in fasting TG +79.4 mg/dL for olanzapine, +6.5 mg/dL for aripiprazole (P<0.05); HDL −3.39 mg/dL for olanzapine, +3.61 mg/dL for aripiprazole (P<0.05). Changes in TC and LDL favored aripiprazole but were not significant: TC +16.3 mg/dL olanzapine, −1.13 mg/dL aripiprazole; LDL+2.27 mg/dL olanzapine, −3.86 mg/dL aripiprazole. Incidence of new dyslipidemias was significantly greater for olanzapine on the basis of elevated TC (>200 mg/dL: 47% olanzapine vs. 17% aripiprazole), LDL (>130 mg/dL: 38% olanzapine vs. 19% aripiprazole), and TG (>150 mg/dL: 50% olanzapine vs. 18% aripiprazole) (P<0.05 for each).



Effects of A


ipids147

Simpson et al. 2004

6-week double-blind, randomized trial in patients with acute schizophrenia/schizoaffective disorder

136 ziprasidone (mean 129.9 mg/day)


Endpoint change in fasting TC was significant for olanzapine (median +19.5 mg/dL, P<0.0001) vs. ziprasidone (median −1.0 mg/dL, P=0.48 from baseline) (P<0.0001 between groups). TG increased median +26 mg/dL for olanzapine (P=0.0003), and decreased a median of 2 mg/dL for ziprasidone group (P=0.77); between-group difference was significant (P<0.003). LDL increased by a median of 13 mg/dL for olanzapine (P<0.0001) and decreased 1 mg/dL for ziprasidone group (P=0.78); between-group difference was significant (P<0.0004). Apolipoprotein B increased 9.0 mg/dL for olanzapine (P<0.0001) and decreased 3.0 mg/dL for ziprasidone (P=0.17); between-group difference was significant (P<0.0001). No impact or between-group differences in HDL, apolipoprotein A1, or lipoprotein (a) levels.

Waage et al. 2004

Case report:1 male, age 42, with chronic

paranoid psychosis and olanzapine-induced pancreatitis

Baseline TC 189 mg/dL. After 7 months, TC 282 mg/dL. At time of admission with pancreatitis, 19 months after starting olanzapine, TC 552 mg/dL and TG 2,044 mg/dL.



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Ball et al. 2005 Case report:1 male, age 42, with

schizoaffective disorder and clozapine-induced hypercholesterolemia and hypertriglyceridemia that resolved after switch to aripiprazole

Peak lipid levels: TC 477 mg/dL and TG 4,758 mg/dL. Patient hospitalized subsequently due to noncompliance, with lipid levels at time of admission: cholesterol 213 mg/dL, TG 298 mg/dL, and LDL 146 mg/dL while taking simvastatin. Trial of aripiprazole, up to 45 mg/day for 5 weeks, with lipids (off of simvastatin): cholesterol 163 mg/dL, TG 145 mg/dL, LDL 100 mg/dL.

Breier et al. 2005

28-week randomized, double-blind study in patients with schizophrenia



All between-group lipid changes significantly favored ziprasidone. Endpoint change in fasting TC for olanzapine (+3.09 mg/dL, P=0.07) vs. ziprasidone (−12.74 mg/dL, P=0.08) (P<0.0001 between groups). TG increased +34.52 mg/dL for olanzapine (P=0.09) and decreased 21.24 mg/dL for ziprasidone (P=0.11); between-group difference was significant (P<0.001). LDL increased by a median of 0.77 mg/dL for olanzapine (P=0.06) and decreased 10.42 mg/dL for ziprasidone (P=0.07); between-group difference was significant (P<0.001). HDL decreased 2.32 mg/dL for olanzapine (P=0.02) and increased 0.77 mg/dL for ziprasidone (P=0.02); between-group difference was significant (P=0.001).



Effects of A


ipids149

Brown and Estoup 2005

Chart review study from Veterans Administration medical center

88 ziprasidone103 olanzapine

Olanzapine associated with significant increases in TC (+16 mg/dL, P=0.01) and TG (+61 mg/dL, P=0.05), but not HDL or LDL. Ziprasidone associated with significant decrease in TC (−15 mg/dL, P=0.01) and LDL (−18 mg/dL, P=0.001), and increase in HDL (+3 mg/dL, P=0.05). Among those who switched between agents, significant differences were found for TC (P=0.05) and LDL (P=0.01).

Graham et al. 2005

Prospective study of resting energy expenditure and metabolic outcomes in 9 adults started on olanzapine and followed 12 weeks

9 olanzapine (range 2.5–20 mg/day)

Median changes were −7 mg/dL for HDL (P=0.19), +1 mg/dL for LDL (P=0.47), +59 mg/dL for TG (P=0.04). The TG change was a 62.8% increase from baseline.

Henderson et al. 2005

Review of data on 96 subjects treated with

clozapine and followed for 10 years

A significant linear increase in TG levels was found for the duration of the follow-up (0.5 mg/dL/month, P=0.04) but not for TC (P=0.13). Elevations in TG and TC were associated with new-onset DM but not cardiovascular mortality.



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Lambert et al. 2005

Case-control study of MediCal claims after schizophrenia diagnosis and exposure to only one antipsychotic within 12 weeks prior to hyperlipidemia claim; cases were age- and gender-matched to patients with schizophrenia who did not develop hyperlipidemia

For the 12-week exposure window, olanzapine (OR 1.20, 95% CI 1.08–1.33) was significantly associated with hyperlipidemia risk compared with typical agents, but not compared with exposure to clozapine, risperidone, or quetiapine. The odds ratio for olanzapine was greater than for risperidone (P=0.002). Increasing the exposure window to 24 or 52 weeks did not affect the results, although clozapine’s association did become significant at 24 weeks (OR 1.22, 95% CI 1.03–1.45).

Lieberman et al. 2005

Phase 1 of CATIE schizophrenia trial (See Tables 6–2 and 6–3)

McKee et al. 2005

Chart review of 41 adults with developmental delays switched from typical antipsychotics to olanzapine or risperidone (and some then to olanzapine) and followed up to 2 years. At endpoint:

33 olanzapine8 risperidone

At endpoint, no significant changes in serum TC, LDL, or TG.



Effects of A


ipids151

Meyer et al. 2005

20-week switch study in overweight or obese olanzapine-treated patients with schizophrenia following metabolic syndrome parameters

71 risperidone

At endpoint, nonsignificant decreases in serum TG (−13.1 mg/dL) and HDL (−1.6 mg/dL). Overall, the prevalence of metabolic syndrome decreased from 53.5% to 36.6% over 20 weeks (P<0.005).

Simpson et al. 2005

6-month continuation of prior 6-week randomized, double-blind study of olanzapine vs. ziprasidone



There were significant within-group median increases from baseline in TC (+13.0 mg/dL, P=0.03) and LDL (+17.0 mg/dL, P=0.04) with olanzapine, and nonsignificant changes in TC (−1.0 mg/dL, P=0.98), and LDL (9.0 mg/dL, P=0.29) with ziprasidone.

Su et al. 2005 Crossover switch study in 15 schizophrenia patients followed for 3 months after switch

7 risperidone → olanzapine8 olanzapine → risperidone

After switch to olanzapine, nonsignificant changes in LDL (−1.0 mg/dL), HDL (+0.4 mg/dL), and TC (+20.5 mg/dL), but significant increase in TG (+84.3 mg/dL, P<0.05). In those switched to risperidone, nonsignificant changes in LDL (+5.9 mg/dL), HDL (+6.8 mg/dL), and TC (−8.6 mg/dL), but significant decrease in TG (−86.0 mg/dL, P<0.05).



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McEvoy et al. 2006

Phase 2 nonresponse arm of CATIE schizophrenia trial

(See Table 6–2, Phase 2b results)

Stroup et al. 2006

Phase 2 intolerability arm of CATIE schizophrenia trial

(See Table 6–2, Phase 2a results)

Meyer et al. 2008a

End of CATIE phase 1 detailed analysis

(See Table 6–3)

Meyer et al. 2008b

CATIE phase 1 nonfasting triglycerides analysis

Mean 3-month changes: quetiapine (+54.7 mg/dL), olanzapine (+23.4 mg/dL), ziprasidone (+0.0 mg/dL), risperidone (−18.4 mg/dL), perphenazine (−1.3 mg/dL).

Note. ADHD=attention-deficit/hyperactivity disorder; BMI=body mass index; CI=confidence interval; CPZ=chlorpromazine;DM=diabetes mellitus; HDL=high-density lipoprotein; LDL= low-density lipoprotein; OR=odds ratio; RR=relative risk; SE=standarderror of measurement; TC=total cholesterol; TG= triglycerides; VLDL=very-low-density lipoprotein.



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ipids153

TABLE 6–2. Exposure-adjusted lipid changes for CATIE schizophrenia trial phases 1, 2a, and 2b (mean±SE)

Clozapine Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone

Cholesterol (mg/dL)

Phase 1 (N=1,460) — 9.4±2.4 1.5±2.7 6.6±2.4 −1.3±2.4 −8.2±3.2Phase 2a (n=444) — 17.5±5.2 — 6.5±5.3 −3.1±5.2 −10.7±5.1

Phase 2ba (n=99) 5.9±4.7 1.0±7.1 — −11.0±8.1 7.4±8.7 —

Triglycerides (mg/dL)

Phase 1 (N=1,460) — 40.5±8.9 9.2±10.1 21.2±9.6 −2.4±9.1 −16.5±12.2

Phase 2a (n=444) — 94.1±21.8 — 39.3±22.1 −5.2±21.6 −3.5±20.9Phase 2ba (n=99) 43.8±21.2 −5.3±32.0 — 7.1±36.2 30.0±39.0 —

aBlood chemistry change from phase 2 baseline to average of two largest values.


TABLE 6–3. Mean changes in high-density lipoprotein (HDL) and fasting triglycerides at end of CATIE phase 1

HDL, mg/dLa Fasting triglycerides, mg/dLb

Whites Nonwhites Below median Above median

Mean exposure (months)

9.2 9.9 9.9 9.8

Olanzapine −1.7 (0.6)(n=171)

−0.9 (0.9)(n=115)

49.0 (10.8)(n=42)

5.2 (17.4)(n=51)

Perphenazine 2.7 (0.7)(n=130)

−1.3 (1.0)(n=88)

28.7 (11.6)(n=36)

−27.5 (22.3)(n=31)

Quetiapine −0.2 (0.6)(n=186)

0.1 (1.1)(n=85)

29.8 (10.8)(n=42)

−13.0 (18.4)(n=46)

Risperidone 0.1 (0.6)(n=162)

0.9 (0.9)(n=109)

19.7 (11.2)(n=39)

−67.1 (21.2)(n=35)

Ziprasidone 0.6 (0.9)(n=90)

4.3 (1.4)(n=51)

26.0 (15.6)(n=20)

−96.4 (28.5)(n=19)

Overall treatment difference

<0.0011 0.0122 NS 0.0113

Note. Table entries are analysis of covariance least-squares adjusted means(standard error of measurement). NS=not significant (P≥0.05).aData presented in separate columns due to significant race× treatment effect.bData presented in separate columns due to significant baseline×treatment ef-fect. Median triglyceride level=148 mg/dL.1Between-group comparisons significant for perphenazine vs. olanzapine(P<0.001) and for perphenazine vs. quetiapine (P=0.002).2Between-group comparisons significant for ziprasidone vs. olanzapine(P=0.002) and for ziprasidone vs. perphenazine (P=0.001).3Between-group comparison significant for olanzapine vs. ziprasidone(P=0.003).


Patient Variables and Possible Mechanisms for Antipsychotic-Related HyperlipidemiaBased on a review of data on certain metabolic outcomes, such as the de-velopment of type 2 diabetes mellitus or diabetic ketoacidosis, ethnicityand obesity stand out as important predictors of risk and are additivewith that imposed by the antipsychotic medication itself (Jin et al. 2002,2004). As of 2008, no important trends regarding patient risk for hyper-lipidemia can be assigned on the basis of ethnicity, gender, patientweight, or even medication dosing within the range commonly used totreat schizophrenia. There are case reports of significant hypertriglycer-idemia with low-dose olanzapine (e.g., 5 mg) (Meyer 2001) but no datafor those medications employed at extremely low doses (relative to theirantipsychotic dosing), such as quetiapine, which is frequently used inthe United States as a sedative at doses of 25–100 mg. The only demo-graphic variable that may be predictive of decreased risk for dyslipi-demia is age, with the caveat that both olanzapine studies in oldersubjects previously cited were performed among subjects in controlledsettings, presumably with controlled diets as well (Barak and Aizenberg2003; De Deyn et al. 2004). Conversely, reports exist of dyslipidemia inadolescents exposed to antipsychotic medications, primarily olanza-pine, so younger age is not protective (Domon and Cargile 2002; Domonand Webber 2001; Martin and L’Ecuyer 2002; Nguyen and Murphy 2001;Penzak and Chuck 2002; Shaw et al. 2001; Stigler et al. 2004).

That an antipsychotic agent can induce dyslipidemia is not entirelysurprising given that hyperlipidemia can occur with a variety of medi-cations, including certain diuretics, progestins, β-adrenergic antago-nists, immunosuppressive agents, protease inhibitors, and someanticonvulsants (Echevarria et al. 1999; Mantel-Teeuwisse et al. 2001;Penzak and Chuck 2002). In their comprehensive review of the subject,Mantel-Teeuwisse et al. (2001) noted that global changes in serum lip-ids are described with some medications, whereas certain agents ap-pear to have specific effects on particular lipid fractions. For example,isotretinoin, acitretin, certain protease inhibitors, low-potency pheno-thiazines, and dibenzodiazepine-derived antipsychotics primarily ele-vate serum triglyceride levels. Moreover, in a manner that parallels thedifferential metabolic effects of the atypical antipsychotics, the proteaseinhibitors also vary dramatically in their metabolic effects (Penzak andChuck 2002).

Any agent may induce hyperlipidemia through several possiblemeans, although none of these has been proven definitively for the


atypical antipsychotics. Nonetheless, several biologically plausiblehypotheses have been advanced, focusing on weight gain, dietarychanges, and the development of insulin resistance, to explain the highincidence of hyperlipidemia with certain antipsychotic medications.

The variation in weight gain liability is quite marked among theatypical antipsychotics (Allison et al. 1999), with clozapine and olanza-pine associated with the greatest gains. Because obesity and weightgain have a demonstrable negative impact on serum lipid profiles,those atypical antipsychotics most likely to cause significant weightgain are also correlated with the greatest impact on serum lipids (Stoneet al. 2005). Nonetheless, recent switch data suggest that the more meta-bolically offending medications may have direct, weight-independenteffects on serum lipids. In a long-term switch study, Weiden et al. (2007)charted the time course of weight and lipid changes over 58 weeks afterswitching subjects from typical antipsychotics, risperidone, and olanza-pine to ziprasidone. Those switching from high-potency typical anti-psychotics experienced no significant lipid changes, but thosepreviously taking olanzapine and risperidone experienced an immedi-ate reduction in lipids (triglycerides more than total cholesterol) overthe first 6 weeks after the switch, as well as slow but steady weight lossover the course of the study. The rapid improvement in serum lipidsduring a time frame when weight loss had been minimal points to a di-rect, weight-independent effect of certain antipsychotic medications onserum lipids.

Accumulating data suggest that the metabolic pathway most likelyto mediate the increase in serum triglycerides relates to the develop-ment of insulin resistance. In those who have become less sensitive tothe action of insulin, the inability of insulin to adequately suppress li-polysis in adipose cells results in an outflow of free fatty acids and dys-lipidemia, characterized primarily by elevated serum triglycerides(Reaven 2005). The literature certainly supports the concept that somepatients who develop new-onset type 2 diabetes mellitus experiencehypertriglyceridemia (Meyer 2001), often with reversal of these prob-lems upon discontinuation of the offending agent (Casey et al. 2003;Meyer et al. 2005; Weiden et al. 2007). Although the majority of patientswith elevated triglycerides related to antipsychotic treatment do nothave overt type 2 diabetes mellitus, many do show signs of insulin re-sistance, as seen in studies of glucose-insulin parameters in patientstaking clozapine or olanzapine (Melkersson and Dahl 2003).

More recent data suggest that quetiapine might induce triglyceridechanges by another mechanism. Prospective data presented at the 2007American Psychiatric Association annual meeting (Newcomer et al.


2007) indicated that quetiapine-exposed patients experienced changesin serum triglyceride levels without an apparent change in glucose tol-erance, as measured by standard glucose tolerance testing. Compellingbiological data support Weiden et al.’s (2007) switch study findings andpoint to direct effects of the more metabolically offending medicationson insulin sensitivity independent of changes in adiposity. Single dosesof medications such as olanzapine and clozapine have been shown toinduce loss of insulin sensitivity in a dose-dependent fashion in labora-tory animals in a manner not seen with risperidone or ziprasidone(Houseknecht et al. 2007). Evidence for this effect can be directly mea-sured within 2 hours of drug exposure, using the hyperinsulinemic-euglycemic clamp technique, as both the decreased ability to metabolizeglucose and the failure to adequately suppress endogenous glucoseproduction from the liver. The means by which clozapine and olanza-pine induce these effects is not known, but the propensity to cause insu-lin resistance with single doses strongly suggests that these two agentshave weight-independent effects on glucose-insulin homeostasis, ef-fects that will be exacerbated by future medication-related weight gain.

Monitoring Recommendations for Hyperlipidemia During Antipsychotic TherapyBecause multiple cardiovascular risk factors exist in patients withschizophrenia (Goff et al. 2005), caution must be exercised in the choiceof antipsychotic therapy to minimize the added morbidity and mortal-ity of hyperlipidemia. Unfortunately, hyperlipidemia is undertreatedin schizophrenia patients (Nasrallah et al. 2006), thereby exposing pa-tients to ongoing substantial additional cardiovascular risk. For exam-ple, for a normotensive smoker exposed to a dibenzodiazepine-derivedatypical antipsychotic, the 10-year risk for a major cardiovascular event(e.g., sudden death, acute myocardial infarction) might be increasedsignificantly from baseline after only 12 weeks of therapy (Daumit et al.2008). Hyperlipidemia is associated with long-term cardiovascular con-sequences, yet monitoring for hyperlipidemia is not solely a long-termissue, because severe hypertriglyceridemia also represents a risk foracute pancreatitis (Koller et al. 2003).

The following guidelines are based on previously published rec-ommendations (American Diabetes Association et al. 2004; De Hert etal. 2006; Marder et al. 2004; Melkersson et al. 2004; Meyer et al. 2006;Sernyak 2007) and my own clinical experience. Some of the consider-


ations inherent in these recommendations include the following: pa-tients with schizophrenia have multiple risk factors for cardiovasculardisease; certain antipsychotics are associated with greater adverse ef-fects on serum lipids; many health care providers outside of the psychi-atric arena are unaware of the potential metabolic complications ofatypical antipsychotic therapy; and schizophrenia patients often receivelimited or no medical care outside of that provided by the mental healthpractitioner, so the burden of medical monitoring necessarily falls onthose who prescribe antipsychotic medications. Although the followingrecommendations are specific to monitoring of serum lipids, these areunderstood to be part of the monitoring recommended elsewhere as partof routine medical care for those taking atypical antipsychotics.

Baseline Assessment• For each patient with schizophrenia, the clinician should document

in the medical record the individual’s smoking status, as well as thepatient’s and first-degree family members’ history of cardiovasculardisease, hyperlipidemia, and glucose intolerance.

• The clinician should obtain weight, waist circumference, blood pres-sure, and (ideally) fasting lipid panel for each patient. Total choles-terol and HDL values are valid on nonfasting specimens, buttriglyceride and LDL levels are not. These measures are recom-mended for all patients with schizophrenia, regardless of medica-tion regimen, given the limited health care access for these patients.

Follow-Up• For patients taking agents associated with lower risk for hyperlipi-

demia (high-potency typical antipsychotics, ziprasidone, risperi-done, aripiprazole), an annual fasting lipid panel is sufficient unlessdyslipidemia is suspected from the baseline evaluation.

• For patients taking agents associated with higher risk for hyperlipi-demia (low-potency typical antipsychotics, quetiapine, olanzapine,clozapine), a quarterly fasting lipid panel is necessary for the firstyear to detect cases of severe hypertriglyceridemia. Testing fre-quency may be decreased to semiannually if fasting lipids remainnormal but should continue on a quarterly basis in those identifiedwith abnormal values.

• All patients with persistent dyslipidemia should be referred forlipid-lowering therapy or considered for switch to a less offendingagent if possible.


Key Clinical Points

◗ Patients with severe mental illness have twice the risk for cardiovascularmortality versus their non–mentally ill counterparts. Therefore, theinduction of hyperlipidemia secondary to antipsychotic treatment rep-resents a serious condition not only because of its impact on cardio-vascular risk but also because it is occurring in a group that possessesconsiderable risk.

◗ High-potency typical antipsychotic agents (butyrophenones) are lipidneutral, whereas low-potency agents (phenothiazines) are associatedwith hyperlipidemia, primarily in the form of hypertriglyceridemia.

◗ The structurally related dibenzodiazepine-derived atypical antipsychot-ics (clozapine, olanzapine, and quetiapine) are associated with greaterelevations in serum triglycerides than in total cholesterol, whereas thenon-dibenzodiazepine agents (risperidone, ziprasidone, and aripipra-zole) have minimal effects on lipids.

◗ Known mechanisms by which antipsychotics cause hyperlipidemia in-clude weight gain, dietary changes, and the direct development of in-sulin resistance.

◗ A thorough baseline assessment in all patients should include a cardio-vascular assessment. Subsequent monitoring for hyperlipidemia is rec-ommended annually for all patients prescribed antipsychotics and asfrequently as quarterly for those prescribed higher risk agents.


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169

CHAPTER 7

The Spectrum ofCardiovascular

Disease in PatientsWith Schizophrenia

Jimmi Nielsen, M.D.Egon Toft, M.D., F.E.S.C.

Life expectancy for patients with schizophrenia in the UnitedStates is 61 years, or 15 years shorter than for the general population(Hennekens et al. 2005), even after controlling for unnatural causes ofdeath (e.g., accidents and suicide). Cardiovascular disease (CVD) is themajor cause of excess mortality in patients with schizophrenia, and thispatient cohort is twice as likely to die of coronary heart disease (CHD)as the general population (Brown et al. 2000). There are multiplesources of increased CVD risk, including sedentary lifestyle, smoking,and the metabolic side effects of antipsychotic treatment. Althoughseemingly of less clinical importance, much attention has also been paidto the increased risk of sudden cardiac death due to tachyarrhythmias,such as torsade de pointes (TdP), that are induced by antipsychotics. In-terestingly, although several antipsychotics have been withdrawn fromthe market due to QTc interval prolongation and concern over torsadede pointes risk, among the antipsychotics associated with increased risk


for CVD mortality mediated by substantial weight gain and dysmeta-bolic effects, none have been suspended. Although the evidence base issparse, the accumulated literature suggests that antipsychotic exposureaccounts for relatively few arrhythmia deaths compared to the ex-pected greater numbers of deaths from myocardial and cerebral infarc-tions occurring secondary to antipsychotic-induced metabolic sideeffects and patient lifestyle factors.

Our purpose in this chapter is to describe the spectrum of CVD, witha particular focus on those specific issues related to schizophrenia andthe medications commonly used for schizophrenia treatment. Thechapter is not a complete guide to CVD, but we hope to equip psychia-trists and other physicians with the basic tools required to meet thechallenge of treating and preventing CVD in patients with schizophre-nia. In this chapter, we first provide the reader with a general back-ground for understanding the relationship between schizophrenia,medication treatment, and TdP, as this information is necessary for theunderstanding of arrhythmia risk related to medication effects, andlater provide an overview of atherosclerotic disease and basic CHD riskmanagement.

Sudden Cardiac DeathThe World Health Organization defines sudden cardiac death (SCD) asunexpected death within 1 hour of symptom onset if witnessed, orwithin 24 hours of the person having being alive and symptom free, ifunwitnessed (Turakhia and Tseng 2007). CHD is involved in up to 70%of sudden death cases, and in many instances the first symptom of CHDis sudden death (Turakhia and Tseng 2007); however, establishing theexact cause of death can be difficult because several causes (overdose,suicide, cerebrovascular events, seizures, etc.) must be excluded. Inmost instances, an autopsy can determine the exact cause of death. If nostructural disease is found, cardiac arrhythmia is the most likely etiol-ogy.

Retrospective data suggest that the overall risk of SCD is increased4.9 times in patients with schizophrenia compared with the generalpopulation (Ruschena et al. 2003), with multiple contributing etiologies.Patients with schizophrenia have more prevalent cardiovascular riskfactors compared to the background population due to lack of exercise,obesity, smoking, diabetes, and dyslipidemia (Leucht et al. 2007). Inschizophrenia patients, the prevalence of type 2 diabetes mellitus is in-creased twofold, smoking threefold, obesity twofold, and dyslipidemia

Cardiovascular Disease 171

up to fivefold. Substance abuse and dependence, especially alcohol andcocaine, are also more common in patients with schizophrenia and arelinked to risk for sudden death. Furthermore, patients with schizophre-nia are less likely to have proper preventive medical care and monitor-ing for metabolic disorders than the general population (Leucht et al.2007) and, when a primary care provider is consulted, are less likely tofollow instructions on diet or exercise.

Antipsychotic treatment has also been linked to increased risk ofSCD. A 2.4-fold increased risk of SCD was found in users of antipsy-chotics versus nonusers in a retrospective cohort study from Tennessee(Ray et al. 2001). Cardiac arrhythmia from previously undiagnosedCHD and risk from antipsychotic medication exposure are the twomost plausible explanations, but other suggestions that have been putforth include respiratory dyskinesia, laryngeal-pharyngeal dystonia,and peripheral vasodilation leading to cardiovascular collapse andoversedation (Haddad and Anderson 2002; Titier et al. 2005).

Although cardiac arrhythmia is the most common etiology for SCD,it is worthwhile distinguishing whether the arrhythmia is primary orwhether it is secondary to structural changes related to cardiomyopa-thy, myocarditis, or acute myocardial infarction. Secondary ventriculararrhythmia is probably the most frequent form of fatal tachyarrhyth-mia, but the exact distribution of deaths due to structural changes(acute myocardial infarction or cardiomyopathy) or nonstructuralchanges (cardiac arrhythmia) is unclear because no large-scale mortal-ity study with autopsy results has been carried out (Michelsen andMeyer 2007). In general, the incidence of drug-induced ventricular ar-rhythmia is largely unknown, partly due to underreporting of sponta-neous adverse effects. Drug-induced TdP is a rare event, so extremelylarge sample sizes would be needed to detect a small increase in SCDrisk. Further complicating the assignment of TdP as the cause of any ar-rhythmic death is the need to confirm the diagnosis with electrocardio-graphic (ECG) recordings obtained at the time of the event.

Electrophysiology of the HeartThe electrophysiology of the heart is complex, and several ion channelsare involved in the repolarization and depolarization of ventricularcells. The depolarization event, which includes the action potential, isprimarily mediated by the rapid influx of sodium and is reflected on theelectrocardiogram as the QRS complex (Figure 7–1). Blocking of thesodium channel is called a quinidine-like effect, named after the class I


antiarrhythmic drug quinidine. This effect can be seen on the electrocar-diogram as a widening of the QRS complex and increased PR interval,and drugs with quinidine-like properties are associated with increasedrisk of SCD due to ventricular arrhythmia. Some antipsychotics, such asthioridazine, have been shown to possess quinidine-like properties athigh dosages, but among commonly used psychotropic medications,only tricyclic antidepressants affect depolarization to any significantextent.

FIGURE 7–1. The role of ion channels during depolarization andrepolarization.A. The monophasic action potential with notations for involved ion channels. B. The corresponding surface electrocardiogram.

Source. Reprinted from Titier K, Girodet PO, Verdoux H, et al: “AtypicalAntipsychotics: From Potassium Channels to Torsade de Pointes and SuddenDeath.” Drug Safety 28:35–51, 2005. Used with permission.

A+45mV

1

It0

2ICa

IK

IKrIKuIKs{

3

IK1 4

Repolarization

IK1

–85mV

0

INa

Depolarization

QT interval

QRST

B


Repolarization is mediated primarily by the efflux of potassium viatwo families of potassium channels: the rapid IKr and the slow IKs chan-nels. The IKr channel is encoded by the human ether-a-go-go relatedgene (HERG), polymorphisms of which are involved in the congenitallong QT syndrome, type II. Patients with congenital long QT syndromehave one or more mutations in the genes encoding for ion channels in-volved in the repolarization and depolarization of the heart, with nineknown genetic variants involved in this disease. The cardinal symp-toms of congenital long QT syndrome are syncope or SCD, and in somecases the first symptom is sudden death (Priori et al. 2003). Many anti-psychotic drugs block the IKr channel to an extent comparable with thatseen in congenital long QT syndrome. Antagonism of IKr channels is themechanism mostly responsible for instances of drug-induced QT pro-longation and is the suspected mechanism for the majority of antipsy-chotic-induced sudden cardiac deaths.

The prolongation of the repolarization process, and thereby of theQT interval, is thought to allow the development of spontaneous con-tractions of non-pacemaker cells called early after-depolarizations(EADs). The induction of EADs, whether drug-induced or genetic as inthe congenital long QT syndrome, can also increase risk for ventriculararrhythmia, as the development of EADs is linked to an increased in-ward current and/or decreased outward current during the repolar-ization phase of the action potential (Glassman and Bigger 2001;Haverkamp et al. 2000).

Torsade de PointesTorsade de pointes (TdP), which literally means “twisting points” inFrench, is a polymorphic ventricular arrhythmia and the most commondrug-induced ventricular arrhythmia. The name is derived from thetwisting of the QRS complex around the isoelectric line, as shown inFigure 7–2A. TdP can be asymptomatic or cause self-limiting palpita-tions, dizziness, syncope, and death. In approximately one-third of pa-tients, TdP will lead to ventricular fibrillation, and in 10% result in SCD(Figure 7–2B) (Abdelmawla and Mitchell 2006). In one Swedish study,the annual incidence of drug-induced TdP was 4 per 100,000 patients,although the real incidence has been estimated to be at least 10 timeshigher (Wysowski and Bacsanyi 1996).


Risk Factors for Torsade de PointesRisk factors for developing TdP are shown in Table 7–1 (Yap and Camm2003). An important issue to consider when exploring drug-relatedcauses is the potential for pharmacokinetic drug-drug interactions thatincrease the plasma levels of an offending drug and result in dose-dependent QTc prolongation. Pharmacodynamic interactions can occurwhen two or more drugs are prescribed that prolong the QTc interval,with the combined effects resulting in significant QT prolongation.Medications with quinidine-like properties (e.g., tricyclic antidepres-sants) given together with QT prolonging antipsychotics is just a singleexample of a combination of psychiatric medications that may increasethe risk of sudden death.

An additional risk is that induced by biological variability. In 10%–15% of patients with drug-induced TdP, mutations or polymorphismswere found in one of the congenital long QT genes (Yang et al. 2002).These patients have smaller repolarization reserve and are thereforemore susceptible to drug-induced changes. Although genetic causesprovide an obvious source of risk, most cases of TdP occur in patientswith structural heart disease or other risk factors (Table 7–1). For thisreason, drug-induced TdP is comparably rarer in young, healthy pa-

FIGURE 7–2. Examples of torsade de points (TdP).A. Electrocardiogram shows a self-limited case of TdP. Notice the typical shiftbetween an upward and a downward pointing of the complexes. B. A case of TdP deteriorating into ventricular fibrillation.

Source. Reprinted from Yap YG, Camm AJ: “Drug Induced QT Prolongationand Torsades de Pointes.” Heart 89:1363–1372, 2003. Used with permission.

A

B


tients than in older individuals, who have a greater likelihood of havingestablished cardiac disease.

Estimating the Risk: Surrogate MarkersGreat interest has been shown in developing surrogate markers for theclinical evaluation of medication proarrhythmic effects, but so far novalid marker has been elucidated. The QTc interval is the most widelyused marker for determining the proarrhythmic effects of any drug, butan exact estimate of risk cannot be derived solely from changes in theQTc interval. Even among patients with prolonged QTc intervals, theactual risk of TdP is often quite low. This fact alone poses great difficul-ties for the identification of patients at risk for TdP and SCD.

The overall safety of an antipsychotic drug rests on the balance be-tween protective and causative factors for SCD. QTc-prolonging drugsmight also have actions that diminish the proarrhythmic risk, such asincreasing the heart rate or altering other ion currents, which counteractthe proarrhythmic effects (Taylor 2003a). Diminished long-term SCDrisk can also result if the medication is associated with limited weightgain (or weight loss) and thereby lowers mortality by decreasing tradi-tional CHD risk associated with obesity. For these reasons, the relation-ship between drug-induced QTc prolongation and the risk of suddendeath is not simple, and false positives are seen with drugs that prolong

TABLE 7–1. Risk factors for developing drug-induced torsade de pointes (TdP)

• Female gender• Hypokalemia (e.g., vomiting and diarrhea)• Structural heart disease (e.g., cardiomyopathy or infarction) • Atrioventricular block • Bradycardia• Prolonged QTc (>450 milliseconds)• Significant T-wave abnormalities • Genetic disposition/congenital long QT syndrome• Prior drug-induced TdP• Multiple QT-prolonging drugs or other drugs that interfere with

their metabolism• Hepatic impairment• Drug-drug interactions

Source. Adapted from Yap and Camm 2003.


the QTc interval but are only rarely associated with TdP. Amiodaroneis a class III antiarrhythmic that is rarely associated with TdP but isknown to significantly prolong the QTc interval (Hohnloser et al. 1994).Other examples include verapamil, ziprasidone, and sertindole, all ofwhich prolong the QT interval significantly, but whose association withTdP is questionable (De Cicco et al. 1999; Haddad and Anderson 2002).Because QT effects by themselves do not always predict TdP risk, sur-rogate markers for drug-induced arrhythmia risk have been studied, aspresented in the next section, including some recent and technologi-cally more advanced parameters developed from electrocardiograms inpatients with long QT syndrome. Although these studies are not com-monly used in routine clinical practice, an understanding of changes inT-wave morphology may be very useful in the near future, and param-eters based on T-wave morphological changes have evolved to the ex-tent that they are expected to be employed in drug studies in the nextfew years (Couderc et al. 2008; Kanters et al. 2004; Struijk et al. 2006).

QT Interval EstimationThe QT interval comprises the entire interval from the beginning of theQRS complex to the termination of the T-wave (Figure 7–3). The end ofthe T-wave is defined as the intercept between the isoelectric line andthe tangent of the steepest part of the descending T-wave. Determina-tion of the exact point of T-wave termination is critical to the estimationof QT interval duration and is subject to certain pitfalls. A U-wave in-corporated in the T-wave often complicates QT measurement and canlead to the erroneous assessment of QTc prolongation because the U-wave is included in the interval. T-wave alterations, such as biphasic orflat T-waves (e.g., due to IKr blockade), can cause similar problems. AU-wave is most often present in lateral precordial leads, whereas bi-phasic T-waves are present in multiple leads. For cases where any ofthese features are present, manual estimation of the QT interval is abetter option, with possible referral to a cardiologist for interpretation.

Manual QT interval measurement should be derived from at leastthree to five cycles, and a mean value calculated across these cycles. Al-though the accuracy level of manual QT interval determination is 20–40milliseconds (Goldenberg et al. 2006), the accuracy of automatic mea-surement of the QT interval varies greatly, because manufacturers havechosen varying algorithms for QT calculations (Goldenberg et al. 2006).The QT interval can be measured in any lead, yet the length of the inter-val can differ between leads. Although there is no consensus on which


leads must be used, V3 and V4 have generally been suggested as thepreferred leads for QT estimation (Malik 2004; Sadanaga et al. 2006).

Another source of potential confusion for QT estimation lies in thefact that the QT interval shortens with increasing heart rate, makingcorrection necessary. Several correction formulas have been suggested(Figure 7–4), of which the Bazett formula is the most commonly used;however, it is less accurate at heart rates above 70 beats per minute(bpm) (Dogan et al. 2005). The Fridericia correction formula performs

FIGURE 7–3. Electrocardiogram.As shown, finding the end of the T-wave can be difficult, particularly in caseswhere a U-wave is interfering. asc.=ascending; desc.=descending; TPTE=time from peak to end of T-wave.

Source. Reprinted from Pater C: “Methodological Considerations in the De-sign of Trials for Safety Assessment of New Drugs and Chemical Entities.”Current Controlled Trials in Cardiovascular Medicine 6:1–13, 2005. Used with per-mission of Biomed Central Ltd.

R

QRS complex

PR interval

P

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T peak T endTPTEinterval

U

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PRsegment

QT interval

S

T asc. T desc.


better than Bazett at heart rates above 70 bpm and is often used innewer ECG machines and by the pharmaceutical industry for drugevaluation. Heart rate correction is especially important in patients re-ceiving antipsychotic drugs, because most antipsychotics increase rest-ing heart rate.

The reference interval for the QTc interval associated with greaterTdP risk is not clearly defined, but most agree that a QTc intervalgreater than 500 milliseconds indicates an area of increased risk. Fe-males tend to have longer QTc intervals, in part related to the fact thattestosterone decreases the QT interval (Gupta et al. 2007; Rautaharju etal. 1992), and 70% of TdP cases occur in women (Vieweg 2002). The im-portance of QT interval prolongation has been suggested to be 1.052X

where X is prolongation above 440 milliseconds divided by 10. For ex-ample, prolongation from 440 milliseconds to 500 and 640 millisecondswould increase the risk for TdP by 1.0526=1.4 and 1.05220=2.8 times, re-spectively (Moss 1993). In the general population, the risk for TdP israre, and therefore a doubling would still mean a small increase in thenumber of cases. Furthermore, these data are based completely on find-ings from individuals with congenital long QT syndrome, and whetherthese calculations can be extrapolated to drug-induced TdP risk is un-clear.

The QT interval length fluctuates throughout the day related to sev-eral factors, including inherent diurnal variation, level of activity, andbody weight. The QTc interval is longest during nights and shortest af-ter awakening (Molnar et al. 1996); moreover, drug-induced prolonga-tion of the QTc interval is greatest during the first half of the menstrualcycle (Rodriguez et al. 2001). The effect of weight gain on QTc prolon-

FIGURE 7–4. The most commonly used correction formulas.The Fridericia formula is recommended and performs better than the Bazett for-mula in cases of tachycardia or bradycardia. QT is measured in millisecondsand RR in seconds. The RR interval used should be the preceding beat to the QTinterval measured. The notation QTcB or QTcF can be used to indicate whetherthe method used was the Bazett or the Fridericia method.

3 RRQT

QTcF =2 RRQT

QTcB =

Bazett Fridericia


gation has been quantified, with a 10-kg weight increase associatedwith an increase of over 5-milliseconds in QTc length (el-Gamal et al.1995). Besides these biological factors, inaccurate measurement of andcorrection for heart rate add to the variation in reported QT intervalsand complicate the assessment of drug-related effects on QTc and levelof TdP risk. As alluded to earlier, some proposed surrogate markers fordrug-related TdP risk have been tested and show promise. These in-clude QT dispersion, time from the peak to the end of the T-wave(Tpeak–Tend, also called TPTE), T-wave morphology, and heart-rate vari-ability (HRV).

QT DispersionThat the QT interval differs between different leads is partly due to dif-ferences in repolarization time between the various myocardial layers.The QT dispersion is the difference in time between the lead with theshortest and the lead with the longest QT interval and is thus a measureof myocardial heterogeneity during the repolarization process. A QTdispersion of more than 100 milliseconds, or an incremental differenceof more than 100%, has been associated with proarrhythmic effects ofmedications (Haddad and Anderson 2002). Amiodarone, a class IIIantiarrhythmic drug that prolongs the QT interval but rarely inducesTdP, was found to decrease repolarization heterogeneity and therebydecrease QT dispersion (Hii et al. 1992; Hohnloser 1997). Risperidonehas been shown to increase the QT interval but without an incrementalincrease in QT dispersion, and thus would be not associated with TdPrisk, a fact borne out by clinical experience (Yerrabolu et al. 2000). Ar-guments against the use of QT dispersion as a surrogate marker relateto the fact that the QT interval itself varies widely and in some leads canbe difficult to estimate. Because QT dispersion relies on QT measure-ments in all 12 leads, there is added variability, leading some to arguethat further studies are needed to determine the validity of QT disper-sion as a surrogate marker for TdP risk.

T-Wave-Related MeasurementsOther proposed surrogate markers rely solely on T-wave-relatedmeasurements. One of these is the time from the peak to the end of theT-wave (see Figure 7–3). TPTE exists as an absolute value and also asa measure of dispersion as calculated in the QT dispersion equation.Although TPTE purportedly reflects transmural dispersion of re-polarization (Antzelevitch et al. 2007), changes in T-wave morphologyare another surrogate marker for TdP risk derived from changes seen in


patients with congenital long QT syndrome (Malik and Camm 2001;Struijk et al. 2006). The congenital long QT syndrome type II is due tomutations in the HERG potassium channel gene, and the electrocar-diogram in these individuals demonstrates T-wave flattening andnotches. Unfortunately, the widespread use of T-wave morphology asa TdP risk marker has been complicated by difficulties in quantifyingthese morphological changes (Taylor 2003a), but newer data, derivedfrom more intensive study of long QT patients, has overcome many ofthe technical hurdles to the extent that this parameter will be used tomonitor TdP risk in future drug studies (Couderc et al. 2008; Kanters etal. 2004; Struijk et al. 2006).

Heart Rate VariabilityDuring inspiration and expiration, the heart rate accelerates and decel-erates, creating an innate source of variability that is a measure of heartresponsiveness. HRV thus relates to these beat-to-beat alterations in theheart rate and is usually derived from a 24-hour Holter recording. HRVreflects peripheral autonomic tone, and drugs with anticholinergicproperties reduce HRV (Rechlin et al. 1998). The importance of reducedHRV for arrhythmia risk is based on findings from post-myocardial in-farction studies indicating that decreased HRV is associated with in-creased mortality (Zuanetti et al. 1996).

Olanzapine and clozapine have been found to reduce HRV, but theimportance of this finding is unclear (Mueck-Weymann et al. 2002;Rechlin et al. 1994). On the other hand, thioridazine, which is associatedwith significant QTc prolongation and sudden death, was found to im-prove HRV (Silke et al. 2002). Interestingly, reduced HRV is seen notonly in antipsychotic-treated individuals but also in drug-naive pa-tients with schizophrenia (Malaspina et al. 2002), suggesting that de-creased HRV might be related to the disease itself, through inherentbiological mechanisms or an inactive lifestyle. As with other markers,more studies are needed to clarify the importance of HRV in studyingthe impact of antipsychotics on SCD risk.

Antipsychotic DrugsVirtually all antipsychotic drugs prolong the QT interval to some mea-surable extent (Figure 7–5), and patients treated with antipsychoticdrugs typically have longer QTc intervals and higher heart rates thando controls (Cohen et al. 2001). A critical issue when estimating the ex-tent of drug-induced QT prolongation is the baseline QT value. Because


patients are rarely drug-free at baseline for most clinical trials, the trueextent of QT prolongation from the drug under study can be underesti-mated if the baseline medication also prolongs the QT interval. Further-more, kinetic or dynamic drug-drug interactions can increase measuredQT prolongation.

In general, atypical antipsychotics are associated with a lower risk ofarrhythmia than conventional antipsychotics (Sicouri and Antzelevitch2008), yet conclusions drawn from such findings often fail to accountfor the long-term impact of metabolic side effects on cardiac risk. Onepaper estimated that 416 patients per 100,000 treated will die from thesequelae of clozapine-induced weight gain within a 10-year period(Fontaine et al. 2001), a figure that is much higher than mortality ratesfrom directly induced drug-related cardiac arrhythmia. Moreover, inthis same 10-year time frame, only 10–15 clozapine-treated patientswould die from agranulocytosis.

Conventional Antipsychotic DrugsConventional antipsychotic drugs were approved at a time when thedemand for cardiac safety data was less strict. As a consequence, manywidely used conventional antipsychotic drugs have not been thor-oughly investigated, although some have gained notoriety based onnewer safety data. Thioridazine and the related compound meso-

FIGURE 7–5. QTc prolongation with antipsychotics.Source. Adapted from Glassman and Bigger 2001.

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ridazine (which is metabolized to thioridazine) received black-boxwarnings in the U.S. market in 2001 due to QTc data that emerged frompremarketing studies for ziprasidone. In these studies, the mean QTcprolongation during treatment with thioridazine was 35 milliseconds(Salih et al. 2007). The Pfizer data were not the sole source for the warn-ing; clinical data indicated an increased risk of developing TdP andSCD with thioridazine (Reilly et al. 2002). In one Finnish study analyz-ing 49 sudden deaths during treatment with antipsychotics, thio-ridazine was involved in more than half of the cases, a finding thatcould not be explained by its relative market share (Mehtonen et al.1991). Other drugs under suspicion or withdrawn from various mar-kets include droperidol and pimozide. In some instances, the suspicionor withdrawal was based solely on measured QTc effects, despite apaucity of clinical cases of drug-induced TdP or SCD.

Haloperidol has been widely used for many years and is in generalconsidered to have a wide margin of cardiac safety based on overdoseand other data accumulated over decades of use. Although haloperidolis associated with an average 5-millisecond QTc prolongation, morethan 20 cases of haloperidol-induced TdP have been published (Yapand Camm 2003). This impression of safety might explain the cases ofTdP, because haloperidol is often prescribed in intensive care units andother critical care hospital settings among a cohort of patients withovert cardiac comorbidity. Patients with cardiac complications aremore vulnerable and often monitored more intensely with electrocar-diography, a fact that might increase the number of detected TdPs,some of which may be incidental to the use of haloperidol and are theresult of underlying comorbid conditions (e.g., electrolyte disturbances,use of other medications).

Atypical AntipsychoticsSertindole was introduced in 1997 as an atypical antipsychotic but wasvoluntarily withdrawn from the market a year later due to a possiblelink to sudden death. Despite the early concerns, subsequent postmar-keting surveillance studies failed to show an increased risk of suddendeath or arrhythmia (Peuskens et al. 2007). The mean QTc prolongationfrom sertindole is 20 milliseconds at therapeutic dosages, but so far noTdP cases with sertindole as the offending agent have been published.Based on further surveillance data documenting a general pattern oflow SCD risk, sertindole was reintroduced in several European coun-tries in 2006 but with restricted use as a second-line agent and withmandatory baseline and follow-up ECG monitoring.


Ziprasidone also prolongs the QTc interval about 20 milliseconds buthas not been associated with TdP (Glassman and Bigger 2001). MaximalQTc prolongation is reached at low therapeutic dosages. Reported ex-posures to ziprasidone dosages above 12 g have not resulted in TdP,confirming the medication’s lack of TdP risk; moreover, the majority ofziprasidone’s metabolism is through the aldehyde oxidase pathway,one that is neither saturable nor inhibitable by medications, a featurethat decreases the risk for drug interactions (Taylor 2003b).

Clinical ImplicationsBasic monitoring for elements of cardiovascular risk should includebody weight, a measure of central adiposity (e.g., waist circumferenceor hip:waist ratio), blood pressure, fasting lipids, and fasting glucose.Whether routine ECG monitoring will decrease morbidity or mortalityin patients with schizophrenia has not been extensively studied; how-ever, electrocardiography is a cheap and noninvasive procedure thatprovides important information about cardiac status. Experts at the2004 Mount Sinai Conference on the Pharmacotherapy of Schizophre-nia concluded that electrocardiography is recommended when pre-scribing thioridazine, pimozide, or ziprasidone only when cardiaccomplications, such as congenital long QT syndrome, known heart dis-ease, history of syncope, or genetic disposition to sudden death (for in-dividuals under age 40), are present (Marder et al. 2004). In contrast, theDanish Health Board recommends obtaining an electrocardiogram atbaseline, after 12 weeks, and annually in all patients treated with anti-psychotic drugs (Sundhedsstyrelsen 2007). The Maudsley PrescribingGuidelines (Taylor et al. 2007) suggest monitoring with electrocardio-graphy when patients are treated with high-dose antipsychotics orcombinations of drugs that have the propensity to prolong the QT inter-val. In conclusion, the evidence for routine ECG monitoring in patientstreated with antipsychotics is sparse, but we recommend ECG monitor-ing in patients with vulnerability to arrhythmia (e.g., electrolyte abnor-malities, bradycardia, structural heart disease) and in those receivingclozapine or drugs that significantly prolong the QT interval, have thepropensity to cause TdP, or have such monitoring mandated in the textof the package insert.

When electrocardiograms are obtained, we recommend using auto-mated calculations of the QTc interval, because most psychiatric clinicsand mental health professionals have less experience with manualreading. Machine-read electrocardiograms tend to overestimate the QTduration compared to manual readings, so in cases of significant QT


prolongation based on machine interpretation, one should seek cardiol-ogist confirmation. Many ECG machines still use the Bazett correctionformula; when that formula indicates that the heart rate is >70 bpm,manual reading and correction using Fridericia’s method are recom-mended. The correction formula used by the machine can be found inthe manual, so one can state in the patient record which formula wasused for QT correction (e.g., QTcF indicates that Fridericia’s formulahas been used).

The following QTc parameters should lead to a discussion with thepatient about discontinuation of potentially offending medications or,at the minimum, a reevaluation of benefits and risks of the current an-tipsychotic treatment (Sicouri and Antzelevitch 2008):

• QTc prolongation >60 milliseconds• QTc interval >500 milliseconds

Drugs that significantly prolong the QTc interval (ziprasidone, sertin-dole) or are associated with TdP (e.g., thioridazine or pimozide) shouldbe avoided in patients with prolonged QTc interval and electrolyte ab-normalities. When significant prolongations of QTc interval are de-tected in patients, serum potassium should be monitored and corrected.Finally, patients experiencing syncope or palpitations should be re-ferred for thorough examination to exclude other physical causes, in-cluding long QT syndrome.

Sudden Death and the Combination of Benzodiazepines and AntipsychoticsBecause the combination of antipsychotics and benzodiazepines hasbeen associated with sudden death, a black-box warning is provided re-garding the use of parenteral olanzapine in combination with paren-teral benzodiazepines (American Psychiatric Association 2005) basedon eight fatal events. Benzodiazepines and sedating antipsychoticshave respiratory depressant effects, and intramuscular administrationincreases the risk for respiratory collapse due to rapid systemic absorp-tion with no first-pass metabolism. Concomitant use of parenteral ben-zodiazepines and sedating antipsychotics (especially clozapine andparenteral olanzapine) should prompt careful monitoring of bloodpressure, respiratory rate, and oxygen saturation using an oximeterwith an alarm (if available). In cases of respiratory depression, flumaze-nil can reverse the effect of benzodiazepines. The risk of sudden deathassociated with the combination of benzodiazepines and an antipsy-chotic has been best described for clozapine and benzodiazepines (Rup-


precht et al. 2004), and this risk is probably due to the sedative andhypotensive effects of clozapine. Especially during the initial titrationof clozapine, when patients are not yet tolerant to its sedative proper-ties, precautions should be taken with the concomitant use of benzodi-azepines (Borentain et al. 2002).

Cardiac Aspects of Clozapine TreatmentClozapine remains the drug of choice for patients with treatment-resistantschizophrenia and for schizophrenia patients with suicidal ideation.According to most treatment guidelines, a trial of clozapine should beinitiated after failed trials of two or three other antipsychotics. The su-perior efficacy of clozapine compared with other antipsychotics hasbeen established in several trials, but clozapine is not considered a first-line drug due to the risk of agranulocytosis. Clozapine is also associatedwith several cardiac complications, and the estimated number of deathsdue to CVD is actually higher than the actual number of deaths due tohematological causes (Fontaine et al. 2001; A.M. Walker et al. 1997). Thehematological monitoring system required for all clozapine patientsprevents the vast majority of agranulocytosis cases from being fatal, butunrecognized cardiac complications remain a potentially serious sourceof morbidity and mortality.

One early retrospective study found that clozapine exposure was as-sociated with 3.8 times increased risk of SCD compared with use ofnonclozapine antipsychotics, based on six deaths in the clozapinegroup; however, the control group was not matched for basic demo-graphic variables such as severity of disease and duration of illness(Modai et al. 2000). The absence of matching is a serious methodologicalissue related to prescription bias, because clozapine is typically pre-scribed for more chronic patients who, by virtue of age and prior med-ication exposure, might possess more SCD risk factors. Furthermore, anautopsy was performed in only one SCD patient, so the etiology of SCDin some cases might be related to other etiologies (e.g., structural dis-eases). Given the small volume of published data, it is not clear whetherclozapine treatment is associated with an increased mortality risk fromSCD compared to treatment with other antipsychotics. Any added mor-tality risk associated with clozapine is ascribable primarily to other car-diac diseases, such as cardiomyopathy or myocarditis, or to thesecondary cardiovascular effects of clozapine-induced weight gain andmetabolic changes (Fontaine et al. 2001).

Myocarditis and Pericarditis. Although clozapine is unlikely to di-rectly induce SCD, clozapine has been associated with some unique


cardiac complications, including myocarditis and cardiomyopathy.Myocarditis is an inflammation of the myocardial cells reported to oc-cur within the first months of clozapine initiation. The development ofthis condition is probably due to immunoglobulin E–mediated hyper-sensitivity, a type 3 allergic reaction, but direct toxic effects on the myo-cardium (Killian et al. 1999) and even low selenium induced byclozapine have also been proposed as mechanisms (Vaddadi et al.2003). The incidence of clozapine-induced myocarditis is estimated tobe 1 in 500 and is fatal in up to 50% of cases (Killian et al. 1999). The pre-sentation of myocarditis includes flulike symptoms, fever, dyspnea, si-nus tachycardia, palpitations, fatigue, respiration-dependent pain, andchest discomfort. Pain is usually present only if the pericardium is in-volved. The primary ECG findings are ST elevations and T-wave inver-sions, and common laboratory abnormalities include elevated serumcreatine kinase, leukocytosis, and eosinophilia. Eosinophilia is commonin patients developing myocarditis but also occurs without myocardi-tis. Usually the eosinophilia is transient.

Within the first months of treatment with clozapine, cliniciansshould carefully examine any patients with flulike symptoms, fever, si-nus tachycardia, and other cardiac symptoms to exclude myocarditis,because the presentation may be subtle. The optimal way to diagnosemyocarditis is to measure blood troponin levels, because troponin re-flects myocardial damage (Kay et al. 2002; Merrill et al. 2006). Some cli-nicians have suggested regular troponin testing during the initialtreatment with clozapine to increase the chances for prompt detectionof myocarditis, but no prospective data exist to endorse this as a routinemeasure (Kay et al. 2002). In cases of myocarditis, clozapine must bediscontinued immediately and treatment with corticosteroids initiated.Rechallenge with clozapine should be performed only in severe refrac-tory schizophrenia cases without other viable treatment options, if thebenefits are considered to outweigh the possible serious risks, and withclose cardiac monitoring (Reid 2001).

Complicating the diagnosis of myocarditis is the finding that ap-proximately 20% of patients treated with clozapine develop benignhyperthermia within the first 3 weeks of treatment (Tham and Dickson2002). Benign hyperthermia is often misdiagnosed as neuroleptic ma-lignant syndrome, flu, or infection; however, the symptoms of benignhyperthermia are similar to those of myocarditis, so in these instances acareful examination must be performed. When benign hyperthermiaoccurs in the beginning of clozapine treatment, a white blood count,electrocardiogram, and troponin levels should be obtained to excludemyocarditis.


Cardiomyopathy. The three types of cardiomyopathy are dilated (con-gestive), hypertrophic, and restrictive. Although dilated cardiomyopa-thy is a rare occurrence in the general population, in patients treatedwith clozapine, it accounts for more than 60% of cardiomyopathy cases(Meyer et al. 2007). Dilated cardiomyopathy typically starts in the leftventricle where myocardial muscle fibers stretch and become thinner,leading to chamber enlargement, and later spread to the right ventricleand to the atria. As with myocarditis, the underlying mechanism is un-clear, but one explanation is that in some patients, clozapine might havea direct toxic effect on myocytes mediated by free radicals that inducemyocardial injury and resultant myopathy. Another explanation relieson the fact that some cases of clozapine-induced cardiomyopathy haveevolved from myocarditis. The hypothesis is that prior myocarditis mayinitiate an autoimmune process that further injures myocardial cells.The myocarditis episode might have been subclinical and resolved with-out treatment, but the latent autoimmune process explains the relativelylate onset of cardiomyopathy during treatment compared with the ear-lier presentation of myocarditis. Clozapine-induced cardiomyopathyhas also been related to low selenium levels, but it is unknown whetherselenium supplementation can reduce the risk of cardiomyopathy ormyocarditis.

Although case reports have been published, there is some debatewhether clozapine increases the risk for cardiomyopathy. Novartis re-ported that patients treated with clozapine had a cardiomyopathy inci-dence comparable to that of the U.S. population (Meyer et al. 2007);however, failure to show a difference may be related to type II error(given the infrequent occurrence in the general population) or might bedue to underreporting of spontaneous adverse events. Killian et al.(1999) estimated the risk of clozapine-induced cardiomyopathy to be51.5 per 100,000 patient-years, a fivefold increased risk over that seen inthe general population. The other issue in ascribing causality relates tothe fact that patients treated with clozapine have several known cardio-myopathy risk factors, including sinus tachycardia (a feature of cloza-pine treatment discussed below), alcohol abuse or dependence, CHD,smoking, obesity, and metabolic disorders.

In more than 65% of reported cases, cardiomyopathy occurs after6 months of clozapine treatment, with a 20% fatality rate (Merrill et al.2005). Because cardiomyopathy is likely underreported, the incidencemay be higher. With cardiomyopathy, as with myocarditis, no dosagedependency has been found. The physical symptoms are those relatedto heart failure: exertional dyspnea, fatigue, peripheral edema, orthop-nea, and chest pain. Diagnosing cardiomyopathy can be difficult in


patients with schizophrenia because many patients already experiencedyspnea, peripheral edema, and fatigue due to poor physical condition-ing. The electrocardiographic findings include sinus tachycardia, atrialand ventricular arrhythmias, and ST-segment, T-wave, and P-wave ab-normalities, but the electrocardiogram can remain normal in earlier, lesssevere stages. Echocardiography is the most sensitive test for diagnos-ing cardiomyopathy, but it is unclear whether routine echocardio-graphy is feasible or cost effective. Nonetheless, it should be performedearly and with short notice in cases where cardiomyopathy is suspected.When cardiomyopathy is diagnosed, clozapine must be discontinued,and the focus of medical treatment should be on treating the complica-tions of heart failure. Clozapine-induced cardiomyopathy can be re-versible if it is detected early and clozapine is promptly discontinued.

Sinus Tachycardia. One-fourth of patients treated with clozapine willdevelop a 10- to 15-bpm increase in pulse rate. This effect is due to thecombination of anticholinergic vagal inhibition and an increase in cir-culation of catecholamines due to α1-adrenergic blockade (Safferman etal. 1991). Clozapine-induced tachycardia is dosage dependent but canoccur at low dosages in sensitive individuals. Sinus tachycardia is par-ticularly prominent during the initial titration, so a slower titrationschedule might resolve the problem in certain individuals.

Sinus tachycardia is often asymptomatic, but some patients complainof increased heart rate. As tachyphylaxis can occur during the first 4–6weeks of treatment, β-adrenergic blocker treatment need not be initiatedduring this period. Clinicians need to remember that tachycardia is asymptom of both myocarditis and cardiomyopathy, so treatment with aβ-adrenergic blocker might complicate the diagnosis of these conditions.

Whether asymptomatic clozapine-induced sinus tachycardia shouldbe corrected is unclear, but in general, persistent tachycardia (>100 bpm)is a known cardiomyopathy risk factor, so β-adrenergic blockers are of-ten used in those patients with chronic tachycardia, although there is nocompelling data that this treatment reduces myopathy risk. Symptom-atic sinus tachycardia should be treated with a cardioselective β-adren-ergic blocker (e.g., metoprolol) to avoid the possible effects of nonspecificbeta blockade (e.g., exacerbation of restrictive airway disease) (Young etal. 1998); monitoring of blood pressure is also recommended.

Nonspecific T-Wave Changes. T-wave changes are common duringtreatment with clozapine, and up to 20% of patients will develop ECGabnormalities when switched to clozapine (Kang et al. 2000). The typicalT-wave changes that occur during clozapine therapy include flattening,


inversion, and depression. The significance of these changes is unknown,and they are most likely benign; however, it is important to exclude otherconditions causing T-wave changes such as myocarditis, myocardial in-farction, or cardiomyopathy. Asymptomatic ST-segment elevation withno relation to ischemia can also occur during treatment with clozapineand probably has no clinical significance. As with certain T-wavechanges, the clinician should thoroughly exclude other potentially seri-ous diagnoses related to ST-segment elevations, such as myocardial inf-arction, ischemia, myocarditis, and cardiomyopathy (Kang et al. 2000). Inaddition to electrocardiogram, other tests—echocardiography, serumtroponin levels, or stress tests—might be indicated on the basis of ECGchanges and the clinical picture so as to rule out other diagnoses.

QTc Prolongation. Clozapine has been associated with QTc prolonga-tion (Kang et al. 2000; Lin et al. 2004), but the ability of clozapine to pro-long the QT interval is questionable, in part due to the commonoccurrence of clozapine-induced sinus tachycardia. Because many ECGmachines use the Bazett formula, the tendency is to overestimate thecorrected QT interval due to Bazett’s limitations at heart rates >70 bpm(Dogan et al. 2005); moreover, the frequent presence of T-wave abnor-malities with clozapine exposure creates further difficulties for the ex-act estimation of the QT interval.

Orthostatic Hypotension. Orthostatic hypotension is defined as asustained decrease in blood pressure exceeding 20 mmHg systolicor 10 mmHg diastolic occurring within 3 minutes of upright posture.Several antipsychotic drugs have the propensity to induce orthostatichypotension due to potent α1-adrenergic antagonism. Among the atyp-ical antipsychotics, clozapine and quetiapine are more often associatedwith orthostatic hypotension, which generally seems to be dosage de-pendent, with dizziness corresponding roughly to the extent of posturalchange. Orthostatic hypotension is often the limiting factor during theup-titration of clozapine, but tachyphylaxis will occur within weeks, soslowing the pace of titration may resolve the problem.

Cardiac Complications With Nonclozapine AntipsychoticsMyocarditis and cardiomyopathy have been reported with antipsy-chotic drugs other than clozapine, but whether these cases are clearlymedication related is unknown. The most common cardiac-relatedcomplications from nonclozapine antipsychotic drugs are due to ortho-


static hypotension and QT prolongation, but one should not discountthe long-term effects of dyslipidemia and weight gain on cardiovascu-lar risk. Orthostatic hypotension is especially problematic for elderlypatients due to poor vasomotor tone and can be troublesome due to theincreased risk of falls. Slower titration schedules may permit toleranceto medication-induced postural changes and thereby diminish the riskof falls and syncope.

Coronary Heart DiseaseCoronary heart disease refers to the failure of coronary circulation,whereas cardiovascular disease reflects all consequences of atheroscle-rotic diseases, including stroke and diseases of the heart. In CHD pa-tients, inadequate circulation to the myocardium leads to ischemia andeventually to angina or acute myocardial infarction. The typical causeof CHD is atherosclerosis due to an accumulation of cholesterol-ladenatheromatous plaques in vessel walls that are prone to inflammationand eventual rupture with vessel thrombosis. CHD is the most commoncause of death in Western societies and is responsible for about 20% ofall deaths (British Heart Foundation 2007).

Using baseline data from the Clinical Antipsychotic Trials of Inter-vention Effectiveness (CATIE) schizophrenia trial, Goff et al. (2005) es-timated 10-year CHD risk with the algorithm derived from theFramingham heart study (see Figures 7–6A and 7–6B) and found thatpatients with schizophrenia had an increased risk for CVD comparedwith matched subjects in the general population: 9.4% versus 7.0% formales and 6.3% versus 4.2% for females. Several factors are involved inthis level of risk, including high smoking prevalence, sedentary life-style, obesity, medication effects, and perhaps the disease itself. Activ-ity in the hypothalamic-pituitary-adrenal axis is increased in patientswith schizophrenia and leads to increased levels of catecholaminesand cortisol (E. Walker et al. 2008). Increased hypothalamic-pituitary-adrenal axis activity increases the risk for CVD, dyslipidemia, hyper-tension, vasoconstriction, and platelet activation, and might be anothermechanism that increases CHD risk in schizophrenia patients.

The CHD risk for any individual represents the sum of both non-modifiable and modifiable factors. Nonmodifiable factors include age,gender, history of CVD, and genetic predisposition. Modifiable factorshave been identified by large prospective trials, such as the INTER-HEART study (Yusuf et al. 2004), and include the following:


• Smoking• Diabetes• Hypertension• Abdominal obesity• Inadequate daily consumption of fruits and vegetables• Psychosocial factors, stress, and depression• Insufficient exercise• Alcohol intake

Risk factors are additive, and several lifestyle risk factors are knownto be increased in patients with schizophrenia. Dyslipidemia is onemodifiable CVD risk factor that is more prevalent in patients withschizophrenia. Certain antipsychotic drugs are associated with delete-rious changes in serum cholesterol and triglyceride levels; moreover,the effects of these changes are compounded by the fact that patientswith schizophrenia are less likely to receive treatment with statins(Hennekens et al. 2005). (See Chapter 6, “Effects of Antipsychotics onSerum Lipids,” for more information about dyslipidemia and antipsy-chotics.) Smoking increases CVD mortality risk by 60%–80%, and up to80% of patients with schizophrenia smoke cigarettes (Hughes et al.1986). Not only is smoking prevalence increased in this patient popula-tion, but smokers with schizophrenia inhale more deeply and extractmore compounds from the cigarettes than do other smokers (Olincy etal. 1997). (For further information about smoking and schizophrenia,see Chapter 9, “Nicotine and Tobacco Use in Patients With Schizophre-nia.”) Diabetes mellitus increases CHD risk by two- to threefold in menand three- to sixfold in women (Hennekens et al. 2005), and the preva-lence of diabetes mellitus and prediabetic states such as metabolic syn-drome are 1.5 to 2 times greater in patients with schizophrenia(Mukherjee et al. 1996) (see Chapter 4, “Obesity and Schizophrenia,”and Chapter 5, “Glucose Intolerance and Diabetes in Patients WithSchizophrenia”). Alcohol and substance use are also more common inpatients with schizophrenia (see Chapter 11, “Substance Abuse andSchizophrenia”). Lastly, a direct effect of antipsychotic drugs on myo-cardial infarction risk has been hypothesized as being mediated by va-sospasm or induction of thrombosis. This suggestion emanates fromepidemiological studies showing that patients receiving psychotropicmedications have an increased risk of cardiovascular events; however,as discussed previously, this might be a confounding by indicationmore than a direct effect of antipsychotics.


HypertensionHypertension is defined as blood pressure >140/90 mmHg and is awell-established risk factor for CVD, including stroke and myocardialinfarction (Wang et al. 2007). Patients with schizophrenia do not seemto be more prone to hypertension, but conflicting data have been re-ported on this subject. Clozapine has been shown in some studies to in-crease blood pressure during long-term treatment, but not all studieshave shown similar findings (Henderson et al. 2004; Lund et al. 2001).However, the increase in weight associated with clozapine and olanza-pine increases future hypertension risk, although this effect is often notseen for years.

Managing Coronary Heart Disease in Patients With SchizophreniaTreatment of CVD in schizophrenia is similar to that for the generalpopulation, although patient factors, including lack of motivation, poorcommunication skills, and poor medication compliance, make it diffi-cult to achieve the same results. The first step in managing CVD risk isto obtain baseline data, including history of CVD, family CVD history,level of physical activity, tobacco and alcohol use, presence of otherphysical diseases conferring risk (especially diabetes and hyperten-sion), and current medications. Obtaining a good medical history takestime, and more than one session might be needed for more severely illpatients. The clinician should talk to the patients about the nature andhistory of prior physical diseases, because some patients will deny or bereluctant to discuss these issues. Furthermore, a thorough physical ex-amination is needed, including weight, central adiposity (waist circum-ference or hip:waist ratio), body mass index, and blood pressure.Laboratory values are also important and must include a fasting glu-cose and lipid panel, as well as an electrocardiogram in certain circum-stances.

The most important aspect of preventive CVD treatment is to reduceor remove modifiable risk factors by promoting smoking cessation,increased exercise, and healthier eating habits. The extent to which anyinterventions are successful will always depend on the patient’s moti-vation; however, one should bear in mind that patients with schizo-phrenia can achieve meaningful results but may need more motiva-tional support. Ten-year risk of CHD can be estimated from theFramingham heart study algorithm (see Figure 7–6). For patients with


two or more cardiovascular risk factors, the clinician should estimatetheir 10-year risk and provide appropriate interventions.

In addition to lifestyle interventions that require active efforts on thepart of the patient, other interventions require activity by the physician.These include treating the patient’s hypertension, recommending aspi-rin therapy, and carefully considering appropriate antipsychotic medi-cation.

Treating HypertensionBefore treating hypertension, the clinician should ensure that the pa-tient has verifiable hypertension and not hypertension due to “white-coat syndrome.” Blood pressure should be measured after having thepatient sit in a chair or lie on a bed for 10 minutes. An end-of-visit bloodpressure reading is likely to be more reflective of the patient’s true rest-ing blood pressure than that obtained when the anxious patient first en-ters the office or clinic. The width of the cuff selected should be at least40% of the circumference of the limb to be used. A common mistake isto use the wrong cuff size: a small cuff tends to overestimate blood pres-sure. Also, blood pressure measures should be repeated at least twotimes at two different occasions before hypertension is diagnosed.

According to consensus guidelines, blood pressure should be moni-tored before antipsychotic treatment is initiated, 12 weeks after initia-tion, and then annually (American Diabetes Association et al. 2004). Noformal guidelines exist for treating hypertension in patients withschizophrenia, but the clinician should inform patients about nonphar-macological interventions (e.g., exercise, weight loss, restriction of saltintake) and allow a period of up to 3 months to assess the effects of life-style modification. When medications are required, possible additivehypotensive effects with other medications should be taken into consid-eration, but otherwise a reasonable approach is to adapt general guide-lines for hypertension treatment.

AspirinAspirin reduces myocardial infarction and stroke risk but at the ex-pense of increased risk for gastrointestinal bleeding. The anticoagulanteffect of aspirin is mediated through irreversible blockade of thrombox-ane A2 formation in platelets. Daily low-dose aspirin (81 mg) should beconsidered for patients with a history of CVD or CVD-equivalent disor-ders (e.g., diabetes mellitus, severe peripheral vascular disease) or forpatients with moderate to high risk. Patients with schizophrenia shouldbe educated about symptoms of gastritis and gastrointestinal bleeding


FIGURE 7–6A. Framingham 10-year cardiovascular risk estimation chartsfor males.

Age Points Age Points

20–34 –9 55–59 8

35–39 –4 60–64 10

40–44 0 65–69 11

45–49 3 70–74 12

50–54 6 75–79 13

HDL mg/dL (mmol/L) Points

≥ 60 (≥1.6) –1

50–59 (1.3–1.5) 0

40–49 (1.0–1.2) 1

< 40 (< 1.0) 2

Systolic BP (mmHg) If untreated If treated

<120 0 0

120–129 0 1

130–139 1 2

140–159 1 2

≥160 2 3

Total cholesterolmg/dL (mmol/L)

Age20–39

Age40–49

Age50–59

Age60–69

Age70–79

<160 (< 4.1) 0 0 0 0 0

160–199 (4.1–5.2) 4 3 2 1 1

200–239 (5.3–6.2) 7 5 3 1 0

240–279 (6.3–7.2) 9 6 4 2 1

≥ 280 (≥ 7.3) 11 8 5 3 1

TobaccoAge

20–39Age

40–49Age

50–59Age

60–69Age

70–79

Nonsmoker 0 0 0 0 0

Smoker 8 5 3 1 1

Point total 10-Year cardiovascular risk (%)

< 0 < 1 11 8

0–4 1 12 10

5 2 13 12

6 2 14 16

7 3 15 20

8 4 16 25

9 5 ≥17 ≥ 30

10 6

10-Year cardiovascular risk (%) Point total


FIGURE 7–6B. Framingham 10-year cardiovascular risk estimation chartsfor females.

Age Points Age Points

20–34 –7 55–59 8

35–39 –3 60–64 10

40–44 0 65–69 12

45–49 3 70–74 14

50–54 6 75–79 16

HDL mg/dL (mmol/L) Points

≥ 60 (≥1.6) –1

50–59 (1.3–1.5) 0

40–49 (1.0–1.2) 1

< 40 (< 1.0) 2

Systolic BP (mmHg) If untreated If treated

<120 0 0

120–129 1 3

130–139 2 4

140–159 3 5

≥160 4 6

Total cholesterolmg/dL (mmol/L)

Age20–39

Age40–49

Age50–59

Age60–69

Age70–79

<160 (< 4.1) 0 0 0 0 0

160–199 (4.1–5.2) 4 3 2 1 1

200–239 (5.3–6.2) 8 6 4 2 1

240–279 (6.3–7.2) 11 8 5 3 2

≥ 280 (≥ 7.3) 13 10 7 4 2

TobaccoAge

20–39Age

40–49Age

50–59Age

60–69Age

70–79

Nonsmoker 0 0 0 0 0

Smoker 9 7 4 2 1

Point total 10-Year cardiovascular risk (%)

< 9 < 1 19 8

9–12 1 20 11

13 2 21 14

14 2 22 17

15 3 23 22

16 4 24 27

17 5 ≥ 25 ≥ 30

18 6

10-Year cardiovascular risk (%) Point total


(e.g., tarry stools, midepigastric pain between meals), and those takingaspirin should be questioned about gastrointestinal side effects becausetheir self-report rates are lower than for the general population.

Type of Antipsychotic MedicationThe metabolic side effects of atypical antipsychotic drugs differ greatly.Although olanzapine and clozapine are associated with greater risk forweight gain than the other atypical antipsychotics, in practice almostany of these drugs is associated with greater weight gain than placebo.Switching from a drug with high metabolic liabilities to a lower-riskdrug can lead to substantial weight loss and other metabolic improve-ment, but in some cases switching to a lower-risk drug is not possibledue to risk of psychotic relapse, especially in patients treated with cloz-apine. For clozapine-treated patients, standard treatment for dyslipi-demia and glucose intolerance should be offered, and some dataindicate that adding a metabolically low-risk atypical antipsychotic(e.g., aripiprazole) combined with judicious reduction of the clozapinedosage can be beneficial, although evidence for this combination re-mains sparse. Treating patients with schizophrenia always requires abalance between efficacy and side effects. Causing diabetes due to di-rect drug-related mechanisms or secondary to antipsychotic-inducedweight gain is devastating, but not treating schizophrenia can be fatal.Any choice of an agent should be balanced by the knowledge that thisis a patient population at high risk for cardiovascular disease and re-lated mortality; therefore, every effort should be made to minimize theiatrogenic contributions to this risk equation.

Access to Somatic TreatmentPatients with schizophrenia are less likely than the general populationto receive proper treatment for their medical comorbidities (Goldman1999), a fact related to patient lifestyle variables, lack of health insur-ance, and systemic health care issues. (See Chapter 1, “Improving Phys-ical Health Care for Patients With Serious Mental Illness,” for morediscussion of these topics.) Patients with schizophrenia often have neg-ative symptoms that result in less motivation to seek care and decreaseddrive to maintain good physical health. Poor communication skills anddecreased pain sensitivity can lead to underreporting of symptoms,making diagnosis of health conditions more difficult (Singh et al. 2006).Marchand (1955) reported that up to 85% of psychotic patients werenoted to have experienced an acute myocardial infarction without hav-ing any pain, compared with 29% of acute myocardial infarction pa-


tients in the Framingham heart study. In acute myocardial infarctioncases presenting without pain, the infarction is often untreated and firstrecognized on a subsequent routine electrocardiogram or postmortemduring an autopsy. This lack of pain sensitivity emphasizes the need formonitoring of cardiovascular risk elements in all patients with schizo-phrenia, because the actual myocardial infarction event may go unrec-ognized and untreated.

An important theme throughout this book is the need for psychiatricproviders to assume responsibility for physical health monitoring ofpatients with schizophrenia. Many patients with schizophrenia do notregularly receive primary care, and primary care providers might be re-luctant to monitor and treat physical disease due to the barriers posedby presence of a severe mental illness. As discussed in Chapter 1, “Im-proving Physical Health Care for Patients With Serious Mental Illness,”several possible models have been proposed for integrating psychiatriccare and medical care for this patient population, but the fact remainsthat all doctors caring for schizophrenia patients must be alert for signsof physical disease and be prepared to perform basic physical healthmonitoring (Brown 1997).

Key Clinical Points

◗ Cardiovascular heart disease is the most common cause of death in pa-tients with schizophrenia.

◗ Drug-induced torsade de pointes is rare and accounts for a fraction ofsudden-death cases.

◗ Reducing risk factors and treating comorbidities (e.g., obesity, hyper-tension, dyslipidemia, smoking) are the cornerstones of the treatmentand prevention of cardiovascular disease.

◗ Clozapine is associated with both myocarditis and cardiomyopathy.Cardiovascular disease attributable to clozapine’s metabolic propertiesis estimated to cause more deaths than agranulocytosis.

◗ Switching antipsychotic medications to a metabolically lower-risk drugcan lead to substantial weight loss and metabolic improvements.


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CHAPTER 8

BehavioralTreatments for

Weight Managementof Patients With

Schizophrenia

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.

An explosion of articles in the last decade has called attention to thehigh prevalence of metabolic abnormalities, such as obesity, diabetes,dyslipidemias, and associated problems, in persons with severe mentalillness. As pointed out in Chapter 2, “Excessive Mortality and Morbid-ity Associated With Schizophrenia,” increasingly robust evidence alsoindicates that in Europe and North America, people with schizophreniaand other serious mental illnesses die 20–25 years earlier on averagethan comparable persons in the general population (Hennekens et al.2005; McGrath et al. 2008; Osby et al. 2000; Saha et al. 2007). Data alsosuggest that the increased prevalence of some risk factors for early mor-tality from cardiovascular disease and diabetes may have been presentin individuals with psychotic illnesses as long as 100 years ago. For


example, long before the advent of modern antipsychotic medications,astute clinicians had noted that recovery in psychotic illness is often ac-companied by weight gain (Jaspers 1923; Kraepelin 1919).

Much of the recent attention to metabolic issues in serious mental ill-ness is linked to the widespread use of novel antipsychotics. However,patients and some observant practitioners had already highlightedmedication-associated weight gain as a common side effect of most an-tipsychotics from the class now called first-generation antipsychotics(see Ganguli 1999 for a review). For example, Buis (1992) reported thatweight gain was one of patients’ most frequent complaints about theside effects of conventional depot antipsychotics. Although some novelantipsychotics, notably clozapine and olanzapine, are associated withespecially high risk of weight gain (and insulin resistance and diabetes),all antipsychotics except molindone result in more clinically significantweight gain than placebo in randomized clinical trials (Casey et al.2004).

Despite the long-standing nature of the problem and its importanceto consumers and to their general health status, few intervention stud-ies have addressed weight gain and its associated risks for people withschizophrenia. From a practical perspective, the interventions thathave been used for persons with schizophrenia have focused almostexclusively on weight reduction. Focusing on weight reduction as astrategy to reduce the risk of cardiovascular disease and diabetes iscompletely consistent with the approach being taken in studies fundedby the National Institutes of Health, such as the LOOK-AHEAD study(Ryan et al. 2003; see also Look AHEAD Research Group 2007), andwith National Heart, Lung, and Blood Institute (1998) recommen-dations. Thus, in this chapter we focus on studies aimed at weight re-duction. With respect to nonpharmacological approaches to weightreduction, the majority of studies have used techniques based on be-havioral therapy principles, so before discussing the approaches, webriefly review the behavioral techniques common to most weight lossprograms.

Principles of Behavioral Approaches to Weight LossAs reviewed by Wing (2004), the systematic application of behavioraltherapy techniques to induce weight loss started in the late 1960s. Theearly studies tended to treat milder forms of overweightness and obe-sity, through a focus on stimulus control rather than on specific calorie-

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intake goals or exercise and activity. In reviewing these early programs,Wadden et al. (2004) noted that weight loss of 4–5 kg was common inprograms typically lasting 10 weeks. During the 1970s and 1980s, as theprevalence of obesity grew, treatments became more sophisticated andcomprehensive, and tended to last for longer. By the mid-1990s, av-erage weight loss in behavioral programs, which typically lasted for6 months, had risen to about 9 kg, or about double what had been re-ported in the 1960s (Wing 2004). Probably one of the most persuasivedemonstrations of the efficacy of behavioral methods for weight losswas the Diabetes Prevention Trial, in which over 3,000 overweight orobese individuals with impaired glucose tolerance were randomized toa lifestyle intervention aimed at weight loss, metformin, or placebo. Notonly was significant weight reduction achieved in the lifestyle group,but progression to diabetes was also reduced (Knowler et al. 2002). Fur-thermore, not only was behavioral treatment twice as effective as met-formin in producing weight loss, but the intervention was so effectivein preventing the progression of prediabetes to diabetes that the trialwas stopped prematurely (Knowler et al. 2002). The key componentsfor the nonpharmacological management of overweight and obesity areidentified in Table 8–1.

Most approaches to the treatment of obesity are described as “behav-ioral” and are based on learning theory (Wing 2004) and the principlesof classical conditioning (Wadden and Foster 2000). In the last 20 yearsor so, cognitive approaches have been added to behavioral therapy torestructure and correct distorted and irrational thoughts that under-mine motivation and progress in treatment (Wadden and Foster 2000).Common components of most behavioral weight reduction programsinclude 1) goal-setting, especially establishing realistic short-term goals(Bandura 1977); 2) self-monitoring (Kazdin 1974) of nutritional intakeand physical activity; 3) a nutritional focus, with teaching and demon-strating of healthy eating habits (Brownell 2004; Wing 1989); and 4)strategies to increase exercise and decrease sedentary behavior (Jakicic2002; Jakicic and Gallagher 2003; Jakicic et al. 2004). Stimulus control, bychanging the environment to alter cues so as to increase appropriate(and decrease inappropriate) eating behavior, was also an early compo-nent of behavioral programs (Ferster et al. 1962; Stuart 1967). Problemsolving (D’Zurilla and Goldfried 1971) is often included to help individ-uals develop strategies individualized to their own unique situations(Wing 2004). Once weight loss is achieved, most programs move partic-ipants to relapse prevention or weight maintenance regimens(Brownell et al. 1986; Jeffery and French 1997; Klem et al. 2000; Perri etal. 2001; Wadden et al. 2004). Because these strategies are often offered


as a package, determining which program components are essential tothe efficacy of the treatments is difficult. Recently, cognitive-behavioraltherapy (CBT) has attempted to distinguish itself from behavioral ther-apy by pointing out that the former specifically includes restructuringcognitive processes (Cooper and Fairburn 2002).

In the studies of weight loss in individuals with schizophrenia, theapproaches have included one or more elements of common behavioralapproaches, but in many instances, the precise theoretical underpin-nings of the program components have not been specified. A selectivereview of interventions for weight loss in schizophrenia follows.

Behavioral and Nutritional Interventions in SchizophreniaOne of the earliest published attempts to assist psychotic patients withweight loss was carried out in a state hospital in the United States, morethan 40 years ago, by Harmatz and Lapuc (1968). This pioneering studyinvolved a rigorous behavioral program using negative reinforcement:

TABLE 8–1. Key components for the management of overweightness and obesity

Component Key points for management

Diet Energy intake should be reduced by 500–1,000 kcal/day.

Dietary fat should be restricted to <30% of energy intake.

Optimal intakes of carbohydrate and protein have not been established.

Exercise Significant health benefits will occur with 150 minutes of moderate exercise (at 55%–69% of maximum heart rate) per week. Overweight and obese individuals should increase moderate exercise to 200–300 minutes per week.

Behavioral therapy

Training should be given in behavioral concepts (e.g., problem solving, goal setting, social support). Such training is associated with improved long-term outcomes.

Source. Adapted from Jakicic et al. (2001).


one group of patients lost money if they failed to lose weight. Two com-parison groups included a group that discussed weight loss strategiesand provided peer support and a group that received nutritional coun-seling. The subjects were randomly assigned to one of the three groups.The group assigned to contingent negative reinforcement had signifi-cantly greater mean weight loss than the other two groups (−7% of ini-tial body weight over 10 weeks). In a second historically importantstudy, Rotatori et al. (1980) recruited patients with psychotic illness re-siding in community-based group homes. Patients were then randomlyassigned to either a 14-week behavioral weight loss group intervention,closely resembling most modern weight loss programs, or to no inter-vention (“usual care”). The group randomly assigned to behavioraltreatment lost significantly more weight (mean −3.3 kg) than the controlgroup (mean +0.02 kg). The Rotatori et al. study is notable for the use ofa well-developed manual for the delivery of treatment, and the behav-ioral techniques employed had already been refined in earlier studies ofpatients with Down syndrome. We highlight these early studies be-cause they dealt with populations that are still relevant today: severelymentally ill persons who are in long-stay hospitals as well as those incommunity residential services.

These early (first-generation) studies also deserve more recognitionfor the following reasons: 1) they demonstrated that patients with psy-chotic illnesses could participate successfully in nonpharmacologicalweight loss interventions, and 2) even though these were pioneeringstudies, they were well-designed randomized trials, in the best tra-ditions of generating evidence for clinical practice. Surprisingly, thesecond generation of published studies was, for the most part, uncon-trolled, or failed to employ random assignment to the intervention orcomparison conditions. Fortunately, the most recent generation (thirdgeneration) of reports is predominantly from randomized controlledtrials, and thus a good evidence base is growing.

Numerous reviews have been published of behavioral and nutri-tional interventions for weight loss in patients with schizophrenia (e.g.,Alvarez-Jiménez et al. 2008; Faulkner and Cohn 2006; Faulkner et al.2007; Ganguli 2007; Loh et al. 2006; Strassnig and Ganguli 2007;Werneke et al. 2003). All reviews concluded that modest short-termweight loss is possible in this population. In a recent meta-analysis thatexamined randomized controlled trials only, Alvarez-Jiménez et al.(2008) reported a statistically significant reduction in mean bodyweight for those in the nonpharmacological intervention groups com-pared with those on treatment as usual (weighted mean difference[WMD]=−2.56 kg, 95% CI −3.20 to −1.92, P<0.001) at the end of treat-


ment. The effect was slightly larger but not significant in studies de-signed to prevent weight gain. Additionally, no statistically significantor practically important differences were evident between therapeuticapproaches using individual compared with group interventions or us-ing CBT compared with nutritional counseling (Alvarez-Jiménez et al.2008).

Rather than review each of the included randomized clinical trials indetail, we summarize them in Table 8–2. Seven of the 12 included trialsinvestigated CBT strategies (Alvarez-Jiménez et al. 2006; Brar et al.2005; Jean-Baptiste et al. 2007; Khazaal et al. 2007; Kwon et al. 2006;McKibbin et al. 2006; Weber and Wyne 2006); three described nutri-tional counseling interventions (Evans et al. 2005; Littrell et al. 2003;Scocco et al. 2006); and two combined nutritional and exercise interven-tions and compared this type of intervention with standard care (Wu etal. 2007) or metformin alone or in combination (Wu et al. 2008). Six trialstested group intervention formats (Brar et al. 2005; Jean-Baptiste et al.2007; Khazaal et al. 2007; Littrell et al. 2003; McKibbon et al. 2006; Weberand Wyne 2006), and the remaining six examined individual interven-tions (Alvarez-Jiménez et al. 2006; Evans et al. 2005; Kwon et al. 2006;Scocco et al. 2006; Wu et al. 2007, 2008). Eight studies were designed totreat weight gain, whereas the remaining four studies were designed toprevent weight gain, typically after patients started taking or wereswitched to an atypical antipsychotic (Alvarez-Jiménez et al. 2006;Evans et al. 2005; Littrell et al. 2003; Scocco et al. 2006). Participants weregenerally outpatients, except three studies included inpatients (Alva-rez-Jiménez et al. 2006; Wu et al. 2007) or a combination (Khazaal et al.2007). Interventions lasted from 8 to 24 weeks, with an average of ap-proximately 15 weeks. Five studies reported a follow-up assessment of8 weeks (Littrell et al. 2003), 24 weeks (Evans et al. 2005; Khazaal et al.2007; Scocco et al. 2006), or 6 months (McKibbin et al. 2006). In the nextparagraphs, we highlight some of these studies that bring up issues weaddress in the discussion, including two studies (Jean-Baptiste et al.2007; Wu et al. 2008) not incorporated in Alvarez-Jiménez et al.’s (2008)meta-analysis.

In the first of the randomized controlled clinical trials, Litrell et al.(2003) provided a 16-week psychoeducational program, focusing onnutrition, exercise, and healthy lifestyle, to patients who had beenswitched to olanzapine from other antipsychotics. That all the patientsin this study were on one drug is notable, because in many other stud-ies, treatment effects are potentially confounded by medication effectsand interactions. Litrell et al. reported little weight change in the inter-vention subjects as opposed to a statistically significant weight gain in

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TABLE 8–2. Randomized, controlled trials of behavioral interventions for weight gain in schizophrenia

Authors and participants InterventionOutcome at final assessment (weight change), compliance, and attrition

Littrell et al. 2003 (N=70)Prior conventional antipsychotics, commencing olanzapine at study entry

16 weekly 1-hour group sessions for diet and exercise education vs. usual care; 2-month follow-up

Intervention: −0.3 kg; usual care: +4.3 kg. Compliance rate of 92% to program sessions. No dropout rate reported.

Brar et al. 2005 (N=72)BMI>26, switched from olanzapine to risperidone

Two sessions per week for 6 weeks then one session per week for 8 weeks of diet and exercise education vs. usual care (encouraged to lose weight)

Intervention: −2.0 kg; usual care: −1.1 kg (NS). 5% weight loss in 32.1% of intervention subjects vs. 10.8% in control group. 15/28 patients attended all 20 sessions. 21% dropout rate in treatment group.

Evans et al. 2005 (N=51)Commenced olanzapine within 12 weeks of study entry

Six 1-hour individual nutrition education sessions over 3 months (every 2 weeks) vs. usual care (plus passive nutrition information)

Intervention: +2.0 kg; usual care: +9.9 kg. Fewer patients in experimental group (13%) than in control group (64%) increased initial body weight by more than 7%. Compliance not reported. 21% dropout rate in treatment group.

210M


Alvarez-Jiménez et al. 2006(N=61)First-episode psychosis and <6 weeks antipsychotic exposure. Treated with: risperidone, olanzapine, haloperidol

10–14 individual sessions (psychoeducation, behavioral therapy, dietary counseling, exercise program) for 3 months vs. usual care

Intervention: +4.1 kg; usual care: +6.9 kg. Fewer patients in experimental group (39.3%) than in control group (78.8%) increased initial body weight by more than 7%. Compliance not reported. No dropouts, and all patients completed study.

Kwon et al. 2006 (N=48)More than 7% body weight gain on olanzapine

Weekly individual sessions with dietitian and exercise coordinator over 12 weeks (weekly for first 4 weeks, then every 2 weeks) vs. usual care

Intervention: −3.9 kg; usual care: −1.5 kg. Diet group: all were over 80% compliant; exercise group: 36% were over 80% compliant. 33% dropout rate in treatment group.

McKibbin et al. 2006 (N=64)Schizophrenia and diabetes diagnosis

Weekly 90-minute group sessions for 24 weeks focused on diabetes education, nutrition, and exercise vs. usual care (plus passive information)

Intervention: −2.3 kg; usual care: +3.1 kg. 5% weight loss in 38% of intervention subjects vs. 12% of control group. 80% of treatment group attended at least half of intervention sessions. No difference in dropout rates between intervention and usual care groups.

TABLE 8–2. Randomized, controlled trials of behavioral interventions for weight gain in schizophrenia (continued)


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Scocco et al. 2006 (N=20)Switched to olanzapine from conventional antipsychotics

8-week individual dietary intervention provided by a nutritionist

Intervention: +0.99 kg; control: +2.96 kg. Compliance not clearly reported. Dropouts: intervention 0/10, control 2/10.

Weber and Wyne 2006 (N=17)BMI>25, taking second-generation antipsychotics

16 weekly 1-hour group sessions for diet and exercise education vs. usual care

Intervention: −2.5 kg; usual care: −0.6 kg (NS). Compliance not reported. No dropout in treatment group.

Jean-Baptiste et al. 2007 (N=18)BMI>30, taking any antipsychotic

Weekly group sessions for 16 weeks with psychoeducation, goal setting, self-monitoring; $25/week for healthy foods

Intervention: −2.8 kg; usual care: +2.7 kg. Compliance not reported. 14/18 completed intervention.

Khazaal et al. 2007 (N=61)>2 kg weight gain over 6 months on any antipsychotic

Weekly 2-hour group cognitive-behavioral therapy plus psychoeducation for 12 weeks vs. a single 2-hour nutrition education session

Intervention: −2.9 kg; usual care: −0.8 kg. At end of treatment, 16.1% of experimental group vs. 13.3% of control group had lost 5% or more of initial BMI. This increased to 22.6% and 16.7% at 12-week follow-up.

Follow-up (12 weeks postintervention): Intervention : −3.5 kg; usual care: +1.7 kg. Compliance not reported. Dropouts: intervention 8/31, control 7/30.



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Wu et al. 2007 (N=56)BMI≥27, clozapine (≥300 mg/day) for at least 1 year

Diet (inpatients) reduced by 200–300 kcal/day; walking (level and stairs) for 60 minutes 3 days a week for 6 months

Intervention: −4.2 kg; usual care: +1 kg. Compliance not reported. No dropouts in treatment group.

Wu et al. 2008 (N=128)First-episode schizophrenia, gained more than 10% of body weight

Psychoeducation, diet, and exercise (lifestyle intervention) over 12 weeks vs. usual care (placebo), metformin, and lifestyle plus metformin

Lifestyle intervention: −1.4 kg; usual care: +3.1 kg; metformin: +3.2 kg; lifestyle plus metformin: −4.7 kg. Compliance: Diet 61%–84%; exercise 50%–60%. Dropouts: Lifestyle plus metformin 2/32, lifestyle only 3/32.

Note. BMI=body mass index; NS=not signficant.




the control group. Thus, the benefit of the intervention might have beento prevent weight gain rather than to produce weight loss. Becauseolanzapine carries a very high risk of clinically significant weight gain(Newcomer 2005), and weight gain in adulthood is a powerful predic-tor of cardiovascular disease (Nanas et al. 1987; Pan et al. 1986), preven-tion of weight gain is a worthwhile benefit of treatment.

Prevention of weight gain was the focus of a study reported by Al-varez-Jiménez et al. (2006). In an early behavioral intervention group,10–14 individual sessions were completed with a clinical psychologistwithin the first 3 months of antipsychotic treatment. The sessions con-sisted of a weight check, agenda setting, review of self-monitoringrecords, and assigning new homework. Modules were available on en-gagement and assessment, psychoeducation, dietary counseling, exer-cise, and behavioral therapy. Selection of the intervention strategieswas based on a collaborative formulation after initial assessment be-tween the therapist and the patient. At the end of treatment, signifi-cantly fewer patients in the intervention group increased their baselineweight by more than 7% (39.3% vs. 78.8%). All participants randomizedcompleted the trial.

Brar et al. (2005) developed a manualized 16-week intervention,adapted from the study conducted by Rotatori et al. (1980). This studyalso controlled for confounding effects of medication by first switchingall subjects to the same antipsychotic (risperidone). This is also one ofthe few studies to use blinded raters. Participants enrolled because theydesired to lose weight. Also of note, regular mental health clinicians, asopposed to specialists in behavioral therapy or nutrition, delivered theintervention, following the manual. This approach was an attempt tomake the results more likely transferable to routine clinical care. Meanweight loss in this study was larger in those randomly assigned to theintervention, but both groups lost weight, and the difference was notstatistically significant. However, the proportion of subjects who lost5% or more of their baseline body weight was three times larger in sub-jects randomized to the intervention than in controls (32.1% vs. 10.8%),and the difference was statistically significant.

Jean-Baptiste et al. (2007) published data from an outpatient studythat used standard behavioral techniques from a widely accepted pro-gram (Brownell 2004); however, to the standard nutrition and exerciseprogram, they added a novel indirect method of food provision. Sub-jects were given lists of “healthy” food choices and then, at weeklygroup sessions, were reimbursed for the cost of these foods, providedthey had receipts showing that they had purchased these food items inthe previous week. Mean weight loss was statistically significantly


greater in the intervention group than in controls. Jean-Baptiste et al.(2007) also conducted a 6-month follow-up and reported continuingweight loss of participants, but the number of subjects was only 12,leaving some uncertainty about the robustness of the results. Neverthe-less, this is a promising rigorous evaluation of a multimodal approachand needs to be followed up.

Focusing on patients with both schizophrenia and diabetes, McKib-bin et al. (2006) recruited patients from board-and-care and communityclubhouse settings. Optimal diabetes management requires active self-management, including weight control and weight loss. Patients withschizophrenia often have difficulty accessing and participating in com-prehensive diabetes management programs. This study illustrates theeffectiveness of a well-constructed intervention geared for patientswith schizophrenia and diabetes. The 24-week training program wasdeveloped in collaboration with a community advisory board that com-prised consumers, family members, and community clinicians and con-sisted of weekly, 90-minute group sessions addressing diabeteseducation, nutrition, and exercise. Educational material was adaptedby limiting text, introducing one or two topics per session, providing anoverview and summary of material, and using a teach-and-query train-ing method and mnemonic aids. Concrete behavior change strategiesincluded weekly weigh-ins, pedometers, healthy food sampling, andreinforcements (raffle tickets for small health gains). Patients in the in-tervention group lost a mean of 2.3 kg, compared with a mean weightgain of 2.7 kg in those receiving usual care (medical follow-up and writ-ten diabetes information). The intervention group also showed signifi-cant improvements in diabetes knowledge and self-efficacy, as well asself-reported physical activity, but not in fasting plasma glucose or gly-cosylated hemoglobin.

In the largest study to date (Wu et al. 2008), 128 first-episode schizo-phrenia patients were randomly assigned to one of the following:12 weeks of placebo, 750 mg/day of metformin alone, 750 mg/day ofmetformin and lifestyle intervention, or lifestyle intervention only. Thelifestyle intervention included psychoeducational, dietary, and exerciseprograms. Psychoeducation focused on the role of eating and activity inweight management. Dietary intervention followed the AmericanHeart Association Step II diet, which recommends less than 30% of totalcalories from fat (<7% saturated fat and <200 mg of cholesterol), 55%from carbohydrates, more than 15% from protein daily, and fiber intakeof at least 15 g per 100 kcal. Participants maintained a 3-day food diaryat baseline, and a dietitian reviewed their diets and provided feedbackat follow-up sessions. In the first week, exercise sessions were directed


by an exercise physiologist, and participants performed exercise (walk-ing or jogging) on a treadmill seven times a week for 30 minutes at eachsession. After the first week, exercise was home-based, with recommen-dations to exercise 30 minutes per day. At the end of the trial, the life-style intervention plus metformin group (−4.7 kg, 95% CI −5.7 to −3.4)had results superior to those of either the lifestyle intervention alone(−1.4 kg, 95% CI −2.0 to −0.7) or the metformin alone (−3.2 kg, 95% CI−3.9 to −2.5) groups. Metformin alone was more effective in weight lossand improving insulin sensitivity than lifestyle interventions alone.

Notably, although considerable rigor is required to induce weightloss, in terms of maintaining a negative energy balance, in all of theidentified randomized clinical trials, dropouts have generally not beena concern in the treatment arm. This might suggest that patients can bemotivated to initiate and then adhere to a lifestyle intervention forweight management, at least in the short term. Dropout rates have notbeen as high as reported in a recent review (Loh et al. 2006), althoughattention must be given to the development of retention strategies tominimize dropouts (Faulkner and Cohn 2006). Furthermore, no adverseeffects explicitly linked to participating in a lifestyle intervention pro-gram have been reported.

DiscussionThe results achieved from weight loss interventions in persons withschizophrenia (WMD=−2.56 kg; Alvarez-Jiménez et al. 2008) are withinthe range of those reportedly obtained by commercial weight loss pro-grams in the general population (Heshka et al. 2003), although not asgreat as suggested by a meta-analysis of randomized clinical trials ofCBT combined with a diet and exercise intervention (WMD=−4.9 kg, CI−7.3 to −2.4; Shaw et al. 2005). However, a reasonable question iswhether such modest improvements actually translate into measurableimprovements in health status or risk of cardiovascular disease and di-abetes. The general agreement is that in obese individuals, even a 5%weight loss can produce measurable health benefits. For example, in theFinnish Diabetes Prevention Study, a modest weight loss of 4.8% of ini-tial body weight was associated with a 58% reduction in the risk of de-veloping diabetes over the following 3 years (Tuomilehto et al. 2001).As little as 3–4 kg of weight loss over 3 years results in clinically signif-icant reductions in systolic and diastolic blood pressure (Mertens andVan Gaal 2000). Also, accumulating evidence from prospective obser-vational studies indicates that increasing physical activity is effective inimproving the health profile of individuals who are overweight and


obese (e.g., Lee et al. 1999). Weight loss might be considered a primarygoal, but clinicians should keep in mind that small, sustained positivechanges in physical activity and dietary intake may be associated withsignificant health benefits irrespective of weight loss per se. With veryfew exceptions, even randomized controlled interventions have rarelyfollowed patients for longer than 6 months. Weight loss is challenging,but even more challenging is weight loss maintenance (Wing et al.2006). Obesity is unquestionably a chronic condition, and it is likely thatlong-term success may require some form of maintenance treatment.Hence, the real health benefits of weight loss interventions, even forthose who respond to interventions, will be known only when datafrom longer studies become available. Fortunately, several ongoingclinical trials have up to 2 years of follow-up in their designs. Overall,interventions will probably need to set realistic goals, be highly struc-tured, provide early and intensive support initially, and offer reducedbut continued support over time if not indefinitely (Faulkner and Cohn2006).

Most currently published research has evaluated pharmacologicaland nonpharmacological treatments for weight loss in separate studies(pharmacological treatments are reviewed in Chapter 4, “Obesity andSchizophrenia”). However, evidence is accumulating that combiningbehavioral and pharmacological weight loss interventions can be moreeffective than either approach alone (Wadden et al. 2005). One study hasbeen published that demonstrates the greater effectiveness of combinedweight loss interventions specifically in patients with schizophrenia(Wu et al. 2008). However, given concerns about potential polyphar-macy, the demands of adding further medication to an existing medicalregimen, and the cost of medication, we suggest that adjunctive phar-macotherapy for weight loss be reserved for patients who do not re-spond adequately to lifestyle interventions alone (Faulkner et al. 2007).Further studies evaluating the combination of behavioral and pharma-cological weight loss therapies are required before routinely recom-mending such a dual approach in clinical practice. Switching a patientto an antipsychotic medication with low liability for weight gain hasalso emerged as an effective strategy for weight loss and metabolic ben-efit, particularly when the increase in weight was clearly associatedwith prior antipsychotic treatment (Weiden 2007; Weiden and Buckley2007) (see Chapter 4). No studies to date have investigated the combina-tion of antipsychotic switching and behavioral strategies for weight loss.


Given that the current system of care for persons with severe mentalillness is routinely described as underfunded and overburdened (Frankand Glied 2006), economic considerations may well determine whichinterventions for weight loss, if any, will make it to the front lines ofcommunity mental health. Thus, cost-benefit analyses should be in-cluded in the evaluation of proposed interventions. At this point, suchanalyses are almost entirely missing from the evidence base on this sub-ject. Even without sophisticated economic analyses, clinicians shouldbe able to evaluate the potential benefit of investing time and resourcesin particular interventions if the published results systematically re-ported the proportions of subjects who benefited and, preferably, thenumber needed to treat for each threshold of response. Unfortunately,most studies already published limit the results to reporting meanchanges in body weight.

ConclusionOn the basis of existing studies, we can conclude that persons withschizophrenia want to and will participate in behavioral weight lossinterventions. For individuals who are unmotivated or difficult to en-gage, consideration could be given to broader environmental interven-tions that aim to shape the environment in ways that are conducive toencouraging greater physical activity while restricting energy intake(Gorczynski et al. 2008). Taken together, the evidence from controlledtrials indicates that patients who do participate in weight loss interven-tions increase their chances of losing weight. The results of simple andpractical interventions are modest but clinically meaningful. The dataon long-term maintenance of weight loss is essentially lacking, butsome ongoing studies will provide data in the next few years. The dataon preventing weight gain in persons with schizophrenia is developingand looking positive. With these observations in mind, standard behav-ioral weight loss interventions should be widely and routinely offeredto patients with schizophrenia who are overweight or obese. In addi-tion, discussion about the risk of weight gain and monitoring of weightshould be routinely offered to all patients with schizophrenia. Giventhat the current trend is for the rates of obesity to continue to increase,research into enhancing the effectiveness of current interventions andthe development of new approaches to weight loss need to be urgentlyfunded.


Key Clinical Points

◗ Education about the health hazards of being overweight or becomingoverweight should be included in the psychoeducational interventionsoffered to persons with schizophrenia, along with simple advice abouthealth nutrition and exercise measures.

◗ Regular measurement of body weight should be part of routine care inmental health settings, and patients should be given feedback on theirown weight regularly. Patients should also be encouraged to weighthemselves.

◗ Patients who ask for active interventions to help them lose weightshould be offered group or individual interventions, preferably withinthe mental health treatment setting.

◗ Referral to specialized programs, including the full range of options forsevere and/or treatment-resistant obesity, should be pursued for pa-tients who are in need of these services.

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223

CHAPTER 9

Nicotine and TobaccoUse in Patients With

Schizophrenia

Andrea H. Weinberger, Ph.D.Tony P. George, M.D., F.R.C.P.C.

Epidemiology and Significance of the ProblemPatients with schizophrenia have a high prevalence of cigarette smok-ing based on clinical (58%–88%) and population-based (45%) samples(Kalman et al. 2005) compared to the general population rate of approx-imately 20.5% (Giovino 2007). Also, smoking cessation rates are lowerin patients with schizophrenia than in nonpsychiatric control smokers

We thank Erin L. Reutenauer, B.A., for assistance with this work. This work wassupported by National Institute on Drug Abuse grants K02-DA16611, R01-DA13672, R01-DA14039 (to Dr. George), and K12-DA000167 (to Dr. Wein-berger); National Alliance for Research in Schizophrenia and Depression(NARSAD) Young Investigator (to Dr. Weinberger) and Independent Investi-gator (to Dr. George) Awards; and the University Chair in Addiction Psychiatryat the University of Toronto (to Dr. George).


(Kalman et al. 2005). Despite the fact that patients with schizophreniaconstitute only about 1% of the general population, the medical andeconomic burden of cigarette smoking on mentally ill persons is enor-mous (Kalman et al. 2005). For example, the rates of smoking-related ill-nesses such as cardiovascular disease and certain cancers appear to behigher in patients with schizophrenia than in the general population(Capasso et al. 2008). Hence, an urgent need exists to address tobaccoaddiction in this population through the development of effective treat-ments, both pharmacological and behavioral. A better understandingof the biology of tobacco addiction in patients with schizophrenia mayassist in the development of better treatments for tobacco use in thisvulnerable population.

Pathophysiology of Schizophrenia: Relationship to Nicotinic, Dopaminergic, and Glutamatergic EffectsOver the past 20 years, scientific understanding of both the neurobiol-ogy of schizophrenia and nicotine addiction has been increasing. Forthe purposes of this discussion, nicotine is assumed to be the active in-gredient in tobacco and cigarette smoking that exerts psychopharmaco-logical effects, although other components of tobacco smoke may beactive in this respect (George and O’Malley 2004). There are three pos-sible reasons for the high comorbid rates of nicotine addiction andschizophrenia: 1) self-medication of clinical and cognitive deficits asso-ciated with schizophrenia by tobacco use; 2) abnormalities in brain re-ward pathways in patients with schizophrenia that make these patientsvulnerable to tobacco (and other drug) use; 3) common genetic and en-vironmental factors that are independently associated with both smok-ing and schizophrenia. We briefly describe next the pharmacologicaleffects of nicotine, including its effects on neurotransmitter systemscritical to the neurobiology of schizophrenia, and how such effects maylink nicotine addiction with schizophrenia.

Nicotine alters the function of neurotransmitter systems implicatedin the pathogenesis of major psychiatric disorders, including dopa-mine, norepinephrine, serotonin, glutamate, gamma-aminobutyric acid(GABA), and endogenous opioid peptides (Dani and Bertrand 2007).Nicotine’s receptor in the brain is the nicotinic acetylcholine receptor(nAChR), where stimulation of presynaptic nAChRs on neurons in-creases transmitter release and metabolism (Dani and Bertrand 2007;Picciotto 2003). The two general families of central nAChRs are high-

Nicotine and Tobacco Use 225

affinity receptors (β2 subunit–containing nAChRs, which exist in a het-eropentameric configuration of α subunits combined with β subunits)and low-affinity receptors (α7 subunit–containing nAChR homopen-tameric complexes) (see Dani and Bertrand 2007 for review). Both high-and low-affinity nAChRs appear to be present on mesocorticolimbicdopamine neurons (Wooltorton et al. 2003), and α7 nAChRs are en-riched in the hippocampus and cortex and appear to facilitate informa-tion processing and sensory integration (Leonard and Bertrand 2001).

Chronic administration of nicotine, unlike most agonists, leads to de-sensitization and inactivation of nAChRs, with subsequent upregula-tion of nAChR sites, a process that might explain why many smokersreport that the most satisfying cigarette of the day is the first one in themorning, at which time upregulated nAChRs are resensitized. Me-solimbic dopamine (reward pathway) neurons possess presynapticnAChRs and may be of particular importance in mediating the reward-ing effects of nicotine through projections from the ventral tegmentalarea in the midbrain to anterior forebrain structures such as the nucleusaccumbens and cingulate cortex (Dani and Bertrand 2007).

Domino et al. (2004) proposed that individuals with schizophreniahave a relative hyperfunction of subcortical dopamine systems and arelative hypofunction of prefrontal cortex dopamine systems. It is awell-known fact that chemical or physical lesioning of the prefrontalcortex produces hyperfunctional mesolimbic dopamine neurons. Pre-clinical studies in nonhuman primates suggest that chronic treatmentwith the N-methyl-D-aspartate receptor antagonist MK-801 produces adepletion of prefrontal cortex dopamine levels, which is accompaniedby an increase in D1 receptor binding and an impairment in workingmemory performance (Tsukada et al. 2005b). Interestingly, acute intra-venous administration of nicotine normalizes prefrontal cortex dopa-mine levels, and D1 receptor binding, and improves working memoryperformance in these MK-801 exposed monkeys (Tsukada et al. 2005a).This animal model of schizophrenia may provide an outstanding op-portunity to study the interactive effects of nicotine on the putativepathophysiological processes associated with schizophrenic disordersand their frequent comorbidity with tobacco dependence (Domino et al.2004).

Converging lines of evidence suggest that dysregulation of bothhigh- and low-affinity nAChRs occur in the brains of individuals withschizophrenia. Evidence indicates that high-affinity nAChR expressionis reduced in postmortem brains of patients with schizophrenia(Leonard et al. 2000) and that the expected upregulation of nAChRswith tobacco exposure is blunted in patients with schizophrenia com-


pared with control smokers and nonsmokers; however, most of thesedata come from cross-sectional comparisons, and within-subjectchanges in nAChR levels have not been studied either with respect tosmoking initiation or smoking cessation.

Schizophrenia is associated with a number of neurocognitive defi-cits, including attention, verbal learning and memory, spatial workingmemory, and executive function (Green et al. 2004), and nicotine isthought to have procognitive effects (Sacco et al. 2005). Acetylcholine isassociated with arousal, learning, and memory, and cholinergic inhibi-tors are used clinically to enhance memory (Levin et al. 2006; New-house et al. 2004; Sacco et al. 2004). The use of selective nAChR agonistsand partial agonists to treat cognitive deficits in schizophrenia isthought to be the most appealing area of treatment possibilities at thistime. The Measurement and Treatment Research to Improve Cognitionin Schizophrenia consortium has identified several classes of com-pounds that may be effective for this purpose; topping this list are α7

nicotinic receptor partial agonists (Marder 2006; Tamminga 2006). Onepromising medication is the α7 agent dimethoxybenzylidene ana-baseine (DXMB-A), which is likely to alter deficits of P50 auditoryevoked potential inhibition and smooth pursuit eye movements in thispopulation (Olincy et al. 2006). In addition, varenicline (Chantix), as anα4β2 nAChR-selective partial agonist, might be considered for its poten-tial effects on visuospatial working memory, attention, and prepulse in-hibition. Other novel medications used off-label, such as galantaminehydrobromide (Razadyne), an nAChR allosteric modulator (Coyle andKershaw 2001), are also currently being used to study nAChR mecha-nisms relevant to neurocognition in patients with schizophrenia andother neuropsychiatric disorders. The development of other novel se-lective nAChR agents will allow more careful exploration of the thera-peutic potential of nicotinic agents for the treatment of neurocognitivedysfunction associated with schizophrenia.

Pharmacokinetic Implications of Smoking for Psychotropic Drug Use in SchizophreniaStrong evidence indicates that tobacco smoking induces the liver cyto-chrome P450 1A2 (CYP1A2) enzyme system, a major route for the me-tabolism of antipsychotic drugs such as olanzapine and clozapine(Kroon 2007). Accordingly, smoking cessation would be expected tolead to increases in plasma concentrations of antipsychotic drugsmetabolized by the CYP1A2 system, a finding demonstrated repeatedly


in both prospective and retrospective studies (Kroon 2007). Such an in-crease in circulating levels would be expected to increase the likelihoodof extrapyramidal reactions and other antipsychotic drug side effects.Although no smoking cessation study of patients with schizophrenia todate has prospectively measured antipsychotic plasma levels beforeand after smoking cessation, several case reports and case series sug-gest increases in medication levels with smoking cessation. In one of thelarger case series, Meyer (2001) reported on serial clozapine levels mea-sured in 11 patients with schizophrenia or schizoaffective disordertreated with stable dosages in a state hospital before and after a hospi-tal-wide ban on smoking. A mean increase of 57.4% was noted in theseclozapine-treated patients who quit smoking; one patient in particularhad an increase in his serum clozapine level to over 3,000 ng/ml thatwas associated with aspiration. In the few published controlled smok-ing cessation trials in this population (Addington et al. 1998; George etal. 2000a), no significant increases in medication side effects have beennoted in patients who quit smoking, including those treated with med-ications known to be metabolized by CYP1A2, but clearly further studyis warranted.

Effects of Smoking on Clinical and Cognitive Deficits Associated With SchizophreniaSeveral cross-sectional studies have examined the effects of cigarettesmoking on psychotic symptoms in patients with schizophrenia, withmixed results (e.g., Barnes et al. 2006; Goff et al. 1992; Patkar et al. 2002;Tang et al. 2007; Ziedonis et al. 1994). Goff et al. (1992) found that com-pared with nonsmokers with schizophrenia, smokers with schizophre-nia had higher Brief Psychiatric Rating Scale (BPRS) total scores andhigher subscale scores for both positive and negative symptoms. Tanget al. (2007) found no differences in overall BPRS scores between smok-ing and nonsmoking patients with schizophrenia but did find thatsmokers had a lower score on the BPRS Depressive and Anxious Symp-toms subscale. Ziedonis et al. (1994) found that patients with schizo-phrenia who smoked had increased positive symptom scores andreduced negative symptom scores compared with nonsmoking patientswith schizophrenia, with heavy smokers having the highest positiveand lowest negative symptom scores. Patkar et al. (2002) found thathigher levels of nicotine dependence were associated with higher


negative symptoms but not with positive symptoms. A study by ourgroup found that patients with schizophrenia who were former smok-ers had higher negative symptoms than current smokers, after adjust-ing for differences in age, depressive symptoms, and education (Georgeet al. 2002a). Two recent reports found no differences in positive or neg-ative symptoms of schizophrenia when comparing patients who weresmokers with those who did not smoke (Barnes et al. 2006; Tang et al.2007). Clearly, the interpretation of data from cross-sectional studies isconfounded by methodological differences.

Few direct studies have been done of the effects of smoking or nicotineadministration on clinical symptoms in patients with schizophrenia. Incontrast to results from cross-sectional studies, controlled laboratorystudies of smoking abstinence (George et al. 2002a) and nicotine patchadministration (Dalack et al. 1999) have not shown significant effects onthe clinical symptoms of schizophrenia. One study (Smith et al. 2002)found that although high-nicotine cigarettes led to a greater decrease innegative symptoms than denicotinized cigarettes, the type of cigarettedid not affect positive symptoms, anxiety, or depression. In this study,nicotine nasal spray did not alter clinical symptoms. Furthermore, datafrom smoking cessation trials (Addington et al. 1998; Baker et al. 2006;Evins et al. 2005, 2007; Gallagher et al. 2007; George et al. 2000a, 2008), allof which used the nicotine patch, found no evidence for significantchanges in psychotic symptoms with smoking abstinence in patientswith schizophrenia. Thus, the effects of cigarette smoking and smokingabstinence on schizophrenia symptoms are not clear. Perhaps some traitdifferences in psychotic symptoms in smokers versus nonsmokers withschizophrenia (e.g., more refractory symptoms in nonsmokers) might ex-plain these findings, independent of smoking status (George et al. 2002a).

Several human laboratory studies have suggested that patients withschizophrenia possess deficits in auditory information processing (P50event-related potentials), which can be transiently normalized by ciga-rette smoking or administration of nicotine gum (Adler et al. 1998).Similarly, Griffith et al. (1998) reported a smaller but still significant im-provement in P50 auditory gating after providing a nicotine patch tosmokers with schizophrenia following a 2-hour period of abstinencefrom smoking. Leonard et al. (2002) found that these P50 response def-icits may be linked to a locus on chromosome 15 (q14) near the codingregion for the α7 nicotinic acetylcholine receptor. This subtype ofnAChR has been strongly implicated in P50 responses, leading to spec-ulation that if some schizophrenia patients possess defective α7

nAChR-mediated neurotransmission, they may smoke heavily to over-come the related neurophysiological deficits.


In addition, patients with schizophrenia have abnormalities in an-other auditory information processing response known as prepulse in-hibition of the acoustic startle reflex. The neural substrates mediatingthis response appear to be distinct from those mediating P50 responses(Swerdlow et al. 1992). Nicotine seems to improve performance onprepulse inhibition for smokers with schizophrenia. Kumari et al.(2001) found that when male patients with schizophrenia were acutelysmoking, their prepulse inhibition was higher than that in smoking-deprived or nonsmoking patients with schizophrenia, whereas Postmaet al. (2006) found that subcutaneous nicotine improves prepulse inhi-bition in smokers with schizophrenia. Moreover, George et al. (2006)showed that deprived smokers with schizophrenia demonstrated re-duced prepulse inhibition but that baseline performance was reinstatedupon resumption of smoking. However, the nicotinic antagonistmecamylamine dose-dependently blocked reinstatement in the schizo-phrenia group, whereas no effect was found in nonpsychiatric controlsubjects, suggesting that stimulation of central nAChRs mediates ciga-rette smoking–induced improvement of prepulse inhibition in patientswith schizophrenia. Thus, patients with schizophrenia may be usingcigarette smoking to ameliorate defects in cognitive function, furthersupporting the self-medication hypothesis of cigarette smoking inschizophrenia.

A growing body of research has examined cognitive function inpatients with schizophrenia and nonpsychiatric control subjects asa function of smoking status. In addition to P50 gating and prepulseinhibition, nicotine appears to enhance areas of cognition includingworking memory and sustained attention. Smokers with schizophreniademonstrate a deficit in visual-spatial working memory function afterovernight abstinence, with an immediate improvement in performancewith resumption of cigarette smoking (Sacco et al. 2005) or after admin-istration of nicotine nasal spray (Smith et al. 2006). Furthermore, suchpersistent effects on visual-spatial working memory are observed withlonger-term abstinence. Smokers who remained abstinent from cigar-ettes over a 10-week period demonstrated enduring decrements invisual-spatial working memory (George et al. 2002a). Similar cognitiveenhancement is achieved with nicotine gum administration, as seenusing an auditory N-back task with a high verbal working memorydemand (Jacobsen et al. 2004), and with nicotine patch, nasal spray, orcigarettes on measures of sustained attention using the Conners’ Con-tinuous Performance Test (Sacco et al. 2005). In summary, nicotineadministration appears to enhance several areas of cognitive functionin patients with schizophrenia, including working memory, specifically


spatial working memory; sustained attention; P50 gating; smooth pur-suit eye movement; and prepulse inhibition.

Effects of Atypical Versus Typical Antipsychotic Drugs on Smoking in SchizophreniaCross-sectional research has shown lower levels of smoking in patientstaking atypical antipsychotic medications than in those taking typicalantipsychotics (e.g., Barnes et al. 2006). Our group has found thatswitching smokers with schizophrenia from typical antipsychoticagents to clozapine leads to reductions in self-reported cigarette smok-ing, especially in heavier smokers (George et al. 1995). Similar findingswere reported by McEvoy and colleagues, who found that the degree ofreduction may be dependent on clozapine plasma levels (McEvoy et al.1995b). A related study found that compared to a baseline medication-free condition, taking the typical antipsychotic drug haloperidol leadsto increased smoking in patients with schizophrenia (McEvoy et al.1995a). Thus, a role for atypical antipsychotic drugs in reducing smok-ing behavior is suggested.

Use of the transdermal nicotine patch (TNP) is known to facilitatesmoking reduction and cessation (Addington et al. 1998; George et al.2000b) in smokers with schizophrenia, albeit at lower rates (36%–42% attrial endpoint) than in healthy control smokers (50%–70%) (George andO’Malley 2004). Nonetheless, nicotine patch use at the dosage of21 mg/day appears to effectively reduce cigarette smoking and nico-tine withdrawal symptoms in smokers with schizophrenia (Addingtonet al. 1998; George et al. 2000b). Other studies indicate that the combi-nation of TNP with the atypical antipsychotic risperidone or olanzapinemay enhance smoking cessation rates compared with the combinationof typical antipsychotic drugs and TNP among smokers with schizo-phrenia with high motivation to quit smoking (George et al. 2000b).Data from a preliminary placebo-controlled trial comparing bupropionversus placebo in smokers with schizophrenia suggest that atypicalantipsychotic treatment significantly enhances smoking cessation re-sponses to bupropion (George et al. 2002b).

One can speculate that in patients with schizophrenia, atypical anti-psychotic drugs may be helpful for smoking cessation compared withtypical neuroleptic agents for the following reasons: 1) atypical agentshave fewer extrapyramidal side effects and improve negative symp-


toms, both of which may be further improved by cigarette smoking;2) treatment with atypical agents is associated with improvement incertain neuropsychological functional deficits, which also appear to bealleviated by smoking; 3) sensory gating deficits (e.g., P50 responses,prepulse inhibition) that are transiently normalized by nicotine admin-istration or cigarette smoking are also ameliorated by atypical antipsy-chotic drugs; and 4) atypical agents are associated with augmentationof dopamine release in the prefrontal cortex in rodent studies, and theseagents may normalize those presumed deficits in cortical dopaminefunction in schizophrenia that are remediated by nicotine administra-tion via cigarette smoking.

Optimizing Cessation Treatments to Prevent Smoking-Related Medical IllnessDespite the enhanced quality of life possibly afforded to individualswith schizophrenia through the use of atypical antipsychotics, smokerswith schizophrenia are more vulnerable than the general population ofsmokers to developing smoking-related morbidity and mortality, in-cluding an increased risk of cardiovascular disease (Capasso et al.2008). Previous epidemiological studies suggested that smokers withschizophrenia were protected against the development of malignancies(Tsuang et al. 1983), and this was thought to relate to neuroleptic drugexposure (Mortensen 1987). In addition, evidence suggests that urinarylevels of the peptide bombesin, a possible marker of precancerous ciga-rette smoking–induced lung damage, are lower in patients with schizo-phrenia than in controls (Olincy et al. 1999). This reduction in urinarybombesin levels is independent of smoking status in patients withschizophrenia, supporting the notion that these patients may be lessvulnerable to the development of cancer. However, several subsequentepidemiological studies have found no evidence for a decreased risk oflung cancer in patients with schizophrenia or other patients with seri-ous mental disorders (Lichtermann et al. 2001). Previous studies mayhave been confounded by selection bias, because rates of these medicalillnesses in older patients with schizophrenia are lower, likely related tothe fact that much of this cohort had died from other causes related totheir psychiatric illness (e.g., suicide) by the time they reached the agewhen cancer risk is substantially increased (age 50 years or older). Thus,disease prevention through smoking cessation or reduction in this pop-ulation is an important public health issue, especially because patientswith schizophrenia constitute 1% of the U.S. population.


Although the interest in smoking cessation by patients with schizo-phrenia is generally thought to be low, approximately 20%–40% havesubstantial desire to quit smoking (Ziedonis and Trudeau 1997), basedon ratings of motivational level using the Stages of Change scale (e.g.,preparation or action stages) (Prochaska and DiClemente 1983). Inmany cases where smoking cessation is not possible, a reduction insmoking consumption (e.g., a “harm reduction” approach) might ac-crue some health benefits for smokers with schizophrenia (McChargueet al. 2002); however, no studies have been published to suggest that re-ducing smoking can reduce the risk of developing smoking-related ill-ness in nonpsychiatric individuals or smokers with schizophrenia. Infact, one study suggests that a 50% reduction in smoking does not re-duce the risk of developing cardiac and pulmonary disease, comparedwith the risk in persistent heavy smokers (Tverdal and Bjartveit 2006).Thus, the approach to treatment of tobacco dependence in these pa-tients should focus on the ultimate goal of smoking cessation, althoughgiven the difficulties of cessation in patients with schizophrenia, moreflexible approaches (McChargue et al. 2002), including reduction as atransition to abstinence, should be encouraged. Thus, an understandingof biological and psychosocial factors that render schizophrenia pa-tients at high risk for developing nicotine addiction and that contributeto their low intrinsic motivation to change smoking behaviors is criticalto guiding efforts directed toward improving smoking cessation treat-ment in this population. One study using a single motivational inter-view versus an educational program in smokers with schizophrenia(Steinberg et al. 2004) found that motivational interventions were asso-ciated with a significant increase in the chance that these smokers initi-ated smoking cessation treatment.

Experience in controlled treatment research studies for smoking ces-sation in schizophrenia has suggested the need to optimize bothpharmacological and psychosocial interventions (see Table 9–1). Al-though use of atypical antipsychotic drugs may be one patient factorthat predicts better smoking cessation or reduction outcomes, the real-ity is that patients with schizophrenia need persistent encouragementto cease smoking through the use of motivational enhancement thera-pies and, once smoking abstinence has been achieved, require ongoingteaching in methods to prevent smoking relapse (Addington et al. 1998;Ziedonis and Trudeau 1997). Steinberg et al. (2004) found that a largerpercentage of smokers with schizophrenia attended a session of tobaccodependence treatment after receiving a motivational interviewing ses-sion than after receiving standard psychoeducational treatment or briefadvice. In addition, educating patients about the dangers of smoking


for their health is helpful, because they often know surprisingly littleabout the adverse effects of tobacco. Finally, drug refusal techniques areimportant, because peer pressure is typically very high on these indi-viduals to resume smoking after successful abstinence. Accrued experi-ence in the Yale Program for Research in Smokers with Mental Illnessindicates that teaching assertiveness skills (in the context of social skillstraining) has been quite effective for helping patients who maintainhigh motivation to remain tobacco-free.

Standard smoking cessation pharmacotherapies approved by theU.S. Food and Drug Administration (FDA), such as the transdermal nic-otine patch (TNP) (Addington et al. 1998; Baker et al. 2006; Chou et al.2004; George et al. 2000b), nicotine nasal spray (Williams et al. 2004),and sustained-release bupropion (Evins et al. 2001, 2005; Fatemi et al.2005; George et al. 2002b; Weiner et al. 2001), appear to be safe and effi-cacious treatments for smoking cessation in patients with schizophre-nia during the course of controlled studies. A summary of treatmentand nontreatment studies directed at addressing tobacco addiction inpatients with schizophrenia is presented in Table 9–1.

The smoking cessation rates of patients with schizophrenia at the endof drug treatment are in the range of 30%–42% with the nicotine patch(Addington et al. 1998; Baker et al. 2006; Chou et al. 2004; George et al.2000b), and 11%–50% with bupropion (Evins et al. 2001, 2005; George etal. 2002b; Weiner et al. 2001), which are modest compared to ratesachieved in nonschizophrenic control smokers (50%–75%) (Hughes et al.1999) but may be improved when patients are prescribed atypical anti-psychotic agents (George et al. 2000b, 2002b). Recently, the combinationof TNP and bupropion has been found to be safe and to increase short-term abstinence rates in comparison to TNP alone (Evins et al. 2007;George et al. 2008). Differences in study design, patient variables (e.g.,level of motivation to quit smoking), medication dosage (in the studieswith bupropion, used at 150–300 mg/day), and criteria used to determinesmoking abstinence may explain the variability in cessation rates acrossthese studies. In studies that have used TNP, patients are expected to stopall smoking on the designated “quit date” (when they begin TNP).

When using the TNP, patients should be cautioned not to smokewhile wearing the patch due to concerns about nicotine toxicity, symp-toms of which can include tremor, nausea and vomiting, dizziness, andin rare cases seizures, arrhythmias, and death. In our research clinic, wehave not encountered nicotine toxicity to be a significant problem, butwe tell patients who feel they must smoke to remove the patch and wait1–2 hours before resuming smoking. The craving to smoke and contin-uing withdrawal symptoms typically indicate incomplete nicotine

234M

edical Illness and SchizophreniaTABLE 9–1. Smoking cessation and reduction approaches using pharmacotherapies in schizophrenia: summary of controlled

studies

Study Sample Study design Short-term abstinence rates Long-term abstinence rates

Nicotine replacement therapyAddington

et al. 199850 outpatients Open-label trial of

TNP+group counseling42% at study endpoint 3 months: 15%;

6 months: 12% George et al.

2000b45 outpatients TNP+group counseling ∼35% ∼10%

Chou et al. 2004

68 inpatients TNP vs. no-patch control group

26.9% vs. 0% 3 months: 26.9% vs. 0%

Williams et al. 2004

12 outpatients Nicotine nasal spray 3 months: 42%

Baker et al. 2006

298 outpatients with nonacute psychotic disorders

TNP+CBT/MI vs. CBT/MI 3 months: 30.0% vs. 6.0%; 6 months: 18.6% vs. 4.0%; 12 months: 18.6% vs. 6.6%

BupropionEvins et al.

200118 outpatients BUP+CBT vs. PLA+CBT 66% vs. 11% (≥50%

reduction in smoking)6 months: 11% vs. 0%

(sustained abstinence)Weiner et al.

20018 outpatients Open-label BUP

+supportive group counseling

0% quit smoking; reduction in CO levels

NA

Nicotine and T

obacco Use

235

George et al. 2002b

32 outpatients BUP+counseling vs. PLA+counseling

50% vs. 12.5% 18.8% vs. 6.3%

Evins et al. 2005

53 outpatients BUP+CBT vs. PLA+CBT 16% vs. 0% 3 months: 4% vs. 3.6%

Fatemi et al. 2005

10 outpatients Crossover design BUP and placebo

Trend for reduction in CO, cotinine, and nicotine levels

Combination treatmentsEvins et al.

200751 outpatients BUP+NRT+CBT vs.

PLA+NRT+CBT36% vs. 19% 6 months: 20% vs. 8%;

12 months: 12% vs. 8%George et al.

200858 outpatients BUP+TNP+counseling vs.

PLA+TNP+counseling34.5% vs. 10.3% 6 months: 13.8% vs. 0%

VareniclineStapleton

et al. 2007111 patients with

“mental health disorders” (31 with psychosis or psychosis+depression)

Open-label varenicline vs. TNP

71.7% vs. 55.2%

TABLE 9–1. Smoking cessation and reduction approaches using pharmacotherapies in schizophrenia: summary of controlled studies (continued)


236M


Evins and Goff 2008

19 outpatients Open-label varenicline 68% 6 months: 68% (4 patients reported slips but regained abstinence within a week)

OtherGeorge et al.

199529 outpatients Retrospective study of

clozapineReduction in smoking

with clozapine treatmentNA

McEvoy et al. 1995b

12 inpatients Within-subjects study of clozapine

Reduction in smoking with clozapine treatment

NA

McEvoy et al. 1999

70 inpatients Within-subjects study of clozapine

Reduction in smoking with clozapine treatment

George et al. 2000b

45 outpatients TNP+counseling; compared ATP vs. TYP medication

55.6% (ATP) vs. 22.2% (TYP)

6 months: 16.7% vs. 7.4%

Note. All abstinence percentage rates are for 7-day point prevalence unless otherwise noted. ATP=atypical; BUP=bupropion;CBT=cognitive-behavioral therapy; CO=carbon monoxide; MI=motivational interviewing; NRT=nicotine replacement ther-apy; PLA=placebo; TNP=transdermal nicotine patch; TYP=typical.

TABLE 9–1. Smoking cessation and reduction approaches using pharmacotherapies in schizophrenia: summary of controlled studies (continued)



replacement; if needed, another patch of 7–21 mg/day can be added totherapy with the 21-mg/day TNP. For bupropion, controlled studieshave started dosing at 150 mg/day orally, with an increase to 150 mgtwice daily by the fourth day of treatment. The “quit date” is typicallyset once levels reach steady-state, usually 3–4 days after beginning thefull 300-mg/day dosage. A history of seizures of any etiology is a con-traindication to the use of bupropion, as indicated by the product label-ing, and we recommend not exceeding 300 mg/day, because someantipsychotic drugs may reduce seizure threshold. At the same time,bupropion at 150–300 mg/day does not appear to worsen positivesymptoms of schizophrenia and may reduce negative symptoms (Evinset al. 2001, 2005; Fatemi et al. 2005; George et al. 2002b; Weiner et al.2001). The typical duration of therapy studied in patients with schizo-phrenia with these agents is 8–12 weeks; studies with longer durationsof treatment in this population have not yet been conducted.

Varenicline tartrate (Chantix in the United States, Champix in Eu-rope and Canada), an α4β2 nAChR partial agonist, is the newest medi-cation approved by the FDA as a first-line smoking cessation agent.Although clinical trials of varenicline with psychiatric smokers havenot yet been published, case reports suggested temporary increases inpsychiatric symptoms in a patient with schizophrenia (Freedman 2007)and a patient with bipolar disorder (Kohen and Kremen 2007). An opencase series of 19 smokers with schizophrenia reported that 13 patientswere able to maintain abstinence (verified by measuring carbon mon-oxide level) for ≥12 weeks (Evins and Goff 2008). Over 6 months, fourpatients reported “slips” and were able to regain abstinence within aweek. None of the 19 patients showed significant worsening of psychi-atric symptoms, psychotic relapse, or hospitalization. Finally, a recentstudy (Stapleton et al. 2007) compared the effectiveness of vareniclineand nicotine replacement in 412 smokers with and without psychiatricdisorders. Of the 111 patients with mental health disorders, 7 werediagnosed with psychosis and 24 were diagnosed with combined psy-chosis and depression. Of those 111 patients with psychiatric disorders,53 patients received varenicline and 58 patients received TNP. The re-sults of this study suggested that varenicline was equally effective inpatients with and without mental illness, that varenicline was more ef-fective than TNP, and that there was no evidence that taking vareniclineexacerbated psychiatric symptoms (Stapleton et al. 2007). Further con-trolled research is needed to determine the safety and efficacy of vareni-cline for patients with schizophrenia and other psychiatric disorders.


Key Clinical Points

◗ Smokers with schizophrenia smoke at higher rates and have lowersmoking cessation rates than the general population. This group ofsmokers also shows higher rates of smoking-related illnesses, makingthe development of effective treatments for this population an impor-tant priority.

◗ Motivation to quit smoking is often low in patients with schizophrenia,and efforts need to be undertaken to increase the awareness of bothpatients and their clinicians of the dangers of habitual tobacco smok-ing. Motivational interviewing and relapse-prevention methods are themainstays of behavioral treatment for tobacco dependence in these pa-tients.

◗ The high rates of comorbid tobacco dependence in patients with schizo-phrenia may relate to abnormal biology of nicotinic receptor systemsand central dopaminergic, glutamatergic, and GABAergic pathways as-sociated with this disorder.

◗ Nicotine administration enhances several areas of cognitive function inpatients with schizophrenia, including working memory (specificallyspatial working memory), sustained attention, P50 gating, smooth pur-suit eye movement, and prepulse inhibition, which may contribute tothe initiation and maintenance of tobacco dependence in these patients.

◗ Controlled studies have suggested that treatments for tobacco depen-dence (e.g., nicotine replacement therapy, bupropion) are safe and im-prove smoking cessation outcomes for patients with schizophrenia.Recent studies have examined the efficacy of combining medicationsand newer pharmacological agents (e.g., varenicline) to further im-prove short- and long-term smoking cessation rates.

◗ Although there is little evidence from controlled clinical studies thatsmoking cessation produces a deterioration of clinical function (e.g.,positive and negative symptoms) in stabilized patients, further researchis needed, especially for newer agents such as varenicline that have notbeen tested in controlled trials. Clinicians should not encourage pa-tients with schizophrenia to quit smoking when they are clinically un-stable, because the likelihood of success is low and the risk of symptomexacerbation may be elevated.


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PART III

Special Topics andPopulations


247

CHAPTER 10

HIV and Hepatitis Cin Patients With

Schizophrenia

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.

Among the chronic health conditions experienced by people withschizophrenia, infection with human immunodeficiency virus (HIV) andhepatitis C virus (HCV) occur with concerning frequency. People whocontract HIV or HCV face chronic illness, the possibility of prematuredeath, complicated medication regimens, barriers to medical care, and theneuropsychiatric sequelae of treatment or infection itself. Estimates arethat approximately one-quarter of those infected with HIV and the major-ity of those with HCV in the United States do not know they are infected(Agency for Healthcare Research and Quality 2002; Marks et al. 2006).

HIV and HCV are acquired by similar routes of transmission, al-though HIV is much more likely to be sexually transmitted than HCV.In the United States, rates of both diseases are higher among AfricanAmericans and Latinos than among Caucasians. Both infections are


overrepresented among people with severe mental illness, includingthose with schizophrenia, especially when comorbid substance use ispresent. Published rates of HIV infection among psychiatric patients inthe United States are 3.1%–23.9% (Cournos and McKinnon 1997; Rosen-berg et al. 2001), at least eight times higher than the general populationestimate of 0.6% (UNAIDS 2007). HIV infection rates among patientswith schizophrenia rarely have been differentiated from rates amongothers with psychotic disorders, but when they have, no significant dif-ferences have emerged. In the United States, estimates of HCV infectionin samples of patients with mental illness, including schizophrenia, haveranged from 8.2% to 38.0% (Al Jurdi and Burruss 2003; Butterfield et al.2003, 2004; Dinwiddie et al. 2003; Freudenreich et al. 2007; Huckans et al.2006; Klinkenberg et al. 2003; Meyer 2003; Rosenberg et al. 2001; Tabib-ian et al. 2008). These rates are higher than the general population rate ofapproximately 1.6% (Centers for Disease Control and Prevention 2008).

Psychiatric symptoms and disabilities may increase risk of HIV orHCV among people with severe mental illness, either by directly affect-ing behavior or by interfering with the opportunity or ability to acquireand/or use information about these illnesses to practice safer behav-iors. Psychiatrists and other mental health care providers often are inthe best position to enhance patients’ skills in modifying risk behaviorsand to connect patients to the medical services they need.

Sexual Risk Behaviors and Psychiatric or Situational FactorsStudies of sexual risk behavior among people with psychiatric disordershave thus far not linked behaviors to biological outcomes, and few stud-ies have differentiated risk behaviors by psychiatric diagnosis. However,risk behaviors among people in psychiatric treatment in the UnitedStates are common, with interview studies revealing that a majority ofpatients were sexually active with a partner in the previous year and thatthe sexual activity of people with severe mental illness is characterizedby having multiple sex partners and by a lack of condom use in a major-ity of sexual occasions for both men and women (Meade and Sikkema2005). Being sexually active has been found to be associated with a diag-nosis of schizophrenia but not with bipolar disorder, and trading sex formoney or drugs was more than three times as likely among patients withschizophrenia than among those with other diagnoses, and more thanfive times as likely among those with certain positive symptoms such asdelusions (McKinnon et al. 1996; Meade and Sikkema 2007). Diagnosis

HIV and Hepatitis C 249

has not been shown to be associated with number of sex partners or con-dom use (Meade and Sikkema 2007), although greater psychiatric symp-toms were associated with increased HIV risk (Rosenberg et al. 2001).

Extended periods of institutionalization on same-sex units in hospi-tals, shelters, or prisons may foster high-risk same-sex activity, oftenamong those who do not self-identify as gay or lesbian. One study thatdirectly compared psychiatric patients with nonpsychiatric groupsfound that psychiatric patients are more likely to engage in same-sex ac-tivity (McDermott et al. 1994). This behavior is particularly risky for men.

Recurrent institutionalization, homelessness, transient living cir-cumstances, alienation from supportive social relationships, and lack ofprivacy can all interrupt long-term relationships, reinforcing the ten-dency to have unfamiliar partners. Studies report that 10%–16% of psy-chiatric patients had sex in the past year with someone they had knownless than 24 hours (Kalichman et al. 1994; Kelly et al. 1992). These con-ditions also may make changing risk behaviors difficult for people withsevere mental illness or may limit sexual opportunities to those thatconfer greater risk. Unemployment, which is common among adultswith severe mental illness, also may contribute to greater sexual risktaking (Meade and Sikkema 2007), possibly through pressures towardsurvival sex or commercial sex work. Sexual victimization, whichincreases the likelihood of unprotected intercourse, has been widelyreported by psychiatric inpatients (Malow et al. 2006). Among outpa-tients, one in eight reported having been pressured, coerced, or forcedinto unwanted sex in the past year (Carey et al. 1997).

Having a sexually transmitted infection, which renders a person bio-logically more susceptible to acquiring subsequent infections when ex-posed, is common among people with severe mental illness. Between 9%and 36% of psychiatric inpatients and outpatients are diagnosed with oneor more sexually transmitted infections at some time in their lives (Careyet al. 1997; Rosenberg et al. 2001). Moreover, some patients may have sex-ually transmitted infections without being aware of them and will likelyremain untreated unless screened for sexually transmitted infections.

Substance Use Risk Behaviors and Psychiatric or Situational FactorsIn the United States, psychiatric patients with identified comorbid alcoholor other drug use disorders have a significantly higher rate of HIV infec-tion than those without (McKinnon and Cournos 1998), even if they havenever injected drugs. In this population, any lifetime drug injection or


needle sharing appears to increase the risk of being infected with HIVmore than sixfold (Rosenberg et al. 2001). As in the general population,HCV infection in psychiatric patients is most strongly associated with in-jection drug use, and to a lesser extent with other drug use (including sniff-ing and smoking forms of cocaine), unsafe sexual practices, and poverty.

A history of drug injection has been noted among 1%–26% of psychi-atric patients, and 5%–12% report having ever shared needles or otherinjection paraphernalia (Carey et al. 1997; Rosenberg et al. 2001). More-over, psychiatric patients who inject tend to do so intermittently ratherthan regularly, so drug injection histories often are overlooked in men-tal health settings, and no conclusive evidence has been found to linkinjection drug use with psychiatric diagnosis, chronicity, level of func-tioning, or psychiatric symptoms. As in the general population, alcoholor other drugs often are part of psychiatric patients’ sexual experienceand may decrease the motivation or ability to have protected sex. Ofpsychiatric inpatients and outpatients, 15%–45% reported using sub-stances during sex in the past year (Carey et al. 1997; Menon and Po-merantz 1997), with comparable rates seen in men and women.

Knowledge About HIV/HCV Among People With Severe Mental Illness and Their ProvidersKnowledge about HIV and acquired immune deficiency syndrome(AIDS) among U.S. psychiatric patients appears to be relatively good.Correct responses to AIDS knowledge questionnaires in a variety ofpsychiatric patient groups ranged from 63% to 80%, a comparable accu-racy rate to that found in the general U.S. population (Meade andSikkema 2005). Still, many psychiatric patients held critical misinterpre-tations about HIV and related risks. In one study, for example, 48% ofoutpatients believed that careful cleansing after sex would provide pro-tection from the virus (Otto-Salaj et al. 1998). Comparable studies aboutHCV knowledge among psychiatric patients have not been completed.

HIV/AIDS: Overview of Course of Illness and TreatmentAs of 2007, approximately 1.3 million persons in North America and33 million persons worldwide were living with HIV (UNAIDS 2007),which was first identified in 1983. HIV infection is a chronic condition


that normally runs its course over many years, with AIDS being a late-stage manifestation of HIV infection, characterized by increasing viralload of HIV in the blood and declining immune function (as measuredby CD4 T-cell counts), leading to a broad spectrum of diseases. Accord-ing to the Centers for Disease Control and Prevention ([CDC] 2008), thediagnosis of AIDS is made in an HIV-positive individual who has atleast one of 25 AIDS-defining conditions (e.g., Pneumocystis cariniipneumonia, HIV-associated dementia, or a CD4 T-cell count lower than200 cells per cubic millimeter). HIV has been identified as the cause ofAIDS (Barre-Sinoussi et al. 1983). The virus invades the nervous system,causes persistent viremia, and weakens the humoral and cellular im-mune response. HIV has a remarkably complex viral genome, whichprobably underlies its profound pathogenicity.

HIV mutates rapidly, making drug resistance a major problem andcontributing to difficulties in producing an effective vaccine. HIV-1 isthe most common type of HIV virus in the United States and much ofthe rest of the world. HIV-2 occurs in West Africa, with scattered casesappearing in Asia. HIV-2 is associated with considerably slower diseaseprogression than HIV-1. Having either virus does not alter the suscep-tibility to infection with the other strain. All vaccine trials thus far havefailed to show protection against acquiring HIV, and one trial even sug-gested increased susceptibility among a subgroup of those vaccinated,leading to a call for more basic science research to further clarify vaccinedevelopment strategies (Walker and Burton 2008).

HIV TransmissibilityAlthough HIV has been isolated from a variety of body fluids, includ-ing blood, semen and preseminal fluid, vaginal secretions, breast milk,urine, saliva, and tears, the risk of transmission is a consequence of theviral load of the fluid. HIV is found in such small quantities in tears, sa-liva, and urine that casual contact with these fluids is a very unlikelymode of transmission. Epidemiological studies indicate that semen andpreseminal fluid, cervical and vaginal secretions, breast milk, and bloodand blood products are the predominant, if not exclusive, vehicles forviral transmission (Staprans and Feinberg 1997).

HIV is typically spread by sexual contact, exposure to infected blood(transfusions, blood products, percutaneous and intravenous injectionswith contaminated syringes or needles, etc.), and through perinataltransmission from mother to child. Although uncommon, infection ispossible through the exposure of cuts in skin or mucous membranes toHIV-infected blood.


Penile-vaginal and penile-anal intercourse are considered the high-est-risk sexual behaviors, in addition to activities that cause a rupture oftissue and the presence of blood. Although infection risk is somewhathigher for the recipient of semen than for the insertive partner, trans-mission has been documented in both directions. Male circumcisionsignificantly reduces the risk of HIV acquisition and transmission bymen during penile-vaginal sex; however, condoms are still needed.Oral sex has also been documented as a mode of transmission for the re-cipient of fluids, as has the sharing of sexual toys, although to a lesserextent. Certain cofactors enhance the risk of sexual transmission of HIV,including the presence of sexually transmitted infections, genital le-sions, or genital or mucous membrane bruising during sexual activity.

Sharing needles or other equipment during injection is a very effi-cient means of transmitting HIV and amounts to a direct inoculation ofviral particles from the infected to the noninfected person. As withother routes of transmission, the likelihood increases with the size ofthe viral inoculum. Even noninjection substance use may increase therisk for HIV by increasing the chance that an individual will engage inhigh-risk behaviors due to lowered sexual inhibitions, impaired judg-ment, increased impulsiveness, or the exchange of sex for drugs ormoney to buy drugs. Transfusion with infected blood and the use of in-fected blood products almost always results in acquisition of HIV, al-though testing of donated blood and blood products has almosteliminated the chances of this occurrence in the industrialized coun-tries.

HIV TestingThe most commonly used HIV test is the enzyme-linked immunosor-bent assay (ELISA), which, if positive, is followed by Western blot test-ing. The Western blot test is needed to rule out false positives on theELISA test. Antibody-based assays are available as rapid (20-minute)tests of either blood or saliva, but the blood test is more accurate; posi-tive results on either test must be confirmed by Western blot. Thesetests detect antibodies produced by the host as an immune response tocertain genetic components of the virus but do not detect the virus itself.Although sensitive and specific, even the Western blot can give false-negative or indeterminate results, especially during the first few weeksof infection. However, direct measurement of viral presence using thepolymerase chain reaction assay will usually show extremely high lev-els of virus during this window period. False-positive results may occuras well. Despite the latter concern, the CDC now recommends routine


opt-out HIV testing (testing for HIV as part of routine medical care un-less the patient refuses) in all medical settings (Branson et al. 2006).

Viral Load and Resistance AssaysViral load, a quantifiable measurement of how many viral particles arepresent in a milliliter of blood, can be determined by several differentassays, some of which detect as few as 50 viral particles per milliliter ofblood. Below that threshold of measurement, the result is reported as“nondetectable.” This does not indicate that there is no virus present inblood at all, nor does it measure the amount of virus in lymphoid tissueor in the central nervous system (CNS). Viral load is a strong predictorof disease progression in untreated patients. For those on antiretroviraltherapy, CD4 T-cell counts are the stronger predictor of clinical out-come. Both CD4 T-cell counts and viral load are used to monitor clinicalresponse to therapy (Hulgan et al. 2007). Predicting responses to antivi-ral medications can be accomplished by testing for drug resistance, aproblem increasingly seen in clinical practice. Resistance assays includegenotyping to examine the patient’s virus for mutations known to con-fer drug resistance; phenotyping to test the susceptibility of the pa-tient’s virus to specific medications; and virtual phenotyping, whichuses a large database that associates genotypes with phenotypes to pre-dict drug susceptibility.

Natural History of HIV DiseaseHIV contains ribonucleic acid (RNA) as its genetic material. HIV targetshost CD4 T-lymphocytes and other susceptible cells by identifying sur-face molecules and attaching to and entering the cells (Staprans andFeinberg 1997). This begins the process of using the viral reverse tran-scriptase enzyme to transcribe viral RNA to deoxyribonucleic acid(DNA), which then allows the virus to use the host cell’s machinery toreplicate itself. The replicated virus particles must be split apart intovirions by the protease enzyme before they are extruded from the hostcell so as to become functional and capable of infecting other CD4+cells, leading to ongoing damage to the immune system. As the hostproduces circulating antibodies against HIV, the host is said to serocon-vert. Genetic information to reproduce the virus is also integrated intothe host cell’s genome. The immune system may initially contain butdoes not clear the infection; the course is set for chronic persistent viralreplication. Without treatment, near complete destruction of the CD4 T-lymphocyte population eventually occurs in the vast majority of in-fected people. A person’s initial viral “setpoint,” the capacity of his or


her immune system to limit viral replication, is the strongest predictorof untreated disease progression (Staprans and Feinberg 1997).

The range and severity of symptoms in acute HIV infection vary con-siderably, with approximately 40%–90% of patients developing a retro-viral syndrome characterized by a variety of symptoms that mayinclude fever, lymphadenopathy, pharyngitis, malaise, myalgia, ar-thralgia, rash, headache, stiff neck, and other meningeal signs andsymptoms. Acute HIV infection is highly transmissible due to transientintense viremia, and is accompanied by an acute fall in CD4 T-cellcounts in the peripheral blood from its normal range of 800–1,200 cells/mm3 (Soogoor and Daar 2005). The more severe this syndrome is, themore likely the untreated patient will progress rapidly to AIDS (Fidleret al. 2008). Although there are reasons to believe that favorable treat-ment during acute HIV infection can alter its long-term course, this isnot yet established beyond question, and patients are encouraged to en-roll in clinical trials studying the course of acute HIV infection (http://www.aidsinfo.nih.gov).

Once the symptoms of primary infection subside and an antiviralimmune response appears, patients usually enter a chronic, clinicallyasymptomatic or minimally symptomatic state despite continuous ac-tive viral replication. This period may last only a few years in some in-fected individuals, but the majority of HIV-positive patients developovert immunodeficiency in approximately 8–10 years, and a small co-hort demonstrates sustained long-term (>10 years), symptom-free HIVinfection (Staprans and Feinberg 1997). During chronic infection, thedevelopment of symptoms, a low CD4 cell count, and a high viral loadshould initiate a discussion between clinician and patient about antiret-roviral treatment. The patient’s ability to adhere to the regimen is, ofcourse, pivotal to the decision.

The spectrum of HIV-associated illnesses that eventually develop in-cludes constitutional symptoms (e.g., weight loss, fatigue, fever, nightsweats) and involvement of multiple organ systems. Opportunistic in-fections (OIs) are multiple and can occur throughout the body. Theseinclude fungal infections (e.g., oral or esophageal candidiasis [thrush],cryptococcal infection, Pneumocystis carinii pneumonia); protozoan in-fections (e.g., toxoplasmosis); mycobacterial infections (e.g., tubercu-losis and Mycobacterium avium complex); and bacterial and viralinfections (e.g., recurrent pulmonary and gynecological infections).Cancers, such as Kaposi’s sarcoma and lymphoma, are other manifesta-tions of severe immunosuppression. Prophylactic regimens can reducethe occurrence of many OIs in immunocompromised patients.

http://www.aidsinfo.nih.gov

http://www.aidsinfo.nih.gov


Neuropsychiatric Manifestations of HIV

HIV infection presents a spectrum of neuropsychiatric sequelae thatcan pose diagnostic and treatment quandaries for clinicians. In patientswith serious and persistent psychiatric illness, some of the early, subtleneuropsychiatric symptoms may be difficult to differentiate from pre-existing symptoms of psychiatric illness. HIV is neurotropic and entersthe CNS soon after infection. Long-term clinical sequelae of CNS infec-tion range from subtle neurocognitive impairment to frank dementia,and their incidence increases with HIV illness progression. Opportunis-tic infections and neoplasms that follow immunosuppression can alsoaffect the CNS, resulting in mood disorders, psychosis, cognitive disor-ders, delirium, and other neuropsychiatric abnormalities. In addition,prescribed and recreational psychoactive substance use may createneuropsychiatric complications and must be considered in the differen-tial diagnosis of patients who present with new mental status changes(American Psychiatric Association 2000; Wainberg et al. 2000).

HIV-associated neurocognitive disorders (HAND) are diagnoses ofexclusion made after other etiologies have been ruled out through acomprehensive evaluation. Table 10–1 describes the diagnostic criteriafor the three categories of HAND: asymptomatic cognitive disorder,mild neurocognitive disorder, and dementia. (Antinori et al. 2007).

HAND are subcortical disorders that affect primarily and initiallythe CNS white matter and, as time progresses, other CNS tissues. Al-though the exact pathophysiology of HAND remains unclear, diagno-sis of HAND is relatively common, particularly in more advancedstages of HIV infection. Effective antiretroviral treatment has dramati-cally reduced the incidence of HAND. Antiretroviral treatment shouldbe initiated or the regimen evaluated following diagnosis of symptom-atic HAND, and other medications can be prescribed to treat associatedsymptoms (e.g., antidepressants, stimulants, testosterone).

Psychiatric symptoms due to HIV-related medical conditions aremost common in advanced stages of illness (American Psychiatric As-sociation 2000). Therefore, among patients with advanced HIV whohave a preexisting severe mental illness, psychiatric changes should notbe attributed to a relapse until a complete medical workup has ruledout other causes. Mental status changes that can have a medical etiol-ogy include shifts in level of consciousness characteristic of delirium,cognitive impairment, mood changes, and psychotic symptoms. Thedifferential diagnosis includes not only the neuropsychiatric manifesta-tions of HIV itself but also opportunistic infections (e.g., toxoplasmosis,


TABLE 10–1. Criteria for HIV-associated neurocognitive disorders (HAND)

HIV-associated asymptomatic neurocognitive impairment (ANI)a

1. Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1 standard deviation (SD) below the mean for age- and education-appropriate norms on standardized neuropsychological tests. The neuropsychological assessment must survey at least the following abilities: verbal/language; attention/working memory; abstraction/executive; memory (learning, recall); speed of information processing; sensory-perceptual and motor skills.

2. The cognitive impairment does not interfere with everyday functioning.

3. The cognitive impairment does not meet criteria for delirium or dementia.

4. There is no evidence of another preexisting cause for the ANI.b

HIV-1–associated mild neurocognitive disorder (MND)c

1. Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1 SD below the mean for age- and education-appropriate norms on standardized neuropsychological tests. The neuropsychological assessment must survey at least the following abilities: verbal/language; attention/working memory; abstraction/executive; memory (learning, recall); speed of information processing; sensory-perceptual and motor skills.

2. The cognitive impairment produces at least mild interference in daily functioning (at least one of the following):a) Self-report of reduced mental acuity or of inefficiency in work,

homemaking, or social functioning.b) Observation by knowledgeable others that the individual has

undergone at least mild decline in mental acuity with resultant inefficiency in work, homemaking, or social functioning.

3. The cognitive impairment does not meet criteria for delirium or dementia.

4. There is no evidence of another preexisting cause for the MND.d


HIV-1–associated dementia (HAD)e

1. Marked acquired impairment in cognitive functioning, involving at least two ability domains; typically the impairment is in multiple domains, especially in learning of new information, slowed information processing, and defective attention/concentration. The cognitive impairment must be ascertained by neuropsychological testing with at least two domains reduced by 2 SD or greater than demographically corrected means. (Note that where neuropsychological testing is not available, standard neurological evaluation and simple bedside testing may be used, but this should be done using well-defined criteria.)

2. The cognitive impairment produces marked interference with day-to-day functioning (work, home life, social activities).

3. The pattern of cognitive impairment does not meet criteria for delirium (e.g., clouding of consciousness is not a prominent feature), or if delirium is present, criteria for dementia need to have been met on a prior examination when delirium was not present.

4. There is no evidence of another, preexisting cause for the dementia (e.g., other central nervous system [CNS] infection, CNS neoplasm, cerebrovascular disease, preexisting neurological disease, or severe substance abuse compatible with CNS disorder).f

aIf the patient had a prior diagnosis of ANI but currently does not meetcriteria, the diagnosis of ANI in remission can be made.bIf the individual with suspected ANI also satisfies criteria for a major de-pressive episode or substance dependence, the diagnosis of ANI shouldbe deferred to a subsequent examination conducted at a time when themajor depression has remitted or at least 1 month after cessation of sub-stance use.cIf the patient had a prior diagnosis of MND but currently does not meetcriteria, the diagnosis of MND in remission can be made.dIf the individual with suspected MND also satisfies criteria for 1) a severeepisode of major depression with significant functional limitations or psy-chotic features or 2) substance dependence, the diagnosis of MND shouldbe deferred to a subsequent examination conducted at a time when themajor depression has remitted or at least 1 month after cessation of sub-stance use.eIf the patient had a prior diagnosis of HAD but currently does not meetcriteria, the diagnosis of HAD in remission can be made.

TABLE 10–1. Criteria for HIV-associated neurocognitive disorders (HAND) (continued)


cryptococcus, tuberculous meningitis), lymphoma, or delirium frommetabolic derangement, substance use, or drug toxicity (Wainberg et al.2000).

HIV/AIDS TreatmentClinical management of HIV/AIDS is intended to maximally and dura-bly suppress viral load, restore and preserve immune function, provideprophylaxis against opportunistic infections as appropriate, treat OIswhen present, and decrease morbidity and mortality. Guidelines for theprophylaxis of OIs are based on the prevalence of each OI at variousstages of immunodeficiency. In addition to the diagnosis of AIDS, otherindications for treatment in an HIV-positive person include pregnancy,HIV-associated nephropathy, symptomatic HAND, and a CD4 cellcount between 200 and 350. The need to treat other infections, such ashepatitis B and tuberculosis, also affects the timing and choice of anti-retroviral agents for HIV. Guidelines for treatment of HIV infection arecontinually updated as new medications and more data from clinicaltrials become available. U.S. recommendations can be found at http://AIDSinfo.NIH.gov. This site, maintained by the U.S. Department ofHealth and Human Services, also includes guidelines for postexposureprophylaxis following either an injury that carries risk in the health caresetting or a sexual exposure.

Part of instituting antiretroviral therapy involves ensuring that pa-tients recognize their HIV infection, have access to health care, developongoing provider relationships, and are motivated to adhere to treat-ment, even during an asymptomatic phase of infection. When patientsare not ready to adhere to antiretroviral therapy (e.g., because of chaotic

fIf the individual with suspected HAD also satisfies criteria for 1) a severeepisode of major depression with significant functional limitations or psy-chotic features or 2) substance dependence, the diagnosis of HAD shouldbe deferred to a subsequent examination conducted at a time when themajor depression has remitted or at least 1 month after cessation of sub-stance use. Note that the consensus was that even when major depressionand HAD occurred together, there is little evidence that pseudodementiaexists and the cognitive deficits do not generally improve with treatmentof depression.

Source. Adapted from Antinori et al. 2007.

TABLE 10–1. Criteria for HIV-associated neurocognitive disorders (HAND) (continued)

http://AIDSinfo.NIH.gov

http://AIDSinfo.NIH.gov


life due to psychiatric instability, substance use, and/or homelessness;lack of motivation; insufficient social supports), barriers to adherenceshould be addressed first. High levels of adherence are required to sup-press fully the replication of virus that is sensitive to the regimen beingadministered and to prevent the emergence of drug resistance. Mentalhealth professionals often have important roles in assessing and pro-moting adherence.

As of June 2008, the U.S. Food and Drug Administration had ap-proved 22 individual antiretroviral medications, which are classifiedinto six categories according to the specific step inhibited in the HIV lifecycle (see Table 10–2). Individually, these agents are not very potent,but by combining three or more agents, effective viral suppression canbe achieved even among many patients with resistant strains. More-over, many regimens are simpler and contain fewer pills than in thepast.

HCV: Overview of Course of Illness and TreatmentApproximately 4 million persons in the United States and 170 millionpersons worldwide are infected with hepatitis C. The virus causes per-sistent infection in a majority of infected people, although most haverelatively mild disease with slow progression. However, chronic andprogressive HCV carries significant morbidity and mortality and is amajor cause of cirrhosis, end-stage liver disease, and liver cancer. Sixdifferent genotypes have been identified. Most people in the UnitedStates who have HCV have genotype 1, which is difficult to treat. De-velopment of an effective HCV vaccine is not imminent but continuesto be pursued, because current therapy for HCV is poorly tolerated andnot effective for a substantial number of patients.

HCV TransmissionHCV is spread primarily through infected blood and is therefore a com-mon complication of injection drug use and sharing of razors or tattoo-ing equipment. HCV may also be spread by maternal fetal transmissionand noninjection drug use activities. Although HCV is sexually trans-missible, its efficiency of transmission via this mode is far less thanother blood-borne viruses, including HIV (Clarke and Kulasegaram2006).


TABLE 10–2. Medications for HIV infection approved by the U.S. Food and Drug Administration as of June 2008

Generic name Trade name

Nucleoside/nucleotide reverse transcriptase inhibitorsAbacavir ZiagenDidanosine Videx ECEmtricitabine EmtrivaLamivudine EpivirStavudine ZeritTenofovir VireadZidovudine Retrovir

Non-nucleoside reverse transcriptase inhibitorsDelavirdine RescriptorEfavirenz SustivaNevirapine Viramune

Protease inhibitorsAtazanavir ReyatazDarunavir PrezistaFosamprenavir LexivaIndinavir CrixivanLopinavir/ritonavir KaletraNelfinavir ViraceptRitonavir NorvirSaquinavir InviraseTipranavir Aptivus

Fusion inhibitorEnfuvirtide Fuzeon

CCR5 inhibitorMaraviroc Selzentry

Integrase inhibitorRaltegravir Isentress

Combination reverse transcriptase inhibitorsAbacavir and lamivudine EpzicomAbacavir, zidovudine, and lamivudine TrizivirEfavirenz, tenofovir, emtricitabine AtriplaTenofovir and emtricitabine TruvadaZidovudine and lamivudine Combivir


HCV TestingTesting for HCV does not involve the counseling, confidentiality, orstigma issues usually associated with HIV testing. Providers varygreatly in how they proceed after identifying HCV-positive patients.Given that about 20%–33% of patients with severe mental illness in theUnited States are infected with HCV, a strong argument can be madethat all such persons should be screened for the virus (Goldberg andSeth 2008). Certainly, all patients known to be infected with HIV shouldbe screened for anti-HCV antibodies as part of their initial evaluation,as should those with high-risk behavior. HCV infection should be con-firmed with qualitative polymerase chain reaction assay if the patient isat low risk and the diagnosis seems in doubt. Moreover, there is a smallbut measurable false-negative rate for antibody testing in patients whoare severely immunosuppressed.

Natural History of HCV DiseaseAcute HCV disease is usually asymptomatic, but 25%–35% of patientsdevelop some constitutional symptoms or jaundice. Serum alanine ami-notransferase levels frequently rise, fluctuate, and fall again, suggestingrecovery from the acute phase. However, following acute infection,HCV is not easily cleared by the immune system, and 75%–80% of acuteHCV infections become chronic, as evidenced by persistent or intermit-tent HCV viremia.

Chronic HCV infection can cause inflammatory infiltration, particu-larly of the portal tracts, as well as focal liver cell necrosis and fibrosisthat bridges between portal tracts. Hepatitis C is the leading cause ofliver transplantation in the United States. About 10%–20% of chroni-cally infected patients progress to cirrhosis within 20–30 years of infec-tion, and among those with cirrhosis, 1%–4% per year will develophepatocellular carcinoma. Patients infected with HCV should be ad-vised to minimize or preferably discontinue intake of alcohol.

Immunosuppression associated with HIV significantly alters the nat-ural history and clinical course of HCV, with HCV-associated cirrhosisoccurring more frequently in patients with HCV/HIV co-infection (33%)than in HCV alone (11%). People with concurrent HCV do not toleratehighly active antiretroviral therapy as well as people with HIV alone, andthis can interfere with effective HIV treatment (Soriano et al. 2008). Liverfailure due to HCV is the leading non-AIDS cause of death in HIV-infected individuals (de Lédinghen et al. 2008). Because of increased riskof severe liver damage, all patients with HCV and/or HIV should bescreened for immunity to hepatitis A and B and immunized accordingly.


Neuropsychiatric Manifestations of HCVHCV-related cognitive impairment was previously assumed to be a con-sequence of cirrhosis-associated hepatic encephalopathy. Recent evi-dence suggests that one-third of people with chronic HCV experiencecognitive impairment even in the absence of cirrhosis and that its occur-rence is unrelated to laboratory values, viral load, and genotype (Perryet al. 2008). Attention, concentration, and psychomotor speed are themost impaired cognitive functions and may influence adherence tomedical care and medications. HCV injury to the brain can occur via in-fection of resident (e.g., astrocytes) and migrating (e.g., macrophages)cells of the central nervous system; adaptation to neural cells; inflamma-tion of basal ganglia and white matter; or neuronal loss (Letendre 2008).

HCV TreatmentDiagnostic testing to determine the presence of HCV viremia and theextent of liver pathology should be completed as early as possible in thecare of a patient infected with HCV. Patients with active HCV infectionor evidence of chronic liver disease should be referred for care to a spe-cialist with experience in treating hepatitis C. Not all patients with HCVrequire or benefit from treatment. Table 10–3 describes the treatmentguidelines according to patient characteristics. In patients who are alsoHIV positive, antiretroviral therapy may need to be modified, delayed,or interrupted to complete an adequate course of therapy for HCV. Theeffectiveness of treatment is assessed by following HCV viral load.

The goal of treatment is cure of HCV infection, manifested by reduc-tion in hepatitis C viral load to undetectable, normalization of transam-inases (alanine aminotransferase and aspartate transaminase), andcessation of liver disease progression. Combination therapy with dailyoral ribavirin and once-weekly subcutaneous peginterferon alpha-2b isthe standard therapy for HCV (Deutsch and Hadziyannis 2008).

Exacerbation of psychotic symptoms during HCV treatment with in-terferon has been reported in sporadic cases, especially in patients witha history of abuse of various drugs, including hallucinogens. Interferonand ribavirin have potential neuropsychiatric side effects, includingapathy, cognitive changes, irritability, depression, psychosis, and sui-cidal thoughts. Prospective studies with psychiatric patients, includingpeople with schizophrenia (n=38), found that the response rates and ad-herence during treatment with standard interferon and ribavirin weresimilar to those of patients in a nonpsychiatric control group (Schaefer etal. 2007). Psychiatric patients were also not at increased risk of worseningdepression or psychosis during antiviral treatment compared with con-


trols. Of note is that clinical trials using interferon as an add-on treatmentfor patients with schizophrenia have shown improvement in psychoticsymptoms and reduction in the daily dosage of antipsychotic medicationneeded (Freudenreich et al. 2007). Nonetheless, patients with depression,psychotic disorders, or drug addiction should be carefully monitored forthe development of psychiatric symptoms during interferon treatment,with interdisciplinary involvement to optimize adherence and responserates and to manage potential side effects. The neurocognitive complica-tions of HCV itself, together with the symptoms of liver failure, such asfatigue, loss of appetite, loss of sexual drive, and impotence, can overlapwith the complications of interferon treatment, the symptoms of psychi-atric disorders, and the side effects of psychotropic drugs.

Unfortunately, the majority of people with schizophrenia are not testedfor HCV, and among those who are tested and are diagnosed with chronic

TABLE 10–3. Hepatitis C virus (HCV) treatment guidelines

Patient characteristics Treatment recommendations

HCV genotype 2 or 3 with persistent HCV viremia

Treat with pegylated interferon plus ribavirin for 24 weeks. Liver biopsy is optional, but treat regardless.

HCV genotype 1 with persistent viremia and

1. liver biopsy showing portal or bridging fibrosis, compensated cirrhosis, ormoderate inflammation or necrosis

Treat with pegylated interferon plus ribavirin if no contraindi-cations (assess risks and bene-fits on a case-by-case basis).If HCV viral load decreases within the initial 6–12 weeks of therapy, continue treatment for 48 weeks; if no decrease, discontinue treatment.

2. no or minimal fibrosis on liver biopsy

Follow with observation, serial alanine aminotransferase measures, and liver biopsy every 3–5 years.

Decompensated cirrhosis, any genotype

Consider evaluation for liver transplant.


HCV infection, few receive treatment. Among a sample of 108 outpatientswith severe mental illness, only 32% reported having been previouslytested for HCV (Goldberg and Seth 2008). Of those newly identified asHCV infected (n=18) within the study, half received an HCV-specificmedical follow-up, and only one person was started on treatment.

Clinical ConsiderationsRisk-Reduction Interventions and Strategies for HIV and HCVThe most successful HIV prevention interventions are those addressingperinatal transmission, which has been reduced to approximately 1% inthe United States with the effective use of antiretroviral treatment, andmay be further reduced by intrapartum delivery strategies (Jamieson etal. 2007). However, a variety of interventions and strategies have beenrecommended to lower the risk of transmitting HIV and HCV.

Harm reduction is the ultimate goal for both drug-related and sexualrisk behaviors. The use of prevention strategies for injection drug users(e.g., syringe exchange and syringe availability at pharmacies) has re-duced HIV and HCV transmission among injection drug users in theUnited States and in a number of other countries (Des Jarlais and Se-maan 2008). No studies have been done of interventions to address theintermittent injection drug use that has been documented in the popu-lation with severe mental illness.

Engaging patients in efficacious individual and group interventionsto practice assertive behaviors and negotiation skills to increase self-protective behaviors, including condom use, is necessary to stem newinfections in this highly affected population. The best predictor of usinga condom is having a condom. Institutional obstacles to condom acqui-sition are likely to impede patients’ initiative and ability to practicesafer sex. Making condoms available anonymously to all patients, in-cluding inpatients with off-ward privileges or who engage in consen-sual sex on the ward, has been shown to be a cost-effective primaryprevention intervention (Carmen and Brady 1990).

HIV prevention programs that primarily dispense AIDS informationhave not been shown to influence risk behavior. As evidence indicates,knowledge is necessary but not sufficient to produce behavioral changes.Intensive, small-group programs that simultaneously target knowledge,attitudes, motivations, and cognitive and behavioral skills have beentried and found to produce reductions in high-risk sexual behaviors, in-cluding some that are substance related, among people with severe men-


tal illness. Effective elements from randomized controlled trials of theseHIV risk-reduction interventions (Wainberg et al. 2007) include 1) pro-viding risk information; 2) enhancing awareness of attitudes, intentions,and readiness for change; 3) acquiring and rehearsing sexual risk-reduc-tion behavioral skills; 4) problem solving for handling triggers for sexualrisk taking; and 5) reinforcing behavior changes between interventionsessions. Mental health programs need to provide an environment inwhich healthy sexuality can be discussed. Patients can benefit from par-ticipating in mixed–HIV serostatus prevention groups; participants neednot reveal their HIV status unless they wish to do so. Whatever thegroup’s composition, group leaders should leave time at the end of eachsession to discuss patients’ personal issues privately and to address theirneeds by making appropriate referrals, including for HIV testing.

Because HCV shares modes of transmission with HIV, groups fo-cused on HIV risk reduction may also wish to impart information aboutHCV infection through high-risk behaviors. Prevention efforts aimed atHCV are essential for patients who are currently (or at risk for) injectingdrugs, because injection drug use is the risk factor responsible for a ma-jority of HCV cases in the United States.

Once staff have received training to do prevention interventions,they typically become motivated to start intervention groups for pa-tients. Groups work best in longer-term day programs and outpatientprograms. On inpatient units, short lengths of stay may limit the num-ber of sessions patients can attend, but that issue should not discouragestaff from setting up such programs.

Individual counseling can reinforce patients’ motivations to protectthemselves and others. Clinicians can encourage patients with HIV orHCV to disclose their illness to drug-use partners or sex partners and touse condoms. Fully informed decisions about risk and protection ofothers are the goals.

Accessing HIV- and HCV-Related Services That Psychiatric Patients NeedMental health service settings vary in their ability to offer HIV- andHCV-related screening, testing, and prevention interventions, and therange of services available may not yet be meeting the needs of peoplewith severe mental illness (Goldberg and Seth 2008; Satriano et al. 2007).

Risk assessment for HIV or HCV is intended to elicit specific informa-tion about patients’ sexual behaviors and drug use. Most patients, whenasked in a direct, nonjudgmental way, are cooperative and forthcoming.Rather than asking “Have you ever...,” asking “How often have you...”


is more likely to elicit useful risk information without raising a patient’s de-fenses by implying that the clinician will judge such behaviors negativelyor consider them unusual. The ease with which the clinician is able to dis-cuss sex and drug use will set the anxiety level for the patient, and normal-izing any patient discomfort can create a more relaxed tone.

HIV testing is guided by regulations that vary from state to state, butthe CDC-recommended opt-out testing does not require counseling. Tobetter prepare patients for potential positive results, mental health pro-grams may want to provide pretest and posttest counseling that is co-ordinated with medical care or conduct the testing themselves.

The initial diagnosis of HIV infection may occur when a patient firstbecomes infected or has advanced AIDS, or any time in between. Shockand disbelief may be followed by depression, anxiety, and fear in ad-justing to having contracted a serious and potentially deadly illness.Like severe mental illness, HIV and AIDS can be highly stigmatizing,possibly resulting in rejection, abandonment, and further social isola-tion. If a worsening of psychiatric symptoms follows the initial HIV di-agnosis, the most effective intervention is individual counseling andsupportive therapy geared to the patient’s current mental status and hisor her knowledge and understanding of HIV infection.

Legal regulations or guidelines for confidentiality and the disclosureof HIV- or AIDS-related information set the stage for upholding hu-mane and responsible individual and public health standards. Contactnotification by physicians may not be required, but legal statutes mayallow doctors or public health officers to inform a contact who is at sig-nificant risk if they determine that a patient will not do so. Laws that areapplicable to the locality should be consulted when making decisionsthat involve confidentiality and contact notification.

For HIV-infected psychiatric patients who are asymptomatic, sup-portive groups may encourage behavioral change and promote ways topreserve physical health in the community and within the psychiatricsetting. This kind of group intervention can prevent worsening of psy-chiatric symptoms and provide a sense of community that can decreasesocial isolation, reinforce safer peer norms, and encourage altruism,which appeals to ego strengths and gives patients a sense of worth andaccomplishment.

Services may be directed at patients on the basis of their suspected orpresumed risks rather than thorough individual risk assessments (Bru-nette et al. 2000; McKinnon et al. 1999). This model of risk evaluation istypically relied upon when there are unmet needs for staff training.Training is one important way to improve service delivery systems.


Testing for HCV can occur at any point and does not require specialconsent. Routine screening for HCV, followed by referral for evaluationof every HCV-positive patient, including those with schizophreniawhose psychiatric condition is stable, is warranted. Clinicians need toexplain the test result to patients found to be HCV positive and to refersuch patients for further evaluation and, as appropriate, hepatitis A andB immunization.

Clinicians may be in the best position to help their patients accessHIV and HCV testing, treatment, and prevention opportunities. Theycan employ many strategies to help their patients determine their riskof acquiring or transmitting HIV or HCV, prevent new infections, pro-mote healthier behaviors, and reduce the impact of HIV- and HCV-related illness on this vulnerable population. Clinicians also areuniquely qualified to help their patients manage the many medicationsrequired to maintain their psychiatric and physical health.

Psychopharmacology for People With HIV or HCV and SchizophreniaImportant points to keep in mind when prescribing psychotropic med-ication to people with schizophrenia who have comorbid HIV or HCVinfection are listed in Table 10–4. Notably, as HIV progresses, peoplewith preexisting psychiatric conditions may develop new or increasedside effects when taking medications they were previously able to tol-erate.

In the course of the medical management of HIV infection, particu-larly in later stages of HIV disease, a large number of medications maybe prescribed, including antibacterial, antifungal, antineoplastic, anti-retroviral, and other antiviral agents (Wainberg et al. 2000). Any at-tempt to diagnose drug-induced neuropsychiatric syndromes requiresan appreciation of both the therapeutic use and potential side effects ofthese medications. Some of these are described in the Practice Guide-lines of the American Psychiatric Association (American PsychiatricAssociation 2000), but new antiretroviral agents are being developed ata rapid pace and existing medications to treat HIV-related infectionsand neoplasms are too numerous to describe fully. Neuropsychiatricside effects of antiretrovirals have been reported most commonly withefavirenz and occasionally with nevirapine. Despite predictions ofdrug-drug interactions (which can be found in handheld databases,through hospital pharmacies, and at a variety of Web sites), experi-enced prescribers generally find they can effectively use the full range


of psychotropic medications. Overlapping toxicities between differentmedications must also be taken into consideration. Because advancedHIV infection is associated with greater sensitivity to both the therapeu-tic effects and side effects of psychotropic medications, the best ap-proach is to start a patient taking the lowest possible dosage andincrease the dosage slowly. Drug levels, if available, should be moni-tored closely, especially when patients are on complex medication reg-imens. Methadone, recreational drugs, and herbal preparations also canaffect medication levels.

Most psychiatric medications are metabolized by the liver and there-fore may require more careful monitoring in patients chronically in-fected with HCV. In particular, for patients who manifest clinical orlaboratory signs of liver failure, medication metabolism can be danger-ously reduced such that the patients may accumulate toxic levels ofdrugs at dosages they were previously able to tolerate.

In general, the use of most psychiatric medications is relatively safewith both HIV and HCV treatments. For patients with HCV illness, pe-riodic liver function tests are the standard of care. Because some psy-chotropic medications (e.g., antidepressants, lithium, valproic acid,carbamazepine) may elevate liver enzymes in HCV-infected patients, itis important to check these at baseline, early after initiation of therapy(after 2–4 weeks), and every 2–3 months thereafter. However, alanineaminotransferase elevations may be due to fluctuations in the HCV it-self or other factors (e.g., unacknowledged alcohol use) (Felker et al.2003). Combined toxicities are important to consider, particularly dur-ing treatment with medications that can have an impact on bone mar-row activity (e.g., clozapine, carbamazepine, zidovudine, interferon,ribavirin) or cause other additive side effects.

Psychiatric patients, like medical patients, are often nonadherent tomedication, which they may perceive as one of the few aspects of theirlives they can control. It is important to time the beginning of an antivi-ral regimen with a commitment to the treatment and to help patientssee that following an HIV or HCV medication regimen can be part ofgaining control. Working with a patient to promote adherence to psy-chotropic medications will be the best predictor of whether the patientcan follow an HIV or HCV medication regimen. The clinician and infec-tious disease specialist must communicate about the patient’s need forand readiness to begin antivirals; select, in concert with the patient, reg-imens that minimize drug-drug interactions; keep the number and dos-ages of pills the patient has to take to the minimum necessary; andcoordinate their treatment plans.


TABLE 10–4. Psychotropic medication in patients with schizophrenia with comorbid HIV and/or HCV infection

Medically asymptomatic and not receiving antiviral treatmentHIV

Most psychotropics can be used as usual.Monitor use of typical antipsychotics for increased incidence of

extrapyramidal side effects.Evaluate for testosterone deficiency if depressed or fatigued.

HCVWhenever possible, avoid drugs that cause liver toxicity.Follow liver enzymes.

Medically ill and/or receiving antiviral treatmentHIV

For most psychotropics, start with low doses and increase slowly.Check for interactions and overlapping toxicities between

psychotropics and antiretrovirals. Note that protease inhibitors are potent inhibitors of one or more cytochrome P450 enzymes, which may have implications for interactions with psychiatric and other medications.

Monitor use of typical antipsychotics for severe and rapid onset of extrapyramidal side effects.

Monitor use of atypical antipsychotics with antiretroviral medications, which overlap in causing metabolic abnormalities.

Avoid carbamazepine, which lowers antiretrovirals.Avoid lithium with HIV-associated nephropathy.Consider that antianxiety drugs metabolized by glucuronidation

have fewer drug interactions with antiretrovirals (i.e., clorazepate, lorazepam, oxazepam, temazepam).

Evaluate for testosterone deficiency if depressed or fatigued.Be aware that antiretrovirals alter levels of methadone and

buprenorphine, usually by decreasing them. Check effects of specific antiretroviral regimens and modify doses as needed.

Caution against St. John’s wort, which lowers antiretrovirals.HCV

Avoid drugs that cause liver toxicity.Follow liver enzymes.Monitor for depression and worsening of psychotic symptoms

while on antiviral therapy; treat as necessary.

Source: American Psychiatric Association 2000 and http://www.nynjaetc.org/cem.html.

http://www.nynjaetc.org/cem.html

http://www.nynjaetc.org/cem.html


ConclusionUnderstanding the HIV and HCV epidemics and their underpinningsamong people with severe mental illness can help clinicians to recog-nize when their patients with schizophrenia are at risk of acquiring ortransmitting these viruses and to intervene appropriately and effec-tively with preventive, counseling and testing, medical, and supportiveservices. It is critical for clinicians to receive training to enhance theirknowledge and skills in these areas, to ask comfortably and nonjudg-mentally about their patients’ risks rather than wait until patients are illto learn about risk behaviors, and to continually access up-to-date infor-mation and technical assistance about how to prevent and treat theseinfections among their patients.

Key Clinical Points

◗ People with schizophrenia are at heightened risk for acquiring HIV andHCV infection, and both of these infections can result in increasedmorbidity and mortality.

◗ Both HIV and HCV enter the central nervous system and can causeneurocognitive symptoms that complicate the psychiatric presentationsand treatment of people with schizophrenia.

◗ Improvements in the treatments for HIV and HCV infections warrantassertive efforts to identify patients who are infected.

◗ Testing for HIV and HCV infection and offering prevention interven-tions should be part of routine care for people with schizophrenia.

◗ Patients who test positive for either HIV or HCV should routinely bereferred to medical providers who can assess and treat these conditions.Mental health care providers need to stay involved to ensure patientadherence to medical care and help manage mental health complica-tions of treatment.

◗ Mental health providers often need to advocate to ensure that peoplewith schizophrenia are not rejected from HIV and HCV treatmentsolely because they have a mental illness.


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CHAPTER 11

Substance Abuse andSchizophrenia

Peter F. Buckley, M.D.Jonathan M. Meyer, M.D.

The co-occurrence of schizophrenia and substance use or abuse iscommon and presents complex issues for mental health practitioners.Approximately 50% of individuals with schizophrenia will develop sub-stance use disorders at some point during their lives, and about half ofthis group will exhibit current substance abuse or dependence (Buckley2006). The abuse of drugs and alcohol by persons with severe mental ill-nesses has a wide range of adverse effects on the course of mental illnessand psychosocial functioning, including compliance, prognosis, andrates of acute service utilization. Overall, substance abuse comorbiditysubstantially complicates the course and management of schizophrenia.In this chapter, we provide a brief overview of the scope of the problem,with a detailed focus on the demographics of substance use, the adverseconsequences of the major drugs of abuse in patients with schizophrenia,and the clinical approach to patients with dual diagnoses.

Demographics of Substance Use in Patients With SchizophreniaThe proportion of patients with schizophrenia who have a comorbiddrug or alcohol use disorder varies tremendously in published studies,


from as low as 10% to as high as 70% (Mueser et al. 1990). This widerange is partially due to variability in the diagnostic criteria employedfor schizophrenia, sample demographic characteristics (e.g., male vs.female, urban vs. rural), types of patient populations studied (e.g., in-patient vs. outpatient), and criteria for defining drug and alcohol disor-ders (e.g., Diagnostic and Statistical Manual of Mental Disorders [DSM]diagnosis, positive urine toxicology screens, rating scales) (Mueser et al.1990). Although structured clinical interviews have been found to pro-duce the most reliable diagnoses, these are time consuming and expen-sive due to the need for trained personnel and, therefore, are not oftenused in clinical studies (Mueser et al. 1995). Surveys conducted exclu-sively in inpatient settings tend to produce higher rates of substance usedisorders, in part because persons with dual disorders (i.e., substanceuse and another major Axis I disorder) are more likely to enter intotreatment because exacerbation of either problem may become a focusof clinical attention (Mueser et al. 1995).

The Epidemiologic Catchment Area (ECA) study revealed that 47%of all individuals in the United States with a lifetime diagnosis ofschizophrenia or schizophreniform disorder met criteria for some formof substance abuse or dependence (33.7% for alcohol disorder and27.5% for another drug abuse disorder) (Regier et al. 1990). In additionto the lifetime prevalence data, the ECA study found that the odds ofhaving a substance abuse diagnosis were 4.6 times greater for personswith schizophrenia compared with the rest of the population, with theodds of having an alcohol disorder over 3 times greater and of havinganother drug disorder 6 times greater (Regier et al. 1990). This findingwas replicated in the National Comorbidity Survey (Kessler et al. 1997)and again in the most recent National Comorbidity Survey Replication(Merikangas et al. 2007). The high rate of comorbidity is comparablewith the range of 40%–60% lifetime prevalence gleaned from an analy-sis of 47 published studies with sample sizes of at least 30 patients withschizophrenia and in which the criteria for abuse or dependence wereclearly delineated (Cantor-Graae et al. 2001). Cantor-Graae et al. (2001)also found that studies in which more than one method of diagnosiswas employed (e.g., chart review plus interview) yielded higher preva-lence rates compared with those that relied on a single method. Regard-less of method, in community samples of patients with schizophreniathat are not comprised solely of inpatient groups, a figure of approxi-mately 50% lifetime prevalence is found repeatedly. Additionally, stud-ies from all over the world confirm a strong association betweenschizophrenia and substance abuse (O’Dely et al. 2005). For example, aSwedish study combining both structured interview and chart review

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of 87 patients with schizophrenia noted a lifetime prevalence of anysubstance use disorder of 48.3% (47.1% for alcohol alone or in combina-tion with other drugs, 26.4% for alcohol alone) (Cantor-Graae et al.2001). A British study of 168 patients prospectively evaluated at thetime of their first episode of psychosis found that 37% of patients wereabusing drugs or alcohol (Cantwell et al. 1999).

Nicotine is clearly the most frequently abused agent by patients withschizophrenia, with prevalences ranging from 70% to 90%, over threetimes greater than use by the general population (De Leon et al. 2002,2007; see also Chapter 9, “Nicotine and Tobacco Use in Patients WithSchizophrenia”). Excluding nicotine use, the ECA study results are con-sistent with other prevalence studies of schizophrenia demonstratingthat alcohol tends to be the most frequently abused agent (20%–60%),followed by cannabis (12%–42%) and cocaine (15%–50%) (Chambers etal. 2001). Use of amphetamines (2%–25%), hallucinogens, opiates, andsedatives/hypnotics is less common. Findings from a British first-episode study (Barnett et al. 2007) indicated that 43% of patients abusedalcohol, 51% abused cannabis, and 38% had a pattern of polysubstanceabuse. Archie et al. (2007) reported a small shift in these abuse patternswhen patients are followed over time. Harrison et al. (2008) reported analmost 50% decline in overall substance use, except smoking (whichrose from 60% to 64%) when patients are reassessed after 1 year. Asidefrom nicotine, alcohol and marijuana were the most frequently abusedsubstances, and this also remained constant after 14 months of meanfollow-up. In the Clinical Antipsychotic Trials of Intervention Effective-ness (CATIE) study, marijuana was the most commonly used drug bypatients with schizophrenia, followed by cocaine and opiates (Swartz etal. 2008). Polysubstance abuse was also common in the CATIE sample.

The most consistent findings with regard to demographic character-istics are that those who are younger, were younger at age of schizo-phrenia onset, or are male are more likely than those who are older andfemale to abuse drugs or alcohol (Barnett et al. 2007; Hambrecht andHafner 2000). Males were more frequent among the abuser group (81%)than among the nonabuser group (69%) in the CATIE study (Swartz etal. 2008). It is important to note, however, that evidence is accumulatingto document that substance use difficulties among women are not suf-ficiently recognized, and that women with schizophrenia and comorbidsubstance disorders are less likely to receive substance abuse treatment(Alexander 1996; Comtois and Ries 1995). The undertreatment ofwomen may lead to unrealistically low prevalence estimates in retro-spective chart review studies, yet even in interview studies male genderappears as an independent risk factor after the disparities in gender


frequency are controlling for among study participants (Cantor-Graaeet al. 2001). Also, evidence from a Malmo, Sweden, cohort (Cantor-Graae et al. 2001) and other studies indicates that the onset of substanceuse in schizophrenia occurs at a younger age in males than in females(O’Dely et al. 2005; Salyers and Mueser 2001).

Conflicting data have been reported regarding the functional capa-bilities of substance-using patients compared with non-substance-using patients with severe mental illness. In one of the first studies toexamine this issue, Mueser et al. (1990) reported findings on 149 re-cently hospitalized patients who met DSM-III-R criteria for schizophre-nia, schizoaffective disorder, or schizophreniform disorder, and foundlower educational levels among those with substance abuse disordersthan among those without substance use disorders. Arndt et al. (1992),in a study of 131 schizophrenia patients with and without comorbidsubstance abuse disorder (n =64 and 67, respectively) matched forsymptomatology and clinical history, noted better premorbid adjust-ment among the so-called pathological substance users (Arndt et al.1992). In another study, Zisook et al. (1992) compared 34 patients withschizophrenia who had histories of substance abuse with 17 patientswith schizophrenia who were abstinent and found that the substanceabusers were more likely to have been married or gainfully employed.In the CATIE study (Swartz et al. 2008), abusers were overall similar interms of marital status and years of education. They were also similaron overall functioning, based on their Clinical Global Impression Scalescores.

Salyers and Mueser (2001) examined 404 patients with a history ofrecent hospitalization (i.e., prior 3 months) recruited from within alarge multicenter psychosocial treatment strategies study. Individualswere ages 18–55, agreed to receive fluphenazine decanoate but notother major psychotropic agents, and received at least three of themonthly assessments of psychiatric symptoms, social functioning, sideeffects, and substance use over the 3- to 6-month follow-up period. No-tably, those who were homeless or transient and patients with activeongoing physical dependence (or suspected drug-induced psychosisbut not schizophrenia) were excluded from the study. In this study,those patients who consistently reported low or no use of substancesscored significantly higher than regular drug or alcohol users on assess-ments of negative symptoms, particularly the social amotivation anddiminished expression scores, although the groups were comparableon ratings of psychotic symptoms (Brief Psychiatric Rating Scale) anddistress (Symptom Checklist–90) (Salyers and Mueser 2001). Also, usersand nonusers had no significant differences in ratings of tardive dyski-

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nesia, parkinsonism, or akathisia, although those who reported thegreatest frequency of social problems had higher akathisia ratings irre-spective of degree of substance use. As one might expect from thosewho manifest greater negative symptomatology, the low- or no-usegroup also demonstrated more severe impairment in leisure activitiesand less frequent social contacts. Although the substance users enjoyeda higher level of social functioning, the drug users in particular re-ported significantly greater interpersonal problems compared to thelow- or no-use group. Interestingly, despite the greater social functionalstatus of substance users, this group had an earlier age of onset for theirmental illness and more hospitalizations than the low- or no-use group.In the CATIE study (Swartz et al. 2008), symptom measures were simi-lar between abusers and nonabusers, although abusers had more priorillness relapses and an earlier age at onset.

Demographic differences exist between urban and rural groups withschizophrenia, especially with regard to housing, and data also suggestthat patterns of substance use differ between the two groups. The useof alcohol alone or in combination with cannabis is common amongschizophrenia patients living in a rural setting, whereas the use of mul-tiple substances, particularly cocaine, is common among those living inurban settings (Mueser et al. 2001).

Also, patients with a dual diagnosis of schizophrenia and substanceuse or abuse tend to engage in a variety of risky behaviors that result ina higher prevalence of human immunodeficiency virus (HIV), hepatitisB, and hepatitis C (Meyer 2003; Wirshing et al. 2005; also see Chapter10, “HIV and Hepatitis C in Patients With Schizophrenia,” in this vol-ume). Whereas the former may be transmitted sexually, hepatitis C inthe United States is transmitted primarily by use of shared needlesamong intravenous drug users. Although patients with schizophreniaare more likely to engage in high-risk behavior resulting in HIV or hep-atitis C infection, limited data are available about the extent of intrave-nous drug abuse by individuals with this disorder. In one large studyof persons with mental illness (65% of whom had schizophrenia orschizoaffective disorder), 62.1% of those infected with hepatitis C(n=145) reported a lifetime history of intravenous drug abuse (IVDA),whereas only 5.1% of the hepatitis C–negative group (n=604) reporteda history of IVDA (Rosenberg et al. 2001). Among the HIV-positive per-sons with severe mental illness, the lifetime prevalence of IVDA was8.6% compared with 1.4% for the HIV-negative group (Rosenberg et al.2001). A smaller study of 91 patients with schizophrenia employing twoself-reporting measures found a 22.4% lifetime prevalence of injecteddrug use; moreover, despite IVDA and high-risk sexual behaviors, 65%


reported no concern with HIV infection, and AIDS knowledge was sig-nificantly lower among the patients with schizophrenia than the controlgroup, particularly among those with long-standing illness and multiplepsychiatric admissions (Grassi et al. 1999). Meyer (2003) showed a highrate of hepatitis exposure in long-stay patients at a state hospital. Wirsh-ing et al. (2005) showed similar findings in the Veterans Administrationdual-diagnosis population (schizophrenia plus substance abuse).

Patterns of Substance Abuse Among Persons With SchizophreniaAlthough substance use disorders occur significantly more frequentlyin persons diagnosed with schizophrenia than in the general popula-tion, little evidence is available to suggest that persons with schizophre-nia abuse substances for different reasons than the general population.Specifically, the literature demonstrates that patients with schizophre-nia do not differentially choose to abuse specific drugs to ameliorate spe-cific psychic states. Multiple studies indicate that patients withschizophrenia do not preferentially abuse certain agents and that choiceof agent does not correlate with extent of psychopathology; rather,these individuals use those substances that are most available and af-fordable (Cantor-Graae et al. 2001; Chambers et al. 2001; Mueser et al.1992). For the most part, research has also failed to find different pat-terns of drug choice between persons with schizophrenia and groups ofpatients with other major mental disorders. Thus, although the causesof dysphoria in schizophrenia may be linked to the illness (e.g., neuro-leptic side effects, negative symptoms, demoralization), data simply donot support the notion that patients with schizophrenia uniquely prefercertain drugs (Degenhardt et al. 2007).

The notion that schizophrenia patients abuse substances to alleviatecertain mental states or medication side effects (the “self-medication”hypothesis) derives from research focusing on patients’ reportedreasons for substance use. Dixon et al. (1991) found that persons withschizophrenia abuse drugs for reasons that are similar to those forpersons without schizophrenia (i.e., to get high, to feel better, to escape,and to be less depressed), rather than for symptom control. Other ob-servational data lend credence to the hypothesis that addictive be-havior occurs independently as an inherent aspect of the neuralabnormalities that contribute to schizophrenia, as opposed to being mo-tivated or driven secondarily by symptoms of the disorder or negativepsychic states induced by medication. In a review of the literature on

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the biological basis for substance abuse in schizophrenia, Chambers etal. (2001) noted that some individuals do report symptomatic improve-ment during substance use, whereas others note symptom exacerbationbut nevertheless persist in the use of substances. Moreover, self-reportsof improvement are often at variance with the clinical observation ofsymptomatic worsening. In addition, substances of abuse have widelydivergent effects on neurotransmitters, thereby weakening the asser-tion that the concurrent use of agents with opposing effects is intendedto ameliorate a specific psychic state.

Dervaux et al. (2001) used diagnostic interview to assess the reasonsfor and extent of substance use in a study of 100 patients with schizo-phrenia. Other assessment tools in this study included the Positive andNegative Syndrome Scale (PANSS), self-report measures of impulsivityand sensation seeking, and a self-report measure of anhedonia. Forty-one percent of this cohort met lifetime criteria for substance abuse ordependence, but this group did not differ from the nonabusing patientswith schizophrenia on the basis of ratings of anhedonia, or in symptomseverity (as rated by PANSS). Interestingly, this study did not find dif-ferences between users and nonusers on the basis of age of first psy-chiatric contact and number of hospitalizations. Nonetheless, thesubstance abusers rated significantly higher on the measures of impul-sivity and sensation seeking, in a manner consistent with substance us-ers without schizophrenia; moreover, these measures were elevatedeven among the subgroup reporting only past abuse or dependence,leading the authors to suggest that impulsivity and drug-seeking be-havior may not be induced by the use of substances, but rather are in-herent aspects of schizophrenia or correspond to the traits of noveltyseeking and impulsivity that are seen in the general population whoabuse drugs. Indeed, Swann et al. (2004) invoked a model of heightenedimpulsivity as well as behavioral sensitization to explain the high ratesof comorbid substance abuse in patients with bipolar disorder. Notably,some studies have found higher reported rates of depression amongpatients with comorbid substance abuse (Duke et al. 1994; Hambrechtand Hafner 2000), although others have not replicated this finding(Drake et al. 1989; Mueser et al. 1990). Recently, Degenhardt et al. (2007)found no difference in depression between schizophrenia patients withand those without cannabis abuse. Additionally, cannabis abuse wasnot associated with worsening of depressive symptoms.

The research on antipsychotic side effects and substance abuse hasgenerally produced mixed results when investigators examined tardivedyskinesia or other measures of extrapyramidal side effects. Akathisiaand related dysphoria have been found in some studies to be associated


with current alcohol use and increased risk of future alcohol use (Dukeet al. 1994; Voruganti et al. 1997). However, these reasons may be lessrelevant in the current era of treatment with second-generation antipsy-chotic medications, which are generally considered to have low rates ofextrapyramidal side effects and to have mood stabilization and enhanc-ing properties (Green et al. 2008).

Other observations suggesting that schizophrenia and addictive be-havior are independent manifestations of common underlying dysreg-ulation of neural circuitry are that use of both drugs and alcoholcommonly precedes psychosis and that 77% of first-episode patients aresmokers prior to neuroleptic treatment (Chambers et al. 2001). The rela-tionship between substance use and symptom onset is thus an area ofintense scrutiny for those who see the predilection toward psychosisand addictive behavior as independent but parallel processes engen-dered by common neuropsychiatric deficits.

In the literature review cited earlier, Cantor-Graae et al. (2001) notedtwo questions involving schizophrenia and substance use that are notclearly answerable with the current body of data. The first is “the extentto which substance use (especially psychoactive substance use) contrib-utes to the development of schizophrenia, whether as an independentrisk factor in itself or by precipitating illness onset in vulnerable indi-viduals” (p. 72). The second, discussed in the following section, is “thedegree to which history of substance abuse is associated with a morechronic clinical course of schizophrenia” (p. 72).

Because comorbidity is not merely a chance co-occurrence of twodisorders and because self-relief of symptoms and side effects also ap-pears to be an inadequate explanation of drug use by people withschizophrenia, a reasonable question is whether drug use actuallycauses schizophrenia. This is a vexing question (and often comes acrossas a “chicken and egg” problem), especially at the first presentation ofpsychosis, where substance abuse is common. Moreover, studies haveproduced some evidence that patients at high clinical risk for psychosiswho abuse drugs during the vulnerable prodromal stage are at greatrisk of conversion to frank psychosis (Cannon et al. 2008). Caton et al.(2005) examined this relationship among patients who were presentingwith their first psychotic episode, all of whom were actively abusingdrugs. On the basis of longitudinal evaluation, the authors reportedthat key predictors can help determine whether a patient has substance-induced psychosis or primary schizophrenia. In the longitudinal evalu-ation of patients who presented as acutely psychotic, 44% were laterclassified as having a drug-induced psychosis and 56% received a diag-nosis of schizophrenia. Patients with a drug-related psychosis had

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fewer positive and negative symptoms but more visual hallucinations.They were also more likely to have a family history of substance abuse.Mathias et al. (2008) pointed out that little is known about substance-induced psychosis. This nosology may get an “extreme makeover” inthe workings toward DSM-V (see Mathias et al. 2008).

Because use of substances, particularly psychotomimetic agents(e.g., hallucinogens) and stimulants, may increase the likelihood of de-veloping psychosis, investigators have attempted to determine thecourse of substance use in relation to onset of psychosis. To assess thetemporal sequence of substance abuse and illness onset, Buhler et al.(2002) performed a structured interview of 232 first-episode patientswith schizophrenia, and then prospectively interviewed and followedanother sample of 115 first-episode patients representing 86% of con-secutive admissions in the local area. The investigators found that 62%of those patients with drug abuse and 51% with alcohol abuse begantheir habit before any signs of schizophrenia were manifest, includingprodromal nonpsychotic symptoms. Importantly, no correlation wasfound between onset of substance abuse and onset of psychotic symp-toms, although the onset of abuse and the psychotic disorder occurredin the same month in 18.2% who abused alcohol and 34.6% who useddrugs, implying that in a subset of schizophrenia patients, developmentof psychotic symptoms was speeded up or precipitated by substanceuse, particularly cannabis use. These data from the combined pools offirst-episode patients are similar to those reported for the originalgroup of 232 first-episode patients analyzed separately (Hambrechtand Hafner 2000), of whom 27.5% had a cannabis use problem morethan 1 year (often more than 5 years) before onset of prodromal schizo-phrenia symptoms, 34.6% had the onset of symptoms and cannabisuse in the same month, and 37.9% had symptoms of schizophreniabefore beginning substance use. Archie et al. (2007) illustrated the op-portunity to reduce the rates of substance abuse early in the course ofschizophrenia.

Impact of Substance Use Disorders on Development and Course of IllnessSome researchers have attempted to determine which drugs, if any,are most likely to affect the development and course of schizophrenia.Despite having other negative medical consequences, alcohol doesnot appear to increase the risk of developing schizophrenia. The evi-dence for illicit drugs such as cocaine, heroin, methamphetamines, and


3,4-methylenedioxymethamphetamine (ecstasy) is at best mixed. Themost compelling evidence exists for cannabis causing schizophrenia.Overall, the prevalence of cannabis abuse disorders in patients withschizophrenia is about 4.5 times higher than in the general population.There is also some (albeit less robust) evidence suggestive of a dose de-pendency in that the more cannabis consumed, the greater the chanceof developing schizophrenia. The public health significance of thesedata is considerable, and these data have fueled fierce debate (espe-cially in England and Canada) regarding the legalization of marijuana.However, most people who abuse cannabis do not develop schizophre-nia, and even if cannabis “causes” schizophrenia, it is probably only ina small minority of patients (O’Dely et al. 2005).

In attempting to tease out this vulnerability, Caspi et al. (2005) con-ducted a genetic analysis of blood samples from participants in a largeepidemiological study of schizophrenia in New Zealand. The authorsreported that adolescents who abused cannabis and who had the mostinefficient allele of the catechol-O-methyltransferase gene had the earli-est onset of schizophrenia. This study is important not just because ofthis finding, but also because it serves as a yardstick for the applicationof neurobiological research probes to the study of dual diagnosis. Kishi-moto et al. (2008) described an association between the dysbindin geneand methamphetamine-related psychosis. This report is of interest be-cause of the already substantial genetic evidence for the dysbindin genein schizophrenia, and this study suggests that this vulnerability mightextend to drug-related psychosis. Yucel et al. (2008) reported on mag-netic resonance imaging in people with no prior psychiatric history whowere chronic abusers of cannabis. They found bilateral loss of hippo-campal and amygdalar tissue. Interestingly, those who were heavyabusers showed a relationship between hippocampal tissue loss andmild paranoia. In an earlier study, Scheller-Gilkey et al. (1999) examineddifferences in magnetic resonance imaging scans for 176 patients withschizophrenia. The investigators noted that the rate of gross brain abnor-malities among both alcohol and drug abusers was less than half the ratefound among patients with no history of alcohol or substance abuse, al-though this finding did not reach the 0.05 level of statistical significance(Scheller-Gilkey et al. 1999). There is now a growing appreciation thatthe shared vulnerability for substance abuse and schizophrenia may bedue to dopamine sensitization (Chambers et al. 2007; O’Dely et al. 2005);in this model, patients may abuse drugs because of chronic dysregula-tion of dopamine, particularly in the amygdala.

Although research on the impact of drug and alcohol use on thecourse of illness has produced variable results, the overwhelming

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weight of evidence points toward substance abuse and dependencehaving adverse short-term and long-term effects. Overall, persons withschizophrenia who abuse drugs and/or alcohol have more psychoticsymptoms and psychotic relapses than do persons with schizophreniawithout substance use disorders (Degenhardt et al. 2007; Harrison et al.2008; Negrete et al. 1986). In one of the first short-term prospective stud-ies of recent-onset schizophrenia patients, Linszen et al. (1994) foundthat significantly more and earlier psychotic relapses occurred in thosewho abused cannabis. This finding was replicated in a long-term fol-low-up case-control study of 39 cannabis-abusing schizophrenia pa-tients without other major drug use matched for age, gender, and yearof admission with 39 non–cannabis using schizophrenia controls (Cas-pari 1999). After a mean 68.7±28.3 months of follow-up, the cannabisabusers had a significantly greater hospitalization rate, higher symp-tom ratings, and greater unemployment.

A larger study of relapse rates was performed in Australia using a re-cently hospitalized sample of 99 patients, ages 18–65, with schizophre-nia or related disorders who were followed prospectively for 4 years(Hunt et al. 2002). Of the 99 who entered into the study, 66 were still be-ing followed after 4 years. Demographically, compared with nonusers,the substance users were more likely to be male, to be younger, and tohave a forensic history, although no differences were found in age ofschizophrenia onset or number of prior hospitalizations. The investiga-tors found that the median time until rehospitalization was 10 monthsfor medication-compliant patients who used substances and 37 monthsfor medication-compliant nonusers. Among medication-noncompliantpatients, the survival times to rehospitalization were 5 months forsubstance users and 10 months for nonusers. Although the medication-noncompliant substance users composed 28.3% of the total study sam-ple, they accounted for 57% of all psychiatric admissions recorded bystudy participants, with an average of 1.5 per year. Overall, the sub-stance users had an average of 3.6 admissions over the 4 years com-pared with 1.1 for nonusers (P<0.05) and were significantly more likelyto be medication noncompliant (users 67% vs. nonusers 34%, P<0.05).In a first-episode study in London, in which patients with dual diagno-sis were followed for 1 year, Harrison et al. (2008) found that overall theextent of substance abuse had fallen by half. Those who continued toabuse drugs or alcohol were more symptomatic.

The abuse of cocaine and stimulants, due to their direct effects ondopamine, has obviously been linked to exacerbation of psychoticsymptoms (Dixon et al. 1990), yet increased severity of positive symp-toms is seen in users of all substances. Caspari (1999) found higher Brief


Psychiatric Rating Scale ratings in a long-term case-control study ofcannabis abusers, some of whom subsequently also abused alcohol butnot cocaine or stimulants. Similarly, Buhler et al. (2002) noted a greaterextent of positive symptoms during 5 years of follow-up in a group of29 first-episode schizophrenia patients who were users of various sub-stances compared with matched nonusing control subjects. In particu-lar, hallucinations were present for 1.8 months per year for substanceusers compared with 0.6 months per year for nonusers (P<0.05). Thestudy’s findings also indicated a trend toward fewer negative symp-toms among users, which reached statistical significance at the 5-yearendpoint (P<0.03).

ViolenceSubstance use disorders in patients with schizophrenia have been asso-ciated with violent behavior toward others, suicide (Barry et al. 1996;Dassori et al. 1990; Drake et al. 1989; Fulwiler et al. 1997), and increasedrisk for contact with the legal system (Buckley et al. 2004; Hunt et al.2002). The association of violence with substance use is not unique toschizophrenia or severe mental illness, and has been observed amongpatients with other mental disorders (Cuffel et al. 1994; Swartz et al.1998); moreover, this association between substance use and increasedrisk for violent behavior among persons with severe mental illness hasalso been described in patient populations outside the United States.Rasanen et al. (1998) completed a prospective study in Finland on an11,017-person unselected birth cohort followed to age 26, whichshowed that men with schizophrenia who abused alcohol were 25.2times more likely to commit violent crimes than men without mental ill-ness, whereas nonalcoholic men with mental illness were only 3.6 timesmore likely to commit violent crimes than males without any psychiat-ric diagnosis. Buckley et al. (2004) found that approximately 50% of pa-tients with schizophrenia who committed violent acts were abusingalcohol or drugs at the time of the incident.

Housing Instability and HomelessnessPersons with comorbid substance use disorders and schizophrenia areat increased risk for homelessness (Drake et al. 1991). In Caton et al.’s(1994) case-control study comparing 100 homeless men with severemental illness with 100 men with schizophrenia who were not home-less, homeless subjects had significantly higher rates of drug abuse.Studies of innovative service models for persons who are homeless andmentally ill have found that persons with substance use comorbidity do

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not benefit as much from these programs as do those who do not usesubstances, in part due to the fact that substance-using patients with se-vere mental illness lead a more transient lifestyle. In one study of asser-tive community treatment for individuals who are homeless andmentally ill, homeless persons with substance use disorders had moremoves during the treatment year than other patients with severe mentalillness (Holohan et al. 1997). Providing residential support is a key as-pect of management for this problem (Drake 2007).

Medical Consequences of the Most Commonly Abused Substances in SchizophreniaAlcoholIn the general population, alcohol is the most widely used substance ofabuse. Sequelae of ethanol use disorders represent the third leadingcause of death in the United States, with an estimated 111,000 deathsper year directly attributable to alcohol ingestion. The most commoncauses of death in alcohol-related disorders are suicide, cancer, heartdisease, and hepatic disease (Schuckit 1999). Chronic liver disease andcirrhosis together are rated the twelfth leading cause of death in theUnited States (Centers for Disease Control and Prevention 2008).

The acute action of ethanol in the central nervous system (CNS) de-rives from two main mechanisms: ethanol 1) facilitates the activation ofgamma aminobutyric acid type A (GABAA) receptors, the main inhibi-tory neurotransmitter system in the CNS, and 2) inhibits the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, the main excita-tory neurotransmitter receptor system in the CNS. The net effects ofGABA are thereby potentiated, leading to sedation, and inhibition ofNMDA receptors via allosteric modulation appears to be responsiblefor the intoxicating effects (Schuckit 1999). Sudden cessation of ethanoluse by a chronic, heavy drinker often results in an uncomplicated with-drawal syndrome characterized by mild confusion associated with dia-phoresis, tremulousness, and increased heart rate, blood pressure, andtemperature, all of which can be blocked by administration of GABA-acting drugs such as benzodiazepines. In about 5%–10% of patientswith alcohol dependence, this syndrome may progress to delirium tre-mens (DTs), characterized by significant autonomic instability, markedconfusion, disorientation, agitation, tremulousness, and hallucinations(auditory, visual, and tactile). The mortality rate for untreated DTs is


approximately 5%. Alcohol withdrawal seizures (“rum fits”) may alsodevelop independently of DTs, typically within the first 24–48 hours af-ter cessation of alcohol use (Schuckit 1998).

Alcohol consumption plays a role in acute or chronic medical illnessthrough a variety of mechanisms, some or all of which may be operativein a specific individual (Schuckit 1998). Repeated exposure may lead toalcoholic hepatitis and eventually cirrhosis, with secondary cognitiveimpairment via hepatic encephalopathy in advanced cirrhosis due tothe accumulation of nitrogenous compounds that are inadequately me-tabolized by the compromised liver. The cirrhotic changes of the liverare also manifested in impaired synthetic function (e.g., decreased pro-duction of clotting factors) and reduced metabolism of exogenous tox-ins such as medications. In the CNS, prolonged alcohol abuse leads tocerebellar degeneration, presenting as unsteady gait and mild nystag-mus, in about 1% of patients with chronic alcoholism. These symptomsare irreversible and often accompanied by global cognitive decline fromdirect or indirect effects of chronic alcohol consumption (e.g., head in-jury, nutritional deficiency, direct neurotoxicity). Finally, peripheralneuropathy is seen in approximately 5%–15% of alcoholics due to nutri-tional deficiency and direct toxic effects of alcohol on neuronal axons(Schuckit 1998).

Alcohol abuse increases blood pressure and serum triglycerides, andmay lead to cardiomyopathy and arrhythmias via toxic effects on car-diac muscle (Schuckit 1998). During the acute intoxication period, testsfor blood alcohol level, serum electrolytes, glucose, aspartate transami-nase, alanine transaminase, gamma-glutamyltransferase, hematocrit,and amylase can be useful. For the chronic alcoholic, additional labora-tory values that should be monitored include albumin, red blood cellindices, white blood cell count, platelet count, prothrombin time, hepa-titis B and C screening, vitamin B12, and folate.

Cocaine and AmphetaminesCocaine is derived from the coca plant, native to South America, and istypically insufflated nasally (snorted), smoked (in the form of freebaseor crack), or injected intravenously. Amphetamines, which are analogsof naturally occurring ephedrine, have been abused in various formssince their original synthesis in 1887. Currently, d-methamphetamine(“crystal meth” or “meth”) is the most popular form of amphetamineabused, and, in some areas of the country, such as the West Coast, abuseof methamphetamine is more prevalent than cocaine. Cocaine acts as acompetitive blocker of dopamine reuptake in the synaptic cleft, which

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increases the concentration in the cleft, with resultant activation ofdopamine type 1 and 2 receptors. In addition, cocaine increases nor-epinephrine and serotonin neurotransmission via reuptake inhibition,but these monoamines do not play the dominant role in its CNS effects(Jaffe 1999b). By contrast, amphetamine increases the availability of allsynaptic monoamines by stimulating the release of catecholamines,particularly dopamine, from the presynaptic terminals. This effect is es-pecially potent for dopaminergic neurons projecting from the ventraltegmental area to the cerebral cortex and limbic areas, known as the “re-ward pathway.”

Patients with schizophrenia who abuse stimulants experience signif-icant increases in the extent of positive symptoms of their psychosis. Incomparison to patients with schizophrenia, cocaine-abusing patientswithout underlying psychotic disorders tend to seek treatment more of-ten for depression and anxiety than for psychosis (Serper et al. 1999).Withdrawal following heavy stimulant use may be associated with sig-nificant lethargy and depression and an increased risk for suicide(Gawin and Kleber 1986).

Cocaine and amphetamines have similar health effects based on theirsimilar pharmacological activities that result in increased synapticdopamine and other monoamines. The resultant sympathomimetic andvasoconstrictive properties of these agents are responsible for many ofthe acute (e.g., myocardial infarction, cardiac arrhythmias, cerebrovas-cular accidents, seizures) and chronic (e.g., hypertension) effects of in-gestion (Jaffe 1999a). The nasal route of administration can lead togeneral sinus congestion and septal perforation due to chronic is-chemia. Not only does the intravenous route of administration increasethe transmission risk of HIV and hepatitis B and C viruses, but intrave-nous and subcutaneous (“skin popping”) use may result in significantcellulitis, bone and joint infections, endocarditis, and renal failure (usu-ally as a result of adulterants to the drug). Smoking cocaine can exacer-bate preexisting asthma or chronic obstructive pulmonary disease, andcan produce specific, fibrotic lung changes known as “crack lung”(Tashkin 2001). Chronic use of stimulants often results in significantweight loss due to the anorexic effects of these agents.

CannabisCannabis plants and derived products (e.g., hashish) contain many sub-stances that are believed to have psychoactive properties, although themost important of these is delta-9-tetrahydrocannabinol (THC). The en-dogenous cannabis receptor is a member of the G protein–linked family


of anandamide receptors, found in the highest concentration in thebasal ganglia, hippocampus, and cerebellum. In animal studies, activa-tion of the receptor has an effect on monoamine oxidase and GABA(Chaperon and Thiebot 1999).

The peak intoxication from smoking cannabis occurs after 10–30minutes. THC and its metabolites accumulate in fat cells and have ahalf-life of approximately 50 hours (Franklin and Frances 1999). In anintoxicated state, behavioral changes include a heightened sensitivity toexternal stimuli, derealization, impaired motor skills, increased reac-tion time, and euphoria. Panic attacks can occur in inexperienced users.The drug is usually smoked, but users may ingest orally (e.g., hashishbrownies). Psychosis can also occur during the intoxicated period, evi-denced by transient paranoid ideation and, rarely, frank hallucinations.Subjective reported effects of acute cannabis intoxication in individualswith schizophrenia include a decrease in anxiety and depression and anincrease in suspiciousness (Dixon et al. 1990). In addition, chronicheavy cannabis use can result in an amotivational syndrome that is de-scribed as passivity, decreased drive, diminished goal-directed activity,decreased memory, fatigue, problem-solving deficits, and apathy thatcan last for weeks following abstinence (Degenhardt et al. 2007). Thishas been described by various authors in uncontrolled studies, al-though controversy still exists regarding the exact nature of the syn-drome (Franklin and Frances 1999).

The deleterious health effects of cannabis are related to route of ad-ministration and direct effects on body systems. Cannabis cigarettes(“joints” or “blunts”) have more tar and respiratory irritants than to-bacco and are more carcinogenic to laboratory animals. Long-term usehas been found to lead to large airway obstruction. Smoking cannabisalso has direct inhibitory effects on pulmonary antibacterial mecha-nisms such as destruction of alveolar macrophages, neutrophils, andlymphocytes. In addition, cannabis can cause variations in heart rateand blood pressure, which can lead to an increase in oxygen consump-tion and increased risk of myocardial infarction in individuals with cor-onary artery disease (Woody and MacFadden 1996).

Screening for Substance UseClearly, case finding remains a priority if patients are to be offered anyform of treatment aimed at reduction in substance use. Simply put, cli-nicians must take the initiative to identify patients who have substanceuse comorbidity. The first step requires screening and assessment. Most

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patients will not spontaneously volunteer that they are using sub-stances. Thus, clinicians must actively seek out this information, withbest results achieved using nonjudgmental forms of inquiry such as“How often have you used.. .” instead of “Do you use. . .” Given theprevalence of substance use, a high index of suspicion is essential. Cli-nicians should routinely ask all patients about use of alcohol or otherdrugs and should continue to inquire on a periodic basis, especiallywith newer patients who may be reluctant to discuss substance abusewith a new clinician. Because patients sometimes deny their drug use,a multimodal strategy is optimal, including urine toxicology screens,interviews with collateral sources, records from recent hospitalizations,and consultation with other care providers or family if permitted by thepatient.

The extent to which each approach adds to the confirmation of sub-stance abuse has been studied. In a French comparative study of self-report versus confirmatory, biological measures of substance abuseamong over 400 inpatients, the authors found that patients underre-ported their abuse of illicit drugs in 52% of cases (De Beaurepaire et al.2007). Patients underreported abuse of alcohol in 56% of cases. In astudy in a U.S. community mental health center using the timeline fol-low-back method (an intensive, research-based retrospective recon-struction of abuse patterns), poor correlation was found betweensubject self-report and collateral information (Stasiewicz et al. 2008).

Once a patient acknowledges using substances, a first step in treat-ment is to conduct a specialized assessment. In addition to questioningthe amount and frequency of substance use, the clinician should get anunderstanding of each patient’s personal economy of using substances.What benefits and costs does the patient perceive to result from usingsubstances? What are the patient’s motivations and expectations? A de-tailed understanding of patients’ perspectives on these questions is crit-ical to engaging them in treatment and helping them to negotiate thephases of treatment to recovery.

Treatment of Patients With Dual DiagnosesThe President’s New Freedom Commission on Mental Health (2003)noted that the failure to integrate substance abuse services and psychi-atric/mental health services leaves people with dual diagnoses in “noman’s land.” These patients present complex addiction, medical, andmental health challenges that are beyond the scope of isolated, indepen-dent services, thus posing administrative, policy, and service delivery


issues that systems of care have been grappling with. Additionally, ad-vocacy and self-help groups have realized that the needs of patientswith dual diagnoses are complex and best served with specialized sup-ports such as Double Trouble in Recovery peer support (rather than Al-coholics Anonymous or Narcotics Anonymous groups).

Treatment of substance use by people with schizophrenia requiresan integrated approach, given the extent to which these problems inter-act and are interconnected (Drake 2007; Hellerstein et al. 2001). Al-though the deleterious effects of comorbid substance use on relapserates are clear, the literature on interventions offers little guidance dueto the paucity of controlled studies. Bennett et al. (2001) noted that onlyseven studies available in the literature through 1998 employed exper-imental designs, five of which examined “inpatient care or intensiveoutpatient case management for serious mentally ill clients (primarilyfor homeless populations), and are not directly applicable to the treat-ment of the broader population of people with schizophrenia living inthe community” (p. 164). Of the remaining two studies, both involvingoutpatient treatment, one was a controlled study that found decreasedsubstance abuse and psychiatric severity among patients who re-mained in treatment over several months, and the other was a semicon-trolled study that found that both behavioral skills training andintensive case management were more effective than a 12-step programon several outcome measures, but with minimal effects on substanceuse. “Interestingly, the behavioral treatment was the most effectiveeven though it was not designed specifically to address substance abuseproblems and sessions were only held once per week” (p. 164).

More recent controlled studies of integrated dual-diagnosis treat-ment have demonstrated the efficacy of this approach (Drake 2007).McHugo et al. (1999) showed that programs with high fidelity to dual-diagnosis treatment principles had markedly greater rates of sobrietythan other treatment strategies. After 36 months, patients in high-fidelityprograms had a 55% rate of stable remission, whereas only about 15%of patients in low-fidelity programs were in stable remission. InManchester, United Kingdom, Barrowclough et al. (2001) conducted acontrolled 12-month study comparing outcomes in 18 patients withschizophrenia and substance use disorders employing an integratedapproach of motivational interviewing, family interventions (includinga family support worker), and cognitive-behavioral therapy, with out-comes in 12 patients receiving care as usual. The integrated care grouphad a high retention rate (94%) and significant improvements com-pared with the usual care group on the Global Assessment of Function-ing scale, PANSS positive symptom scores, and relapse rates. The

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benefits of a combined, integrated approach, particularly with respectto retention, are also seen in the results of a randomized controlledstudy by the Combined Psychiatric and Addictive Disorders Program(COPAD) at Beth Israel Medical Center in New York. The componentsof the COPAD treatment approach include supportive group substanceabuse counseling, a multifaceted educational program (mental illness,psychiatric medications, alcohol and drug abuse, HIV), ongoing assess-ment of substance use via weekly urine toxicology, encouragement toattend self-help groups, monthly psychiatric medication visits, regularcommunication with other clinicians involved in the patient’s care, andas-needed communication with family members (Hellerstein et al.2001). After 8 months, 11 of 23 patients in the COPAD cohort remainedin treatment versus only 6 of 24 usual-care patients.

Bennett et al. (2001) delineated what they perceived to be the neces-sary qualities of a dual-diagnosis program geared toward patients withschizophrenia in their description of the Behavioral Treatment for Sub-stance Abuse in Schizophrenia (BTSAS) model. The special require-ments of an effective substance abuse treatment program for theschizophrenia population derive from the findings of low motivationfor decreasing substance use (41%–60% depending on the substance[s]abused) in schizophrenia patients, and the cognitive and social skillsdeficits present with schizophrenia. In creating the BTSAS program, theinvestigators relied on social skills training, “a behavioral approach forrehabilitation of schizophrenia patients that has been successfully em-ployed for the past 25 years. . .that employs instruction, modeling, role-playing, and social reinforcement” (p. 165).

The components of BTSAS include monthly motivational interviewsto discuss treatment goals; urinalysis with rewards for abstinence; so-cial skills training, which teaches patients how to refuse offers of drugs;education on the effects of drug use in schizophrenia; and problem-solving and relapse prevention training to help patients cope withurges and high-risk situations. Most skills groups meet twice per week,a similar frequency to the group counseling in COPAD. Recognizingthat schizophrenia patients have difficulty in changing behavior andthat many are abusing multiple substances, the BTSAS model does notmandate need to be abstinent or commitment to total abstinence to par-ticipate. Any decrement in use is seen “as a positive step that will re-duce patients’ overall level of harm” (p. 165) and bring the patientcloser to an eventual goal.

Drake et al. (2001, 2007) described several other critical componentsfor integrated programs, including staged interventions for those atdifferent stages of the recovery process, assertive outreach to engage


clients (especially the homeless), the need to maintain a long-term per-spective on the chronic and relapsing problems of substance use, andcultural sensitivity. They also noted the barriers that exist in imple-menting such integrated programs, including administrative issues(policy, programmatic barriers), clinician barriers due to lack of dual-diagnosis training, and consumer barriers due to denial or low motiva-tion. Although the preceding models have not focused on intensive casemanagement, the problems with medication noncompliance, housing,and psychosocial issues associated with substance use often warrant acase management approach, especially for those who are frequent uti-lizers of inpatient services. The federal government has also articulatedwhat the best practices are for treating recurring disorders (SubstanceAbuse and Mental Health Services Administration 2008).

For all schizophrenia patients, including those with dual diagnoses,antipsychotic medication is a fundamental aspect of treatment. Al-though medication-compliant substance users have psychotic relapsesat higher rates than nonusers, the greatest risk for relapse is with medi-cation-noncompliant substance users (Hunt et al. 2002). In general, thereare no absolute contraindications to the prescription of antipsychoticsfor patients with schizophrenia currently using substances, apart fromthose who are medically compromised (e.g., hepatic disease, HIV), inwhom dosage adjustment may be necessary. However, clinicians mustuse reasonable caution in the use of the more sedating agents in patientsabusing alcohol or other CNS depressants such as opiates.

That antipsychotic medication will reduce the likelihood of psy-chotic relapse, even in the presence of ongoing use, is substantiated bydata from an Australian 4-year prospective study (Hunt et al. 2002), yetfindings from some recent studies indicate that the use of atypical an-tipsychotics might be associated with reductions in substance use. Thedata are most compelling for clozapine (Green et al. 2008). One 3-yearprospective study of 151 patients with dual diagnoses found that 79.0%of patients taking clozapine (n=36) achieved full remission from alco-hol use for 6 months or longer, compared with 33.7% of clozapine non-recipients (Drake et al. 2000).

Some relatively less convincing support has been published for theuse of other antipsychotics in patients with schizophrenia and drugabuse diagnoses. Several studies have shown that aripiprazole mightreduce abuse in this group (Green et al. 2008; Littrell et al. 2001; Smelsonet al. 2002). Some studies also support the use of risperidone, olan-zapine, and quetiapine (Green et al. 2008). Also, an ongoing study(P. Buckley, principal investigator) is being done of risperidone micro-spheres in this patient group. No information is available yet on pali-

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peridone in this group, although the pharmacokinetic profile of thisdrug should be more favorable for patients with dual diagnoses and al-cohol-related liver damage. There is no information directly on ziprasi-done in this group, apart from what can be gleaned from the CATIEstudy (Swartz et al. 2008). This examination of CATIE data from phaseshowed that the superiority of olanzapine over ziprasidone in pro-longing time to discontinuation of treatment was still present but wasattenuated in the subgroup of substance users compared with the non-abusing sample. Curiously, some case reports describe abuse of que-tiapine (Paparrigopoulos et al. 2008) and olanzapine (Reeves 2007). Inany regard, the evidence (albeit not compelling) is strongest for cloza-pine, although of course clozapine is not indicated for substance abuseand is only indicated for treatment-refractory or antipsychotic-intoler-ant patients. Although patients with dual diagnoses may be more sen-sitive to the extrapyramidal side effects and the side-effect profile offirst-generation antipsychotics (Green et al. 2008; Voruganti et al. 1997),their higher rate of medical comorbidity should lead to careful consid-eration about the use of second-generation antipsychotic medications,which have a greater risk of diabetes mellitus and metabolic syndrome(Green et al. 2008; see also Chapter 3, “Medical Outcomes From theCATIE Schizophrenia Study,” in this text). The study of medications inpatients with dual diagnoses is advancing more rapidly now in an eraof more effective, pragmatic treatment trials. The treatment options fornicotine dependence in schizophrenia are reviewed by Montoya andVocci (2007), as well as in Chapter 9, “Nicotine and Tobacco Use in Pa-tients With Schizophrenia,” in this volume.

ConclusionSchizophrenia appears to carry with it the propensity for substanceabuse, an independent but parallel process that often precedes by manyyears the onset of psychotic symptoms (Buckley 2006). The most com-monly abused substances by patients with schizophrenia are alcohol,cocaine, and cannabis, with the choice of substance based on affordabil-ity and availability, and not on inherent aspects of psychopathology.Because the medical sequelae of abuse are numerous, periodic monitor-ing of urine toxicology and appropriate laboratory values should beconsidered as part of the routine care for schizophrenia patients withestablished or suspected substance use disorders. Given the likelihoodthat any schizophrenia patient has a past or ongoing substance useproblem, a high index of suspicion must be maintained even withpatients who deny or minimize the extent of their substance abuse. The


greatest chance for optimizing outcomes and reducing the morbidity ofsubstance abuse comes from identification of patients and enrollmentinto an integrated dual-diagnosis treatment modality designed specifi-cally for substance-abusing or substance-dependent persons withschizophrenia (Drake et al. 2007). Routine screening for and increasedrecognition of substance use disorders in those with schizophreniamust be considered a standard part of psychiatric and medical care forthis population (Substance Abuse and Mental Health Services Admin-istration 2008).

Key Clinical Points

◗ The odds of having any substance use disorder are 4.6 times greaterfor persons with schizophrenia than for the rest of the population.

◗ Substance use is an inherent aspect of the neurobiology of schizophre-nia, and increased rates of substance abuse can be seen in prodromalpatients.

◗ Little evidence is available to suggest that substances are used specifi-cally to ameliorate certain symptom states.

◗ The impact of substance use on poor psychiatric outcomes is mediatedprimarily by medication nonadherence.

◗ Screening for substance use disorders includes open-ended nonjudg-mental inquiry, routine biological fluid testing, and screening for asso-ciated medical disorders (e.g., hepatitis C, HIV).

◗ Effective programs for patients with schizophrenia who use substancesmust account for the lower levels of motivation and the cognitive def-icits seen in this population, and must strongly emphasize role-playing,social reinforcement, and problem solving as core aspects of relapseprevention, typically in ongoing skill-building group sessions.

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CHAPTER 12

Sexual Dysfunctionand Schizophrenia

Heidi J. Wehring, Pharm.D., B.C.P.P.Deanna L. Kelly, Pharm.D., B.C.P.P.

The sexuality of people with schizophrenia has received relativelylittle attention in the past. Evidence suggests that patients with schizo-phrenia identify sexual function and medication-related sexual side ef-fects as important issues, yet much remains unknown regarding sexualdysfunction in this population. Multiple factors have contributed to thislack of knowledge, including lack of basic information on what consti-tutes “normal” sexual functioning of patients with schizophrenia. Ear-lier studies and theories suggested that sexuality is best not discussedwith patients with schizophrenia, that identifying and treating sexualissues and side effects might exacerbate illness or lengthen recovery,and that sexual activity could even contribute to the development ofschizophrenia (Pinderhughes et al. 1972). This perception has changeddramatically in recent years, and modern data indicate that the sexualactivity, desire, fantasies, and expectations of patients with schizophre-nia, although more autoerotic in nature, are not likely to be much dif-ferent from those of the general population (Kelly et al. 2006).

Although addressing clinical symptoms in patients with schizophreniagenerally takes precedence over discussions of sexual function, cliniciansoften underestimate the prevalence of sexual dysfunction and the signifi-cance that sexual side effects may have on psychotropic adherence andoutcomes. In one prevalence study, sexual dysfunction occurred in more


than 50% of subjects with schizophrenia, yet the treating nurses and phy-sicians reported significantly lower rates of sexual dysfunction in thesesame individuals (Dossenbach et al. 2005). In responding to a survey, pa-tients with schizophrenia rated the area of “sexual expression” as the thirdmost significant unmet treatment need (Grinshpoon and Ponizovsky2008). One contributing element to the underrecognition of sexual dys-function and its importance for patients with schizophrenia could be thatthis patient population may be unwilling or embarrassed to broach thetopic of sexual concerns and not comfortable in discussing their sexuality.Moreover, because clinicians do not routinely focus on sexual symptomsor issues, patients with schizophrenia may think that clinicians do not takethese concerns seriously or believe that their concerns are important.

Given the high prevalence of sexual dysfunction in patients withschizophrenia and the fact that its occurrence may be associated withlower quality of life and poorer psychiatric outcomes, this chapter is in-tended to serve as a guide for clinicians on the extent of and contribu-tors to these problems and the means to address unmet needs in thisarea. Improving the focus on this domain of treatment could lead tomore integrated and comprehensive psychiatric and medical care anda better step toward the path to recovery.

PrevalenceSexual dysfunction is common in the general population, with estimatesof 43% of women and 31% of men in the United States reporting sometype of sexual dysfunction (Laumann et al. 1999). The prevalence of sexualdysfunction in patients with schizophrenia has been more difficult to as-certain but is considered to be higher than in the general population, withreported rates averaging 50%–75% (Kelly and Conley 2004).

Several reasons may explain the wide range of reported prevalencerates in patients with schizophrenia, including the nature of the patientpopulation studied (illness severity and acuity, location of study, men vs.women, partner vs. no partner), medication status of patients (treated vs.untreated, type of antipsychotic medication and concomitant medica-tions used), method of data collection (spontaneous report vs. standard-ized assessment tool), source of data (clinician vs. patient), time frame ofstudy, and definition of sexual dysfunction measured. Some studieshave suggested that higher psychopathology rating scores have been as-sociated with greater impairment in sexual function (Fan et al. 2007;Kockott and Pfeiffer 1996); however, these findings have not been widelyreplicated, and more work is needed to ascertain this relationship. Anti-psychotic treatment is known to cause sexual impairment, yet some

Sexual Dysfunction 305

authors (Aizenberg et al. 1995; Bitter et al. 2005) have reported sexualdysfunction in treatment-naive patients with schizophrenia, suggestingthat a treatment-independent factor contributes to this clinical problem.

Evidence indicates that males and females experience differentforms of sexual dysfunction and at different rates, but the bulk of theschizophrenia literature has focused on males, possibly due to report-ing bias. Although a review by Howes et al. (2007) found that the oddsratios of patients with schizophrenia having sexual dysfunction, com-pared with the general population, were 15.2 and 3.7 for women andmen, respectively, one recent study of 827 patients on antipsychoticmedications found that 58% of women but only 43% of men reportedsexual dysfunction (Üçok et al. 2007). Despite higher sexual dysfunc-tion rates, females are less likely to spontaneously complain about sex-ual dysfunction in treatment settings, leading to an underestimation ofprevalence. A survey study in a diagnostically heterogeneous group ofpsychiatric outpatients found that among those with sexual side effects,80% of women versus 26.7% of men “never or infrequently” discussedtheir sexual lives with clinicians (Rosenberg et al. 2003).

Another methodological issue in interpreting sexual dysfunction prev-alence rates relates to the fact that many studies include only those withsexual partners, thereby excluding a significant portion of the schizophre-nia population, because patients with schizophrenia are less likely to bemarried or in a relationship than those in the general population (Aizen-berg et al. 2001). Medications, other mental and physical comorbidities,and substance and tobacco use may also affect sexual function. The preva-lence rates of environmental exposures to substances and tobacco varyconsiderably between schizophrenia patients and the general population.

Types of Sexual DysfunctionSexual dysfunction in patients with schizophrenia may occur in any ofthe areas of the sexual response cycle. Generally speaking, this cycle in-cludes the following domains:

• Interest (libido)• Arousal (vaginal lubrication in women, erectile function in men)• Orgasm

The breadth of what is covered by the term sexual dysfunction and whathas been measured in studies varies greatly, sometimes causing diffi-culty in providing consensus regarding types of sexual dysfunction thatmay occur in the schizophrenia population.


MenMen with schizophrenia who have sexual dysfunction typically com-plain of decreased libido and erectile, ejaculatory, and orgasmic dys-function. The reported erectile and ejaculatory disturbances aregenerally related to difficulty achieving and maintaining erections, de-layed or inhibited ejaculation, and diminished orgasm quality. Theprevalence of these sexual impairments ranges widely; however, mostreports indicate that problems with desire and arousal as well as prob-lems with ejaculatory disturbances are present in up to 60% of men withschizophrenia (Bobes et al. 2003; Olfson et al. 2005). Spontaneous andpremature ejaculation also occurs more commonly in men with schizo-phrenia than in the general population (Aizenberg et al. 1995).

Galactorrhea and gynecomastia are uncommon in men but may oc-cur in males treated with antipsychotics. Gynecomastia has been re-ported in 1%–2% of men taking antipsychotic medications, with someestimates up to 11%, whereas galactorrhea is thought to occur morerarely (Byerly et al. 2007). Priapism is an infrequently reported but seri-ous side effect associated with antipsychotic medications. Priapism, aprolonged, painful erection not usually associated with sexual stimuli,requires emergency urological evaluation to minimize potentially seri-ous long-term consequences such as erectile dysfunction (Compton andMiller 2001).

WomenWomen may experience sexual dysfunction across any area of sexualresponse, including libido, arousal, and orgasm. Women can also expe-rience dyspareunia associated with vaginal atrophy and dryness, andare at risk of suffering menstrual disturbances and galactorrhea, partic-ularly if they are taking prolactin-elevating antipsychotics. Many of thereports in the literature cite high rates (>60%) of loss of libido andarousal, including problems with vaginal lubrication and pleasure (Fanet al. 2007; Teusch et al. 1995; Üçok et al. 2007). Additionally, womenwith schizophrenia report low rates of orgasm, with papers suggestingthat over half of women with schizophrenia have never experienced anorgasm (Friedman and Harrison 1984).

The reported prevalence of galactorrhea in women treated with an-tipsychotics ranges from 10% to 90% but differs according to the type ofantipsychotic (Byerly et al. 2007). Although not directly related to sex-ual function, menstrual abnormalities are frequently co-occurring an-tipsychotic adverse effects that often go unrecognized in clinical trials


because this information is not volunteered and clinical investigatorsmay not specifically evaluate this side effect. Numerous cross-sectionalstudies of menstrual irregularities in antipsychotic-treated women withschizophrenia indicate that the propensity to elevate prolactin remainsa common mechanism for this complaint. In these studies, the occur-rence of menstrual abnormalities ranges from 25% to 100%, with the av-erage prevalence around 50% (Kelly and Conley 2004).

Impact of Sexual Dysfunction on Patient OutcomesLong-term quality-of-life outcomes in schizophrenia are often less thanideal, with reduced life expectancy, high suicide rates, and low rates ofmarriage and employment. The mental health field is increasinglyaware of the need to strive for recovery and to incorporate both medicaland psychological care along with psychiatric symptom control intotreatment planning. Sexuality, which is a vital component of the selfand provides a sense of personal satisfaction, remains a significant un-met need hindering full recovery for patients with schizophrenia. Im-portantly, sexual dysfunction has negative effects on critical aspects ofcare necessary to achieving sustained psychiatric outcomes, namelymedication adherence and self-rated quality of life and well-being.

AdherenceAdherence to antipsychotic treatment is the cornerstone of schizophre-nia management and relapse prevention, yet nonadherence rates typi-cally range from 40% to 50% (Lacro et al. 2002). A myriad of factorscontribute to nonadherence, including the following:

• Lack of illness insight• Poor relationship to health care provider• Belief that treatment may not improve symptoms or prevent recur-

rence of symptoms• Negative attitude toward medications• Medication side effects

Sexual dysfunction is distressing to patients, particularly when per-ceived as a side effect of psychotropic medications, and the limited re-search on this topic indicates that impairment in sexual function cannegatively affect adherence to antipsychotic medications. In a survey of


outpatients with severe mental illness, Rosenberg et al. (2003) foundthat 43% of those who experienced sexual dysfunction said they hadconsidered stopping medications because of sexual side effects, and27.5% claimed that they had actually stopped medications one or moretimes due to sexual side effects. As discussed in the later section on eti-ology, sexual dysfunction has many possibly etiologies, yet severalstudies report that patients often attribute their sexual dysfunction toantipsychotic treatment (Lambert et al. 2004; Olfson et al. 2005).

Quality of LifeQuality of life is a broad term that includes subjective well-being and bothmental and physical function, and has become an outcome of great interestin the treatment of schizophrenia. Those with schizophrenia experiencingsexual dysfunction may report any of the following (Olfson et al. 2005):

• Poorer quality of life• Lower levels of enjoyment in life• Low satisfaction with the quality of romantic relationships• Fewer romantic partners

Although limited formal data have been reported in this area, the fewexisting studies document that sexual dysfunction is associated withlower quality of life among patients with schizophrenia. These patientsdescribe sexual dysfunction as a troublesome side effect associated witha worse subjective quality of life, with some men complaining that med-ication-related impotence is more bothersome than their psychoticsymptoms (Finn et al. 1990). Not surprisingly, one study found thatmen with schizophrenia who reported sexual dysfunction also reporteda lower global quality of life compared with male patients without sex-ual dysfunction (Olfson et al. 2005). Moreover, in a large study assess-ing satisfaction and quality of life in patients with schizophrenia, lackof sexual activity was one of the top four reasons for low ratings of lifesatisfaction (S. Chan and Yu 2004).

EtiologyMultiple factors contribute to sexual dysfunction in patients withschizophrenia, and the etiologies for any one patient can be complex.The symptoms of schizophrenia, including psychosocial difficulties, alack of personal relationships, negative symptoms, anhedonia, andimpulsivity, are potential contributing factors. The following physical


effects of antipsychotic treatment may also contribute to sexual dys-function (Kelly and Conley 2004):

• Obesity and weight gain• Sedation• Tardive dyskinesia• Extrapyramidal side effects

Over 100 medications or classes of medications have been associatedwith sexual dysfunction, although the quality of evidence is not uni-form (Thomas 2003) (see Table 12–1). A lengthier discussion of medica-tion effects follows in the next section, but it is worthwhile noting herethat other physical and mental illnesses can affect sexual functioning,including the following:

• Diabetes• Cardiovascular disease• Hypertension• Alcoholism• Peripheral neuropathy• Depression

Human sexual physiology is complex, involving endocrine, centralnervous, peripheral nervous, and vascular systems. The endocrine sys-tem is thought to be responsible for libido, so reductions in sex hor-mones such as testosterone may impair erectile function and libido inmales. In females, low testosterone levels have been theorized to be as-sociated with low sexual desire and sexual dysfunction; however, thishas not been supported by direct evidence, and some conflicting re-ports failed to find low androgen levels to be predictive of low sexualfunction in women (Davis et al. 2005). The limbic system mediatesarousal mechanisms, and neurohormones in the central nervous system(CNS) also mediate sexual function, with the monoamine neurotrans-mitter serotonin acting primarily in an inhibitory role and dopamine ina stimulatory role. Because dopamine is related to motivation and re-ward in the CNS, dopaminergic receptor antagonism may contribute todecreased libido. Additionally, dopamine antagonism may lead to pro-lactin elevation and associated consequences of sexual dysfunction, asdescribed later in this section.

The peripheral nervous system participates in sexual functionthrough sensory input mediated by adrenergic (sympathetic) and cho-linergic (parasympathetic) stimulation (Thomas 2003), with ejaculation


TABLE 12–1. Medications associated with sexual dysfunction (not a comprehensive list)

Medications (U.S. brand name), by class

Reported effect on sexual function

AnticonvulsantsMedications inducing

cytochrome P450 enzymesCarbamazepine (Tegretol)Phenytoin (Dilantin)

Increased metabolism of androgens, possibly affecting sexual function

AntidepressantsMonoamine oxidase inhibitors

Isocarboxazid (Marplan)Phenelzine (Nardil)Tranylcypromine (Parnate)

Differences in risk of sexual side effects may exist between medications in class (inhibited ejaculation, decreased libido)

Selective serotonin reuptake inhibitorsCitalopram (Celexa)Escitalopram (Lexapro)Fluoxetine (Prozac)Fluvoxamine (Luvox)Paroxetine (Paxil)Sertraline (Zoloft)

Differences in risk of sexual side effects may exist between medications within class (decreased libido, delayed orgasm/ejaculation, anorgasmia, decreased vaginal lubrication)

Other antidepressantsMirtazapine (Remeron) Decreased libido, delayed

orgasm/ejaculation, anorgasmia, erectile dysfunction, decreased vaginal lubrication

Antihypertensivesα-Adrenergic blockers

Prazosin (Minipress)Terazosin (Hytrin)

Ejaculatory disturbances (retrograde)

Mixed α-β-adrenergic blockerLabetalol (Normodyne, Trandate)

Inhibited ejaculation

β-Adrenergic antagonistsAtenolol (Tenormin)Metoprolol (Lopressor)Propranolol (Inderal)

Erectile dysfunction, decreased libido


in particular mediated by α-adrenergic and β-adrenergic systems, aswell as motor nerves. Potent α-adrenergic blockade has been associatedwith ejaculatory disturbances and priapism (Compton and Miller 2001;Wang et al. 2006). Cholinergic receptor antagonism may affect erectilefunction, and calcium channel blockade may also contribute to sexualdysfunction (Cutler 2003; Gitlin 1994; Haddad and Wieck 2004). Sero-tonergic neurotransmission in the peripheral system has vasoconstric-tion/vasodilatory effects and plays a role in the normal sexual responsecycle, and serotonin agonists (typically in the form of selective seroto-

Centrally acting agentsClonidine (Catapres)Methyldopa (Aldomet)Reserpine (Reserpine)

Erectile dysfunction, decreased libido (methyldopa and reserpine)

DiureticsSpironolactone (Aldactone)Thiazides (various)

Spironolactone: decreased libido, breast swelling, erectile dysfunction

Thiazides: erectile dysfunctionAntihypertensives, other

Guanethidine (sympathetic nerve blocker) (Ismelin)

Erectile dysfunction, ejaculatory disturbances (retrograde)

Cardiac medicationsDigoxin (Lanoxin) Erectile dysfunction,

gynecomastia

Gastrointestinal medicationCimetidine (Tagamet) Decreased libido, impotence,

gynecomastiaOther

Hormonal contraceptives (various)

Decreased libido

Source. Adapted from American Association of Clinical EndocrinologistsMale Sexual Dysfunction Task Force: “American Association of Clinical Endo-crinologists Medical Guidelines for Clinical Practice for the Evaluation andTreatment of Male Sexual Dysfunction: A Couple’s Problem—2003 Update.”Endocrine Practice 9:77–95, 2003.

TABLE 12–1. Medications associated with sexual dysfunction (not a comprehensive list) (continued)

Medications (U.S. brand name), by class

Reported effect on sexual function


nin reuptake inhibitor [SSRI] antidepressants) are notorious inducers ofsexual dysfunction. Finally, sedation and diminished arousal due tohistamine receptor antagonism may also contribute to sexual dysfunc-tion.

Cigarette smoking status should be obtained during the inquiry intosexual complaints, because up to 80% of persons with schizophreniasmoke (Kelly et al. 2007), and smoking is associated with erectile dys-function. Smoking is also a risk factor for coronary heart disease and pe-ripheral vascular disease, with the result that smoking-inducedinflammation and dyslipidemia become important contributors to vas-cular erectile dysfunction and must be considered in all males witherectile complaints, regardless of the type of antipsychotic treatment.

Given the complex neurobiology of sexual function, antipsychoticmedications can be associated with sexual dysfunction through any ofthe mechanisms described, including effects on the following systems:

• Dopaminergic• Cholinergic• Adrenergic• Histaminic• Serotonergic

As noted in the later section on medication effects, certain classes ofantipsychotics are associated with specific risks for sexual dysfunction,but prolactin elevation is a common problem with many antipsychotics.Prolactin elevation from antipsychotic treatment primarily occurs bydopamine blockade at the pituitary level and is the cause of the majorityof sexual dysfunction specifically attributable to antipsychotic treat-ment. A recent article indicated that prolactin elevation explained 40%of all sexual dysfunction present in patients with schizophrenia (Kneg-tering et al. 2008). Prolactin inhibits gonadotropin-releasing hormoneand, by function of feedback loop between pituitary and hypothalamus,subsequently inhibits luteinizing hormone and follicle-stimulating hor-mone. Hyperprolactinemia may be associated with a decrease in test-osterone levels, which is thought to lead to reduction in sexual activity(Barnes and Harvey 1993). Direct correlations between sexual dysfunc-tion and prolactin levels have not been routinely found in all studies,but those individuals with higher prolactin levels generally have higherrates of sexual dysfunction (Byerly et al. 2007).

The effects of hyperprolactinemia include both sexual and hormonalconsequences. Hyperprolactinemia is associated with galactorrhea, gy-necomastia, oligomenorrhea, amenorrhea, and libido changes in


women; with galactorrhea, gynecomastia, changes in libido, and erectileand ejaculatory dysfunction in men; and possibly with effects on bonemineral density and risk of cancer (Haddad and Wieck 2004). Althoughnot a sexual side effect, galactorrhea can be very distressing and hasbeen reported in 10%–90% of women treated with prolactin-elevatingantipsychotics (Byerly et al. 2007). As noted earlier, gynecomastia andgalactorrhea occur only rarely in men exposed to antipsychotics.

Prolactin and OsteoporosisAccumulating evidence suggests that hyperprolactinemia may increasethe loss of bone mineral density in patients with schizophrenia duringlong-term antipsychotic drug treatment, either through secondaryhypogonadism or hyperprolactinemia itself. Previous studies havedemonstrated that between 32% and 65% of patients treated with anti-psychotic drugs suffer from bone mineral loss, leading to osteoporosis(Meaney et al. 2004). One study found that among women with schizo-phrenia treated with haloperidol, 18 of 21 (86%) had significant bonemineral density loss compared with 9 of 23 (39%) normal control sub-jects (Jung et al. 2006). Bone fractures in patients with schizophreniataking antipsychotics also occur more frequently than in the nonpsychi-atric population. Other evidence suggests that amenorrhea and pro-lactin-elevating antipsychotic drugs are associated with a higher riskfor osteoporosis and fracture (Becker et al. 2003; Bilici et al. 2002;Csermely et al. 2007; Meaney and O’Keane 2007).

Prolactin and Cancer RiskLong-term treatment with antipsychotics in mice has led to the devel-opment of pituitary adenomas and adenocarcinomas. Pharmacovigi-lance studies in humans have found a significantly greater proportionof pituitary tumors reported with risperidone than with the other avail-able antipsychotics (Doraiswamy et al. 2007), although the increasedlevel of prolactin monitoring (and subsequent computed tomographicor magnetic resonance imaging) in risperidone-treated patients may ac-count for a significant aspect of this discrepancy. Another prospectivestudy found that pituitary volume significantly increases over 1 year inpeople treated with prolactin-elevating antipsychotics (MacMaster et al.2007), although the true risk of pituitary tumor with prolactin-elevatingmedications remains unclear. Among the few studies that have ad-dressed whether dopamine receptor antagonists increase risk of breastcancer, results have been conflicting (Wang et al. 2002). Some recent ev-idence suggests that endometrial cancer is related to a hormonal imbal-


ance and that endometrial thickening and cancer may be related toprolactin elevations secondary to antipsychotic treatment (Yamazawaet al. 2003). One report estimated a fivefold increase in endometrial can-cer risk with use of prolactin-raising antipsychotics in premenopausalwomen (Yamazawa et al. 2003).

In summary, the etiology of sexual dysfunction in schizophrenia iscomplex, although elevated serum prolactin levels contribute to a ma-jority, but not all, of the impairments noted in the schizophrenia popu-lation. Hormonal side effects are clearly related to prolactin elevation;however, other effects of hyperprolactinemia on osteoporosis and can-cer risk remain somewhat speculative and warrant further study.

Medication Effects and Sexual DysfunctionAs mentioned above, medications can be associated with sexual dys-function through a variety of mechanisms, and Table 12–1 lists commondrugs that have been associated with impairments in sexual function-ing. In this chapter, we focus primarily on antipsychotic medicationsbut also comment on sexual dysfunction associated with other com-monly used treatments in this population.

First-Generation AntipsychoticsFirst-generation antipsychotics (FGAs) have been associated with a va-riety of symptoms of sexual dysfunction. Diminished libido, orgasmchanges and/or anorgasmia, erectile dysfunction, delayed or retro-grade ejaculation, oligomenorrhea, amenorrhea, galactorrhea, and gy-necomastia have all been reported in patients treated with FGAs.Overall estimates of sexual dysfunction in patients treated with FGAsrange from 30% to 70% (Dossenbach et al. 2006). Smith et al. (2002) re-ported that males treated with FGAs were 6.3 times more likely to com-plain of sexual dysfunction and have 3.7 times greater rates of erectiledysfunction and 16.4 times greater rates of ejaculatory dysfunction thanthe general male population, whereas females treated with FGAs were9.6 times more likely to complain of orgasmic dysfunction than the gen-eral female population.

Haloperidol and other high-potency dopamine antagonists are asso-ciated with greater prolactin elevation and hormonal side effects com-pared with low-potency agents, with data suggesting a correlationbetween serum haloperidol concentrations and serum prolactin levels(Byerly et al. 2007; Shim et al. 2007). Studies have reported that three-fourths of females and one-third of males experience hyperprolactin-


emia when taking FGAs (Smith et al. 2002). The prevalence of sexualdysfunction among patients receiving haloperidol may reach 70%and includes reduced libido in up to 68% and erectile dysfunction in40%–50% (Dossenbach et al. 2006; Olfson et al. 2005). The lower-potency phenothiazines are associated with ejaculatory problems andretrograde ejaculation, the result of α-adrenergic blockade. Retrogradeejaculation may occur in up to 60% of males treated with thioridazine,and priapism is also reported with certain low-potency antipsychotics,most notably chlorpromazine and thioridazine.

Second-Generation AntipsychoticsCompared with the FGAs, second-generation antipsychotics (SGAs)are associated with fewer overall sexual disturbances, with the excep-tion of risperidone and paliperidone, which have a relatively high affin-ity for the dopamine D2 receptor and which are associated withhyperprolactinemia to a greater degree than the more potent dopamineantagonist haloperidol. With the exception of these two agents, com-parative studies have shown lower rates of sexual dysfunction with theSGA class. The following text details information regarding prolactinelevations and sexual dysfunction with use of the SGAs available in theUnited States.

Risperidone. Risperidone, a serotonin-dopamine antagonist, is associ-ated with a greater risk for hyperprolactinemia compared with mostantipsychotics (Kelly and Conley 2006). Mean prolactin levels mayreach 30–60 ng/mL at therapeutic dosages of risperidone (Knegteringet al. 2003); however, prolactin levels are typically higher in women andhave been reported to be 60–150 ng/mL in women at routine risperi-done dosages (Kelly and Conley 2006). In the Clinical AntipsychoticTrials of Intervention Effectiveness (CATIE) schizophrenia trial, risperi-done was associated with an exposure-adjusted prolactin increase of13.8 ng/mL during treatment; however, the data were not brokendown by gender, and the population was 74% male (Lieberman et al.2005).

Risperidone treatment has been reported to cause dysfunction in allareas of sexual response—libido, arousal (erectile dysfunction, ejacula-tory difficulties, decreased vaginal lubrication), and orgasm—as well asto result in hormone-related effects such as menstrual irregularities,amenorrhea, galactorrhea, and gynecomastia (Dossenbach et al. 2006;Kelly and Conley 2004). In observational studies, sexual dysfunctionduring risperidone treatment occurs in 60%–70% of patients with


schizophrenia (Dossenbach et al. 2006). Results from comparative stud-ies also indicate that risperidone is associated with higher rates of sex-ual dysfunction compared with other antipsychotics (Kelly and Conley2006). In the CATIE trial, 27% of subjects taking risperidone had de-creased sex drive, arousal, or ability to reach orgasm; 4% experiencedgynecomastia or galactorrhea; and 18% of the women reported men-strual irregularities. These rates may be underestimates due to the lackof specific rating instruments for assessing these side effects (Lieber-man et al. 2005). Of 860 subjects treated with risperidone for 12 monthsin the Intercontinental Schizophrenia Outpatient Health Outcomesstudy, 60% experienced loss of libido and 46% had impotence and othertypes of sexual dysfunction (Dossenbach et al. 2006). Other reports onrisperidone have noted rates of menstrual abnormalities as high as50%–100% (Kelly and Conley 2006). Risperidone’s α-adrenergic antag-onism is also thought to play a role in the occurrence of sexual side ef-fects, and this may partially explain why prolactin elevations withrisperidone are not always correlated with sexual dysfunction in males.

Olanzapine. Olanzapine causes transient elevations in plasma prolac-tin levels due to its antagonist properties at the D2 receptor, but the in-hibitory potential (Ki) is approximately one-third that of risperidone.The mean prolactin level of patients during daily treatment with olan-zapine at dosages of 10–30 mg is 17 ng/mL, which is higher than that ofnormal controls, drug-free patients, and clozapine-treated patients(Markianos et al. 2001). In most studies, olanzapine has been shown tocause less prolactin elevation than haloperidol and risperidone, and itsimpact on serum prolactin levels appears to be a dosage-related phe-nomenon (Crawford et al. 1997). With prolonged olanzapine exposure,prolactin levels generally return to normal in most patients (Kelly andConley 2004); however, in a 28-week study one-third of olanzapine-treated patients continued to have measurable elevations in prolactinlevels (Tran et al. 1997). In the CATIE schizophrenia trial, prolactinchange during olanzapine treatment was –8.1 ng/mL (exposure-adjusted mean) (Lieberman et al. 2005). Because olanzapine use in treat-ment-naive subjects is associated with modest increases, this decreasein serum prolactin represents the removal of prolactin-elevating effectsof previous treatments.

Dossenbach et al. (2006) reported in one comparative clinical trialthat the odds of patients perceiving sexual problems or being unable toperform sexually was greater in risperidone and haloperidol groupsthan in the olanzapine group, and that females taking olanzapine (14%)or quetiapine (8%) experienced fewer menstrual irregularities than


those taking risperidone (23%) or haloperidol (29%). Other researchershave also reported fewer sexual impairments in patients taking olanza-pine than in patients taking FGAs or risperidone (Bobes et al. 2003;Knegtering et al. 2006). In the CATIE schizophrenia trial, decreased sex-ual drive, arousal, or ability to reach orgasm occurred in 27% of patients(Lieberman et al. 2005), and menstrual abnormalities occurred in 12% ofwomen. Prescribing information derived from olanzapine clinical trialscites dysmenorrhea rates of 2%, which are equal to or less than placebo,and infrequent (<1%) complaints of abnormal ejaculation, amenorrhea,breast pain, decreased menstruation, female lactation, gynecomastia,impotence, increased menstruation, menorrhagia, and metrorrhagia(Zyprexa Prescribing Information 2008). However, as has been reportedwith other medications, these percentages are likely to be underes-timates of the true sexual dysfunction incidence in a real-world popu-lation. Priapism associated with olanzapine use is rare but has beenreported in the literature, as has one case report of olanzapine-associatedclitoral priapism (Bucur and Mahmood 2004; Childers et al. 2003;Compton and Miller 2001; Jagadheesan et al. 2004; Songer and Barclay2001).

Quetiapine. Quetiapine is a serotonin-dopamine antagonist with a lowaffinity for the D2 receptor and a quick rate of dissociation. Quetiapinehas not been shown to have a propensity to increase prolactin levels,which suggests that the risk of hyperprolactinemia-related adverse ef-fects is less than with other antipsychotic agents such as risperidoneand paliperidone. Prolactin levels have been reported to decrease dur-ing quetiapine treatment, and did not differ from placebo in clinical tri-als (Arvanitis and Miller 1997). In the CATIE schizophrenia trial,exposure-adjusted mean prolactin changes decreased 10.6 ng/mL dur-ing quetiapine treatment, although this probably represents a removalof prior drug effect rather than any direct prolactin-lowering propertyof quetiapine.

Despite the prolactin-sparing effects of quetiapine, sexual side effectshave been reported, and published studies have noted sexual dysfunc-tion occurring in 8%–50% of patients treated with quetiapine (Kelly andConley 2006). In a study of 36 patients with schizophrenia receivingquetiapine for over 4 weeks, Atmaca et al. (2005) found that diminishedlibido occurred in about one-third of male and female patients. In astudy of schizophrenia patients, Bobes et al. (2003) reported that sexualdysfunction occurred in 18% of quetiapine-exposed subjects comparedwith almost 40% of patients taking haloperidol. Byerly et al. (2006a), ina one-time rating of a large group of patients with schizophrenia or


schizoaffective disorder, also found the severity of sexual dysfunctionto be lower in the quetiapine group than in the risperidone or olanza-pine group. In a randomized, open-label, 6-week trial, Knegtering et al.(2004) found that 4 of 25 (16%) quetiapine-treated patients and 12 of 24(50%) risperidone-treated patients experienced sexual dysfunction. By-erly et al. (2004) performed an open-label switch to quetiapine andfound that eight patients (seven switched from risperidone and onefrom haloperidol) who described significantly improved sexual func-tion had decreased prolactin levels. Fewer menstrual irregularities alsooccur in females taking this medication compared with risperidone andFGAs, with the prevalence in the CATIE schizophrenia trial reported at6% (Kelly and Conley 2006; Lieberman et al. 2005). Finally, a 12-weekdouble-blind trial comparing quetiapine to risperidone found that que-tiapine was associated with better improvement in sexual functioncompared with risperidone or fluphenazine (Kelly and Conley 2006),but that approximately one-half of subjects taking quetiapine were ex-periencing sexual dysfunction, indicating that prolactin-independentmechanisms may be at work in the etiology of sexual complaints.

Prescribing information for quetiapine lists the following as adverseeffects: infrequently reported adverse effects in clinical trials included(<1%) dysmenorrhea, menorrhagia, impotence, abnormal ejaculation,amenorrhea and leucorrhea, while gynecomastia was rarely (<0.1%) re-ported (Seroquel Prescribing Information 2008). Several case reports ofquetiapine-associated priapism have been reported, including one re-ported in quetiapine overdose (Casiano et al. 2007; Davol and Rukstalis2005; Harrison et al. 2006; Pais and Ayvazian 2001).

Ziprasidone. Ziprasidone is a serotonin dopamine antagonist with a D2

affinity lower than that of risperidone and higher than that of olanza-pine. It is associated with only minor prolactin-elevating effects, whichare measurable but are generally transient and not clinically problem-atic. In a 52-week double-blind study, prolactin levels at endpoint were19 ng/mL for ziprasidone, compared with 60 ng/mL for risperidone(Ananth et al. 1998). Scattered case reports of prolactin elevation haveappeared in the literature, but in the CATIE schizophrenia trial, the ex-posure-adjusted mean prolactin decreases were –5.6 ng/mL duringziprasidone treatment (Lieberman et al. 2005). The effects of ziprasi-done on sexual dysfunction have not been extensively reported in thepublished literature, but the CATIE study found decreased sex drive,arousal, and ability to reach orgasm in 19% of ziprasidone-treated sub-jects and menstrual irregularities in 14% of women. Prolonged erec-tions and priapism have rarely been associated with ziprasidone use,


but in clinical trials, impotence, abnormal ejaculation, amenorrhea,menorrhagia, female lactation, metrorrhagia, male sexual dysfunction,and anorgasmia were listed as infrequent (<1%) adverse effects, and gy-necomastia was listed as a rare (<0.1%) adverse event (Geodon Pre-scribing Information 2007). Again, these reported rates in pivotalclinical trials likely underestimate the true prevalence of sexual dys-function.

Aripiprazole. Aripiprazole differs in mechanism from other SGAs inthat it acts as a partial dopamine agonist at D2 receptors. The mecha-nism of action suggests a lack of prolactin elevation, which has beenconfirmed in the published literature. Aripiprazole exerts dopamineagonism in pituitary cells at the molecular level; thus, lactotroph cellsare not inhibited by aripiprazole treatment. Serum prolactin levels havebeen found to decrease significantly from baseline during treatment tri-als with aripiprazole. In a 6-week, double-blind, randomized trial byKane et al. (2007), mean prolactin levels decreased in the aripiprazolegroup from 33.4 ng/mL to 5.2 ng/mL, whereas prolactin levels in theperphenazine group remained unchanged (35.8 ng/mL to 35.5 ng/mL).In a 4-week study, prolactin levels decreased significantly in the ari-piprazole group (–9.0 ng/mL), whereas the risperidone group experi-enced a mean increase of 55.4 ng/mL (H.Y. Chan et al. 2007).

The prevalence of sexual dysfunction with aripiprazole has not beenwidely studied. In a recent review of antipsychotic trials published be-tween 2002 and 2008, Baggaley (2008) reported aripiprazole to be asso-ciated with the lowest rate of sexual dysfunction. An open-label studyfound improvements in prolactin levels, hormonal side effects, and sex-ual dysfunction in patients who switched to aripiprazole or who hadaripiprazole added to current regimens (Mir et al. 2008). In a random-ized, double-blind trial, adding adjunctive aripiprazole to haloperidolsignificantly decreased prolactin levels and improved hormonal sideeffects in the majority of women (Shim et al. 2007), although this studydid not measure sexual dysfunction. In premarketing trials, less than1% of patients complained of irregular menstruation, amenorrhea,breast pain, or erectile dysfunction, and less than 0.1% of patients com-plained of gynecomastia and priapism (Abilify Prescribing Information2008), although two cases of priapism have been reported in patientstreated with aripiprazole (Mago et al. 2006; Negin and Murphy 2005).

Paliperidone. Paliperidone is the active metabolite of risperidone(9-hydroxyrisperidone), with similar affinity for D2 receptors, but ismarketed as a unique drug entity. Data from three 6-week industry-


sponsored trials showed that median prolactin elevations were 81 ng/mL for women and 24 ng/mL for men in a pooled analysis of all dos-ages. Four percent of patients receiving extended-release paliperidone15 mg/day reported potential prolactin-related adverse events,whereas 1%–2% of patients receiving placebo or extended-release pali-peridone 3–12 mg/day spontaneously reported potential prolactin-related events (Meltzer et al. 2008).

No controlled trials specifically addressing sexual dysfunction in pa-tients using paliperidone have been published to date, but paliperi-done’s propensity to increase serum prolactin is nearly identical to thatof risperidone, and most of the information regarding this compoundhas been reported in studies using the parent compound, risperidone.Knegtering et al. (2005) and Melkersson (2006) demonstrated in smallstudies of risperidone that plasma concentration of 9-hydroxyrisperi-done correlated with increases in prolactin and may be the main con-tributor to increased levels of serum prolactin in many patients treatedwith risperidone. One double-blind, 6-week, randomized, placebo-controlled study (Marder et al. 2007) of 444 subjects (222 receiving pal-iperidone) found that prolactin-related adverse effects were reported intwo men and one woman taking paliperidone (lactation and decreasedlibido) and two patients taking placebo. No systematic assessment ofsexual function was utilized, however.

Clozapine. Clozapine has weak affinity for D2 receptors and dissociatesfairly quickly, resulting in only transient prolactin elevations (Volavkaet al. 2004). These transient changes are measurable in the laboratory,but clinical hyperprolactinemia generally does not occur with this an-tipsychotic. Not surprisingly, most studies suggest that clozapine hasless impact on sexual functioning than do other antipsychotics, espe-cially risperidone and FGAs. Nonetheless, clozapine does have high af-finity for muscarinic cholinergic and α-adrenergic receptors, and mayinduce sexual dysfunction through these mechanisms. An open-labelstudy of 103 subjects taking clozapine found that 57 (55%) patients re-ported sexual side effects. Interestingly, only three of the patients re-ported these complaints based on an open question as to whether theyexperienced side effects from clozapine, whereas the other 54 patientsreported sexual dysfunction during systematic inquiry (Yusufi et al.2007). Although prolactin-related adverse effects are unlikely to occur,anticholinergic and antiadrenergic activity of clozapine can be associ-ated with ejaculatory or erectile problems in males. Case reports of pri-apism and impotence have been reported with clozapine treatment(Compton and Miller 2001). According to prescribing information, 1%


of patients may experience abnormal ejaculation (Clozaril PrescribingInformation 2005). In the United States, clozapine is reserved for use inpatients with schizophrenia that is refractory to other antipsychotics;thus, it is difficult to determine whether illness severity or other poten-tial differences within this patient population may impact sexual dys-function prevalence.

Other Frequently Used Medications. People with schizophrenia are of-ten treated with other psychotropic medications that have the potentialto cause sexual dysfunction. Antidepressants may be associated withsexual side effects in differing degrees, based on their mechanisms ofaction. Although most published data regarding sexual side effects inpatients treated with antidepressants have come from the depressionliterature (e.g., Clayton and Montejo 2006; Segraves 2007; Werneke et al.2006), it is expected that these medication effects would generalize toother populations, such as patients with anxiety or schizophrenia.

• SSRIs are associated with anorgasmia and delayed orgasm in up to30%–40% of treated patients, decreased libido in up to 20% of pa-tients, and erectile difficulties in up to 10% of patients.

• Tricyclic antidepressants, due to varied noradrenergic, serotonergic,cholinergic, and histaminic effects, have been associated with sexualdysfunction.

• Monoamine oxidase inhibitors may be associated with sexual dys-function through effects on the serotonergic system.

• Trazodone, at dosages ≥150 mg, has been associated with priapism inrare cases, thought to be at least partially explained by α-adrenergicantagonism.

• Other antidepressants, such as mirtazapine, are thought to exertfewer sexual side effects; however, erectile dysfunction may occuras a result of noradrenergic activity.

• Venlafaxine, duloxetine, and bupropion have been associated withless sexual dysfunction than have SSRIs.

Valproate, although not extensively reported to cause sexual dys-function, has also been associated with reproductive endocrine abnor-malities (Morris and Vanderkolk 2005). Limited data are availableregarding sexual dysfunction risk from other mood-stabilizing agentsand benzodiazepines; however, reports suggest that treatment with thefollowing may contribute in varying degrees to sexual dysfunction:lithium; anticonvulsants such as carbamazepine, valproate, or lamot-rigine; and benzodiazepines (Ghadirian et al. 1982; Herzog et al. 2005).


AssessmentThe assessment of sexual dysfunction among patients with schizophre-nia has not been uniform in clinical research or practice. Few standard-ized and validated instruments have been used in studies of sexualdysfunction for this patient population, and definitions of sexual dys-function and the parameters measured within these instruments arequite heterogeneous. Nonetheless, the higher prevalence rates reportedfollowing focused inquiry suggest that in clinical practice, directly ad-dressing sexual function may be the most effective way to identify pa-tient concerns about sexual disturbances. According to several reports,patients may be unlikely to spontaneously report sexual dysfunction fora number of reasons, and women may be less likely to report sexual dys-function or suspected sexual side effects than men (Knegtering et al.1999). Knegtering et al. (2006) demonstrated that although only 8.7% ofpatients complained of sexual dysfunction spontaneously after 6 weeksof antipsychotic treatment, 30.4% of patients in the study reported sex-ual dysfunction in response to a semistructured interview. In a survey ofindividuals with severe mental illness (not exclusively schizophrenia),patients reported various reasons they had not discussed sexual func-tion with their clinicians, including they thought it would be embarrass-ing for them (28%), they thought nothing could be done (20%), and theirsexual function did not bother them (16%) (Rosenberg et al. 2003).

Recommendations from consensus panels, such as the Mt. Sinai Con-ference on Health Monitoring of Patients With Schizophrenia, indicatethat mental health providers should directly question patients aboutchanges in menstruation, libido, galactorrhea, and erectile and ejacula-tory function. If patients are receiving a prolactin-elevating antipsy-chotic, direct patient questioning should occur at each visit until astable dosage is reached, then at least yearly thereafter (Marder et al.2004). Clinicians should understand that broaching the subject of sexualbehavior and questioning patients about changes in sexual function areintegral to the treatment of patients with schizophrenia, because ofquality-of-life reasons and the impact that sexual side effects may haveon medication adherence.

Measuring sexual dysfunction in patients with schizophrenia has re-ceived far less attention than in the general population, and few biolog-ical indices may be reliably measured to screen for sexual dysfunction.Serum prolactin levels can be assessed, but these do not reliably predictsexual dysfunction (Knegtering et al. 2008). Most assessment tech-niques have employed rating instruments, but Kelly and Conley (2004)noted that for studies published prior to 2002, a total of 15 different


scales were employed in the 16 published studies. Since then, a fewscales have become validated and more widely used in this patient pop-ulation, yet no gold-standard instruments exist. Patients with schizo-phrenia have fewer partners and relationships than do people in thegeneral population; therefore, not all rating instruments reliably assesssexual complaints of schizophrenia patients.

Much of the existing literature for sexual assessment in patients withmental illness comes from studies in depression. Clayton (2001) putforth criteria for assessment tools to measure sexual dysfunction in pa-tients with depression, and subsequent authors (Kelly and Conley 2004)suggested that these criteria may also be useful in the schizophreniapopulation. Among those elements thought to be most useful for anyassessment of sexual dysfunction in patients with schizophrenia are thefollowing:

• Assess premorbid and lifelong function compared to current function

• Track changes across time• Assess phase-specific sexual functioning• Separate medication effects from illness• Include gender-specific questions• Be brief• Be nonintrusive

Table 12–2 summarizes some of the most commonly used rating scalesand information to help guide clinicians in the assessment of thesesymptoms.

Management

Psychosocial Issues to DiscussBoth men and women have reported that one area with the highestproportion of unmet needs is counseling about intimate relationships.Additionally, studies addressing sexual issues have generally concludedthat patients with schizophrenia are prepared and open to discuss issuesrelating to sexual activity, and the majority of patients with schizophre-nia believe that discussing sexual issues may actually be beneficial fortheir outcomes (Lewis and Scott 1997). Furthermore, concern about sex-ual dysfunction may exacerbate psychiatric symptoms (Sullivan andLukoff 1990).

324M

edical Illness and SchizophreniaTABLE 12–2. Rating instruments for sexual function used in schizophrenia

Assessment AuthorsAdministration format

Number of items Domains

Used in schizophrenia or antipsychotic studies?

Antipsychotics in Sexual Functioning Questionnaire

Bous et al. 2003

Semistructured interview

Based on UKU sex-ual dysfunction items (4 for men, 5 for women)

Based on UKU; libido, orgasm, erection/ejaculation, vaginal lubrication

Yes

Arizona Sexual Experience Scale

McGahuey et al. 2000

Self-report 5 for men5 for women

Drive, arousal, penile erection, vaginal lubrication, orgasm satisfaction

Yes. Validated, found reliable (Byerly et al. 2006b)

Changes in Sexual Functioning Questionnaire

Clayton et al. 1997

Semistructured interview

36 for men34 for women

Sexual desire/frequency, desire/interest, sexual pleasure, arousal/interest, orgasm/completion

Yes

Dickson Glazer Scale

Dickson et al. 2001

Self-report, computerized

32 for men40 for women

Sexual desire, arousal, frequency of activity, orgasmic function, satisfaction, sexually related problems; questions on perceptions of sexual side effects

Yes

Sexual Dysfunction

325

International Index of Erectile Function

Rosen et al. 1997

Self-report 15 for men Erectile function, orgasm, desire, intercourse, satisfaction, overall

Yes

Sexual Functioning Questionnaire

Burke et al. 1994

Structured interview

15 for men Frequency of sexual thoughts, erections, masturbation over past 2 years and immediate 2 weeks; changes in specific aspects of sexual function

Yes

Udvalg for Kliniske Undersogelser(sexual items)

Lingjaerde et al. 1987

Clinician rated 48 items related to adverse effects; 10 items on sexual/reproductive issues

3 components: adverse effects (psychic, neurological, autonomic, other), global assessment of presence/absence of interference in daily performance due to adverse effects, and indication of consequences of clinician taking action to address side effects

Yes

Note. UKU=Udvalg for Kliniske Undersogelser.

TABLE 12–2. Rating instruments for sexual function used in schizophrenia (continued)

Assessment AuthorsAdministration format

Number of items Domains

Used in schizophrenia or antipsychotic studies?


Patients who are switched to less sexually adverse medications mustbe counseled regarding the expected impact on all aspects of sexual andhormonal functioning. Because symptoms may improve, libido and thedesire to engage in intimate relationships may increase. Several caseshave been reported of patients being switched to an SGA from an FGAwith resultant unplanned pregnancies, potentially related to improve-ments in sexual function as well as the return of fertility (Dickson andHogg 1998; Neumann and Frasch 2001; Tényi et al. 2002). Patients withschizophrenia often have poor judgment and report fairly frequent sex-ual activity with people who are known to be injection drug users. Fiftypercent of patients with schizophrenia in one study were reported to beinvolved in sex exchange behavior (sex bought or sold for money,drugs, or goods), and condom use was particularly low, with less than10% of these individuals using protective measures (Cournos et al.1994). Moreover, women with schizophrenia not wishing to becomepregnant do not commonly use contraception (Miller 1997). Sexualactivity also occurs with those known to be infected with human im-munodeficiency virus (HIV) or who are at risk, with documented HIVinfection rates that are higher in patients with severe mental illnesscompared with the general population (Blank et al. 2002). Furthermore,rates of HIV infection have been increasing substantially in adults withserious mental illness (Otto-Salaj and Stevenson 2001). (For a more ex-tensive discussion of HIV, see Chapter 10, “HIV and Hepatitis C inPatients With Schizophrenia.”)

Women with schizophrenia also have more abortions and are moreoften victims of violence during pregnancy than those without mentalillness (Miller and Finnerty 1996). Therefore, clinicians should be readyto deal with these issues and refer patients for additional counseling ifneeded. To help with the sexual dysfunction of patients with schizo-phrenia, clinicians should arrange for family planning, education, andcontraceptive counseling as an integral part of the comprehensive treat-ment plan.

Prolactin MonitoringDespite variations in serum prolactin levels, both within and across in-dividuals, a reasonable consensus exists regarding the upper limit ofthe normal range. Conservative reports consider >18–20 ng/mL in menand >24 ng/mL in women as the standard for the upper limit (Jung etal. 2005, 2006; Kinon et al. 2003, 2006). Not all prolactin elevations aresymptomatic, however, and levels associated with sexual dysfunctionand hormonal side effects vary widely. Nevertheless, women have sig-


nificantly greater elevations from dopamine antagonists than do males,and prolactin levels of 80–150 ng/mL are in most cases correlated withclinically evident hormonal side effects. The recommendations from the2004 Mt. Sinai Conference on Health Monitoring of Patients WithSchizophrenia include directly asking patients about changes in men-struation, libido, erectile or ejaculatory function, and galactorrhea,which may be prolactin-related adverse effects, and if patients are re-ceiving antipsychotics with greater propensity to elevate prolactin, theauthors recommend “more frequent“ assessment. With a positivescreen for these adverse events, prolactin levels should be drawn and,if possible, other potential causes for these symptoms should be ruledout (Marder et al. 2004). In the Practice Guideline for the Treatment of Pa-tients With Schizophrenia, the American Psychiatric Association (2004)suggests initial or baseline screening for symptoms of hyperprolactine-mia, and, if indicated on the basis of clinical history, a baseline serumprolactin level. These guidelines recommend follow-up screening forsymptoms of hyperprolactinemia at each visit until stable, then yearlyif the patient is taking an antipsychotic known to increase prolactin.Prolactin levels at follow-up are recommended if indicated on the basisof clinical history.

Medication ManagementNo universal guidelines exist for managing sexual dysfunction inschizophrenia. Once sexual symptoms are identified, the degree of dis-comfort and dissatisfaction associated with the symptoms should be as-sessed, especially because sexual side effects are often of concern topatients and may affect medication adherence if the patient attributessexual dysfunction to his or her treatment regimen. Interventions for themanagement of sexual dysfunction in patients with schizophreniashould be undertaken after careful consideration of all etiologies be-cause sexual disturbances are complex and may arise from varioussources. In addition to antipsychotic treatment, symptoms of schizo-phrenia itself and the psychosocial problems it entails are likely to im-pact sexuality. Other mental and physical conditions and diseases (e.g.,depression, diabetes, nicotine dependence, cardiovascular disease) andmedications (e.g., antidepressants, anticholinergic agents, antihyper-tensives) may contribute to sexual dysfunction. When possible, elucida-tion of the likely source of sexual dysfunction will assist in preparing aplan for management, beginning with the identification and eliminationof potential nonpsychiatric causes. Management of sexual dysfunctionrelated to schizophrenia also depends, in part, on the presenting symp-


toms. When addressing symptoms thought to be related to hyperpro-lactinemia, other reasonable clinical alternatives should be discardedprior to focusing on the potential to alleviate the prolactin elevation.

Dose Lowering and Antipsychotic Switching. As recognized previouslyin this chapter, different antipsychotic agents lead to different sexualdysfunction risks, with FGAs as a group contributing greater sexualside effect burden than SGAs. Among the SGAs, risperidone and ex-tended-release paliperidone are more likely to be associated with in-creases in prolactin and the risk of sexual and neuroendocrinedysfunction. Lowering the dosage of the antipsychotic is a consider-ation, but clinicians must use caution to avoid decreasing an antipsy-chotic below its therapeutic threshold for a specific patient; moreover,antipsychotic agents with high levels of dopamine antagonism are as-sociated with prolactin elevation even at low dosages, and no formalstudies have been published to support a dosage reduction for sexualside effects (Costa et al. 2006).

Switching to another antipsychotic with less propensity to cause sex-ual side effects entails some risk of psychotic relapse during the switch,but this option may be effective for certain patients (Marder et al. 2004),with some positive data indicating the benefits of successful antipsy-chotic switching. Kinon et al. (2006) openly switched 27 stable schizo-phrenia patients with hyperprolactinemia to olanzapine, and foundreductions in mean serum prolactin, increased free testosterone levels,and improvements in sexual functioning. Nakajima et al. (2005) exam-ined the effects of openly switching 25 female schizophrenia patientswith hyperprolactinemia to quetiapine. Although eight patientsdropped out due to psychotic exacerbation, the 17 patients who com-pleted the 8-week study (68%) showed significant decrease in serumprolactin without significant change in illness severity. Byerly et al.(2008) reported the differential effects of switching patients with schizo-phrenia and sexual dysfunction to quetiapine versus continuing ris-peridone. Forty-two patients with risperidone-associated sexualdysfunction were randomized to double-blind quetiapine versus ris-peridone for 6 weeks. This study did not find significant differences inrated levels of sexual dysfunction between the quetiapine and risperi-done groups, although total scores were slightly lower in the switchgroup at endpoint. Mir et al. (2008) reported data from an open-labelswitch to aripiprazole from other antipsychotics (N=27), and found re-duced prolactin levels, improved libido, reduction of menstrual andejaculatory difficulties, and reduced menstrual dysfunction, accompa-nied by overall improvement in satisfaction in sexual functioning. By


the end of the study, over half of the patients were still taking their orig-inal antipsychotic in addition to aripiprazole.

Adjunctive Treatment. The use of adjunctive medication for the treat-ment of sexual dysfunction in patients with schizophrenia has not beenas widely studied as the treatment of sexual dysfunction in the generalpopulation. The lack of large, well-designed, controlled longitudinaltrials for the treatment of sexual dysfunction in patients with schizo-phrenia gives rise to difficulties in recommending any interventionwith a high degree of confidence. Most of the information regardingmanagement of sexual dysfunction in schizophrenia is focused on thosesymptoms thought to be adverse effects of the antipsychotic agents andconsists mainly of small open-label studies and case reports, although afew small, randomized, placebo-controlled studies have been pub-lished.

Sildenafil, an agent that improves erectile dysfunction via selectiveinhibition of cyclic guanosine monophosphate–specific phosphodi-esterase type 5 (PDE5), has been used in schizophrenia in one double-blind, placebo-controlled, crossover study (Gopalakrishnan et al. 2006);two open-label trials (Atmaca et al. 2002; Aviv et al. 2004); and severalcase reports. In the double-blind trial, sildenafil 25–50 mg was given to32 patients with schizophrenia or delusional disorder and antipsy-chotic-induced erectile dysfunction. Sildenafil was superior to placeboon all measures, including erections and satisfaction with sexual inter-course. In a subgroup with elevated prolactin (n=22), sildenafil differedfrom placebo in satisfactory erections, duration of erections, and satis-faction with sexual intercourse. Adverse events were consistent withtrials in the population without schizophrenia and included nasal stuff-iness and headache (Gopalakrishnan et al. 2006). One open-label studyreported that the use of sildenafil 50–100 mg in 10 patients with olanza-pine-induced erectile dysfunction resulted in significant differences inerectile dysfunction scores (Atmaca et al. 2002). The second study foundthat sildenafil 25–75 mg in 12 male patients with schizophrenia takingrisperidone resulted in either partial or great improvement in 67% ofpatients during open-label treatment (Aviv et al. 2004).

Vardenafil is another PDE5 inhibitor with data for use in patients withschizophrenia. One open-label 12-week trial of 21 completing outpatientsfound that vardenafil 10–20 mg was associated with significant improve-ments in orgasmic function, sexual desire, intercourse satisfaction, andoverall satisfaction. Improvements in sexual function were also associ-ated with improvement in quality of life as measured by the Quality ofLife Scale (Mitsonis et al. 2008). Adverse events, which were similar to


those reported with other PDE5 inhibitors, most commonly includedheadache, flushing, nasal congestion, dyspepsia, and orthostatic hy-potension. One subject withdrew from the study due to headache.

Bromocriptine is a dopamine agonist that has been reported to im-prove libido in patients with hyperprolactinemia (Kelly and Conley2004). Although use of the dopamine agonists has been concerning dueto the potential for exacerbating psychotic symptoms, three small stud-ies have investigated bromocriptine for sexual dysfunction. A small,open-label study of bromocriptine 5–10 mg/day resulted in a resump-tion of normal menstrual cycles in 55% of women and relief of galactor-rhea in 33%, but smaller effects were seen with erectile and ejaculatorydysfunction (Beau and Guillard 1980). In an open-label trial of bro-mocriptine 5–7.5 mg/day, of the 35 patients (24 female, 11 male) stud-ied, improvement in impotence was seen in 66% of male subjects, andreturn of menstrual cycle and relief of galactorrhea were seen in over50% of the females with these complaints (Matsouka et al. 1986). A thirdstudy compared bromocriptine to the herbal supplement Peony-Glycyrrhiza Decoction (PGD) in the treatment of risperidone-inducedhyperprolactinemia. In this randomized study, 20 women with schizo-phrenia taking risperidone received PGD or bromocriptine 5 mg/dayfor 4 weeks, and were then crossed over to other treatment after a4-week washout. Neither treatment was associated with worsening ofpsychotic symptoms, and similar decreases in serum prolactin werefound with both agents; however, 56% of subjects taking PGD but only17% of subjects taking bromocriptine had improvement in side effects(Yuan et al. 2008).

Cabergoline, a dopamine agonist, has been found effective in a fewcases for reducing prolactin elevation in patients with antipsychotic-associated hyperprolactinemia without worsening of psychiatric symp-toms (Cohen and Biederman 2001; Tollin 2000). One open-label pilotstudy reported the results of 19 patients with schizophrenia and risperi-done-associated hyperprolactinemia who were treated with caber-goline 0.125–0.250 mg/week for 8 weeks. Treatment with cabergolinewas associated with a statistically significant decrease in prolactin, and11 patients reported alleviation of clinical signs of hyperprolactinemia.Cabergoline was not associated with a change in psychopathology(Cavallaro et al. 2004). A black-box warning has been issued, however,due to significant concern regarding cardiopulmonary toxicity with useof cabergoline and, to a lesser extent, bromocriptine. Fifteen cases ofvalvular heart disease in patients taking cabergoline had been reportedto the U.S. Food and Drug Administration by the end of 2002 (Flowerset al. 2003).


Selegiline, a monoamine oxidase inhibitor, was examined in one ran-domized trial for its potential use for sexual dysfunction in schizophre-nia. Ten men with schizophrenia reporting sexual dysfunction whilebeing treated with an FGA (perphenazine or haloperidol) were ran-domly assigned to receive selegiline 15 mg/day or placebo for 3 weeks,with a 2-week washout before a crossover to 3 weeks of the other treat-ment. No significant differences were found between the selegiline andplacebo phases on measures of sexual function, although prolactin lev-els decreased during selegiline exposure (Kodesh et al. 2003). Side ef-fects were not reported in the manuscript.

Amantadine has been explored for the treatment of neuroendocrineside effects and/or sexual dysfunction because it purportedly causesdopamine release at neuronal terminals, and therefore may be effectivein decreasing prolactin levels that are elevated as a result of antipsy-chotic use. Two open-label studies have been reported. Correa et al.(1987) found reductions in prolactin, gynecomastia and galactorrhea,breast tenderness, decreased libido, and amenorrhea in 10 patients withschizophrenia who were treated with open-label amantadine 200–300mg/day in a 7-week study. In the other study, Valevski et al. (1998) re-ported the effects of amantadine on sexual dysfunction in males withschizophrenia who were treated with antipsychotics. Open-label aman-tadine 100 mg/day for 6 weeks was shown to improve patient scores ondesire, erection, and satisfaction from sexual performance. Amantadine,however, is associated with a theoretical risk of worsening psychosis orother psychiatric side effects due to its effects on dopamine, as well asother dopaminergic adverse effects such as orthostatic hypotension.

Aripiprazole has not been systematically studied for its effects on im-proving sexual dysfunction; however, adjunctive aripiprazole has beenshown in a randomized, double-blind, 8-week trial to normalize ele-vated prolactin levels and improve hormonal side effects. In the ari-piprazole group, 88.5% of patients at week 8 had normalized prolactinlevels compared with 3.6% of patients in the placebo group. Among the11 female patients with menstrual disturbances randomized to ari-piprazole, seven regained menstruation during the study (63.6%),whereas no female patients did in the placebo group (Shim et al. 2007).A number of other open-label studies (Mir et al. 2008) and case reportsof adjunctive aripiprazole with existing antipsychotics have also beenpublished that support the results of larger trials.

Several case reports and small studies have been published, mostlyin the Japanese literature, describing the use of herbal supplements inthe treatment of hyperprolactinemia associated with antipsychotics.One study and a case report using Shakuyaku-kanzo-to, or TJ-68, an


herbal product, have found significant reductions in prolactin levelsand hormonal side effects (Yamada et al. 1997, 1999). In one small, ran-domized, crossover study, the preparation Peony-Glycyrrhiza Decoc-tion (PGD) was compared to bromocriptine in 20 women withschizophrenia and risperidone-associated hyperprolactinemia experi-encing oligomenorrhea or amenorrhea. In this small study, PGD wasmore beneficial than bromocriptine for improving side effects, althoughprolactin decreases were similar (Yuan et al. 2008). Little information isavailable regarding the pharmacology or side effects of these agents.

ConclusionSexual dysfunction is a frequently occurring problem in patients withschizophrenia, yet its recognition and significance have been overlookedby clinicians. Multiple etiological factors (e.g., schizophrenia itself, vas-cular disease, diabetes, smoking) are likely to exist beyond the effects ofpsychotropic medications, and these should not be overlooked. Manyantipsychotic medications are associated with sexual dysfunction, andprolactin elevations contribute to a large proportion of sexual com-plaints, but hyperprolactinemia is not always associated with hormonaland sexual side effects. Anticholinergic and α-adrenergic mechanismsmay also be particularly important for certain patients, with males es-pecially vulnerable to erectile problems from the latter.

The management of patients with sexual dysfunction involves opti-mal communication between the patient and clinician, careful explora-tion of potential causes and contributing factors, and assessment ofimpact on the patient’s attitude toward treatment and quality of life.Identifying and eliminating nonpsychiatric causes may be helpful inaddressing this problem. Treatment changes based on sexual dysfunc-tion should be carefully considered and, when possible, targeted to thespecific symptoms. Switching an antipsychotic medication to one lesslikely to cause sexual dysfunction, or in some cases reducing the dos-age, has been proposed but may not always be the practical or recom-mended approach for certain patients. The best approaches for thetreatment of hyperprolactinemia and sexual dysfunction currently ap-pear to be either initiating treatment with prolactin-sparing antipsy-chotics or decreasing prolactin levels through the use of dopamineagonists or aripiprazole adjunctively, if the side effects are definitelysecondary to prolactin elevations. The use of PDE5 inhibitors may be ofparticular value in cases with a less clear association between sexualdysfunction and elevated prolactin, particularly in males who, for in-


stance, smoke or have diabetes; however, studies are needed to helpguide evidence-based treatment. As clinicians strive to reach recoveryin patients, better communication on sexuality and sexual dysfunctionwill assist greatly in this endeavor.

Key Clinical Points

◗ Sexuality and sexual dysfunction in patients with schizophrenia have re-ceived little attention in the past.

◗ Sexual dysfunction has been difficult to measure accurately in patientswith schizophrenia, but its prevalence is generally considered to behigher in these patients than in the general population. Reported preva-lence rates vary widely, with most publications citing rates of 50%–75%.

◗ The types and prevalence of sexual dysfunction are likely to differbetween men and women. Males with schizophrenia who have sexualdysfunction typically complain of decreases in libido and erectile,ejaculatory, and orgasmic functions, whereas women may experiencedisturbances in libido, vaginal lubrication, and orgasm, as well as dys-pareunia and menstrual disturbances.

◗ Sexual dysfunction, especially if it is perceived by the patient to be aneffect of antipsychotic medication, may be a factor that impacts treat-ment adherence.

◗ Multiple factors may contribute to sexual dysfunction, including life-style factors, symptoms of schizophrenia and other comorbidities, med-ications or substances used, and cigarette smoking.

◗ The mechanisms by which medications affect sexual function likelydiffer. Although many neurotransmitter systems (dopaminergic, sero-tonergic, adrenergic, cholinergic, histaminic) that are affected by anti-psychotics may contribute to sexual dysfunction, elevation of serumprolactin is thought to account for a significant proportion of sexualdysfunction seen in patients.

◗ The effects of prolactin elevation should be considered when screeningpatients at clinic visits, especially those patients taking prolactin-elevatingantipsychotics.

◗ First- and second-generation antipsychotics have both been associatedwith sexual dysfunction, although differences exist both within andamong the different classes.


◗ Risperidone, paliperidone, and some FGAs have been associated withthe greatest increases in prolactin levels among patients treated withantipsychotics.

◗ The assessment of sexual dysfunction has not been widely studied. Sev-eral instruments exist, but no gold standard has been identified. Becausepatients may be hesitant to broach the subjects themselves, directly ques-tioning patients about sexual function and dysfunction should be incor-porated into the treatment plan and may result in detecting dysfunction.

◗ The management of sexual dysfunction in patients with schizophreniais complex. Psychosocial issues should be addressed. Medication man-agement may be necessary, and adjunctive medications have sometimesbeen reported in the literature. Only limited data exist to evaluate theefficacy of these interventions.

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Yusufi B, Mukherjee S, Flanagan R, et al: Prevalence and nature of side effectsduring clozapine maintenance treatment and the relationship with cloza-pine dose and plasma concentration. Int Clin Psychopharmacol 22:238–243, 2007

Zyprexa Prescribing Information. Indianapolis, IN, Eli Lilly, 2008

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CHAPTER 13

Managing the HealthOutcomes ofSchizophrenia

Treatment in Childrenand Adolescents

Christoph U. Correll, M.D.

In children and adolescents, antipsychotics are used in increas-ing quantities for schizophrenia, other psychotic disorders, and variousnonpsychotic conditions (Olfson et al. 2006). For youth, as for adults,the majority of antipsychotics used are second-generation agents,partly because children and adolescents are especially sensitive to theadverse neuromotor effects of first-generation antipsychotics (Correll etal. 2006). At the time of this writing, the U.S. Food and Drug Adminis-tration (FDA) has approved only four antipsychotics—haloperidol and

This work was supported in part by the Zucker Hillside Hospital National In-stitute of Mental Health Advanced Center for Intervention and Services Re-search for the Study of Schizophrenia grant MH 074543-01, and the NorthShore–Long Island Jewish Health System Research Institute National Institutesof Health General Clinical Research Center grant M01 RR018535.


thioridazine, which are first-generation antipsychotics (FGAs), and ris-peridone and aripiprazole, which are second-generation antipsychotics(SGAs)—for use in pediatric schizophrenia, with approval for the twoFGAs being based predominantly on adult data and small studies inyouths.

However, with the increasing use of SGAs, their effects on bodyweight and metabolic health have become increasing concerns (Correlland Carlson 2006). Weight gain and obesity have known associationswith diabetes, dyslipidemia, and hypertension, all of which are leadingrisk factors for future cardiovascular morbidity and mortality (Ebbelinget al. 2002). Moreover, data suggest that obesity during childhood pre-dicts poor metabolic outcomes for adults even better than obesity dur-ing adulthood (Must et al. 1992). In this chapter, I review the availablepediatric data on the side effects of antipsychotics with adverse healthimpact, aiming to inform antipsychotic prescribing and monitoringpractices in this vulnerable population. Data from studies of childrenand adolescents with schizophrenia are highlighted, augmented by pe-diatric data from studies of other disorders where appropriate. Basedon the far-reaching implications of age-inappropriate weight gain andmetabolic abnormalities, adequate monitoring, management, and,whenever possible, prevention of adverse health outcomes in youths iscrucial to promoting long-term physical and psychological well-being,sustained treatment adherence, and adequate role functioning and at-tainment of developmental milestones.

Developmental ConsiderationsChildhood through adolescence is a period of unparalleled develop-ment, biologically, psychologically, and socially. Although data regard-ing the bioavailability and bioactivity of medications in pediatricpopulations are relatively slim, drug uptake, distribution, and metabo-lism in youth are affected by several factors that differ from those inadults. Some of these factors relevant for medication treatment includeactive tissue growth, reproductive hormone release beginning in ado-lescence, a higher ratio of liver organ-to-tissue mass, greater intracellu-lar and extracellular tissue water and glomerular filtration rate, lowerprotein binding, and reduced fat tissue mass in youths compared withadults (Paxton and Dragunow 1993). Clinically, these differences trans-late into the general need for higher dosages per kilogram of weight inchildren and adolescents compared with adults in order to reach com-parable serum levels and achieve therapeutic efficacy; also, more fre-

Managing Health Outcomes in Children and Adolescents 345

quent doses during the day may be required in prepubertal children(Woods et al. 2002).

Efficacy of Antipsychotics in Children and Adolescents With SchizophreniaTwelve, mostly recent, randomized, controlled antipsychotic trials(N=1,014) have shown efficacy as monotherapy in pediatric schizo-phrenia (Kumra et al. 2008b). Superior efficacy of antipsychotics versusplacebo in reducing scores on the Positive and Negative SyndromeScale (PANSS) and/or the Brief Psychiatric Rating Scale (BPRS) wasdemonstrated in three randomized, placebo-controlled trials of patientsages 13–17 with schizophrenia. The SGAs used in these studies werearipiprazole (N=294, using fixed dosages of 10 mg/day, mean 9.56 mg/day, and 30 mg/day, mean 27.8 mg/day) (Robb et al. 2007), olanzapine(N=107, using flexible dosages of 2.5–20 mg/day, mean 11.1 mg/day)(Kryzhanovskaya et al. 2005), and risperidone (N=158, using flexibledosage range of 0.5–3 mg/day, mean 2.6 mg/day, and 4–6 mg/day,mean 5.3 mg/day) (Haas et al. 2007). In one additional, currently un-published study, risperidone (N=279) was dosed at 1–6 mg/day (mean4.0 mg/day) and compared to a pseudo-placebo with a dosage range of0.1–0.6 mg/day (mean 0.5 mg/day) in pediatric patients with schizo-phrenia (Janssen Pharmaceutica, unpublished data). In all four trials,compared with patients taking the placebo or the pseudo-placebo doseof risperidone, the patients taking the SGA had superior primary out-come, consisting of the total mean score change on the PANSS or BPRSfrom baseline to endpoint. In an older, 4-week, placebo-controlled trial(Pool et al. 1976), both haloperidol (n=25, mean 9.8 mg/day) and loxa-pine (n =26, mean 87.5 mg/day) were associated with significantlygreater reductions in BPRS scores compared with placebo, but therewere no differences between the two active medication groups.

The remaining antipsychotic studies in pediatric schizophrenia wereall active-controlled trials, comparing different antipsychotics and lack-ing a placebo arm, thereby precluding a conclusive assessment of the ef-ficacy of the tested antipsychotics. In the three studies not involvingclozapine that lasted between 4 and 8 weeks, no statistically significantdifferences in efficacy were found between the tested antipsychotics,including comparisons of thiothixene (mean 16.2 mg/day) andthioridazine (mean 178 mg/day) (N=21; Realmuto et al. 1984); halo-peridol (mean 5.0 mg/day), olanzapine (mean 12.3 mg/day), and ris-peridone (mean 4.0 mg/day) (N=50; Sikich et al. 2004); and molindone


(range 10–140 mg/day, target 65 mg/day), olanzapine (range 2.5–20mg/day, target 12.5 mg/day), and risperidone (range 0.5–6 mg/day,target 3 mg/day) (N=119; Sikich et al. 2008). On the other hand, in rel-atively small, active controlled trials, clozapine at mean dosages be-tween 176 mg/day and 403 mg/day was superior on several efficacymeasures compared with haloperidol (N=21, mean 16 mg/day; Kumraet al. 1996), olanzapine (N=13, mean 18.1 mg/day; Shaw et al. 2006), and“high”-dose olanzapine (up to 30 mg/day) (N=39, mean 26.2 mg/day;Kumra et al. 2008a).

Taken together, findings from these studies show that antipsychoticsare superior to placebo in youth with schizophrenia, as in adults, andthat the differences between antipsychotics other than clozapine maybe relatively small. Therefore, differences in adverse effects, and espe-cially adverse effects that can impair health outcomes and longevity,are to be taken seriously when prescribing this class of medications topediatric patients, who often suffer from a severe form of the disorderand who are likely to require antipsychotic treatment for long periodsof time.

Adverse Effects Associated With Antipsychotics in Children and AdolescentsChildren and adolescents seem to be more sensitive than adults to mostantipsychotic adverse effects, including sedation, extrapyramidal sideeffects (except akathisia, which occurs at similar rates), withdrawal dys-kinesia, prolactin elevation (especially in postpubertal patients), weightgain, and related metabolic abnormalities (Correll et al. 2006). On theother hand, adverse effects that require a longer time to develop phys-iologically (e.g., diabetes mellitus) and/or that are related to medica-tion dosage and lifetime exposure (e.g., tardive dyskinesia) seem toemerge less frequently in pediatric cohorts, at least during follow-updurations that are relatively short (Correll et al. 2006). Actually, theseadverse events may not occur at a reduced frequency in youths, whohave a relatively large reserve of pancreatic beta cells and striataldopamine neurons, but may rather be delayed and show up earlier inadulthood, depending on how early antipsychotic treatment was initi-ated during childhood and adolescence. Clearly, longer-term follow-upstudies of youths in whom antipsychotics are initiated are required toclarify this issue further.


Weight Gain and Metabolic Adverse EffectsAlthough pediatric data are limited, children and adolescents with psy-chiatric disorders seem to be at increased risk for being overweight orobese (Patel et al. 2007), especially when exposed to antipsychotics forlonger periods of time (Laita et al. 2007). Age-inappropriate weight gainis of particular concern in children and adolescents because weight gainis associated with health and psychosocial issues at a time in human de-velopment when self-esteem and body image are being formed andconsolidated. Weight gain can be associated with the development ofeating disorders and depression, and the medical consequences ofweight gain may adversely affect pulmonary, gastrointestinal, renal,musculoskeletal, cardiovascular, and endocrine systems in a mannerthat is both enduring and detrimental (Ebbeling et al. 2002). These med-ical comorbidities and complications can impair patients’ quality of lifeand shorten life expectancy.

Antipsychotic-Related Weight Gain. Reasons for weight gain and obe-sity in patients with psychiatric illness are multifactorial and complex, in-cluding effects of the underlying psychiatric illness, consequences oflifestyle behaviors (particularly sedentary lifestyle and unhealthy diet),and direct and indirect effects of psychotropic treatment. A recent reviewof data suggested that the weight gain potential of SGAs for pediatric pa-tients follows roughly the same rank order as that for adults (American Di-abetes Association et al. 2004) but that the magnitude is greater (Correlland Carlson 2006). Exceptions may be a greater relative weight gain pro-pensity of risperidone in youth (Safer 2004), a greater likelihood of ari-piprazole and ziprasidone to not be weight neutral in subgroups ofpediatric patients, and possibly greater olanzapine-induced weight gaincompared with clozapine in treatment-refractory youth, although resultsdiffer depending on the studies and patient groups (Correll 2008b; Correlland Carlson 2006). Research studies have not yet resolved whether thegreater antipsychotic-related weight gain in pediatric patients than inadults is due to physiological differences between growing children andadults that are related to mechanisms regulating food intake and energyhomeostasis, whether the greater weight gain is due to less lifetime anti-psychotic exposure, or whether it is due to a combination of both of thesefactors. The latter is suggested by findings of substantial amounts ofweight gain in adults who are antipsychotic naive or in a first episode ofschizophrenia (Alvarez-Jiménez et al. 2008).

In an 8-week, randomized study of 25 patients ages 7–16 years, cloza-pine and olanzapine resulted in similar weight gain (3.8±6.0 kg and


3.6±4.0 kg, respectively) (Shaw et al. 2006). In an earlier, randomizedtrial of patients ages 10–18 years with early-onset schizophrenia, cloza-pine and haloperidol produced similar and quite modest weight gain(0.9±6.5 kg and 0.9±2.9 kg, respectively) (Kumra et al. 1996). On theother hand, in a naturalistic study, olanzapine was associated withgreater weight gain (4.6±1.9 kg) than clozapine (2.5±2.9 kg), which hadcomparable weight gain to that of risperidone (2.8±1.3 kg) (Fleisch-haker et al. 2006). However, because clozapine was used in treatment-refractory patients, weight gain in clozapine-treated children couldhave been attenuated by prior antipsychotic exposure and resultantweight gain.

Similar to the study by Fleischhaker et al. (2006), Sikich et al. (2004)found a higher weight gain in youths ages 5–17 years with psychoticdisorders who were randomly assigned to receive olanzapine for8 weeks (7.1±4.1 kg) than in youths randomized to either risperidone(4.9±3.6 kg) or haloperidol (3.5±3.7 kg). After only 8 weeks of treat-ment, all treatment groups had mean observed weight gain that was se-vere and disproportionate to that expected from normal growth. In aprior open-label study, Ratzoni et al. (2002) reported on weight changein adolescents with schizophrenia treated for 12 weeks using the samethree antipsychotics. Both statistically and clinically significant weightgain was observed with olanzapine (7.2 ± 6.3 kg) and risperidone(3.9±4.8 kg), but the mean weight change with haloperidol (1.1±3.3 kg)was not significant. Finding weight gain of ≥7% from baseline to theend of 12 weeks in 90.3% of patients taking olanzapine, 42.9% takingrisperidone, and 12.5% taking haloperidol, the authors concluded thatthe weight gain in their adolescent sample was more extreme than thatobserved in adult studies. Similarly, high weight gain has been re-ported in preschool-age children (ages 4–6 years); during only 8 weeksof treatment, children treated with olanzapine and risperidone had amean increase in weight of 12.9%±7.1% and 10.1%±6.1%, respectively(Biederman et al. 2005).

In a 6-month naturalistic, unmatched study of 66 patients with fewerthan 30 days of antipsychotic exposure and treated with olanzapine(n=20), risperidone (n=22), or quetiapine (n=24), age- and sex-adjustedweight gain, measured as body mass index (BMI) z-scores, was signifi-cant in the olanzapine (1.1±0.82) and risperidone (0.48±0.73) groups,but not in the quetiapine group (0.27±0.86) (Fraguas et al. 2008). In thissmall sample, a transition to an adverse health outcome—that is, >85thBMI percentile plus at least one adverse health outcome related toblood pressure or lipid or glucose metabolism (Correll and Carlson2006)—occurred significantly compared to baseline in the olanzapine


group (15.0%–60.0%), but not in the risperidone (22.7%–36.4%) or que-tiapine (15.5%–20.8%) groups.

Due to the confounding effects of nonrandom assignment and smallsample sizes in the studies mentioned previously, larger, placebo-controlled trials are more informative. Because none of the four 6-week,randomized, placebo-controlled studies of SGAs in adolescents withpediatric schizophrenia have been published and only three have beenpresented at scientific meetings, at this point, data on absolute weightgain are available for only two of these trials. In a study comparingfixed-dosage aripiprazole 10 mg (n=102) and 30 mg (n=100) with pla-cebo (n=100), a slight but significant difference (P<0.05) in weight gainwas reported in adolescents taking placebo (−0.8 kg) versus aripipra-zole 10 mg (0 kg) and 30 mg (0.2 kg) (Findling et al. 2007), although theweight change with aripiprazole was minimal in this study and com-parable to what has been reported in adults. On the other hand, treat-ment with olanzapine (n=72) at dosages between 2.5 and 20 mg (mean11.1 mg) was associated with a 4.3-kg weight gain, which was signifi-cantly greater (P<0.0001) than the 0.1-kg weight gain in patients on pla-cebo (n=35) (Kryzhanovskaya et al. 2005).

Because mean weight change can easily obscure substantial weightgain in a subset of patients due to weight loss in another subgroup withdifferent past antipsychotic exposure and other characteristics, an im-portant consideration is the proportion of patients who gained at least7% of weight in the recent placebo-controlled trials with SGAs. Figure13–1 summarizes the data from the three double-blind, placebo-controlled studies of atypical antipsychotics in adolescents with schizo-phrenia for which data are available on the proportion of patients whoexperienced at least 7% of weight gain during 6 weeks of treatment(Correll 2008b). Results suggest that similar to adult studies, the great-est weight gain occurred in patients taking olanzapine (45.8%) versusplacebo (1.7%) (Kryzhanovskaya et al. 2005). Risperidone was associ-ated with intermediate risk, with at least 7% weight gain occurring in15% of the 1- to 3-mg group and 16% of the 4- to 6-mg group, comparedwith 2% of the placebo group (Haas et al. 2007). Finally, aripiprazolewas associated with the lowest risk, with at least 7% weight gain in 4%of patients on 10 mg and 5.2% of patients on 30 mg of aripiprazole, com-pared with 1% of patients on placebo (Findling et al. 2007). The result-ing numbers needed to harm (NNH) in patients with adolescentschizophrenia were 3.2 for olanzapine, 7.1–7.7 for risperidone, and24.4–33.3 for aripiprazole (Correll 2008b). Data from the completedtreatment of early-onset schizophrenia spectrum disorders study(Sikich et al. 2008), which compared risperidone, olanzapine, and


molindone, will add to this picture, but more randomized head-to-headstudies of antipsychotics in youths are needed to directly compare risk-benefit ratios.

Of note, currently available data suggest that combined treatmentwith an SGA plus a stimulant does not seem to substantially attenuateSGA-induced weight gain (Aman et al. 2004; Calarge et al., in press). Onthe other hand, at least with olanzapine, risperidone, and possibly que-tiapine, combined treatment with an SGA plus a mood stabilizer seemsto be associated with greater weight gain than monotherapy with amood stabilizer or even combination treatment with lithium plus val-proic acid, as suggested by trials in youths with bipolar disorder (Cor-rell 2007b).

Adverse Metabolic Effects. With the widely reported age-inappropriateweight gain in children and adolescents treated with antipsychotics, aworsening of metabolic indices, such as triglycerides, cholesterol, andinsulin resistance, is expected to occur. However, methodologicallysound, conclusive, and long-term prospective data regarding metaboliceffects of antipsychotics in pediatric patients are largely lacking. In across-sectional study with metabolic data from 80 to 95 pediatric pa-tients, total cholesterol levels (P<0.001) and low-density lipoprotein(LDL) cholesterol levels (P=0.018) were significantly higher in youthsreceiving antipsychotics for 12 months or longer than in similar patientsgiven antipsychotics for less than 1 month (Laita et al. 2007). Despitelarge differences in BMI (i.e., 24.1 in youth with longer-term exposurevs. 20.4 in youth with shorter-term exposure), triglyceride levels (whichcorrelate with insulin resistance) were not statistically different (94.7±48.3 mg/dL vs. 82.7±48.9 mg/dL). Although this lack of a significantdifference for triglycerides is somewhat surprising, these results couldhave been due to any of the following: the sample size was relativelysmall, groups were not randomized or closely matched, weight changesmay have occurred largely within the normal weight range, youthsmight be able to draw upon intact and effective compensatory mecha-nisms, and some of the assessments were from nonfasting patients. Al-though the link between antipsychotic treatment and adverse metabolicconsequences such as dyslipidemia, hyperglycemia, diabetes, and met-abolic syndrome has been established in adults (American Diabetes As-sociation et al. 2004), the few published retrospective and prospectivepediatric studies (Biederman et al. 2005, 2007; Malone et al. 2007; Martinand L’Ecuyer 2002; Sikich et al. 2004) have produced almost exclusivelynegative results, in that antipsychotic exposure and weight gain wereassociated with no significant metabolic abnormalities. However, the

Managing H

ealth Outcom

es in Children and A

dolescents351

FIGURE 13–1. Proportion of adolescents (ages 13–17 years) with schizophrenia gaining >7% of baseline weight in 6-week, double-blind, placebo-controlled trials with atypical antipsychotics.

0

10

20

30

40

50

Perc

enta

ge o

f pat

ient

s

Placebon=100

Aripiprazole 10 mgn=102

Aripiprazole 30 mgn=100

Placebon=54

Risperidone 1–3 mgn=55

Risperidone 4–6 mgn=51

Placebon=35

Olanzapine 2–20 mgn=72


interpretation of these results is limited by small sample sizes, varyingtreatment histories, and mostly the inclusion of random glucose assess-ments.

In a pooled analysis of 24 medication trials of antipsychotic-treatedyouth with bipolar disorder, nonfasting glucose and lipid changes werenonsignificant in the only two atypical antipsychotic trials with avail-able data (N=61) (Correll 2007b). Moreover, as briefly reported (Correlland Carlson 2006), interim results from a large-scale, naturalistic cohortstudy presented at a scientific meeting suggested the emergence of rel-evant rates of new-onset dyslipidemia and increases in insulin resis-tance in several of the SGA groups after only 3 months of exposure inthe subgroup of antipsychotic-naive patients. This preliminary report isconsistent with another recent study of 66 pediatric patients (67% male,mean age 15.2 years) with psychotic disorders, treated naturalisticallywith either olanzapine (n=20), risperidone (n=22), or quetiapine (n=24)(Fraguas et al. 2008). Importantly, as in the preliminary report by Cor-rell et al. (2006), patients had minimal prior antipsychotic use—all hadfewer than 30 days lifetime exposure, and 38% were antipsychotic na-ive. After 6 months of antipsychotic exposure in this nonrandomizedand unmatched sample, total cholesterol levels increased significantlyin the olanzapine group (P=0.045) and the quetiapine group (P=0.016),but not in the risperidone group. Although weight gain was significantin all three groups, triglyceride, LDL, high-density lipoprotein (HDL),and glucose levels did not increase significantly compared with base-line levels over the 6-month period in this small group of patients.

As recently summarized (Correll 2008b), short-term, placebo-controlled trials with aripiprazole, risperidone, and quetiapine inyouths with schizophrenia or bipolar disorder found no significantmean changes in lipid or glucose parameters. The same was true for arecently presented placebo-controlled trial with ziprasidone in pediat-ric patients with bipolar disorder, who experienced minimal weightgain (DelBello et al. 2008). Conversely, compared with placebo, olanza-pine resulted in significant increases in triglycerides in adolescents withschizophrenia (P=0.029), as well as significant increases in blood glu-cose (P=0.002), total cholesterol (P=0.010), and uric acid (P=0.026) inpediatric patients with bipolar disorder (Tohen et al. 2007). Moreover,in patients with pediatric bipolar disorder, new-onset abnormal meta-bolic values that occurred at any time during the study were signifi-cantly more frequent with olanzapine than with placebo; these valuesincluded abnormally elevated total cholesterol (19.1% vs. 2.1%,P=0.004), low HDL (10.9% vs. 0.0%, P=0.016), and hypertriglyceri-demia (49.1% vs. 14.8%, P=0.003) (Tohen et al. 2007).


Although individual case reports of diabetes in pediatric patients tak-ing antipsychotics have been published (for specific reports, see Correlland Carlson 2006), methodologically rigorous, prospective studies ofmetabolic syndrome and diabetes in youths exposed to antipsychotics,especially for longer periods of time, are almost absent. Despite the ab-sence of such long-term studies, long-term prospective data in nonpsy-chiatric pediatric populations followed into adulthood indicate that age-inappropriate weight gain has particularly deleterious effects when oc-curring early in life. In follow-up studies, obesity, metabolic abnormali-ties, and weight gain during childhood have been shown to stronglypredict obesity, metabolic syndrome, hypertension, cardiovascularmorbidity, sleep apnea, osteoarthritis, and malignancy risk in adult-hood (Baker et al. 2007; Dietz and Robinson 2005; Freedman et al. 2004;Must et al. 1992; Srinivasan et al. 2002). Clearly, these data strengthenthe concern about the magnitude of the antipsychotic-related weightgain that is observed in short-term studies of pediatric populations.

Prolactin-Related Side EffectsAs previously summarized (Correll and Carlson 2006), FGAs and sev-eral SGAs are associated with clinically relevant prolactin elevations inchildren and adolescents. Hyperprolactinemia can result in sexual andreproductive system side effects, such as amenorrhea or oligomen-orrhea, erectile dysfunction, decreased libido, hirsutism, and breastsymptoms, such as enlargement, engorgement, pain, or galactorrhea.However, in open-label (Findling et al. 2003; Masi et al. 2003; Saito et al.2004) and randomized (Aman et al. 2002) studies with youth, serumprolactin levels are not tightly correlated with these side effects, and notall patients with hyperprolactinemia develop these signs and symp-toms (Masi et al. 2003). Like adults, many pediatric patients continueto have normal gonadal function and no overt reproductive-systemside effects, despite moderately elevated serum prolactin (Findlinget al. 2003). Available data also suggest that hyperprolactinemia isdosage dependent, may normalize over time in some patients, andresolves after antipsychotic discontinuation. Similar to the patternseen in adults, the relative potency of antipsychotic drugs in inducinghyperprolactinemia in pediatric patients is roughly the following:paliperidone ≥ risperidone> haloperidol> olanzapine > ziprasidone>quetiapine>clozapine>aripiprazole.

Due to prepubertal status and less sexual activity and familiaritywith their developing sexuality, many pediatric patients exposed toantipsychotics may not experience, notice, or report sexual or reproduc-tive system dysfunction, making it more difficult to determine if hyper-


prolactinemia is present through history taking or even physicalexamination (Correll and Carlson 2006). Studies suggesting that levelsof hyperprolactinemia that cause hypogonadism (i.e., that suppressgonadotropin-releasing hormone and, thus, sex hormone levels) areassociated with osteoporosis and increased risk of bone fractures areespecially concerning, because adolescence is the prime time of bonemineralization development (Byerly et al. 2007). Other potential but un-confirmed risks from childhood hyperprolactinemia might include anegative effect on pubertal development (Correll and Carlson 2006) anda risk for breast cancer or pituitary tumors (Byerly et al. 2007).

In a review of antipsychotic effects on prolactin levels in youths withschizophrenia spectrum disorders (Kumra et al. 2008b), risperidone andhaloperidol were noted to have the greatest effect on prolactin levels; que-tiapine, clozapine, and aripiprazole were noted to have the least effect onprolactin levels; and olanzapine and ziprasidone appeared to have inter-mediate effects. In a 3-week study of 161 children and adolescents, olanza-pine treatment was associated with a greater baseline-to-endpoint increasein prolactin levels compared with placebo, as well as with surprisinglyhigh incidence rates of hyperprolactinemia, particularly among boys (inboys, 62.5% with olanzapine vs. 5% with placebo, P<0.001; in girls, 25.7%with olanzapine vs. 0% with placebo, P=0.007) (Tohen et al. 2007).

A pooled analysis of several pediatric risperidone studies in childrenages 5–15 years treated with mean dosages of 0.02–0.06 mg/kg/dayfound that the biggest increase in prolactin levels occurred in the first 1–2 months (N=550) (Findling et al. 2003). However, results of this studyhave to be interpreted within the limitations that they are based on asample with an inherently relatively low hyperprolactinemia risk, con-sisting of prepubertal individuals, predominantly boys, treated with lowdosages of risperidone, and cotreatment with stimulants was allowed.

One larger study (N=222) examined the effects of risperidone onheight and sexual maturation (Dunbar et al. 2004). Boys ages 10–15 yearsand girls ages 9–15 years were evaluated for sexual maturation by Tan-ner staging and followed for 11–12 months. Encouragingly, this studyfound no correlation between prolactin levels and either height or sexualdevelopment; however, firm conclusions from this single study are pre-cluded by sample heterogeneity in age and pubertal stage, combinedwith follow-up of only 1 year.

QTc ProlongationAs discussed extensively in Chapter 7, “The Spectrum of Cardiovascu-lar Disease in Patients With Schizophrenia,” antipsychotics can differ-


entially prolong the heart rate–corrected QT interval (QTc) of theelectrocardiogram. QTc prolongation may be associated with torsadede pointes, a potentially fatal arrhythmia (Blair et al. 2004). Concerns inpediatric patients include the notion that the developing cardiac con-duction system may be especially vulnerable to these effects. In adults,QTc prolongation is usually minimal with antipsychotics compared toplacebo, except with certain medications (e.g., thioridazine), but amongthe SGAs, ziprasidone has been associated with the greatest QTc pro-longation compared to baseline (Glassman and Bigger 2001), althoughwithout known incidence of torsade de pointes.

Cardiac conduction effects of ziprasidone have been studied in chil-dren and adolescents, and QTc prolongation to >430 milliseconds hasbeen described in three of 20 pediatric patients treated prospectivelywith ziprasidone (mean QTc prolongation of 28 ± 26 milliseconds,P<0.01) (Blair et al. 2005). Although no relationship to ziprasidone dos-age was found in this study, dosages were very low (mean 30±13 mg/day, range 30–60 mg/day). In a small study in only 12 youths, a statis-tically significant increase in QTc (14.7±21.0 milliseconds, P=0.04) wasreported at a mean ziprasidone dosage of 98.3 (range 40–160) mg/day(Malone et al. 2007). On the other hand, QTc changes were reported tohave been nonsignificant in studies of 12 (McDougle et al. 2002), 16(Sallee et al. 2000), and 21 patients (Biederman et al. 2007) at ziprasidonedosages of 57.3 (range 20–120) mg/day, 28.2 (range 5–40) mg/day, and59.2 (range 20–120) mg/day, respectively. Moreover, no patient in anyof these studies reported cardiac side effects, such as dizziness, palpita-tions, or syncope. Thus, the clinical relevance of this degree of QTc pro-longation, which did not reach the generally accepted pathologicalthreshold of >500 milliseconds or an increase in QTc over baseline of>60 milliseconds (Glassman and Bigger 2001), is unclear, and theoreti-cal concerns about QTc prolongations with ziprasidone need to beweighed against the more certain benefits regarding the relative risk forweight gain and metabolic abnormalities. (For more discussion, seeChapter 7, “The Spectrum of Cardiovascular Disease in Patients WithSchizophrenia.”)

Monitoring and Management of Adverse EffectsPediatric patients taking antipsychotics must be monitored carefully andproactively for adverse effects, particularly medical adverse effects that canshorten life expectancy, decrease quality of life and functioning, or nega-


tively affect treatment alliance and adherence. If results of monitoringshow clinically relevant adverse events, actions should be taken to mini-mize their impact on patient health and other outcomes. Importantly, theseadverse effects may have to be identified and managed by mental healthprescribers because young patients are most often seen by pediatriciansonly once per year for routine checkups. Because physical health is veryimportant and also related to psychiatric treatments and outcomes, thepsychiatrist needs to take the initiative to monitor medical effects of psychi-atric medications, initiate referrals for a consultation, and actively coman-age the patient’s physical health in addition to the patient’s mental health.

Monitoring StrategiesSeveral assessments of adverse effects should be made at baseline andat regular intervals to monitor the impact of antipsychotic treatmentson pediatric patients (see Table 13–1). Importantly, as children and ad-olescents undergo normal developmental changes, the adverse effectassessment and monitoring has to take into consideration developmen-tal norms and thresholds that can differ substantially from those foradults (see Table 13–2).

At baseline and annually, personal and family histories of metabolicand endocrine complications should be assessed. At each visit, the clini-cian should inquire about the status of health lifestyle behaviors related todiet, activity, sleep, and substance use, unless the patient’s weight andmetabolic status are healthy and stable. The elicited information should becompared with recommended behaviors in the general pediatric popula-tion (American Medical Association 2007) or those that were adapted foryouth with psychiatric illness (Correll and Carlson 2006) (see Table 13–3).

Height, Weight, and Body CompositionBeing dynamic parameters in youths, height and weight should be mea-sured and recorded at each visit. Height measurement can be difficult andrequires adequate tools—ideally a wall-mounted stadiometer—andtrained personnel who measure height several times and make sure pa-tients stand erect, place their heels against the wall, and keep their headstraight. The clinical measures used most often to monitor body weight in-clude absolute weight change (kilograms, pounds), percent weightchange (weight change/baseline weight), and change in BMI(BMI=[weight in kilograms]/[height in meters2] or [weight in pounds]/[height in inches2]×703). Although all measures are easily obtained andvalid in adults, these measures are only useful in pediatric patients whoare followed for periods of 3 months or less because they do not take into


account age-appropriate development. Therefore, BMI values need to beadjusted for age- and sex-dependent growth velocities, using freely avail-able growth charts (http://www.cdc.gov/growthcharts) or calculators(http://www.kidsnutrition.org/bodycomp/ bmiz2.html). The adjustedBMI values are the BMI z-score and the BMI percentile, where a z-score(i.e., standard deviations) of zero and the 50th BMI percentile representthe population mean, and where continuation on the same BMI z-score orpercentile over time indicates stable age- and sex-adjusted body weight inrelationship to height. Because BMI z-scores are not “capped” at the zeroor 99th percentile, z-scores are preferably used to track weight change.BMI percentiles, on the other hand, are useful to determine the weight cat-egory that a pediatric patients belongs to, where a BMI percentile of <5 isunderweight, 5–84.9 is healthy weight, 85–94.9 is overweight, and ≥95 isobese (see Table 13–2). Although waist circumference is preferred overBMI in adults as a metabolic syndrome criterion and is highly predictiveof metabolic syndrome (Straker et al. 2005), the American Medical Associ-ation Expert Committee did not recommend waist circumference mea-sures in pediatric patients because cutoffs are less well established andassessments are liable to measurement error (Correll 2008c).

Despite the importance of age-inappropriate weight gain in pediatricpatients, no consensus exists in the general pediatric literature regard-ing the cutoff for clinically meaningful weight change during develop-ment. Rather, a BMI in the 85th percentile is the accepted lowerintervention threshold in youths (American Medical Association 2007)(see Table 13–2). However, in psychiatric care, where the underlyingdisorder together with adverse treatment effects can lead to rapid andoften significant weight gain, clinicians require guidance at what pointto consider changing therapy or using adjunctive treatments to addressclinically relevant weight gain. In patients with psychiatric illness, clin-ically “significant” weight gain or abnormal weight status that requiresa reconsideration of the current treatment plan has recently been oper-ationalized as 1) >5% weight gain during 3 months, or any of the follow-ing three conditions at any time during treatment: 2) an increase ≥ 0.5in BMI z-score; 3) BMI percentile ≥85–94.9 plus one adverse health con-sequence (hyperglycemia, dyslipidemia, hyperinsulinemia, hyperten-sion, orthopedic, gall bladder, or sleep disorder); or 4) BMI ≥ 95thpercentile or abdominal obesity (> 90th percentile) (Correll et al. 2006).

Fasting Blood Glucose and LipidsAlthough no generally accepted pediatric guidelines regarding fastingglucose and lipid monitoring have been published, one proposedschedule requires monitoring at baseline, after 3 months of treatment,

http://www.cdc.gov/growthcharts

http://www.kidsnutrition.org/bodycomp/bmiz2.html

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edical Illness and SchizophreniaTABLE 13–1. Suggested monitoring strategies in children and adolescents treated with antipsychotic agentsa

Assessment BaselineEach visit

During titration and at target

dosage At 3 monthsEvery 3 months

Every 6 months Annually

Lifestyle behaviorsb

✓ ✓

Height, weight (calculate BMI percentile, BMI z-score)

✓ ✓

Sexual/reproductive dysfunction

✓ ✓ ✓ ✓

Fasting glucose and lipids

✓ ✓ ✓

Blood pressure and pulse

✓ ✓ ✓

Personal and family medical historyc

✓ ✓

Managing H

ealth Outcom


dolescents359

Electrolytes, full blood count, renal function

✓ If symptomatic, mandatory CBC

for clozapineElectrocardiogram If on

ziprasidone or clozapine

If on ziprasidone or if symptomatic

on clozapineProlactind Only if

symptomaticOnly if

symptomaticOnly if

symptomaticOnly if

symptomaticOnly if

symptomaticOnly if

symptomatic

Note. BMI=body mass index; CBC =complete blood cell count.aMore frequent assessments of abnormalities occur if patient is at very high risk for specific adverse events by personal or family history.bLifestyle behaviors include diet, exercise, smoking, substance use, and sleep hygiene.cMedical history includes components of the metabolic syndrome (obesity, arterial hypertension, diabetes, dyslipidemia); past medicalhistory for coronary heart disease or coronary heart disease equivalent disorders (i.e., diabetes mellitus, peripheral arterial disease, ab-dominal aortic aneurysm, and symptomatic carotid artery disease); history of premature coronary heart disease in first-degree relatives(males <55 years and females <65 years); and past efficacy and adverse effect experiences in patients and/or family members.dIn case of abnormal sexual symptoms or signs, prolactin is drawn fasting in the A.M. and approximately 12 hours after the last antipsy-chotic dose.

TABLE 13–1. Suggested monitoring strategies in children and adolescents treated with antipsychotic agentsa (continued)

Assessment BaselineEach visit

During titration and at target

dosage At 3 monthsEvery 3 months

Every 6 months Annually


TABLE 13–2. Clinically relevant thresholds for body weight and metabolic parameters in children and adolescents

Variables Children and adolescents

Body weight category

Underweight *BMI<5th percentile for sex and agea

Normal weight *BMI 5th–<85th percentile for sex and agea

Overweight (previously “at risk for overweight” in pediatric patients)

*BMI 85th–<95th percentile for sex and agea

Obese (previously “overweight” in pediatric patients)

*BMI ≥95th percentile for sex and agea

Blood lipid abnormalities

Total cholesterol *≥170 mg/dL

LDL cholesterol *≥130 mg/dL

HDL cholesterol *<40 mg/dL in males and females

Triglycerides *≥110 mg/dL

Blood glucose abnormalities

Fasting hyperglycemia (“prediabetes”)

100–125 mg/dL

2-hour oral glucose tolerance test result

140–199 mg/dL

Fasting diabetes (needs to be repeated)

≥126 mg/dL

2-hour post–glucose load diabetes ≥200 mg/dL

Insulin abnormalities and insulin resistance

Fasting hyperinsulinemia *>20 μmol/L

Homeostatic model assessmentb *≥4.4

Triglycerides:HDL cholesterol ratio *? >3.5


Metabolic syndrome ≥ three out of five criteria required

Abdominal obesity criterion *Waist circumference ≥90th percentile, or BMI ≥95th percentile for sex and agec

Fasting triglycerides criterion *≥110 mg/dL

Fasting HDL cholesterol criterion *<40 mg/dL in males and females

Blood pressure criterion *≥90th percentile for sex and aged

Fasting glucose criterion ≥110 mg/dL

Adjusted fasting glucose criterion ≥100 mg/dL

Note. BMI=body mass index; HDL=high-density lipoprotein; LDL=low-density lipoprotein.

*Thresholds specific for children and adolescents.aBMI=[weight in kilograms]/[height in meters2] or [weight in pounds]/[height in inches]×703. Sex- and age-adjusted BMIs are expressed in percen-tiles (population norm: 50th BMI percentile). Alternatively, they can be ex-pressed as BMI z-scores (population norm: 0 BMI z-score). Growth charts areavailable at http://www.cdc.gov/growthcharts, and Web-based calculatorsare available at http://www.kidsnutrition.org/bodycomp/bmiz2.html. Sta-ble age- and sex-adjusted weight is indicated by absence of any change in BMIpercentile z-score over time.bHomeostatic model assessment (HOMA)= fasting insulin (μmol/L)×glucose(mmol/L)/22.5, where glucose mmol/L=glucose m/dL/17.979797, or fast-ing insulin (mg/dL)×glucose (mg/dL)/405.cSex- and age-adjusted waist circumference percentile tables (Fernandez et al.2004).dSex- and age-adjusted blood pressure percentiles tables (“Fourth Report onthe Diagnosis, Evaluation, and Treatment of High Blood Pressure in Childrenand Adolescents” 2004).

TABLE 13–2. Clinically relevant thresholds for body weight and metabolic parameters in children and adolescents (continued)

Variables Children and adolescents

http://www.cdc.gov/growthcharts

http://www.kidsnutrition.org/bodycomp/bmiz2.html

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edical Illness and SchizophreniaTABLE 13–3. Healthy lifestyle recommendations to treat age-inappropriate weight gain and weight status in children and

adolescents with psychiatric disorders and those who are overweight and obese in the general population

Correll and Carlson’s (2006) recommendations to patients

American Medical Association’s (2007) stage I recommendations for clinicians

GeneralTarget group Pediatric patients <18 years receiving

psychotropic medications associated with weight gain

General pediatric population ages 2–19 years; prevention and intervention for individuals who are overweight (≥85th BMI percentile) or obese (≥90th BMI percentile)

Parenting style Encourage child to self-regulate meals; encourage authoritative parenting stylea that supports increased physical activity and reduced sedentary behavior, and provides tangible and motivational support; discourage overly restrictive parenting styleb

Family involvement Yes Yes

DietSugar-containing

beveragesReplace sugar-containing drinks, including

“diet” drinks, with water or moderate amounts of unsweetened tea or milk

Suggest curtailing sugar-sweetened beverages; assess for excessive consumption of 100% fruit juice

Meal frequency Eat 4 to <6 separate meals per day, with no more than 2 meals in the evening or at night

Assess for meal frequency (including quality)

Breakfast Avoid skipping breakfast Encourage daily breakfast

Managing H

ealth Outcom


dolescents363

Meal portions Have small meal portions Assess for consumption of excessive portion sizes for agePacing of food

consumption Eat slowly and take second helpings only

after a delaySugar content Preferentially eat food with a low glycemic

index (i.e., of 55 or less—http://www.glycemicindex.com)

Assess for excessive consumption of foods that are high in energy density

Fat content Reduce saturated fat intake, but avoid extensive consumption of processed fat-free food items

Recommend diet with balanced macronutrients (calories from fat, carbohydrate, and protein in proportions for age, as recommended by Dietary Reference Intakes)

Fiber content Eat at least 25–30 g of soluble fiber per day Promote diet high in fiber, with five or more servings of fruits and vegetables per day

Snacks Avoid snacking in a satiety state; replace high-fat, high-calorie snacks with fruits and vegetables

Assess for snacking patterns (including quality); limit consumption of energy-dense foods

Outside meals/fast food

Limit fast food to no more than once per week

Suggest limiting meals outside the home, especially in fast-food restaurants; encourage family meals at least 5–6 times/week

TABLE 13–3. Healthy lifestyle recommendations to treat age-inappropriate weight gain and weight status in children and adolescents with psychiatric disorders and those who are overweight and obese in the general population (continued)



http://www.glycemicindex.com

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ExerciseSedentary behavior Limit sedentary behaviors, such as

watching TV or playing computer/video games to less than 2 hours per day

Recommend limiting screen time to 2 or fewer hours per day, and not having a television in the room where the child sleeps

Exercise Perform moderate level physical activity for at least 30–60 minutes/day

Encourage 1 hour or more of daily physical activity

Note. BMI=body mass index.aAuthoritative parents are demanding and responsive. “They monitor and impart clear standards for their children’s conduct. They areassertive, but not intrusive and restrictive. Their disciplinary methods are supportive, rather than punitive. They want their children tobe assertive as well as socially responsible, and self-regulated as well as cooperative” (Baumrind 1991, p. 62, as cited in American MedicalAssociation 2007).bRestrictive parents heavily monitor and control a child’s behavior (American Medical Association 2007).

TABLE 13–3. Healthy lifestyle recommendations to treat age-inappropriate weight gain and weight status in children and adolescents with psychiatric disorders and those who are overweight and obese in the general population (continued)




and then every 6 months (Correll 2008a). Glucose and lipid measure-ments have been recommended more frequently in children and ado-lescents than in adults because of the relatively greater proclivity ofpediatric patients to gain weight when taking antipsychotics and alsobecause of early indications of a risk, at least, for lipid abnormalities(Correll et al. 2006; Fraguas et al. 2008; Kryzhanovskaya et al. 2005;Laita et al. 2007; Tohen et al. 2007). Importantly, similar to the adjust-ment of weight and BMI assessment for normal growth, developmentallyappropriate thresholds also need to be used for identifying metabolic ab-normalities in pediatric patients. Although fasting glucose thresholds forprediabetes (100–125 mg/dL) and diabetes (≥ 126 mg/dL) are similar forpediatric and adult patients, lipid thresholds differ (Correll 2008a) (seeTable 13–2). Abnormally high fasting total cholesterol levels and triglyc-eride levels in youths are 170 mg/dL and 110 mg/dL, respectively, in-stead of 200 mg/dL and 150 mg/dL in adults. Furthermore, becausechildren and adolescents generally have sufficient pancreatic beta cell re-serve, hyperglycemia is an unlikely and rather late adverse event, and itis preceded by insulin resistance, signified by insulin levels that are suffi-ciently increased to keep the fasting glucose levels within the normalrange. Although not used routinely, a relatively easy way to measure in-sulin resistance is the homeostatic model assessment (HOMA) method:fasting insulin (μmol/L)×glucose (mmol/L)/22.5, where glucose mmol/L= glucose mg/dL/17.979797.

Based on the U.S. pediatric general population, HOMA values >4.39have been defined as being indicative of insulin resistance in adoles-cents (Lee et al. 2006). Although not validated in youths, a cheaper andsimpler alternative would be to use a lipid-based measure of insulin re-sistance (McLaughlin et al. 2005). This proxy measure consists of the ra-tio of fasting triglycerides divided by HDL cholesterol, wherebyincreased values over time indicate decreased insulin sensitivity, witha threshold of >3.5 possibly indicating insulin resistance.

Blood PressureBlood pressure should be measured with a large enough cuff in pediat-ric patients that 80% of the upper arm is covered by the cuff bladder. Todetermine whether a patient has arterial hypertension (i.e., ≥90th per-centile for sex and age; see Table 13–2), the patient’s height percentileneeds to be calculated (e.g., https://www.nutropin.com/patient/3_5_3_growth_charts.jsp) and the measured blood pressure comparedwith population norms from children of the same age, sex, and height(“The Fourth Report on the Diagnosis, Evaluation, and Treatment ofHigh Blood Pressure in Children and Adolescents” 2004).

https://www.nutropin.com/patient/3_5_3_growth_charts.jsp

https://www.nutropin.com/patient/3_5_3_growth_charts.jsp


Sexual and Prolactin-Related Side Effects

If a patient develops hyperprolactinemia, other reasons than antipsy-chotic effects need to be ruled out first. These include hormonal contra-ception or pregnancy, hypothyroidism, and renal failure, all of whichcan be assessed by taking a detailed history and measuring serum hu-man chorionic gonadotropin, thyroid-stimulating hormone, and/orcreatinine, where appropriate. To identify hyperprolactinemia-relatedhypogonadism, clinicians should inquire at baseline, during drug titra-tion, and quarterly about menstruation patterns, nipple discharge,breast enlargement or pain, sexual functioning, and (if appropriate) pu-bertal development. Currently, because the extent of physiological ef-fects of subclinical prolactin elevations have not been established inadult or pediatric patients, prolactin measurements are generally rec-ommended only if clinical symptoms or signs are present. Because pro-lactin undergoes diurnal variations and increases with food intake,exercise, and stress, prolactin should be measured in the morning, afterfasting, and 8–12 hours after the last medication dose. Prolactin thresh-olds are usually laboratory dependent and higher for postpubertal thanprepubertal individuals and in females (upper level ∼20–30 ng/ml)than males (upper level: ∼11–15 ng/ml or 0+age).

Management of Antipsychotic-Related Adverse Effects With Adverse Health Outcomes

Weight and Metabolic Dysfunction

Healthy lifestyle and medical health strategies for pediatric patientstreated with antipsychotics were recently summarized (Correll 2007a).Three levels of strategies are included. Primary preventive strategies include1) educating about and maximizing adherence to healthy lifestyle behav-iors (see Table 13–3) and 2) choosing a medication with the lowest likeli-hood of adverse effects on body weight and metabolic health. Secondarypreventive strategies in overweight patients and those with mild baselinemetabolic abnormalities, significant weight gain, or beginning metabolicabnormalities (see Table 13–3) during antipsychotic therapy include 1) in-tensification of healthy lifestyle instructions; 2) consideration of switchingto a lower-risk agent; and 3) a nonpharmacological weight loss treatmentor adjunctive pharmacological interventions that target normalization or


reversal of weight abnormalities. Tertiary preventive strategies in patientswho are obese or have clinically defined related abnormalities (i.e., hyper-glycemia, diabetes, dyslipidemia, or hypertension; see Table 13–3) requireintensified weight reduction interventions; attempts at switching to or ini-tiating lower-risk medications for the underlying psychiatric condition;and targeted treatments of these suprathreshold metabolic or endocrineabnormalities, often in conjunction with a subspecialist.

The first line of treatment for abnormalities in body weight or meta-bolic health includes nonpharmacological lifestyle education and modifi-cation strategies. (See Chapter 8, “Behavioral Treatments for WeightManagement of Patients With Schizophrenia,” for an extensive review ofbehavioral means to control weight gain.) Although such strategies andprograms have been tested and shown to be successful to a certain degreein adults (Faulkner et al. 2007), the effects of healthy lifestyle programs inantipsychotic-treated youths have not been reported. The recent Ameri-can Medical Association (2007) Stage 1 recommendations for healthy life-style behaviors in pediatric patients are summarized in Table 13–3. After3–6 months of treatment, if no improvement has occurred in a patient’sunhealthy BMI and weight, and if the patient and/or family indicatereadiness to change, progression to the Stage 2 structured weight manage-ment protocol is indicated. Stage 2 interventions can be implemented by aprimary care physician or allied health care provider highly trained inweight management and include the following: 1) dietary and physicalactivity behaviors—that is, a) plan development for utilization of a bal-anced macronutrient diet emphasizing low amounts of energy-densefoods, b) increased structured daily meals and snacks, c) supervised activeplay of ≥60 minutes/day, and d) screen time of ≤1 hour/day; 2) increasedmonitoring (e.g., dietary intake, restaurant logs, screen time, physical ac-tivity) by provider, patient, and/or family; and 3) goal setting of weightmaintenance that results in a decreasing BMI as age and height increase.

If no improvement in BMI and weight occurs after 3–6 months, thepatient should be advanced to Stage 3, consisting of a comprehensivemultidisciplinary protocol (American Medical Association 2007). At thisstage, the patient should be referred to a multidisciplinary obesity careteam. The eating and activity goals are the same as in Stage 2. Additionalactivities should include 1) a structured behavioral modification pro-gram, including food and activity monitoring, as well as developmentof short-term diet and physical activity goals, and 2) involvement ofprimary caregivers in behavioral modification for children under age12 years and training of primary caregivers for all children. The goal atthis stage should be weight maintenance or gradual weight loss until thepatient’s BMI is lower than the 85th percentile.


If staged behavioral measures alone provide insufficient results, phar-macological weight loss interventions may be added. Data in obese youthswithout a primary psychiatric illness support the use of sibutramine(serotonin-norepinephrine reuptake inhibitor), orlistat (enteric lipase in-hibitor that blocks absorption of about 30% of dietary fat), and metformin(insulin sensitizer) (Correll 2008c). Sibutramine (e.g., 5–15 mg/day) andorlistat (e.g., 120 mg three times daily) are FDA approved for weight lossin adolescents. Sibutramine, which is approved only for patients ages16 years and older, may increase blood pressure and should not be giventogether with other serotonin-enhancing drugs (i.e., antidepressants,stimulants, or lithium) to avoid serotonin syndrome. Therapies that havehad some reported success in leading to weight loss in pediatric patientsreceiving antipsychotics include metformin (e.g., 250 mg/day threetimes daily if patient’s weight is <50 kg, or 500 mg/day three times dailyto 1,000 mg/day twice daily if patient’s weight is ≥50 kg titrated up over3–4 weeks), topiramate (e.g., 25–400 mg/day), amantadine (e.g., 100 mgtwice daily), and orlistat (Correll 2008c).

Dyslipidemia should also be treated initially with diet and exercise. Ifthese changes are not sufficient, drug therapy may be given, as in adults,with a fibric acid derivative (e.g., gemfibrozil, fenofibrate), a statin, fish oil,or niacin, if appropriate. Diabetes may be treated with diet, oral hypogly-cemic agents, or insulin, as needed, but diabetes induced by atypical anti-psychotic agents sometimes disappears when the drug is stopped orchanged to a lower-risk agent (Correll and Carlson 2006). Whereas treat-ment for age-inappropriate weight gain may be managed by the primarypsychiatric care provider, treatments for dyslipidemia and hyperglycemiamost likely will be initiated by a pediatrician or pediatric endocrinologist.

Hyperprolactinemia and Related AbnormalitiesIf the patient’s serum prolactin is <200 ng/mL, the clinician can attempt re-ducing the dosage of the antipsychotic or changing the prescription to aprolactin-sparing drug, such as aripiprazole, quetiapine, or, in treatment-resistant patients, clozapine (Correll and Carlson 2006). If serum prolactinis >200 ng/mL or is persistently elevated despite a switch to a prolactin-sparing drug, a magnetic resonance imaging (MRI) scan of the sella turcicashould be obtained to rule out presence of a pituitary adenoma or parasel-lar tumor. If the MRI scan is normal, sex steroids (e.g., oral contraceptivesfor women of menstrual age, testosterone for men) can be replaced to treatthe hypogonadism, or drugs such as bisphosphonates (e.g., alendronate,risedronate) can be given to prevent or treat osteoporosis. Prolactin levelscan also be lowered by adding a dopamine agonist (e.g., amantadine,


bromocriptine), or by adding a partial dopamine agonist (e.g., aripiprazole5–15 mg/day), which has been shown to be effective in adults (Shim et al.2007). The use of ergot derivatives (e.g., cabergoline) is not recommendeddue to known risks for valvular heart disease from these agents.

QTc AbnormalitiesAlthough a very uncommon complication of antipsychotic treatment,any QTc value of ≥500 milliseconds, confirmed by manual reading,should prompt a discontinuation of the antipsychotic, unless hypo-magnesemia or hypokalemia is present that can be corrected or unlessother QT-prolonging agents can be discontinued successfully. (SeeChapter 7, “The Spectrum of Cardiovascular Disease in Patients WithSchizophrenia,” for monitoring recommendations.)

ConclusionAlthough more data are needed, children and adolescents exposed toantipsychotics appear to be vulnerable to developing hyperprolactine-mia and age-inappropriate weight gain, with the related potential formetabolic dysfunction, at least for lipid abnormalities. Determiningwhether the risk for diabetes in youths is lower than in adults or is sim-ply delayed requires long-term follow-up studies, but data in the gen-eral population suggest the latter.

Because of the relevant adverse effects of antipsychotics in youths,proactive and routine monitoring of antipsychotic efficacy and risks, aswell as timely management of clinically relevant adverse effects withnegative impact on health and adherence, should be part of generalclinical practice. Clinicians should ideally make measurement-basedand shared treatment decisions. They should use age-appropriate side-effect measures and thresholds and define abnormal values dependingon the patient’s developmental status. In addition, safety and efficacydata should inform a carefully weighed antipsychotic selection thattakes into account the illness severity, current and past response pat-terns, side-effect probabilities and occurrences, and each patient’s andfamily’s preferences. Finally, because adverse effects are generallymore readily predicted than therapeutic efficacy, and because antipsy-chotics’ differences in efficacy are generally smaller than their differ-ences in adverse effects, treatment decisions may need to be guided toa relevant degree by the individual and varying adverse effect profilesacross antipsychotic agents.


Key Clinical Points

◗ Children and adolescents appear to be particularly susceptible to de-veloping prolactin elevation, antipsychotic-induced age-inappropriateweight gain, and, to some degree, lipid abnormalities.

◗ Ranking order of antipsychotic adverse effects on body weight andmetabolic health is similar in children and adolescents compared withadults, with a potentially greater effect of risperidone, possibly a lessereffect of clozapine, and greater weight gain liability with medicationsthat are generally considered weight neutral in adults.

◗ Although diabetes and metabolic syndrome have not been researchedsufficiently in pediatric patients exposed to antipsychotics, the onset ofthese longer-term adverse effects may generally be delayed in youths,who more often than adults have less lifetime antipsychotic exposureand who have greater pancreatic beta cell reserve.

◗ Sustained, age-inappropriate weight gain is of great concern due to theknown relationship between obesity in childhood and adverse cardiacoutcomes in adults in the general population.

◗ Patients and families should be counseled about the probability of spe-cific adverse effects, which should inform the most appropriate medi-cation choice to concurrently achieve sustained symptom benefits,adherence, and physical health.

◗ Education about and proactive assessment of antipsychotic adverse ef-fects on the health status in youths should be routine clinical practiceof mental health practitioners prescribing antipsychotics.

◗ Safety assessments must utilize developmentally adjusted measures andthresholds for growing children and adolescents.

◗ Although adverse effects need to be balanced against efficacy gains,clinicians should be prepared to change antipsychotic treatment or ini-tiate interventions to reduce bothersome as well as physically problem-atic adverse effects to improve overall outcomes.


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CHAPTER 14

Medical Health inAging Persons With

Schizophrenia

Samantha Brenner, M.P.H.Carl I. Cohen, M.D.

A potential health crisis is emerging in mental health care. Ap-proximately 1% of the population ages 55 and older—more than one-half million persons—has schizophrenia (Cohen et al. 2008). Over thenext two decades, this number will double as postwar baby boomersreach old age. Moreover, these individuals will be at increased risk forphysical illness as they age. More than four-fifths of the general olderpopulation have one or more chronic medical conditions (Kovar 2001),and these disease combinations can act synergistically to produce muchhigher levels of functional disability than associated with either diseasealone (Verbrugge et al. 1991). Thus, physical diseases co-occurring withschizophrenia may have greater impact on adaptive functioning thanthey might in persons without mental disease. Unlike the previous gen-erations of older persons with schizophrenia who spent much of their

This work was supported in part by grant S06 GM74923 from the National In-stitute of General Medical Sciences.


later years in mental institutions, approximately 85% of older personswith schizophrenia now live in the community, in settings other thannursing homes or hospitals (McAlpine 2003). A critical issue for the newgeneration of older persons with schizophrenia is whether they will beable to negotiate a health and social service system that may be ill pre-pared to deal with them.

The aim of this chapter is to provide an overview of medical healthissues of the aging schizophrenia population. In so doing, we focus firston the epidemiology of physical disorders, both general physical healthand specific medical disorders, then examine treatment issues, includ-ing medication-related issues, barriers to health care, and concernsabout competency.

BackgroundOnly 1% of the literature on schizophrenia has been devoted to issuesof aging (Cohen et al. 2008), and few papers have specifically addressedissues of health among aging individuals with schizophrenia. Researchin this area has been limited by the fact that the majority of schizophre-nia studies cover a wide age range, with the predominant focus onyounger patients. Comparisons between studies are also hampered bythe differences in types of patients (inpatients, outpatients, Veterans Af-fairs [VA] hospital patients), use of disease prevalence versus incidencein populations, and diverse geographical locations for the study popu-lations. Despite these limitations, we have tried in this chapter, wher-ever possible, to make comparisons between older schizophreniapatients and their age peers in the general population or with other psy-chiatric populations, and to make comparisons between older andyounger patients with schizophrenia. To expand our data sources, wehave also extrapolated from studies of schizophrenia patients in gen-eral by using mean values and standard deviations and by incorporat-ing any findings in which there was a breakdown by age.

General Physical HealthPersons with schizophrenia are generally believed to have worse healththan their age-matched peers in the general population, and their con-ditions often go undiagnosed and untreated (Dixon et al. 1999). For ex-ample, increased rates of comorbid physical illness in patients withschizophrenia have been reported to occur primarily in the categoriesof non-insulin-dependent diabetes mellitus, cardiovascular disease, in-

Medical Health in Aging Persons 379

fectious diseases, respiratory diseases, some forms of cancer, and a va-riety of other illnesses (Dixon et al. 1999). Also, persons withschizophrenia may have more severe forms of disorders (Jeste et al.1996), which may be exacerbated by the side effects of antipsychoticmedications (e.g., anticholinergic, cardiovascular, metabolic effects)and by the psychotic illness itself, and significant correlations have beenfound between positive symptoms and the number of medical condi-tions (Dixon et al. 1999; Jeste et al. 1996). Moreover, other clinical symp-toms commonly found in schizophrenia, such as levels of depressionand neurocognitive impairment, also may be associated with increasedrates of comorbid medical conditions (Chwastiak et al. 2006a, 2006b).

Because older persons with schizophrenia are survivors comparedwith their younger counterparts, an important consideration is whetherthe older group has more medical comorbidities than the youngergroup. In a large study of 8,083 patients using the National Patient CareDatabase of the Veterans Health Administration, Kilbourne et al. (2005)found that schizophrenia patients ages 60 years and older were indeedmore likely to have medical comorbidities compared with youngerschizophrenia patients. They also found that older patients were lesslikely to have substance abuse or hepatic diagnoses. Although thosefindings may have been expected, they had not been confirmed previ-ously using a large population.

Because results of investigations such as the Patient Outcomes Re-search Team (PORT) study (Dixon et al. 1999) have suggested that thediagnosis of schizophrenia in general confers greater risk for physicalillness, one might assume that older persons with schizophrenia wouldbe more medically ill versus age-matched peers. Nevertheless, studieshave yet to determine whether aging interacts with schizophrenia suchthat the older cohort is disproportionately more ill than age peers com-pared with a younger cohort of patients with schizophrenia. To thisend, researchers in San Diego, California (Jeste et al. 1996; Lacro andJeste 1994), found that middle-aged and older persons with schizophre-nia had fewer medical illnesses (mean =1.0) than persons with Alz-heimer’s disease (mean=1.4) and major depression (mean =2.4), andtheir severity index on the Cumulative Illness Rating Scale for Geriat-rics was comparable to that of an older normal comparison group. Sim-ilarly, a study in New York City of 198 patients with schizophrenia ages55 years and older (mean 61.5 years) and an age-, gender-, and race-matched comparison group found no significant differences in thenumber of physical disorders, 1.3 and 1.1, for the schizophrenia andcommunity groups, respectively (C.I. Cohen, unpublished data). Oneconfounding issue for the San Diego investigations was that the normal


comparison group was 12 years older; however, in the New York Citystudy, the comparison group was only 1.5 years older. Interestingly, theSan Diego study found a significant correlation between physicalsymptom severity and positive symptoms of schizophrenia, depres-sion, and overall psychopathology, whereas the New York City studyfound a correlation only between symptom severity and depressivesymptoms, which is consistent with the geriatric literature on depres-sion and health (Diwan et al. 2007).

Results from the studies in New York City and San Diego do not sug-gest that older outpatients with schizophrenia have more physical dis-orders or that their disorders are necessarily more severe than their agepeers from comparable backgrounds, although results of the San Diegostudies were more equivocal due to age differences between compari-son groups. One possible explanation for these findings is that personsin the schizophrenia samples were all involved to some extent in clini-cal programs, most of which encouraged or provided physical exami-nations. Moreover, because psychopathology tends to diminish withage, older persons may be more apt to attend to medical problems andbe better received by other health professionals. The San Diego re-searchers interpreted the significant correlation between positivesymptoms and physical health as reflecting the fact that physical symp-toms may seem less important or be overlooked in the presence of floridpsychosis and, conversely, more apt to be addressed when the patienthas fewer schizophrenia symptoms. A “survivor effect” may be anotherplausible explanation for the lack of differences between the older pa-tients with schizophrenia and community persons. That is, becausemortality rates among patients with schizophrenia substantially exceedthose of the general population throughout their lifetime, those withschizophrenia who are oldest are presumably the heartiest, both phys-ically and emotionally. For example, with respect to the latter, Rockettet al. (2007) found that the percentage of suicides due to schizophreniadeclined in patients ages 65 and older, whereas suicide rates for othermental illnesses such as depression remained constant.

Specific Medical DisordersDiabetesThe association between diabetes and schizophrenia is discussed atlength in Chapter 5, “Glucose Intolerance and Diabetes in Patients WithSchizophrenia.” Nonetheless, it bears noting that although diabetes in-creases with age and affects about 20% of the geriatric population


(Marsh 1997), the prevalence rates of diabetes among persons withschizophrenia seem to be consistently higher versus their nonpsychiat-ric age peers only in the younger and middle-aged groups, whereas dif-ferences in the geriatric population may be minimal. Researchers havefound that disordered glucose homeostasis is significantly worse inolder patients with schizophrenia than in younger persons with schizo-phrenia (Subramaniam et al. 2003), although similar age differences ex-ist in the general population. When compared with patients with otherpsychiatric disorders, middle-aged and elderly patients with schizo-phrenia were found by Jeste et al. (1996) to have no significant differ-ence in prevalence of diabetes. Similar results were found in a study ofolder patients with schizophrenia in New York City; self-reported ratesof diabetes were not significantly greater among schizophrenia patients(25%) than among the comparison community group (19%) (C.I. Co-hen, unpublished data). Two studies (Mukherjee 1995) of VA inpatientsand outpatients have confirmed the increasing prevalence of diabetesamong patients with schizophrenia as they age, with rates of 0% and1.6% among those under age 40 years, and 25% and 50% in those ages70 and older, for inpatients and outpatients, respectively. In anotherstudy, conducted in Italy, Mukherjee et al. (1996) studied a sample of95 patients with schizophrenia and found that the prevalence of diabe-tes increased from 0% in those younger than age 50 years, to 12.9% inthose ages 50–59 years, 18.9% in those ages 60–69 years, and 16.7% inthose ages 70–74 years.

Although antipsychotic medication, particularly the atypical agentsolanzapine and clozapine, may have an impact on glucose tolerance,the PORT study concluded that people with schizophrenia had agreater risk of developing diabetes than the general population evenbefore the widespread use of the newer agents (Dixon et al. 2000). Sim-ilarly, Murkherjee et al. (1996) observed, “It bears emphasizing thathigh rates of insulin resistance and impaired glucose tolerance had beennoted in schizophrenia patients before the introduction of neurolep-tics” (p. 71).

Several recent studies, some of which provide strong evidence be-cause they are longitudinal, have found that the use of atypical antipsy-chotics is the principal cause of the rise in the prevalence of diabetes inpersons with schizophrenia, although the evidence is less convincingamong older adults. From 1988 to 2002, after the introduction of atypi-cal antipsychotics to the U.S. market, a net increase occurred in theprevalence of obesity and diabetes mellitus among inpatients withschizophrenia of all ages (Reist et al. 2007). Likewise, a study conductedfrom 1979 to 2001 found that trends in diabetes mellitus prevalence


were comparable among inpatients with schizophrenia and inpatientswithout mental illness during the years before the introduction of atyp-ical antipsychotics, whereas from 1996 to 2001, the net difference in theprevalence of diabetes between inpatients with schizophrenia and in-patients without mental illness grew at an increasing rate of 0.7% peryear (Basu and Meltzer 2006). Studying a large group of VA outpatientswith schizophrenia, Sernyak et al. (2002) found that when effects of agewere controlled, patients who received atypical neuroleptics were 9%more likely to have diabetes than patients who received typical anti-psychotic medications. By contrast, Barak and Aizenberg (2003) foundthat in a small sample of older patients (mean age 72 years), the associ-ation between atypical antipsychotics and lipid abnormalities did nothold true.

With respect to treatment, the PORT study, based on data from719 schizophrenia outpatients (mean age 43 and approximately 17%above age 55), found that 86% of patients with schizophrenia who re-ported having diabetes mellitus said they were receiving treatment forit (Dixon et al. 1999). This is consistent with data from the study of olderpatients with schizophrenia in New York City, which was cited earlier,in which 86% of persons with diabetes reported receiving treatment(Vahia et al. 2008). However, although treatment rates may not differwith respect to diabetes, outcomes may differ. For example, Weiss et al.(2006) found that older diabetic patients with schizophrenia did not dif-fer significantly from diabetic controls in the appropriateness of theirtreatment regimens; however, there was a significant difference in theclinical quality benchmarks for cholesterol and low-density lipoproteinlevels in the schizophrenia group. As such, persons with schizophreniawere more likely to have prescriptions for the older lipid-loweringagents, as well as a higher rate of missed appointments. In a study ofmiddle-aged and elderly VA outpatients with schizophrenia, Dolder etal. (2003) found that the 12-month mean compliant fill rates for antipsy-chotic, antihypertensive, dyslipidemic, and glucose control medica-tions ranged from 52% to 64%, regardless of whether patients were onatypical or typical antipsychotics.

On the positive side, a recent study of a broad age range of patients inthe VA health care system found that both quality of care and interme-diate diabetic health outcomes were the same for age-matched diabeticpatients with and without serious mental illness, suggesting that compa-rable care and access are achievable for patients in the VA system (Kreinet al. 2006). However, outside of the VA system, researchers have ques-tioned the ability of health care workers to successfully communicateappropriate diabetic care to elderly patients with schizophrenia. In a


small study with 100 patients, Dickerson et al. (2005) found that patientswith schizophrenia scored significantly lower on a standardized diabe-tes knowledge test than did psychiatrically healthy diabetic controls.

Cardiovascular DiseaseCardiovascular diseases are among the most common disorders foundamong persons with schizophrenia. They are reported to occur more fre-quently and to be responsible for increasing mortality rates among indi-viduals with schizophrenia than among those in the general population(Dixon et al. 1999; Fors et al. 2007; Goff et al. 2005; Ösby et al. 2000; Tsu-ang et al. 1983). Mortality from increased cardiovascular morbidity ismost likely a result of increased rates of smoking, obesity, diabetes, andhypertriglyceridemia in the population with schizophrenia, whereas therelationship of mortality to antipsychotic drug usage is less clear (Engeret al. 2004; Goff 2005; Jerrell and McIntyre 2007; Seeman 2007).

Some controversy is apparent in the literature as to the effect of an-tipsychotic usage on cardiovascular disease. Straus et al. (2004) foundthat current use of antipsychotic medications, even in low dosages, isassociated with an increased risk of sudden cardiac death. The OxfordRecord Linkage Study, using data derived from hospital activity analy-ses and mental health inquiry systems, amassed information on 2,314persons with schizophrenia across all age groups, of whom one-thirdwere ages 55 and older. The authors found that this patient cohort hada significant increase in relative risk for atherosclerotic heart disease,but not for other forms of cardiac, hypertensive, or circulatory diseases(Baldwin 1979). More recent data from a study with 240 subjects (meanage 42±11.5 years) showed that compared with U.S. adult populationrates, male patients with schizophrenia had a greater 10-year risk ofmyocardial infarction, whereas female patients with schizophrenia didnot show increased risk (Cohn et al. 2004). Similarly, Enger et al. (2004)found that those schizophrenia patients being treated with typical an-tipsychotics (mean age 38±14 years) had a fivefold increased risk of my-ocardial infarction compared with psychiatrically healthy controls.However, cardiovascular mortality risk was inversely associated with“intensity” of use of antipsychotic drugs (i.e., proportion of follow-updays taking medication), suggesting that the observed risks may not bedue to a simple or direct effect of drugs.

The limited data on older samples have tended in some instances tocontravene the findings for schizophrenia in general. Sajatovic et al.(1996) studied 49 patients with schizophrenia (96% male) ranging in agefrom 65 to 85 years (mean age 72 years), at the Cleveland Veterans Af-fairs Medical Center. The authors reported that the most frequent rea-


sons for medical hospitalization of the patients with schizophrenia werecardiovascular or pulmonary disease, but they did not provide a com-parison with nonpsychiatric patients. Sheline (1990) reported that car-diovascular disease was the most prevalent physical illness seen ingeriatric psychiatric inpatients (age range 60–85 years). Although per-sons with schizophrenia accounted for 20% of the study population, theauthors did not report medical diagnoses specific to the individuals withschizophrenia. In a study by Lacro and Jeste (1994), elderly patients withschizophrenia had the lowest prevalence of hypertension, coronary ar-tery disease, and congestive heart failure when compared with otherelderly psychiatric patients. Finally, in the New York City study of olderoutpatients with schizophrenia cited previously, no significant differ-ences were apparent between the schizophrenia group and the commu-nity comparison group on self-reported rates of heart disease (22% vs.14%) and hypertension (38% vs. 38%) (C.I. Cohen, unpublished data).

Results from several recent studies suggest that older adults withschizophrenia and comorbid cardiovascular disease are receiving sub-optimal care. For example, Piette et al. (2007) found that schizophrenia pa-tients with both diabetes and cardiovascular disease were selective abouttheir medication adherence, favoring antipsychotic medications overmedications for their comorbid conditions. Moreover, in studies in whicholder patients with both schizophrenia and hypertension had similar lev-els of antihypertensive medication adherence versus their age peers, per-sons with schizophrenia were still significantly less likely to have theirblood pressure controlled, have their lipids assessed regularly, or havetheir body weight monitored (Dolder et al. 2005; Hippisley-Cox et al.2007a; Paton et al. 2004). Druss et al. (2000) found that after an acute myo-cardial infarction, patients with schizophrenia were 59% less likely to un-dergo cardiac catheterization than were those individuals without mentaldisorders. These researchers also found a 19% increase in 1-year mortalityrisk among persons with schizophrenia that disappeared after adjustingfor five quality measures, which included the timely prescription of beta-blockers, angiotensin-converting enzyme inhibitors, and smoking cessa-tion counseling. Their findings, corroborated by further research (Druss etal. 2001), lend support to the notion that much of the mortality differenceseen between patients with schizophrenia and their age peers is a directresult of deficits in the quality of the medical care received.

Respiratory DisordersUntil 50 years ago, respiratory diseases such as pneumonia and tuber-culosis accounted for much of the excessive mortality rates among in-


stitutionalized patients with schizophrenia (Alstrom 1942; Baldwin1979; Odegard 1951). These findings were not specific to patients withschizophrenia, but rather were observed in institutionalized psychiatricpatients as a whole. Recent studies continue to point to disproportion-ately higher rates of respiratory morbidity and mortality in schizophre-nia populations, although the usual proviso about lack of data amongolder patients with schizophrenia applies for respiratory disorders aswell (Joukamaa et al. 2001).

In a 10-year study by Sajatovic et al. (1996) of hospital utilization ofelderly veterans with bipolar disorder (n = 23) and schizophrenia(n=49), respiratory disease was found to be one of the most frequentcauses of medical hospitalization (18%) (cf. 22% for cardiovascular dis-ease). Hussar (1966) examined the autopsy reports, collected from29 VA hospitals, of 1,275 white male patients with chronic schizophre-nia with a mean age at the time of death of 63 years; they found an in-creased number of deaths due to pneumonia in comparison to the ratein the age-matched general population. Weiner and Marvit (1977)found increased morbidity from respiratory disease in their middle-aged schizophrenia population, whereas Dynes (1969) and Saku et al.(1995) found respiratory disease to be a leading cause of death in theirschizophrenia population of all ages. Finally, Daumit et al. (2006) foundthat versus hospitalized patients without schizophrenia, patients withschizophrenia (mean age 55) had at least twice the adjusted odds ratiofor intensive care unit admission and death secondary to respiratoryfailure or sepsis.

Immune FunctionHypotheses about the link between immune dysfunction and schizo-phrenia date back to the early 20th century, and in the 1960s an auto-immune-mediated process was implicated in the etiology ofschizophrenia (Rappaport and Delrahim 2001). Paradoxically, studiesof specific immunological disorders have generally supported lowerprevalence rates among schizophrenia populations. For example,Ehrentheil (1957) and Lipper and Werman (1977) noted a decreased in-cidence of asthma, hay fever, and other allergic reactions in patientswith schizophrenia. Other studies, such as that of Sabbath and Luce(1952), have shown an alternating pattern of coexisting psychosis andallergies.

The strongest evidence for a negative association between schizo-phrenia and a disease exists with rheumatoid arthritis. Nissen andSpencer (1936) may have been the first to point out that rheumatoid


arthritis and schizophrenia do not appear to exist together. Eaton et al.(1992) reviewed 14 epidemiological studies conducted between 1934and 1985 and concluded that ample evidence supported the negativeassociation between these two disorders. A more recent study by Gor-wood et al. (2004) continued to confirm earlier studies finding a low rel-ative risk between the two disorders. Underdiagnosis also has beenproposed as an alternative explanation for the negative association ob-served between the two disorders (Mors et al. 1999).

Although rheumatoid arthritis has been the most widely studied dis-order, Juvonen et al. (2007) found a significantly lower incidence rate ofschizophrenia in a Finnish cohort of individuals with type 1 diabetes.Several mechanisms have been postulated to explain this phenomenon,including immunological, biochemical, and genetic mechanisms. Onthe other hand, evidence also indicates that persons with schizophreniamay be more prone to certain infectious agents such as Toxoplasma gon-dii and are more likely to have increased serointensity (parasitic loadfound in blood) compared to psychiatrically healthy controls. Giventhat serointensity was significantly associated with C-reactive proteinlevels and leukocyte counts, researchers hypothesize that the increasedserointensity in persons with schizophrenia is a result of the shifted T-helper cell balance between Th1 and Th2 cell types found in schizophre-nia (Hinze-Selch et al. 2007). Moreover, patients with schizophreniahave been found to have down-regulated levels of cytokines in situa-tions where activation of the immune system would be appropriate andbeneficial (Na and Kim 2007). Although the exact mechanisms have yetto be determined, both immunoprotective and immunologically harm-ful immune states have been correlated with schizophrenia. The lattermay be especially pernicious in older adults.

CancerRelative prevalence rates of the different types of cancers vary betweenthe schizophrenia population and the general population. Comparisonsacross studies are difficult because some studies focus on mortalityrates and others focus on disease incidence or prevalence rates. In Is-rael, the incidence for all cancers over a 10-year period was 42% lowerin the schizophrenia population than in age- and gender-matched con-trols (Barak et al. 2005; Grinshpoon et al. 2005). Some studies indicatethat compared with the overall population, the schizophrenia popula-tion seems to have a lower rate of lung cancer and higher rates of diges-tive and breast cancers (Catts et al. 2008; Hippisley-Cox et al. 2007b;Schoos and Cohen 2003). The apparent lower prevalence of lung cancerin patients with schizophrenia is surprising in light of the high number


of smokers in this population (Jeste et al. 1996). However, a Britishstudy of 370 patients with schizophrenia ages 16–66 years (Brown et al.2000) found mortality rates for lung cancer in patients with schizophre-nia to be twice the expected values. Because the majority of these pa-tients were also heavy smokers, cigarette smoking likely accounts forthe higher mortality rate. However, in a large study, Hippisley-Cox etal. (2007b) found no differences in lung cancer incidence in patientswith schizophrenia versus their age peers; in fact, after controlling forsmoking exposure, they noted that the subjects with schizophrenia hadlower rates. A meta-analysis by Catts et al. (2008) found that much likedecreased respiratory cancer rates in patients with schizophrenia,pooled overall cancer incidence in their siblings and parents is signifi-cantly reduced, supporting the hypothesis that schizophrenia may pro-vide a protective effect against certain neoplasms.

In Denmark, researchers examined a cohort of 1.3 million women ofwhom 7,541 had been hospitalized for schizophrenia between 1970 and1997. Within this group, researchers found that after adjusting for age,menstrual period, age at first birth, and number of births, the preva-lence of breast cancer was not different between women with schizo-phrenia and controls. The authors postulated that previous studies maynot have accounted properly for parity and other environmental riskfactors for breast cancer (Dalton et al. 2003). However, by contrast, anIsraeli group of researchers found, in a cohort of 3,226 persons withschizophrenia, that breast cancer rates were reduced by 10%–63% whencompared with those of age-matched controls (Barak et al. 2005).

Looking at age-specific trends, Mortensen and Juel (1993) concludedthat no significant increase in cancer mortality exists in any age group ofpatients with schizophrenia, but there is a trend toward decreased cancermortality in older patients. Based on a schizophrenia study populationconsisting of 555 females (65% ≥60 years) and 389 males (81% ≥60 years),Malzberg (1950) found increased cancer mortality in young patients butsignificantly decreased rates in elderly patients, which was further bro-ken down to show lower rates in males than in females. Baldwin (1979)also reported that long-term hospitalized elderly patients with schizo-phrenia had significant reductions in lung cancer, gastrointestinal cancer,and prostate or bladder cancer. Compared with the general population,mental patients as a whole appear to have excess cancer mortality rateswhen hospital stays are short but diminished cancer mortality rates whenhospital stays are long, especially among those ages 65 and older (Bald-win 1979; Fox and Howell 1974). Although these studies included patientswith schizophrenia, they were not specific to schizophrenia. Baldwin(1979) posits two possible explanations for the increased mortality rates


among short-stay patients, including greater age or reasons for the ad-mission (i.e., selection biases). Lower cancer mortality rates amonglonger-stay older persons has led some authors to propose that the envi-ronment of the hospital, rather than schizophrenia per se, could be a fac-tor in protecting elderly patients from some cancers (Tsuang et al. 1983).

Controversial data exist with respect to neuroleptic use and cancermorbidity and mortality. Mortensen (1986) proposed that phenothiazinetreatment may be an environmental factor that protects against malignantneoplasia. Studies have shown an association between high-dosage neu-roleptics and reduced incidence of bladder and prostate cancer and be-tween nonphenothiazine neuroleptics and a decrease in lung and breastcancer (Mortensen 1989, 1992; Mortensen and Juel 1990). However, Ettigiet al. (1973) observed that breast cancer may be more common with phe-nothiazine treatment. Goode et al. (1981) suggested that neuroleptics maypotentially cause an increased incidence of breast cancer by elevating theprolactin level, although their study in a large psychiatric hospital over adecade noted that breast cancer rates were not higher among these psychi-atric patients despite their use of antipsychotic drugs. More recent re-search on neuroleptic usage from a large study in Denmark indicated thatafter controlling for a significant number of potential confounders, includ-ing age, menstruation, pulmonary disease, liver cirrhosis, alcoholism,chronic nonsteroidal anti-inflammatory drug usage, hormone therapy,age at first birth, and number of children, the use of neuroleptic medica-tions was not related to a reduced risk of cancer, except for suggestive de-creases in cancers of the rectum, colon, and prostate (Dalton et al. 2006).

HyponatremiaOlder persons in general are at greater risk for developing hyponatre-mia, with data indicating that older persons with schizophrenia have aneven greater susceptibility. Results from studies by de Leon’s group (deLeon 2003; de Leon et al. 1994) indicate that 10% of chronic psychiatricinpatients have hyponatremia, and up to 20% of chronically institution-alized patients with schizophrenia may have polydipsia. Jos et al. (1986)found that polydipsia was seen most frequently in white male inpa-tients with schizophrenia.

The pathophysiology of hyponatremia in patients with schizophre-nia is still under investigation in the literature, but studies indicate that1) persons with schizophrenia may have increased antidiuretic hor-mone (ADH) release and abnormal osmotic regulation (Kawai et al.2001); 2) effects of antipsychotic medications on ADH release result inhyponatremia; 3) susceptibility to polydipsia is genetic (Fukunaka et al.


2007; Meerabux et al. 2005); 4) polydipsic hyponatremic patients withschizophrenia have anterior hippocampal pathology that contributes totheir syndrome (Goldman et al. 2007b, 2008); and 5) polydipsic hy-ponatremic patients with schizophrenia have a differential response topsychological stressors, resulting in prolonged rises in plasma adreno-corticotropin (ACTH) and cortisol levels relative to polydipsic nor-monatremic patients with schizophrenia, implicating dysregulation inthe cortisol-ACTH-hippocampal axis either independent of or second-ary to antipsychotic medications (Goldman 2000; Goldman et al. 2007a,2007b; Madhusoodanan et al. 2002, 2003). In one earlier study, 70% ofhyponatremic patients with schizophrenia were taking anticholinergicdrugs versus 8% of the normonatremic patients with schizophrenia,leading to a conclusion that dry mucous membranes induced thirst andincreased water consumption (Gleadhill et al. 1982). However, recentstudies in which patients were taking both different classes and dos-ages of antipsychotic medications demonstrated that antipsychoticmedication was not correlated with serum sodium levels or changes inneurosecretory activity of vasopressin (Jessani et al. 2006; Malidelis etal. 2005). Because most patients with schizophrenia are heavy smokers,the stimulating effects of nicotine on ADH release may also play a role.

Musculoskeletal DiseaseLimited research interest has been shown in musculoskeletal disease inpatients with schizophrenia despite its importance among aging pa-tients with schizophrenia. The literature is somewhat divided regardingthe epidemiology of decreased bone mineral density in the schizophre-nia population. In one of the larger studies, Howard et al. (2007) foundthat taking prolactin-raising antipsychotics was independently associ-ated with hip fracture, but schizophrenia per se was not a risk factor ineither men or women. However, some studies have found decreases inbone mineral density in patients with schizophrenia compared withcontrols for either men or women, but not both (Bilici et al. 2002; Halbre-ich et al. 1995; Jung et al. 2006; Lehman and Meyer 2005). The acceleratedrates of osteoporosis in patients with schizophrenia have been attributedto at least six different pathophysiological mechanisms: 1) nutritional al-terations, 2) reduced calcium levels due to smoking, 3) hypogonadotro-pic hypogonadism, 4) hyperprolactinemia associated with decreasedestrogen and testosterone secondary to antipsychotic medication, 5) al-coholism, and 6) polydipsia (Lambert et al. 2003; Misra et al. 2004).

With regard to the hyperprolactinemia induced by antipsychotic med-ications, individuals being treated for schizophrenia have been found to


have lower bone mineral density compared with controls irrespective oftheir exercise or vitamin D intake levels, which suggests that the durationof hyperprolactinemia that a patient sustains creates lower bone mineraldensity as a result of the inhibition of the hypothalamo-pituitary-gonadalaxis (Kishimoto et al. 2008). Thus, researchers have postulated that clini-cians treating older persons with schizophrenia should be aware of thesepotential side effects and screen for loss in bone mineral density, so thatdecreases can be treated early by reducing patients’ antipsychotic dos-ages or switching to a prolactin-sparing agent, or by prescribing estrogenreplacement in hypoestrogenic female patients (Haddad and Wieck 2004;Meaney and O’Keane 2007). Given the increase in bone demineralization,the finding that elderly patients with schizophrenia who fall are approx-imately 1.5 times more likely to sustain injury than psychiatricallyhealthy controls is not unexpected (Finkelstein et al. 2007).

Visual ImpairmentVisual impairment is another medical comorbidity that is commonlyoverlooked in patients with schizophrenia. In a national study conductedin Finland in adults ages 30 years and older (mean age 53 years), personswith schizophrenia were five times as likely as controls to have visual im-pairment for distance and six times as likely for near vision. Thus, their vi-sual acuity was significantly more likely to be impaired (Viertiö et al.2007). These researchers contend that although some antipsychotic medi-cations are associated with increased risk of cataracts, retinopathy, and vi-sual impairment secondary to comorbidity with diabetes, the mostsignificant cause of visual impairment in patients with schizophrenia is in-sufficiently corrected refractive errors. Unfortunately, as the authorspointed out, visual impairment can lead to many negative consequencesfor this patient population, including greater difficulties performing dailyactivities, increased risk of injuries and falls, worsened visual perceptionand memory, and increased social isolation, all of which exacerbate con-ditions for which patients with schizophrenia are already predisposed.

Mortality RatesSeeman (2007) pointed out that whereas the mean life expectancy of thegeneral U.S. population is 76 years, the corresponding figure for the pop-ulation with schizophrenia is 61 years. Thus, compared with the generalpopulation, persons with schizophrenia have a 20% reduced life expect-ancy. (For an extensive discussion of mortality in patients with schizophre-nia, see Chapter 2, “Excessive Mortality and Morbidity Associated With


Schizophrenia.”) Death rates from all causes remain higher among per-sons with schizophrenia across the lifespan (Capasso et al. 2008; Laursenet al. 2007; Seeman 2007). Enger et al. (2004) found that the all-cause mor-tality rate among patients with schizophrenia across age groups was fourtimes higher than among age- and gender-matched controls in the samehealth plan. Furthermore, this elevated risk remained constant regardlessof treatment with typical or atypical antipsychotic drugs. However, someenvironmental and lifestyle factors do account for the excess mortality ratein persons with schizophrenia, such as their high prevalence of smoking(Brown et al. 2000) or living in urban versus rural areas (Fors et al. 2007).Older persons with schizophrenia are also likely to face higher mortalityrates as inpatients. Among all inpatients who died in VA hospitals during2002, patients with schizophrenia had a twofold increased risk of unfore-seen deaths compared with controls without schizophrenia (Copeland etal. 2006). Likewise, in a study of long-stay psychiatric patients (i.e., thosewith greater than 6 months of continuous hospitalization), of which 80%were persons with schizophrenia, researchers found an increased mortal-ity risk among these patients versus the standardized mortality rates in thegeneral population (Rasanen et al. 2003).

Interestingly, despite maintaining higher mortality rates than thegeneral population, older patients with schizophrenia have been foundto have lower than expected mortality in relation to other older psychi-atric patients (Wood et al. 1985). Explanations may include 1) a differentsort of lifestyle (environment) for patients with schizophrenia, 2) a pos-sible protective mechanism of neuroleptics on cardiovascular function,and 3) the possibility that elderly patients with schizophrenia are heartysurvivors in that they have survived a weeding-out process in whichdisproportionately more physically ill patients with schizophreniahave already died. Indeed, Heila et al. (2005) reported that the highestage-adjusted rates of increased mortality occur within the first 5 yearsof diagnosis with schizophrenia. The lower mortality rates in older pa-tients with schizophrenia are observed for nearly all causes, with the ex-ceptions being heart disease and cancer. Cancer mortality in patientswith schizophrenia is higher than in other psychiatric patients butlower than in the general population (Wood et al. 1985).

Subjective Health StatusSelf-rated health status is an important measure of subjective well-being. Although it tends to correlate with more objective measures ofhealth, it is based on personal perception and judgments, which in turnmay be influenced by health problems in the past, the level of health of


other persons in the subject’s social sphere, and the subject’s aspirationsfor the future. Therefore, individuals may underestimate the severity oftheir illnesses and postpone seeking treatment.

Only a few studies have examined subjective health status in agingschizophrenia populations. One study by Krach (1993) used the OlderAmericans Resources Survey to obtain information on physical healthfrom 20 older patients with schizophrenia (mean age 61 years). Ratingsof excellent/good and fair/poor physical health were reported by 60%and 40% of the sample, respectively. Mental health ratings were similar,with 70% and 30% reporting excellent/good and fair/poor mentalhealth, respectively. Based on the level of physical disorders and re-ports of impairment in activities of daily living (e.g., 35% had moderateor severe impairment in activities of daily living), Krach concluded thatthese patients overrated their physical health status and underreportedmedical symptoms, although the author provided no objective mea-sures of physical health. Indeed, in contradistinction to Krach’s conclu-sions, the authors of the PORT study (Dixon et al. 1999) maintained that“persons with schizophrenia have the capacity for reasonable appraisalof their medical conditions that can be a useful tool to promote positivehealth behaviors” (p. 501). This conclusion was based on the finding ofa significant association between the number of medical conditions andself-rated health. In the PORT survey, lower educational level andnumber of comorbid medical disorders were the only variables associ-ated with poorer self-rated physical health. Other variables such as gen-der, race, age, comorbid alcohol or drug disorder, geographic location,or patient setting were not associated with self-health ratings, althougholder subjects tended to perceive their health as better.

Self-health assessments conducted in the previously cited study of olderpatients with schizophrenia in New York City supported the conclusionsof the PORT study. Identical percentages of persons in the schizophreniasample and the community comparison sample rated themselves in poor/fair health (33%) or good/excellent health (67%), which was consistentwith the findings that they had a similar number of physical disorders (C.I.Cohen, unpublished data). Thus, older patients with schizophrenia seemable to provide reasonable assessments of their overall health.

Treatment IssuesPharmacokinetic FactorsBecause older patients with schizophrenia are usually taking antipsy-chotic medications, the addition of drugs for physical disorders or other


psychotropic drugs requires a sophisticated understanding of the po-tential risks for adverse effects. In this section, we summarize some ba-sic concepts of pharmacokinetics and pharmacodynamics as they affectolder persons in general.

Pharmacokinetics, or how a drug moves through the body, becomesincreasingly important as people age. Age affects the absorption, distri-bution, metabolism, and elimination of medications to varying degrees(Jacobson et al. 2002). Absorption may be affected by physiologicalchanges associated with aging, which include decreased gastric acidity,a decline in small bowel surface area, and diminished blood flow to thesmall bowel, although no clinically significant decreases in drug ab-sorption attributable to aging have been reported. However, use of ant-acids, fiber supplements, or anticholinergic agents may slow drugabsorption and the onset of medication action.

The distribution of drugs to peripheral sites is substantially affectedby aging, because adipose tissue increases and lean body mass de-creases. Thus, older bodies have a larger volume of distribution forfat-soluble drugs, which includes nearly all psychotropic medications.Several consequences result from this age-related change. The half-lifeof lipophilic drugs increases, leading to accumulation of drugs takenchronically and greater potential for toxicity, and increased uptake inthe peripheral sites (e.g., fat tissues) may result in less of the drug reach-ing the brain and potentially a shorter duration of drug action after asingle dose than seen in younger persons. Conversely, total body waterdecreases with age so that the volume of distribution of water-solubledrugs decreases and more of the drug is present in the circulation andproportionately more reaches the brain. Thus, water-soluble drugs(e.g., ethanol and lithium) may have increased effects in older persons.Elderly persons also have a diminished lean body mass so drugs (e.g.,digoxin) that bind to muscle may show increased concentrations at anygiven strength. Finally, the concentration of plasma proteins such asalbumin tends to decrease in older persons, and this decline may be fur-ther exacerbated by physical illness and poor nutrition. For protein-bound drugs, lower albumin concentrations affect the free fraction(percent bound vs. unbound) but do not affect the measured total drugconcentration. The principal concern is that laboratory measurement ofdrug concentration is based on total drug concentrations; therefore,where the free fraction is high because of lower albumin levels, the mea-sured concentration of the drug will underestimate the amount of ac-tive drug at the target organ. This is important in assessing blood levelsof highly protein-bound drugs (e.g., digoxin, warfarin, theophylline,and phenytoin) with narrow therapeutic indices.


The rate of drug metabolism by the liver is determined by hepaticfunction and blood flow. Hepatic mass and functioning hepatocytes de-crease with age, and hepatic blood flow is reduced by 0.3%–1.5% peryear after age 25 (Chutka et al. 1995). This results in a substantial reduc-tion in the first-pass metabolism of a drug through the liver, so more ofthe active drug remains available. Phase I hepatic metabolism is per-formed by the microsomal oxidase cytochrome P450 (CYP450) system.Initially, these oxidative conversions may produce pharmacologicallyactive metabolites, and subsequent oxidations produce progressivelymore water-soluble compounds that can be excreted by the kidneys andgut. Some of the cytochrome enzymes are affected by aging, most nota-bly CYP1A2 and CYP3A4 (Jacobson et al. 2002). The latter is one of themost abundant of the CYP enzymes and is important in the metabolismof a wide variety of drugs (e.g., retroviral agents, antibiotics, antifun-gals, quinidine, calcium channel blockers, statin drugs, various seroto-nin reuptake inhibitors, and several antipsychotics including haloperi-dol, quetiapine, clozapine, ziprasidone). The CYP1A2 enzyme isinvolved in the metabolism of clozapine, olanzapine, theophylline, andcaffeine, whereas CYP2D6 is involved in the metabolism of many anti-psychotics (e.g., risperidone), antidepressants, mood stabilizers, anal-gesics, and beta blockers, and does not seem to be affected by age.

Phase II hepatic metabolism involves the conjugation of drugs ortheir metabolites with glucuronide, sulfate, or acetyl moieties to producepolar, pharmacologically inactive, hydrophilic compounds that can beexcreted. These processes are typically not affected by normal aging, al-though they may be slowed by malnutrition and extreme old age.

Clearance depends on the removal of a drug from systemic circula-tion by the liver and kidney. As noted above, age-associated declines inhepatic function and blood flow affect liver clearance, whereas age-associated reductions in renal blood flow and glomerular filtration rateaffect kidney clearance. Renal blood flow and glomerular filtration rateare reduced about 35%–40% in the elderly compared with normalyounger persons. Thus, clearance of various drugs that undergo renaleliminations such as digoxin, gentamicin, procainamide, gabapentin, orlithiums will be affected by aging.

Pharmacodynamic FactorsPharmacodynamics, which is the end-organ responsiveness to medica-tions, is also affected by aging, although it has been much less studiedthan pharmacokinetic changes. Some of the pharmacodynamic changesnoted with aging, depending on the type of medication, include


reduced density of muscarinic, opioid, and D2 dopamine receptors;impaired ability to up-regulate and down-regulate postsynaptic recep-tors; reduction in most enzyme activities affecting neurotransmitters;and increased or decreased receptor sensitivity (Jacobson et al. 2002).The clinical conclusion is that older persons are more susceptible to theadverse effects of medications, particularly of psychotropic drugs.Among the principal effects are the following (Zubenko and Sunder-land 2000):

• Peripheral anticholinergic effects, such as memory impairment, drymouth, constipation, blurred vision, and urinary retention

• Central nervous system effects (anticholinergic and antihistaminic),such as confusion, sedation, and memory impairment

• Motor effects, such as tremor, impaired gait, extrapyramidal symp-toms, falling, and postural instability

• Cardiovascular effects, such as orthostatic hypotension, cardiac con-duction delays, and tachycardia

• Miscellaneous effects, which include gastrointestinal disturbances,headache, agitation, sexual dysfunction, hyponatremia, and im-paired insulin response

Pharmacogenetic FactorsThe newest genetic research regarding both schizophrenia and its treat-ment has adumbrated several promising avenues for clinical care. Ge-netic single-nucleotide polymorphisms have been discovered at everylevel of the pathophysiological pathway of schizophrenia, from thegenes that predispose patients to the disease and particular manifesta-tions and symptomatology, to the genes that are involved with the pa-tient’s ability to respond to medication, to the genes that predisposecertain patients to particular side-effect profiles. Thus, the pharmacoge-netic considerations may eventually shape clinicians’ understanding ofboth the pharmacokinetic and pharmacodynamic aspects of psycho-pharmacology in the elderly schizophrenia population.

Some experimental techniques have been reported in the literatureas methods of evaluating the consistency of pharmacotherapy exposureby measuring population pharmacokinetics. Determination of expectedantipsychotic levels is useful for a clinician in deciding whether a pa-tient has been adherent to medication or has an atypical pharmacoki-netic profile (Bies et al. 2002). By elucidating polymorphisms in CYP450genes that affect the metabolism of antipsychotic drugs (Dahl 2002), re-searchers have been able to clinically characterize CYP polymorphisms,


resulting in the status of patients as poor metabolizers, slow metaboliz-ers, or ultrarapid metabolizers (Arranz and de Leon 2007; Fang andGorrod 1999). Patients who are poor or slow metabolizers will requirelower antipsychotic dosages, whereas patients who are ultrarapid me-tabolizers will require increased drug dosages (Arranz and de Leon2007; de Leon et al. 2005; Ozaki 2004). Although some centers are begin-ning to use such markers, it remains to be seen whether these markerswill be used routinely for determining dosing levels in those patientswho might be particularly sensitive or unresponsive to an atypical an-tipsychotic medication.

Research concerning the relationship between genetic polymor-phisms for receptor types and patients’ responsiveness to medicationsis also in its infancy; however, investigators continue to identify prom-ising candidates for clinically relevant genetic testing. A variety of re-ceptor types, especially dopamine receptors, have been found to becorrelated with antipsychotic response (Potkin et al. 2003; Reynolds etal. 2005; Xing et al. 2007; Zhao et al. 2005); moreover, proteins that inter-act with dopamine receptors (e.g., dopamine receptor–interacting pro-tein, molecular transporters at the blood-brain barrier) have beenelucidated (Lin et al. 2006; Strous et al 2007; Yasui-Furukori et al. 2006).Finally, certain genetic markers have been linked to enhanced drug ef-ficacy and side effects (Arranz and de Leon 2007; Campbell et al. 2008;Malhotra et al. 2007). All these discoveries need to be assessed with re-spect to age; however, they may provide additional tools in navigatingthe narrow pathway between therapeutic efficacy and adverse effects ingeriatric pharmacotherapy.

Drug InteractionsBecause at least 90% of persons ages 65 years and older take at least onemedication daily, and most take two or more (Chutka et al. 1995), clini-cians need to be aware of various mechanisms underlying drug interac-tions. Potential kinetic interactions may be due to 1) effects of one drugon the metabolism of the other so that blood levels of one or both drugsmay be raised or lowered, thereby producing a transient increase in thefree concentrations of one or both drugs through competition for pro-tein binding sites, or 2) concomitant administration of two drugs withsimilar side-effect profiles, which could exacerbate the level of adverseeffects (pharmacodynamic effects). Thus, several key points emergewith respect to the use of medications, particularly the coadministra-tion of antipsychotic agents with other medications, in older personswith schizophrenia:


1. Determine whether the patient has any hepatic, renal, neurological,nutritional, or other medical disorders that are likely to enhancemedication side effects.

2. Determine whether any newly prescribed drug is an inhibitor or in-ducer of CYP enzymes that are involved with the clearance of thepatient’s antipsychotic medication.

3. Review the side-effect profile of any new medication to be sure thatit does not add to the side effects of the patient’s antipsychotic med-ication. For example, the anticholinergic effects of tolterodine (De-trol) may enhance the anticholinergic effects of olanzapine orclozapine.

4. Obtain baseline measures and periodically monitor electrocardio-grams; white cell counts; serum sodium; fasting glucose, triglycer-ides, and cholesterol; weight; and vital signs including bloodpressure sitting and standing—values that should be watched dueto an increased propensity of various antipsychotic agents to affectcardiac conduction, induce leukopenia, create insulin resistanceand glucose intolerance, cause hyponatremia, induce hyperlipi-demia, and produce orthostatic hypotension. Other drugs that canalso affect these indices should be used cautiously and may requireeven more frequent monitoring.

5. Monitor medication blood levels, taking into account low levels ofalbumin or competition between highly bound drugs. If one ofthese situations is present, the total concentration of the drug(which is the result reported by the laboratory) may remain thesame, although the free drug concentration has increased. Thiscould result in toxicity at seemingly therapeutic dosages of themedication.

6. Be aware that the increasingly complicated medication regimens ofolder adults result in decreased patient medication adherence.Work with primary care physicians to coordinate and simplify thetreatment regimens of older adults with schizophrenia (Piette et al.2007).

Health Care IssuesBecause of the psychiatric and medical requirements of older individ-uals with schizophrenia, their health care costs are among the highestfor any disorder that affects the geriatric population. Bartels et al.(2003) found that Medicaid and Medicare expenditures for patientswith schizophrenia ages 65 and older exceeded those of persons with


dementia, depression, or “medical disorders only.” According to find-ings from the PORT study, in which one-sixth of the patients withschizophrenia were ages 55 and older, more than 30% of the patientswho reported current physical problems, with the exception of diabetesand hypertension, were not receiving treatment for those problems(Dixon et al. 1999).

A variety of patient, physician, and systemic factors have been iden-tified as potential impediments to health care for persons with schizo-phrenia in general. For example, patients may lack insight into aphysical condition, have impaired ability to communicate with a physi-cian, or have emotional or behavioral problems that interfere with anevaluation. Also, physicians may be more apt to conduct inadequatephysical examinations, take a poor history, fail to repeat labs or othertests as needed, misinterpret physical symptoms as manifestations ofpsychosis, or passively accept consultative recommendations (Felker etal. 1996).

Systemic factors may also affect health care, especially among olderpatients with schizophrenia. Many older persons with schizophreniareceive Medicaid, either alone or with Medicare. However, Medicaidreimbursement, eligibility requirements, and coverage vary widelyacross the nation, and Medicaid generally lacks the flexibility in choiceof provider that may be available with Medicare alone. Medicaid pa-tients are often relegated to public sector health programs that are over-crowded and not well equipped to deal with older persons with psychi-atric problems. On the other hand, persons who receive only Medicarehave virtually no coverage for psychiatric day programs, prescriptionmedications, home attendants, case management, home visits, trans-portation, and other essential outpatient services. Slade et al. (2005) re-ported that patients who received only Medicare were 25%–45% lesslikely to have utilized case management, rehabilitation services, and in-dividual therapy with nonpsychiatrist mental health providers thanwere patients with schizophrenia in private mental health treatment or-ganizations. The authors concluded that the discrepancy in patient costsharing and gaps in Medicare coverage account for the different pat-terns of patient utilization of services. Moreover, outpatient psychiatrictreatment by Medicare patients requires a 50% copayment. Thus, Medi-care copayments for outpatient psychiatric treatment continue to be2.5 times those for other medical specialties, and reimbursable servicesare heavily weighted toward inpatient care.

Differential treatment also occurs regarding the types of medicationsthat are prescribed to patients with schizophrenia who have public ver-sus private insurance. Sankaranarayanan and Puumala (2007) found


that patients with schizophrenia who were older (ages 41–64 years)versus younger (ages 18–40 years) and those with public as opposedto private insurance were, respectively, 39% and 41% less likely toreceive atypical versus typical antipsychotic medications. The impactof the new Medicare drug benefit on persons with schizophrenia hasnot yet been fully assessed. Studies prior to the introduction of the newMedicare drug benefit found that beneficiaries with both Medicare andMedicaid were significantly more likely to receive their requisite anti-psychotic medication than their Medicare-only peers (Yanos et al.2001).

Despite the concerns about inadequate health care for persons withschizophrenia, data from the previously cited New York City study ofolder persons with this diagnosis suggested a more nuanced picture.Eighty-nine percent of the sample had seen a physician other than apsychiatrist in the previous year, and roughly one-third visited a phy-sician on a monthly basis (C.I. Cohen, unpublished data). Visits to non-psychiatric health care providers by patients with schizophrenia wereactually somewhat greater than similar visits by individuals in the com-munity comparison group. Only 11% of the patients with schizophreniafelt that they required more frequent medical services. In addition, 48%of this sample had seen a dentist in the past year. On the other hand,among persons with at least one of four common medical problems(heart disease, diabetes, hypertension, gastrointestinal ulcers), the pa-tients with schizophrenia were significantly less likely than their agepeers to receive medication treatment for two of these conditions (i.e.,hypertension and heart disease) (Vahia et al. 2008). Thus, older urbanoutpatients with schizophrenia have access to treatment but not neces-sarily adequate care. Access to treatment was facilitated by the avail-ability of health insurance (Medicare and Medicaid in most instances),easier access to public transportation and ambulette services, wideravailability of home attendant services to assist patients and to accom-pany them to medical visits, and their participation in programs thatencouraged physical assessments. Notably, a lack of adequate treat-ment was found to be associated with more positive symptoms andmore depression. Thus, clinical symptoms may play a role in affectingtreatment (Vahia et al. 2008). Because distance to health care may affectuse of services among persons with serious mental illness (McCarthyand Blow 2004), the aforementioned findings regarding accessibilitymay be applicable only to those older patients living in urban settings.

In an exploratory study in New York City, Jones et al. (2008) foundthat primary care physicians’ anticipated behavior toward older adultswith schizophrenia was favorable, although some mild negative stereo-


typing and attitudes were present. More important, communication ofinformation about the patient, especially from psychiatrist to primarycare provider, was identified as a problem and may account for some ofthe problems in adequacy of care. The authors recommended a double-pronged approach to facilitate interdisciplinary communication alongwith an expansion of medical education programs regarding the care ofaging adults with schizophrenia.

With the expansion of managed care programs for Medicaid andMedicare recipients, a critical issue will be whether persons withschizophrenia will be better off in so-called carved-in or carved-out pro-grams (Cohen et al. 2000). The former provides mental health coverageas part of an overall package. The potential advantage is better in-tegration of medical and psychiatric care, and older persons in theseprograms might have greater access to preventive as well as ongoingmedical care. The disadvantage is that such programs may underfundpsychiatric treatment and attempt to exclude those persons with moresevere and persistent mental disorders. The carved-out programs allowfor separate coverage for physical health and psychiatric care. The ad-vantage is that such programs, if adequately funded, may allow formore appropriate services for older patients with chronic psychiatricillness. The disadvantage is that the potential integration of health andpsychiatric services is lost.

At the practical level, psychiatric clinicians may have to employ a va-riety of strategies to enhance medical care of older persons with schizo-phrenia. First, they should try to ensure that all persons eligible forMedicaid apply for such services because it can fill many of the gaps inservices not provided by Medicare, such as prescription medication,home care services, day treatment, psychosocial rehabilitation, and soforth. In many instances, persons may be eligible for “buy-ins” for Med-icaid based on their monthly medical expenditures. Second, cliniciansshould ensure that all patients obtain the optimal Medicare Part D drugplan. Because plans vary with respect to which drugs are covered, pa-tients and clinicians must work together to select the optimal plan foreach patient. For those not on Medicare, or for patients entering theMedicare “doughnut hole” where drug reimbursement is reduced, cli-nicians can work with patients to obtain free medications through pa-tient assistance programs offered by most pharmaceutical companies orthrough enrollment in state-operated prescription programs for seniors(e.g., the Elderly Pharmaceutical Insurance Coverage program in NewYork). Some of these programs allow eligible persons to have annual in-comes as high as $35,000 and, unlike Medicaid, do not count personalassets. In many communities, public and voluntary health facilities may


offer care with sliding scales that may include prescription medications,and the VA is an excellent, low-cost option for eligible veterans.

For older patients who are resistant to seeking formal medical care,clinicians can use a number of potential strategies. First, an arrange-ment might be made for a primary care doctor, physician’s assistant,nurse practitioner, or phlebotomist to provide services at a mentalhealth facility, particularly if the professional can see multiple patientsduring a single time block. Some health services can be arranged at pa-tients’ homes through mobile health units, local medical laboratories,and the visiting nurse services; the latter can arrange for physical ther-apy in the home, medication monitoring, and home health aides forphysical health problems of limited duration. In general, these homehealth services are covered by Medicare. Finally, psychiatrists mayneed to serve temporarily as primary care doctors for their older pa-tients until suitable ongoing health care services can be arranged. Theextent to which a psychiatrist should serve as a primary care physicianremains controversial, although many geropsychiatrists routinely con-duct periodic physical assessments of their patients, and it is not diffi-cult to oversee the management of uncomplicated common medicalproblems such as hypertension, gastritis, osteoarthritis, or non-insulin-dependent diabetes.

Finally, capacity and competency can be thorny problems in the caseof older persons with schizophrenia. A judgment about a person’s ca-pacity is made by a clinical evaluator concerning the person’s functionalability to make independent, authentic decisions about his or her life,whereas a judgment about competency is made by the court about suchabilities (Grossberg and Zimny 1996). When the person is competent, heor she may create a legal document (power of attorney) designatingsomeone to act on his or her behalf if the person becomes incompetentto do so. Alternatively, the older person may sign a health care proxy,designating someone to act on his or her behalf regarding medical mat-ters and end-of-life decisions. If prior arrangements have not beenmade, surrogate management arrangements can be establishedthrough the use of a representative payee, guardian, or conservator.

Issues of competency are more problematic for older individualswith schizophrenia because the demarcation of incapacity becomesmurkier. In younger patients with schizophrenia, incapacity is typicallydue to psychotic processes, although substance abuse can confound theetiology of the disturbance. In older patients with schizophrenia, inaddition to the effects of psychoses, the effects of neuropsychologicaldeficits and medical disorders must be carefully considered. Althoughas many as three-fourths of patients with schizophrenia evince some


neuropsychological deficits within the first few years of their illness,roughly one-fifth of persons with schizophrenia have a very poor long-term outcome with respect to psychopathology and cognition (Davis2002). In their 7th and 8th decades of life, such persons reach levels ofcognitive deficits comparable to persons with moderate to severeAlzheimer’s disease, although no neuropathology of the latter ispresent (Davis 2002). In a larger group of patients with schizophrenia,as part of the normal aging process, some modest decline in cognitivefunctioning occurs (Cohen and Talavera 2000). Because many of thesepersons also had some mild cognitive deficits at the onset of their ill-ness, this further decline in cognitive functioning with age places manyolder patients with schizophrenia into a level comparable with mild tomoderate dementia.

Researchers have shown that the strongest correlates of capacity,particularly of understanding and appreciation of information, are cog-nitive test scores. However, negative symptoms are also correlated withdiminished capacity, such that clinicians should be aware of their po-tential impact (Palmer and Jeste 2006). Moreover, in patients withschizophrenia who have mild and severe cognitive impairments, cogni-tive status can be worsened by undiagnosed or poorly treated medicalconditions, increased sensitivity to psychotropic and other medica-tions, adverse drug interactions, small vessel disease in the brain, sen-sory impairments, or lack of environmental stimulation and isolation.Although older patients with schizophrenia often show considerableimprovement in their psychopathology, especially positive symptoms,they remain functionally impaired because of cognitive deficits. More-over, unlike Alzheimer’s disease in which cognitive decline is more ap-parent over a few years, cognitive decline in schizophrenia is insidious,and clinicians may not be aware that a patient’s cognitive functioninghas become grossly abnormal.

Thus, apart from their risk of developing a primary dementia such asAlzheimer’s disease or vascular dementia, a risk that is no higher thanthat of their age peers, older patients with schizophrenia may developdiminished capacity due to the following: psychoses, cognitive decline,and medical or environmental factors. Although any of these factorsalone may not be sufficiently severe to reach levels to affect compe-tency, several factors occurring in concert may result in more pro-nounced deficits. Therefore, the practicing clinician should regularlymonitor the cognitive status of older patients with schizophrenia (e.g.,using Folstein et al.’s [1975] Mini-Mental State Examination); carefullyreview laboratory results, especially those that may be more likely to af-fect cognition (e.g., B12, folate, thyroid indices, sodium, glucose, blood


levels of lithium and other mood stabilizers); and be vigilant for anydrug interactions that might affect cognition. Some researchers havesuggested that as an alternative to the Mini-Mental State Examination,a targeted brief questionnaire can be used as a screening tool for capac-ity (Palmer et al. 2005). Because they are at increased risk for diminishedcapacity, middle-aged and elderly patients with schizophrenia who arecurrently competent should be encouraged to complete a health careproxy or to establish a power of attorney.

ConclusionAlthough patients with schizophrenia in general are thought to haveworse physical health than their age peers, available data suggest thatcompared to their age peers, older persons with schizophrenia in treat-ment programs do not have more physical problems, whereas the se-verity of their medical conditions may be slightly worse. Althougholder adults with schizophrenia consider health a top priority (Lester etal. 2003), their ability to receive optimal health care is often caught be-tween the Scylla of psychiatrists who may disregard physical problemsbecause they believe that the primary care physician is addressingthem, and the Charybdis of primary care physicians who may find thattheir physical assessments are confounded by patients’ mental disor-ders (Lambert et al. 2003).

Key Clinical Points

◗ Clinicians must ensure that older patients with schizophrenia are ap-propriately and regularly screened for medical conditions and diseases.

◗ Frequent communication between medical and psychiatric treatmentteams caring for older persons with schizophrenia must become an es-sential part of an adequate standard of care. Some pilot studies haveused health care managers to facilitate communication among healthproviders as well as to enhance patient adherence to medical and psy-chiatric regimens (Bartels et al. 2004).

◗ Clinicians must be cognizant of the pharmacokinetic changes associatedwith aging, especially decreased clearance and potential drug-druginteractions, and the pharmacodynamic changes associated with aging,particularly heightened sensitivity to certain medication side effects.


◗ Although a high proportion of older patients with schizophrenia maysee a nonpsychiatric physician (perhaps due to the availability of Medi-care and Medicaid), psychiatrists need to develop alternative ap-proaches to ensuring health care for these patients, including use ofmobile health teams, home phlebotomy, visiting nurse services, and theadoption of a primary care role.

◗ Although positive symptoms tend to decline with age, many older pa-tients with schizophrenia have appreciable levels of cognitive impair-ment that can be exacerbated by medical illness, medication sideeffects, environmental understimulation, and psychosis. To avoid fu-ture problems related to competency, clinicians are advised to encour-age currently competent middle-aged and elderly patients withschizophrenia to complete a health care proxy or to establish a powerof attorney.

◗ In tandem with the changes in the number and ethnic diversity of olderpersons with schizophrenia that will occur over the next two decades(Cohen et al. 2008), a dramatic increase in research is needed to ad-dress the huge gaps in knowledge concerning the health needs andtreatment of aging persons with schizophrenia.

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CHAPTER 15

Managing HealthOutcomes of Women

With SchizophreniaDuring Pregnancyand Breastfeeding

Adele C. Viguera, M.D., M.P.H.Mackenzie Varkula, D.O.Katherine Donovan, B.A.

Ross J. Baldessarini, M.D.

Schizophrenia occurs in approximately 1% of women in the gen-eral population, and the disorder most commonly begins or is presentduring the childbearing years (Seeman 2008). Its prevention and treat-ment are particularly important and can be complicated for women whoare pregnant or nursing. However, remarkably little is known about theimpact of the female reproductive life cycle—the menstrual cycle, preg-nancy, postpartum period, nursing, and menopause—on the course ofschizophrenia (Miller 1997; Miller and Finnerty 1998; Seeman 2008). Phy-sicians caring for pregnant women with schizophrenia face a complexclinical challenge in trying to minimize risk to the fetus while limiting the


impact that maternal morbidity, which might result from potentially se-vere untreated psychiatric illness, would have on the mother, her unbornoffspring, and her family. Effective care of women with schizophrenia orother psychotic disorders has the potential to improve outcomes of preg-nancy and delivery, and to limit adverse effects on the fetus and new-born (Seeman 2008). In this chapter, we consider information about thecourse of schizophrenia during pregnancy and the postpartum period,the reproductive safety data of antipsychotic drugs, and the safety oftheir use during breastfeeding. We also consider treatment guidelines forimproved clinical care of pregnant women with schizophrenia.

Outcomes of Sexuality, Reproduction, and Family Planning Among Women With SchizophreniaThe reproductive and family planning needs of women with schizo-phrenia appear to be poorly met by most contemporary health care de-livery systems (Miller and Finnerty 1998; Seeman 2008). Althoughfertility rates in women with schizophrenia are lower than in the gen-eral population, the majority of women with schizophrenia have chil-dren (Howard 2005; Howard et al. 2001; Svensson et al. 2008). Thistrend may be due to deinstitutionalization and greater prescribing ofthe atypical antipsychotics that do not suppress the hypothalamic go-nadal axis. Also, compared with women without mental illness, womenwith schizophrenia experience higher rates of unplanned and un-wanted pregnancies, and are more likely to be victims of sexual abuse,exploitation, and violence during pregnancy (Miller 1997; Miller andFinnerty 1998). Moreover, women with schizophrenia tend to be lessknowledgeable about or attentive to use of contraception, and they en-counter more obstacles in using and obtaining birth control (Miller andFinnerty 1998). They are also less likely to receive prenatal care andmore likely to abuse alcohol or drugs or to smoke heavily (Bennedsenet al. 1999; Howard 2005; Miller 1997; Sacker et al. 1996). Studies also in-dicate that the majority of women with schizophrenia lose custody oftheir children because they have difficulty meeting their children’s ba-sic needs (Miller and Finnerty 1998; Seeman 2008). In addition, they areless likely to have another caregiver or partner helping to raise theirchildren (Miller and Finnerty 1998).

Women with psychiatric illness generally, and schizophrenia in par-ticular, may encounter significant obstacles from the professional com-

Health Outcomes During Pregnancy and Breastfeeding 417

munity in planning for pregnancy, and are often counseled to avoidbecoming pregnant or to terminate an established pregnancy so as toprevent fetal exposure to potentially teratogenic medications or toavoid the risk of recurrent illness or symptom exacerbation (Einarson etal. 2001; Viguera et al. 2002). Women with schizophrenia who pursuepregnancy, even those with frequently exacerbated or chronic illnesses,may risk illness by discontinuing treatment after conception and arelikely to perceive psychotropic drugs as more dangerous or less neces-sary than other medications during pregnancy (Bonari et al. 2005; Co-hen et al. 2006; Coverdale et al. 2002; Einarson et al. 2001). In addition,women with chronic mental illness are often treated with multiplemedications in contemporary U.S. psychiatric practice (Centorrino et al.2008; Peindl et al. 2007). Despite the high rates of polypharmacy, manypatients receive suboptimal treatment for psychiatric illnesses (Howard2005; Peindl et al. 2007).

Maternal Outcomes During Pregnancy and the Postpartum PeriodWhether pregnancy favorably or unfavorably affects the risk of psy-chiatric decompensation in women with schizophrenia is surprisinglyuncertain (Howard et al. 2004; McNeil et al. 1984). Some clinical obser-vations suggest that pregnancy may reduce the risk of acute psychiatricillness and specifically protect against exacerbation of psychotic dis-orders and suicide (Marzuk et al. 1997; Nott 1982; Pugh et al. 1963;Terp and Mortensen 1998). Other studies have found rates of psychiat-ric hospitalization to be either somewhat lower or unchanged duringpregnancy (Kendell et al. 1987; Lier et al. 1989). A few reports suggestthat some women with schizophrenia are less likely to decompensateduring pregnancy than during the postpartum period, whereas otherreports indicate improvement in psychotic symptoms during preg-nancy (Lier et al. 1989; Trixler et al. 1995). Nevertheless, several reportshave noted that the majority of women with schizophrenia (over 60%)experienced symptom exacerbation during pregnancy, especially whenmaintenance medication was discontinued (Casiano and Hawkins1987; McNeil et al. 1984; Nishizawa et al. 2007).

Previous studies have suggested that women with schizophrenia donot experience an increased risk for symptom exacerbation in the post-partum period, somewhat contrary to the findings of high rates of symp-tom exacerbation during the postpartum period in women with moodand anxiety disorders (Davies et al. 1995; Kendell et al. 1987; McNeil 1986;


Terp and Mortensen 1998). However, other findings suggest that thepostpartum period is indeed a period of high risk for psychotic relapse inwomen with schizophrenia. Findings from one study indicated that atleast 50% of women with schizophrenia experienced an exacerbation oftheir psychotic illness (Howard et al. 2004). In a prospective study ofwomen with psychotic disorders, 24% of women with schizophrenia be-came acutely psychotic within 6 months postpartum (McNeil 1986, 1987).

Other researchers have noted that women with schizophrenia whopresent with an affective component are at especially high risk of post-partum relapse (Davies et al. 1995). When relapse or exacerbation oc-curs, women with schizophrenia tend to experience these episodesmuch later in the postpartum period and to have significantly longerhospitalizations compared with women who have mood disorders(McNeil 1987). Despite the potential increased risk for recurrence dur-ing the postpartum period, no studies have specifically examined therole of postpartum prophylaxis with antipsychotics.

Another important finding regarding postpartum illness course isthat women with schizophrenia appear to be at a twofold increased riskfor developing postpartum depression compared with controls(Howard 2005). This observation has important clinical implications forwomen with schizophrenia, because maternal depression itself may ad-versely affect child development (Murray and Cooper 1997; Newport etal. 2002). In contrast, compared with women with affective disorders,women with schizophrenia are at lower risk of developing postpartumpsychosis, a rare but potentially dangerous condition for the motherand her infant (Howard 2005).

Given that little evidence supports a protective effect of pregnancyagainst exacerbations of schizophrenia, it is important to consider thegrowing findings in nongravid women that indicate a high risk of relapseassociated with discontinuation of maintenance antipsychotics (Baldes-sarini et al. 1999; Suppes et al. 1997; Viguera et al. 1997, 1998). For example,among patients with schizophrenia, approximately half experience clini-cally important exacerbations of symptoms within 6 months of discon-tinuing antipsychotic treatment (Viguera et al. 1997). This risk is muchhigher and earlier following abrupt rather than gradually tapered discon-tinuation of antipsychotic drugs (Baldessarini et al. 1999; Viguera et al.1997). Similar findings have been noted in patients diagnosed with unipo-lar major depression, bipolar disorder, and anxiety disorders who arewithdrawn from maintenance medications, especially when discontinua-tion occurs rapidly or abruptly, as is common early in pregnancy due tothe desire to avoid adverse drug effects on fetal development (Suppes etal. 1997; L.Tondo et al., unpublished data, 2008; Viguera et al. 1997, 1998).


In light of these findings, the cessation during pregnancy of ongoingpharmacotherapy used to treat schizophrenia must be viewed as poten-tially dangerous. Inadequately treated maternal psychiatric illness mayresult in poor prenatal care and nutrition, exposure to additional drugsor herbal remedies, increased use of alcohol and tobacco, deficits inmother-infant bonding, and disruption within the family environment(ACOG Committee on Practice Bulletins—Obstetrics [ACOG] 2008).Accordingly, decisions to discontinue maintenance treatment shouldbe made only after careful consideration of the potential negative im-pact of untreated illness on maternal and fetal outcomes (Newport et al.2002; Weissman et al. 2006).

Risk of Obstetric ComplicationsCompared to women in the general population, those with schizophre-nia, especially if the illness is acutely symptomatic, are at increased riskfor obstetrical complications (Nilsson et al. 2002; Sacker et al. 1996;Wrede et al. 1980). These complications include a broad spectrum of ad-verse pregnancy outcomes, including fetuses that are small for ges-tational age, preterm delivery, low-birth-weight infants, placentalabnormalities and antenatal hemorrhage, increased rates of congenitalmalformations (especially cardiovascular system), and higher inci-dences of stillbirth or neonatal death and sudden infant death syn-drome (Bennedsen et al. 1999, 2001; Jablensky et al. 2005; Nilsson et al.2002; Wrede et al. 1980).

Women with schizophrenia are also at increased risk for labor induc-tion, assisted vaginal delivery, and cesarean section (Bennedsen et al.2001; Reis and Kallen 2008). Causes of such obstetrical outcomes arecomplex and may include effects of compromised socioeconomic cir-cumstances and inferior clinical and self-care during pregnancy, in ad-dition to possible effects of abused substances or psychotropic drugs(Howard 2005; Miller 1997). Given an association between a history ofobstetrical complications and greater lifetime risk of schizophrenia,prevention of obstetrical complications through improved prenatalcare might also limit future risks of mental illness in the offspring ofwomen with schizophrenia (Howard 2005; Seeman 2008).

Potential Risks of PharmacotherapyAll psychotropic medications diffuse readily across the placenta andthe blood-brain barrier, and no psychotropic drug has been approved


by the U.S. Food and Drug Administration (FDA) for use during preg-nancy. For ethical reasons, conducting randomized placebo-controlledstudies on medication safety in pregnant women is virtually impossi-ble. Accordingly, most information about the reproductive safety ofdrugs derives from case reports, case series, and retrospective studies,and few reports involve prospective designs (ACOG 2008; Altshuler atal. 1996). To guide physicians seeking information about the reproduc-tive safety of various prescription drugs, the FDA has established a sys-tem that classifies medications into five risk categories (A, B, C, D, andX) based on data derived from human and animal studies (Table 15–1).Category A medications are designated as safe for use during preg-nancy (no psychotropic drugs currently have this rating), whereas cat-egory X drugs are contraindicated by having demonstrated fetal risksthat outweigh any benefit to the patient. Drugs in Categories B, C, andD are considered to have intermediate risks, which increase from B toD. Most psychotropic drugs are classified as category C, agents forwhich adequate human studies are lacking and for which risk cannot beruled out and clinical judgment is required to balance potential risksand benefits. Experience has shown, however, that the FDA’s preg-nancy categories for drugs do not correlate well with information onteratogenicity from other sources and are not informative in clinicalpractice (Holmes et al. 2004; U.S. Food and Drug Administration 2001).Recently, the FDA proposed major revisions to prescription drug label-ing to provide more accurate and helpful information on the effects ofmedications used during pregnancy and breastfeeding (U.S. Food andDrug Administration 2008). At present, prescribers and patients are leftto rely on limited peer-reviewed studies and treatment consensusguidelines sponsored by professional organizations as sources of infor-mation when recommending the use of psychotropic medications dur-ing pregnancy (ACOG 2008).

An important realization is that random fetal anomalies are remark-ably common in the general population and represent a high back-ground rate against which to compare teratogenic effects suspected asbeing related to exposure to psychotropic agents. The baseline inci-dence of major congenital malformations in newborns in the UnitedStates is approximately 2%–4% (Holmes et al. 2002). Basic formation ofmajor organ systems takes place early in pregnancy and is virtuallycomplete within the first 12 weeks after conception. However, preg-nancy is often not diagnosed for 6–8 weeks, during which time criticalsteps in major organ development have already occurred. Teratogensare chemical agents, including drugs, that interfere with organ develop-ment to produce malformations of varying severity. Each organ system


appears to be vulnerable to teratogenic effects during relatively specificand limited time periods during the first trimester.

Fetal Risks Associated With Medications Used to Treat SchizophreniaReproductive safety of typical or first-generation neuroleptics, such aschlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine,and trifluoperazine, is supported by extensive data accumulated overthe past 50 years, especially from experience in using such agents to treathyperemesis gravidarum (Altshuler et al. 1996; Einarson 2005; Trixler etal. 2005). No significant teratogenic effect has been documented withchlorpromazine, haloperidol, and perphenazine, in particular (ACOG2008). However, one meta-analysis found a small increase in the relativerisk of congenital malformations in offspring exposed to low-potencytypical antipsychotics compared with high-potency antipsychotics (Alt-shuler et al. 1996). In general, the higher- and mid-potency typical anti-psychotics (e.g., haloperidol, perphenazine) tend to be recommendedbecause they are less likely than lower-potency antipsychotics to haveassociated sedative or hypotensive effects (Altshuler et al. 1996; Diav-Citrin et al. 2005).

TABLE 15–1. FDA classification of teratogenic drug risk

Category Description of risk

A No fetal risk shown in controlled human studies

B No human data available, and animal studies show no fetal risk, or animal studies, but not human studies, show fetal risk

C No controlled studies on fetal risk available for humans or animals, or fetal risk is found in controlled animal studies with no human data (benefit of drug use must clearly justify potential fetal risk in this category)

D Studies show fetal risk in humans (use may be acceptable even with risks, such as in life-threatening illness or where safer drugs are ineffective)

X Risk to fetus clearly outweighs any benefits from these drugs

Source. U.S. Food and Drug Administration 2001.


A report from the Swedish Medical Birth Register examined malfor-mation rates among 576 infants exposed to antipsychotics, includingtypical and atypical agents (Reis and Kallen 2008). The overall odds ratiofor clinically significant malformations among exposed infants was 1.52(95% CI 1.05–2.19). Specifically, among the first-generation antipsychot-ics, this risk was 4.8% overall (by class: butyrophenones, 2.50%; phe-nothiazines, 2.75%; thioxanthenes, 7.20%), with somewhat lower riskswith second-generation antipsychotics and no statistically increased riskwith any particular drug. These findings suggest a modest increaseabove the baseline malformation rate. However, these findings are lim-ited by the relatively small study sample, as well as unidentified con-founding factors, such as maternal alcohol use (Altshuler et al. 1996; Reisand Kallen 2008).

Although atypical antipsychotics have been available since the mid-1990s and are used widely by women of reproductive age, reliable dataregarding the reproductive safety of these compounds remain limited(ACOG 2008; Gentile 2008a, 2008b; Yaeger et al. 2006). Of the six atypicalantipsychotics prescribed by physicians in the United States (i.e., ari-piprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasi-done), the FDA has categorized clozapine as pregnancy category B andthe remaining five compounds as category C, alerting women and theirclinicians that although animal studies have been conducted, no ade-quate and well-controlled trials have been conducted in pregnant fe-males. Most of the information on the reproductive safety of these agentsderives from published case reports and manufacturers’ postmarketingdata. Thus far, the available evidence does not demonstrate a “signal” foran increased risk for major malformations or for any specific pattern ofabnormalities among atypical antipsychotic–exposed infants. However,such spontaneous reports have an inherent bias and cannot provide de-finitive information about reproductive safety.

In one of the only prospective studies completed on the reproductivesafety of the atypical antipsychotics, investigators observed no in-creased risk in children exposed to atypical antipsychotics (N=151), in-cluding olanzapine (n=60), risperidone (n=49), quetiapine (n=36), andclozapine (n=6), compared with a nonexposed control group (McKennaet al. 2005). The investigators observed one malformation in an infantexposed to olanzapine and two malformations in the nonexposedgroup. The investigators also observed higher proportions of low-birth-weight babies and of mothers with greater body mass index among theexposed group than the control group. In addition, a recent report fromthe Swedish Medical Birth Register examined malformation ratesamong 147 infants exposed to atypical antipsychotics (Reis and Kallen


2008). The major malformation rate was 4.1% overall (clozapine, 5.60%;olanzapine, 3.80%; quetiapine, 0.00%; and risperidone, 3.90%). Interpre-tation of these findings is limited by the small sample size for each in-dividual drug and other potential confounding variables.

For olanzapine, data from the manufacturer’s case registry, which in-cluded approximately 37 prospective pregnancy outcomes, demon-strated no cases of malformations, but among 11 retrospective cases,one infant had a dysplastic kidney (Goldstein et al. 2000). Other indi-vidual reports and case series involving over 60 cases demonstrated norecurrent pattern in the two reported major malformations (Gentile2008a; Yaeger et al. 2006).

For clozapine, retrospective data include 102 pregnancies with 59 de-liveries resulting in 61 births. Data for 22 pregnancies were unavailable.Five infants had major malformations, and five had perinatal difficul-ties that were not specified, but no data were reported on developmen-tal outcomes (Dev and Krupp 1995; Gentile 2008a; Yaeger et al. 2006).Prospective data are limited to about 19 cases with two reports of peri-natal/neonatal seizures and one child born prematurely with severalanomalies and delayed development at 7 months. However, normal de-velopment was reported in seven subjects evaluated up to 5 years ofage. Of note, gestational diabetes and/or pregnancy-induced hyperten-sion complicated five pregnancies (Gentile 2008a; Yaeger et al. 2006).

The manufacturers of risperidone recently reported pregnancy andneonatal outcomes from a postmarketing database including 713 preg-nancies. Among the 68 prospectively reported pregnancies, organ mal-formations occurred in 3.8%, a finding consistent with backgroundrates in the general population. Among the 197 retrospective cases, therate of malformations was substantially higher at 6%, with the most fre-quently reported malformations involving the heart, brain, lip, and/orpalate. Moreover, 37 retrospectively reported pregnancies involvedperinatal syndromes, of which 21 cases involved behavioral or motordisorders, including tremor, jitteriness, irritability, feeding problems,and somnolence (Coppola et al. 2007). Among the approximately 60prospectively identified cases of fetal exposure to risperidone, no con-genital malformations were reported and two cases of normal develop-ment up to 1 year postpartum were reported (Gentile 2008a; Yaeger etal. 2006).

The manufacturer of quetiapine reported 446 prospective and retro-spective cases of pregnancy exposure in an international database(P. Fontana, written communication, March 2005). Of these, outcomeswere reported for 151 (34%), including eight reports of congenitalanomalies. No specific pattern of major malformation was noted. In


addition, another 39 prospectively identified cases of fetal exposure toquetiapine (including 36 in the study by McKenna et al. 2005) resultedin no reports of congenital malformations, and one case demonstratednormal development at 6 months (Gentile 2008a; Yaeger et al. 2006).

Thus far, the safety of aripiprazole in human pregnancy has been in-vestigated in only three case studies (Gentile 2008a). In one of the cases,the baby had no structural anomalies or neurodevelopmental impair-ment; however, at delivery, symptoms attributable to poor neonatal ad-aptation (e.g., neonatal tachycardia) were observed. In the other twocases, the outcome was a healthy term infant.

Finally, to our knowledge, no reports have been published on hu-man fetal exposure to ziprasidone.

Another report, based on prospective data collected from the UnitedKingdom National Teratology Information Service, similarly foundthat infants exposed to atypical antipsychotics (i.e., either clozapine orolanzapine) had a significantly higher incidence of being large for ges-tational age and having a heavier mean birth weight compared withnonexposed controls (Newham et al. 2008). In addition, data from theSwedish Medical Birth Register suggested that compared with controls,antipsychotic-exposed pregnant women had almost a twofold in-creased risk for gestational diabetes and for cesarean delivery (Reis andKallen 2008). Unfortunately, the investigators did not examine differ-ences in risk between typical and atypical antipsychotics.

Based on these data, patients taking an atypical antipsychotic maychoose to discontinue their medication or replace treatment with a bet-ter characterized typical antipsychotic agent, such as haloperidol; how-ever, many women do not respond well to typical agents or have sucha severe illness that changes to their existing regimen may place themat significant risk for relapse. Although the available manufacturers’ in-formation and existing prospective data are not a guarantee of repro-ductive safety, they are somewhat reassuring. Further studies areclearly needed, however, to make more definitive conclusions aboutteratogenic risks for the newer compounds.

Pregnancy registries have emerged as an effective and systematicmethod for assessing fetal risks from exposures in pregnancy. The Na-tional Pregnancy Registry for Atypical Antipsychotics was establishedin 2008 at Massachusetts General Hospital and is the first hospital-basedpregnancy registry in the United States to systematically and pro-spectively collect data on pregnancy outcomes following exposure toatypical antipsychotics (http://www.womensmentalhealth.org). An-other registry has been established in Australia for assessing a variety ofpsychiatric and health outcomes for pregnant women with a history of

http://www.womensmentalhealth.org


psychosis, including neonatal outcomes following exposure to first- andsecond-generation antipsychotics (Kulkarni et al. 2008). Such registrieswill provide a rapid and efficient means of collecting important pro-spective data on the reproductive safety of the newer antipsychotics.

Risk for Neonatal SymptomsSeveral studies have reported obstetrical and neonatal complications fromexposure to both atypical and typical neuroleptics. Recently, a prospectivestudy examined the placental passage ratios and obstetrical outcomes forinfants exposed to antipsychotics, including olanzapine, haloperidol, ris-peridone, and quetiapine (Newport et al. 2007). Placental passage ratioswere estimated to be highest for olanzapine (72%), followed by risperidone(49%), haloperidol (42%), and quetiapine (24%). In addition, investigatorsfound tendencies toward higher rates of low birth weight and neonatal in-tensive care unit admission among neonates exposed to olanzapine.

Other reports have documented symptoms of poor neonatal adapta-tion in neonates exposed to typical neuroleptics in utero. These symp-toms, which include motor restlessness, tremor, hypertonicity, dystonia,and parkinsonism, are typically transient, followed by apparently normalmotor development (ACOG 2008). Little information is available regard-ing the reproductive safety of medications, including amantadine,diphenhydramine, benztropine, or trihexyphenidyl, that are used to man-age extrapyramidal side effects. In a case-control study, oral clefts weremore common in infants with a significantly higher rate of prenatal expo-sure to diphenhydramine than in controls (Saxen 1974). A possible associ-ation between exposure to benztropine or trihexyphenidyl and increasedrisk for congenital anomaly has also been described (Heinonen et al. 1977).In contrast, several other studies evaluating the use of diphenhydramineduring pregnancy failed to reveal a heightened risk of organ malforma-tion (ACOG 2008). Moreover, studies of beta-blockers, including propra-nolol and atenolol, during pregnancy (sometimes used to manageakathisia with both first- and second-generation antipsychotic agents)have revealed no teratogenic risk (Altshuler et al. 1996; Reiter et al. 1987).

Approach to Treatment of Schizophrenia During PregnancyWomen of childbearing age who have schizophrenia, especially thosewith severe or chronic illness or major disability, should be counseledabout family planning. They should also be made aware of the atten-


dant risks of antipsychotic medications and encouraged to considercontraception. Planning for pregnancy while the patient is relativelyclinically stable provides opportunities for thoughtful treatment selec-tion and avoids the risk of precipitous treatment changes in response toan unplanned pregnancy (Cohen and Nonacs 2005). An important con-sideration is that switching from a prolactin-elevating antipsychoticagent, such as risperidone, paliperidone, or a high-potency older neu-roleptic, to an agent lacking such effects can increase the risk of becom-ing pregnant (Volavka et al. 2004). Pregnant women with schizophreniashould be considered potential high-risk obstetrical patients, giventheir increased risk for obstetrical complications as well as for exacerba-tions of psychotic illness. Additional clinical monitoring during preg-nancy, ideally with close psychiatric and obstetrical collaboration, isimperative to support early detection of impending psychotic relapsewith rapid and anticipated intervention.

Decisions regarding whether to continue, change, or discontinuetreatment during pregnancy must reflect an assessment of the follow-ing factors: 1) the highly variable but often poorly quantified risks of fe-tal exposure to maternal psychotropic drugs commonly used to treatschizophrenia; 2) substantial risks to the patient, fetus, and family fromuntreated maternal psychotic illness; and 3) typically high risk of earlyand potentially severe relapse or exacerbation associated with discon-tinuation of maintenance treatment, particularly if it is abrupt (Baldes-sarini and Viguera 1995). The psychiatrist who treats women withschizophrenia should discuss with patients the risks associated withcontinuing or discontinuing treatments during pregnancy. Our own re-search and clinical experience suggests that patients given similar infor-mation, including women with comparable clinical illness histories,make very different decisions about medication use during pregnancy(Cohen et al. 2006; Viguera et al. 2002). These risks should be discussedfrankly and repeatedly, both before and after conception, and the pa-tient’s psychiatrist, obstetrician, and other clinicians should have col-laborative and effective communication. These discussions should bedocumented in the clinical record, for both clinical and legal purposes.

Evidence-based guidelines are lacking for the treatment of schizo-phrenia during pregnancy. Given the severity and chronicity of schizo-phrenia, maintenance treatment with an antipsychotic before andduring pregnancy may be the safest option for the mother and fetus. Incertain cases of refractory illness, a clinician may decide to use a medi-cation for which information regarding reproductive safety is sparse.For instance, a woman with severe schizophrenia who has respondedonly to a newer atypical antipsychotic for which reproductive safety


data are unknown may choose to continue this medication during preg-nancy rather than risk relapse by discontinuing or switching to anotheragent. In another scenario, patients with schizophrenia who presentclinically late in the first trimester or early second trimester and who arealready stable on a newer neuroleptic may also choose to continue theircurrent treatment, given that fetal exposure has occurred and switchingmedications may jeopardize maternal stability.

For patients presenting with active psychosis, hospitalization may berequired, and electroconvulsive therapy can be considered if additionaldoses of antipsychotic medication are not sufficient (Miller 1994). Elec-troconvulsive therapy may also be helpful in the clinical managementof postpartum psychotic illnesses that arise spontaneously without ahistory of chronic or recurrent psychotic illness (Greenhalgh et al. 2005;Sit et al. 2006).

Antipsychotic dosing should be cautious and conservative through-out pregnancy but kept at an effective dose. Clinicians sometimes riskundertreating psychiatric illness in an attempt to minimize fetal expo-sure. Drug dosage can be increased following delivery, if required clin-ically, but such changes should be balanced against consideration ofdecisions about breastfeeding. Pregnancy and the postpartum periodrequire flexible and responsive treatment, and both the patient andphysician should be prepared to reevaluate treatment decisions overthe course of pregnancy and the puerperium as clinical conditions maychange.

BreastfeedingThe inherent benefits of breastfeeding for a mother with schizophreniaand her infant need to be weighed against the risks of neonatal expo-sure to antipsychotics through breast milk. Women are often encour-aged to continue their antipsychotic regimen following delivery,because the postpartum period can be particularly difficult and stress-ful for women with schizophrenia (Seeman 2008; Sit et al. 2006). If a par-ticular medication was effective during pregnancy, the recommendedpractice is to avoid switching to an alternative antipsychotic for breast-feeding, if only to avoid exposing the infant to multiple medications.

Considerable uncertainty exists regarding the relative safety of par-ticular psychotropic drugs during lactation and the degree to whichnursing infants are exposed to these medications (ACOG 2008; Gentile2008b; Stowe 2007). Data regarding drug excretion into human breastmilk and infant exposures are rare and usually limited to small studiesof particular agents. All psychotropic medications are secreted in breast


milk, although medication exposure for the nursing infant is consider-ably less than in utero placental transfer for the atypical antipsychotics(Newport et al. 2007; Stowe 2007). Olanzapine, in particular, was foundin low serum concentrations in nursing infants and did have adverse ef-fects (Gardiner et al. 2003; Goldstein et al. 2000). Among older agents,chlorpromazine was studied in only seven nursing infants, none ofwhom exhibited developmental deficits at 16-month and 5-year follow-up evaluations (Kris and Carmichael 1957), but three breastfeeding in-fants exposed to maternal treatment with chlorpromazine and halo-peridol exhibited suggestive developmental delays at 12–18 months(Yoshida et al. 1998). The limited available data preclude firm conclu-sions regarding safety of antipsychotics to nursing infants (Burt et al.2001; Stowe 2007; Viguera et al. 2007).

ConclusionClinicians caring for women with schizophrenia should be aware of themyriad challenges these women face, including high rates of victimiza-tion, substance abuse, perinatal complications, poor psychosocial sup-port, difficulties in parenting, and barriers to family planning andmedical and prenatal care. Although robust data on the course ofschizophrenia during pregnancy are lacking, any potential protectiveeffects of pregnancy are unlikely. Risks for morbidity associated withdiscontinuation of ongoing maintenance antipsychotic treatment, par-ticularly abruptly or rapidly, are likely to be high for both the mothersand their babies. Therefore, maintenance pharmacotherapy is recom-mended, in addition to appropriate psychosocial intervention. Concep-tualizing pregnant women with schizophrenia as high risk emphasizesthe importance of close clinical monitoring and the need for coordi-nated care among a multidisciplinary team.

Key Clinical Points

◗ Pregnant women with schizophrenia should take a single medication ata higher, possibly divided, dose instead of multiple drugs at low doses.

◗ Data are lacking regarding long-term outcomes for the offspring ofwomen treated with antipsychotics during pregnancy.

◗ The postpartum period may be a time of particular risk of recurrencesor new psychotic illness.


◗ Strong social and collaborative clinical supports for women with schizo-phrenia benefit pregnancy outcomes.

◗ Medications should be maintained during pregnancy for women diag-nosed with schizophrenia, particularly those with a history of repeateddecompensations, chronic illness, or substantial disabilities.

◗ Maintenance antipsychotic treatment during pregnancy may actuallylimit total drug exposure if the maintenance treatment prevents acuteillness and the associated need for higher doses.

◗ Little evidence is available to support the practice of completely stoppingmedications (vs. gradually reducing doses), either early in pregnancy orbefore delivery, in efforts to avoid clinical or legal responsibilities for ad-verse neonatal outcomes. Doing so probably increases the risk of re-lapses, with distress to the mother, infant, and family.

◗ No scientific support indicates the value of monitoring neonatal serumdrug levels during breastfeeding.

◗ Nursing should be stopped if an infant develops symptoms of adverseeffects from antipsychotic or other psychotropic treatment; thesesymptoms are likely to resolve when the child is bottle fed.

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http://www.fda.gov/fdac/features/2001/301_preg.html#categories

http://www.fda.gov/fdac/features/2001/301_preg.html#categories

http://www.fda.gov/cder/regulatory/pregnancy_labeling/default.htm


435

Index

Page numbers printed in boldface type refer to tables or figures

Abilify. See AripiprazoleAccidents, as mortality cause, 17–18,

19, 20Acoustic startle response, prepulse

inhibition of, 229–230Acquired immunodeficiency

syndrome (AIDS), 250–251, 254, 266. See also Human immuno-deficiency virus (HIV) infection

treatment for 258–259Addictive behavior, 282. See also

Substance abuse disordersAdipokines, 62Adolescents. See Children and

adolescentsAdrenocorticotropin (ACTH), 389Aging persons. See also Aging

persons with schizophreniaadverse drug effects in, 394–395body fat in, 63drug interactions in, 396–397health care proxy for, 401pharmacodynamics in, 394–395pharmacogenetics in, 395–396pharmacokinetics in, 392–394

Aging persons with schizophrenia, 377–413

antipsychotic medication-exacerbated disorders in, 378, 379

as baby-boomer generation, 377

cancer in, 378–379, 386–388cardiovascular disease in, 378–

379, 383–384comparison with

nonschizophrenic peers, 379–380, 391

deficiencies in health care for, 384depression in, 379, 380diabetes mellitus in, 378–379,

380–383general physical health of, 378–

380health care issues affecting, 397–

403hyponatremia in, 388–389immune dysfunction in, 385–386mortality rates of, 390–391musculoskeletal disorders in,

389–390neurocognitive impairment in,

379prevalence of medical disorders

in, 377–380respiratory disorders in, 378–379,

384–385schizophrenia prevalence in, 377,

378subjective health status of, 391–

392“survivor effect” in, 380, 391treatment issues affecting, 392–397


Aging persons with schizophrenia (continued)

visual impairment in, 390Air Force/Texas Coronary

Atherosclerosis Prevention Study, 120

Akathisia, 278–279, 281–282, 346subtle, 67

Alcohol abuse, 281–282, 284–285and breast cancer, 26central nervous system effects of,

284, 287–288demographics of, 275–279medical consequences of, 29, 287–

288and mortality, 29and osteoporosis, 389during pregnancy, 416prevalence of, 171and sexual dysfunction, 309

Alcohol withdrawal, 288Allergies, 385Alzheimer’s disease, 28, 379, 402Amantadine, as weight loss

medication, 80–81, 331Amenorrhea, 312–313, 314American Association of Clinical

Endocrinologists, 39American Diabetes Association, 39,

92, 105–106, 108American Heart Association, criteria

for metabolic syndrome, 42American Psychiatric Association, 39Amiodarone, 176Amisulpride, effect on weight, 70Amphetamines, 277, 288, 289Anhedonia, 281Anticholinergic effects, of

antipsychotic medications, 395, 397

Anticonvulsants, effect on sexual function, 310–311

Antidepressantseffect on sexual function, 321effect on weight, 61, 76

Antidiabetic drugs, 65Antidiuretic hormone, release of,

388–389Antihypertensives, 65, 382

effect on sexual function, 310–311Antipsychotics, 394–395. See also

Atypical antipsychotics; Neuroleptics; names of specific antipsychotics

and cancer risk, 387–388and cardiovascular disease risk, 383choice of, 196comparative metabolic profiles of.

See Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)

compliance with, 21–22dosage in pediatric schizophrenia

patients, 344–345effect on serum lipids, 125–159effect on weight, 204fetal/neonatal risks associated

with, 421–425first-generation, 343–344and galactorrhea, 306and gynecomastia, 306health insurance coverage for,

398–399and mortality, 29–30nonadherence to, 307–308and obesity risk, 61–62, 69–72overdose, as suicide method, 21proarrhythmic effects of, 175–176prolactin-elevating, 306, 312–314,

389–390. See alsoHyperprolactinemia

second-generation, 343–344sexual side effects of. See Sexual

dysfunctionsmoking and, 282as substance abuse treatment,

294–295teratogenicity of, 421use during pregnancy, 415–416,

418–419, 425–427

Index 437

use in aging patients with schizophrenia, 382

Antipsychotic switching, 76–78, 107–108, 156, 157, 328–329

Antiretroviral therapy, 255, 258–259, 260, 264, 267–268, 269

Anxiety, in cocaine users, 289Apolipoprotein B100, 121–122Aripiprazole

adverse health effects of, 3–4effect on fasting glucose levels,

53, 56effect on prolactin levels, 319effect on serum lipids, 130, 131,

138, 146, 148, 159effect on weight, 78, 104, 107, 349,

351metabolic profile of, 53, 56as sexual dysfunction treatment,

331sexual function effects of, 319,

328–329as substance abuse treatment, 294use in pediatric schizophrenia

patients, 343–344, 345, 349, 351

Arousal disorders, 305, 306Arrhythmias, 169–181, 170, 171

surrogate risk markers for, 175–176, 179–180

Aspirin, cardioprotective effects of, 193, 196

Atherosclerosis, 94, 122Atypical antipsychotics, 91. See also

names of specific atypical antipsychotics

adverse effects of, 3–4, 5cardiovascular effects of, 180–190choice of, 109and diabetes mellitus risk, 98–103,

109efficacy in pediatric

schizophrenia patients, 345–346

extrapyramidal side effects of, 91

fetal/neonatal risks associated with, 422–425

and metabolic disorder risk, 108–109

and obesity risk, 6, 66, 109Auditory information processing

defects, 228–229

Baby-boomer generation, 377Bariatric surgery, 82Basal metabolism, 66–67Behavioral treatment

for obesity, 203–222, 206, 209–212in pediatric schizophrenia

patients, 367–368principles of, 204–206

for substance abuse, 292, 293Behavioral Treatment for Substance

Abuse in Schizophrenia (BTSAS) model, 293

Benzodiazepinesin combination with clozapine,

184–185sexual function effects of, 321

Betahistine, 79Bipolar disorder, 248, 281, 352, 385Birth control. See ContraceptivesBladder cancer, 387Blood-brain barrier, 419–420Blood pressure. See also

Hypertension; Hypotensionmeasurement of, 72–73, 193, 365weight loss–related reduction in,

215Body mass index (BMI), 62–63, 64,

66, 72–73in metabolic syndrome, 42–43in pediatric schizophrenia

patients, 350, 356–357, 360–361

Breast cancerin aging persons with

schizophrenia, 386, 387dopamine receptor antagonists

and, 313


Breast cancer (continued)hyperprolactinemia and, 354and mortality, 25, 31prevalence in schizophrenia, 24,

26Breastfeeding, 420, 427–428Brief Psychiatric Rating Scale (BPRS),

227, 278, 285–286, 345Bupropion

sexual function effects of, 321use in smoking cessation, 233,

234–236, 237Butyrophenones

and congenital malformation risk, 422

effect on serum lipids, 123, 124, 125–126, 133, 159

Cabergoline, 330Calcium channel blockers, effect on

sexual function, 311Calcium deficiency, 389Cancer. See also specific types of cancer

in aging persons with schizophrenia, 378–379, 386–388

alcohol abuse and, 287human immunodeficiency virus

(HIV) infection and, 254hyperprolactinemia and, 312–314and mortality, 23, 24, 25, 25, 387–

388negative correlation with

schizophrenia, 387smoking and, 224

Cannabis (marijuana), 277demographics of use of, 279depression and, 381medical consequences of, 289–290psychosis-exacerbating effect of,

285–286Cannabis receptors, 289–290Capacity, 401, 402Cardiomyopathy, 4–5, 187–188, 189

Cardiovascular disease, 98, 169–202, 395

in aging persons with schizophrenia, 378–379, 383–384

alcohol abuse and, 287, 288clozapine and, 100comorbidity with diabetes

mellitus, 94, 384definition of, 190diabetes mellitus and risk of, 94,

117–118hospitalization for, 383–384and mortality, 18, 23, 24, 25, 25,

26–27, 100, 118–119, 169, 181, 190, 384

prevalence of, 27–28prevention of, 103risk estimation for, 118, 192–193,

194–195schizophrenia and risk of, 203–204and sexual dysfunction, 309smoking and, 224, 312

Care. See Health careCarved-in/carved-out programs, in

mental health insurance coverage, 400

Cataracts, 45CATIE. See Clinical Antipsychotic

Trials of Intervention Effectiveness

Central nervous system disorders, 24, 25

alcohol abuse and, 284, 287–288human immunodeficiency virus

(HIV) infection and, 255–258Child custody, 416Children and adolescents,

schizophrenia treatment in, 343–375

adverse effects of, 346–369, 351,370

management of, 355–361, 365–369, 370

Index 439

antipsychotic medication dosage, 344–345

antipsychotic medication efficacy, 345–346

developmental considerations in, 344–345

dyslipidemia and, 155lifestyle interventions, 356, 362–

364, 366–368QTc interval prolongation in,

354–355weight and metabolic parameters

for, 355–366, 358–359, 360–361Chlorpromazine

effect on glucose levels, 97effect on serum lipids, 123reproductive safety of, 421secretion in breast milk, 428and sexual dysfunction, 315typical antipsychotics and, 123–

125Cholesterol, total, 51, 58, 119. See also

Hypercholesterolemia; National Cholesterol Education Program

Cholinergic receptor antagonists, 311Cirrhosis, 262, 287, 288Clinical Antipsychotic Trials of

Intervention Effectiveness (CATIE), 37–57, 41, 42–43, 66, 95, 98, 99, 118, 124, 129, 130, 190, 277, 278, 279, 295

baseline data, 40–44buildup to, 38–40cardiovascular risk estimates of,

41demographics of, 40health care access data of, 41, 44hyperprolactinemia data, 315, 317inflammatory marker data, 49, 55phase 1, 38, 44–53, 46, 47, 48, 50,

51, 52phase 2 , 38, 39, 47, 50, 51, 52, 53, 54phase 3, 39, 53purpose of, 37

sexual dysfunction data, 316, 317, 318

Clinics, integrated-care, 8–10Clozapine

cardiovascular effects of, 100, 184–189

in combination with benzodiazepines, 184–185

and diabetes mellitus risk, 99–100, 106–107, 109

and diabetic ketoacidosis, 99, 101–102

effect on cognitive function, 98effect on heart rate variability, 180effect on serum lipids, 46, 53, 125–

127, 137, 139–143, 148, 149,153, 159

effect on sexual function, 320–321effect on sugar intake, 95–96effect on weight, 39, 46, 47, 70, 71,

80–81, 100, 104, 156, 181, 204, 212, 347–348, 351

fetal/neonatal risks associated with, 423

and glucose intolerance, 99, 381and hypertension, 192and insulin resistance, 157metabolic disorder treatment and,

196metabolic profile of, 39as resistant schizophrenia

treatment, 107smoking cessation and, 227, 236as substance abuse treatment, 294and sudden cardiac death risk,

184–185treatment resistance and, 91use in pediatric schizophrenia

patients, 345–346, 347–348, 351, 359

Cocaine, 277medical consequences of, 288–289prevalence of abuse of, 171schizophrenia and, 283–284


Cognition, nicotine and enhancement of, 229–230

Cognitive-behavioral therapy, for weight loss, 206, 208, 211, 215

Cognitive deficits, 401–402alcohol abuse and, 288effect of atypical antipsychotics

on, 98hepatitis C and, 262human immunodeficiency virus

(HIV) infection and, 255–258, 256–258

nicotinic acetylcholine receptor treatment for, 226

Cognitive status monitoring, 402–403

Comorbidity, health care access and, 4–5

Competency, 401–403Condoms, 248–249, 252, 264, 326Congenital malformations

antipsychotics and, 422–425prevalence of, 420

Congestive heart failure, 384Contraceptives, 311, 326, 416, 425–

426condoms, 248–249, 252, 264, 326

Coronary artery disease (CAD), 94in aging persons with

schizophrenia, 384cannabis and, 290

Coronary heart disease (CHD), 103, 169

antipsychotics and, 190–191hyperlipidemia and risk of, 119–

123management of, 192–197obesity and risk of, 64, 65risk estimation for, 41

Cortisol, 389C-reactive protein, 49, 53, 55Cumulative Illness Rating Scale for

Geriatrics, 379Cytochrome P450 (CYP) enzymes

CYP1A2, 226–227, 394

CYP3A4, 394CYP2D6, 394drug interactions of, 397genetic polymorphisms of, 395–

396Cytokines, 386

Death, sudden cardiac, 169, 170–171, 175–176, 173, 182, 184–186, 383. See also Mortality

Delirium tremens (DTs), 287–288Dementia, 398, 402

human immunodeficiency virus (HIV) infection and, 255–258

Dementia praecox, 17Dental care, 399Depression, 28

in cocaine users, 289lack of health care and, 399metabolic disorders and, 44and sexual dysfunction, 309substance abuse and, 281in suicidal persons, 21

Diabetes awareness and rehabilitation training (DART) program, 5–6

Diabetes mellitus. See also Diabetic ketoacidosis; Glucose intolerance; Hyperglycemia; Insulin resistance

in aging patients with schizophrenia, 378–379, 380–383

antipsychotics and, 39, 70, 99–100, 107–108, 381–382

atypical antipsychotics and, 3, 91–92, 98–103

behavioral management of, 214cancer associated with, 378–379cardiovascular complications of,

94, 117–118, 383, 384CATIE data on, 40diagnostic criteria for, 92–93monitoring and screening of, 105–

108

Index 441

and mortality, 18, 25, 25, 26, 27, 29neurological complications of, 94obesity and risk of, 64, 65, 205, 215ophthalmic complications of, 94pathophysiology of, 9–93in pediatric schizophrenia

patients, 346, 367prevalence of, 27–28, 41, 118, 170–

171, 380–381prevention of, 215renal complications of, 94respiratory disease associated

with, 378–379schizophrenia and risk of, 203–

204and sexual dysfunction, 309treatment for, 382

in pediatric schizophrenia patients, 368

pharmacological treatment, 65type 1, 92, 93

negative correlation with schizophrenia, 386

in unmedicated schizophrenic persons, 96

Diabetes Prevention Trial, 205“Diabetic foot,” 94Diabetic ketoacidosis, 92, 93–94, 99,

100, 101–102, 103, 107definition of, 94screening for, 106

DietAmerican Heart Association Step

II, 214–215and diabetes mellitus risk, 95–96effect of antipsychotics on, 95–96evaluation of, 74high-fat, low-fiber, 30and mortality risk, 17in obesity treatment, 206, 208,

209–212, 213–215for pediatric schizophrenia

patients, 362–364, 367role in obesity, 68–69, 74, 205, 206,

367

Digoxineffect on sexual function, 311renal clearance of, 396

methoxybenzylidene anabaseine, 226

Diureticseffect on serum lipids, 155effect on sexual function, 311

Dopaminecocaine abuse and, 288–289role in sexual function, 309substance abuse and, 284, 285

Dopamine agonists, 330, 368–369Dopamine D2 receptor(s), 315Dopamine D2 receptor agonists, 319,

320Dopamine D2 receptor antagonism,

316Dopamine receptor(s), 396Dopamine receptor antagonism, role

in sexual function, 309Dopamine receptor antagonists

and breast cancer risk, 313and hyperprolactinemia risk, 315,

326–327Dopaminergic neurons, 225Down syndrome patients, 207Drug(s), therapeutic. See also

Pharmacodynamics; Pharmacogenetics; Pharmacokinetics; names of specific drugs and drug classes

absorption, 393clearance, 394distribution to peripheral sites, in

elderly, 393effect on sexual function, 311metabolism, 394teratogenic, 419–425, 421

Drug abuse. See also Substance abuse disorders; specific drugs of abuse

central nervous system effects of, 284

during pregnancy, 416Drug interactions, 396–397


Drug interactions (continued)effect on cognition, 402–403

Drug-seeking behavior, 281Dual diagnoses. See Substance abuse

disorders, in patients with schizophrenia

Duloxetine, effect on sexual function, 321

Dyslipidemia, 94–95. See alsoHyperlipidemia

and cardiovascular disease risk, 191

in pediatric schizophrenia patients, 352, 360–361, 367, 368

prevalence of, 41, 170–171undertreatment of, 118

Edema, pulmonary, 4–5Efavirenz, neuropsychiatric side

effects of, 267Ejaculatory disorders, 306, 309, 310–

311, 312–313, 314, 320–321, 328–329

Elderly. See Aging persons; Aging persons with schizophrenia

Electrocardiography (ECG), 177,183–184

Endocrine disorders, and mortality, 24, 26

Endocrine system, role in sexual function, 309

Endometrial cancer, 313–314Energy balance, 66–67, 68Environment, “obesogenic,” 69Epidemiologic Catchment Area

(ECA) study, 276, 277Erectile dysfunction, 305, 306, 309,

312–313, 314, 315, 318, 332smoking and, 312treatment for, 329–330, 332–333

Estrogen, 389Exercise, 69

health benefits of, 215–216in pediatric schizophrenia

patients, 364

role in weight management, 205, 206, 209–212, 214–216

Extrapyramidal side effects, of antipsychotics, 29, 91, 309


Family medicine, psychiatrists’ training in, 9–10

Family planning, 416–417, 425. See also Contraceptives

Famotidine, as weight loss medication, 80–81

D-Fenfluramine, as weight loss medication, 80–81

Fetus, antipsychotic drug exposure in, 419–425, 421

Fluoxetine, as weight loss medication, 80–81

Fluperlapine, 125, 132Fluphenazine

effect on serum lipids, 133, 140reproductive safety of, 421sexual function effects of, 318

Fluphenazine decanoate, 278Follicle-stimulating hormone (FSH),

312Food and Drug Administration, U.S.,

(FDA), 38–39, 39, 420, 421Food aspiration, as mortality cause, 23Framingham Heart Study, 121, 196–

197cardiovascular disease risk

algorithm of, 118, 192–193, 194–195

Fusion inhibitors, 260

Gabapentin, renal clearance of, 396Galactorrhea, 306, 312–313, 314, 316,

330Galantamine hydrobromide, 226Gallbladder cancer, 25Gastrointestinal cancer, in aging

persons with schizophrenia, 386, 387

Index 443

Gastrointestinal disorders, as mortality cause, 24, 25

Genetic factors. See alsoPharmacogenetics

in diabetes mellitus, 93in schizophrenia, 284, 395

Genitourinary diseases, 28as mortality cause, 24, 25

Genotyping, 253Gentamicin, renal clearance of, 396Geodon. See ZiprasidoneGlucose, plasma levels of

fasting, 42–43, 53, 56, 63, 92, 357, 358–359, 365

monitoring of, 107Glucose intolerance, 91–115, 108

in aging persons with schizophrenia, 381

antipsychotics and, 99, 381atypical antipsychotics and, 91–

92, 98, 99conventional antipsychotics and,

96–97definition of, 92medical complications of, 93–96in unmedicated schizophrenic

persons, 96Glucose metabolism,

pharmacological improvement of, 104

Glucose monitoring, in pediatric schizophrenia patients, 358–359,360–361, 365

Glycohemoglobin, 48, 107Gonadotropin-releasing hormone

(GRH), 312, 354Gynecomastia, 306, 312–313, 314,

316, 318–319

Hallucinations, 21, 282–283, 286, 287Hallucinogens, 277Haloperidol

cardiac effects of, 182and diabetes mellitus, 97effect on bone mass density, 313

effect on prolactin levels, 354effect on serum lipids, 123, 132,

133, 135, 137, 138, 140, 141effect on sexual function, 315, 331effect on weight, 71, 210, 348fetal/neonatal risks associated

with, 425and hyperprolactinemia, 314–315,

316–317reproductive safety of, 421use in pediatric schizophrenia

patients, 343–346, 348, 354Health care

compliance with, 30, 397for the geriatric population, 384,

397–403integration with psychiatric care,

2–12patients’ utilization of. See Health

care accessHealth care access

effect of health insurance coverage on, 399

of homeless persons, 31–32lack of, 4–5, 10–11, 31–32, 41, 44,

196, 397–403, 398models for improvement of, 5–10obstacles to, 398

Health care costsof the geriatric population, 397–

398, 400obesity and, 65

Health care insurance coverage. See also Medicaid; Medicare

for antipsychotic medication, 398–399

carved-in/carved-out programs of, 400

effect on health care access, 399lack of, 11for psychiatric care, 398

Health care proxy, 401Health care skills training, 5–6, 12Health habits, 30Health maintenance, 29–32


Health status, self-reported, 391–392Heart. See also Cardiovascular

diseaseelectrophysiology of, 171–173, 172

Heart rate variability, 180Height measurement, 356, 358–359Hemoglobin, glycosylated, 48Hepatitis B, substance abuse and,

279, 288Hepatitis C, 259, 261–264

alcohol abuse and, 288comorbidity with human

immunodeficiency virus (HIV) infection, 261, 269

course of, 259natural history of, 261neuropsychiatric manifestations

of, 262prevalence of, 248psychiatric patients’ knowledge

about, 250psychopharmacology for, 267,

268, 269risk assessment for, 265–266risk reduction strategies for, 264,

265substance abuse and risk of, 250,

279testing for, 261, 267, 270transmission of, 259treatment for, 262–264, 263

Herbal preparationsas hyperprolactinemia treatment,

331–332interaction with antiretroviral

therapy, 268Heroin, 283–284High-density lipoprotein (HDL), 41,

43, 119, 154Histamine receptor(s), 71–72Histamine receptor agonists, as

weight loss medication, 79Histamine receptor antagonists

and sexual dysfunction, 312

as weight loss medications, 79,80–81

Homeless persons, with schizophrenia, 4

mortality rates in, 31–32substance abuse among, 278, 286substance abuse treatment for,

292, 293–294Hospitalization

effect on cancer mortality rate, 388

during pregnancy, 417, 427rate of, 28for respiratory disease, 385of schizophrenia patients, 383–

384of substance-abusing patients, 285

Human immunodeficiency virus (HIV) infection, 247–274, 289

access to patient services for, 265–266, 267

antiretroviral therapy for, 255, 258–259, 260, 264, 267–268, 269

CD4 T-cell count in, 251, 253, 254comorbidity with hepatitis C, 261,

269confidentiality regarding, 266counseling for, 266course of, 250–251infection rates of, 326natural history of, 253–254neuropsychiatric manifestations

of, 255–259opportunistic infections

associated with, 254, 255perinatal transmission of, 264prevalence of, 248psychiatric patients’ knowledge

about, 250risk assessment for, 265–266risk reduction strategies for, 264–

265sexual risk behaviors and, 248–

249, 250

Index 445

substance abuse and risk of, 249–250, 279–280

support group-based interventions for, 266

symptoms of, 254testing for, 252–253, 266, 270transmission of, 251–252, 264treatment for, 255, 258–259, 260,

261, 264, 267–268, 269viral load in, 253

Human immunodeficiency virus (HIV) vaccine, 251

Hypercholesterolemia, statin therapy for, 120

Hyperglycemia, 92, 93, 96, 97, 101, 105, 109

atypical antipsychotics and, 3–4in pediatric schizophrenia

patients, 360–361, 365, 367, 368

screening for, 106Hyperinsulinemia, 93Hyperlipidemia, 117–167

and coronary heart disease risk, 119–123

mechanisms of, 155–157, 159monitoring of, 157–158, 159obesity and, 64patient variables in, 155–157, 159in pediatric schizophrenia

patients, 360–361second-generation antipsychotics

and, 39typical antipsychotics and, 125–

159Hyperprolactinemia, 389–390

and cancer risk, 312–314first-generation antipsychotics

and, 314–315monitoring for, 326–327and osteoporosis risk, 313in pediatric schizophrenia

patients, 346, 353–354, 368–369, 370

second-generation antipsychotics and, 315

and sexual dysfunction, 312–313treatment for, 328–332, 368–369

Hypertension, 365in aging patients with

schizophrenia, 384alcohol abuse and, 288antipsychotics and, 192and cardiovascular disease risk,

94–95, 120–121complications of, 4–5definition of, 192as metabolic syndrome

component, 63obesity and risk of, 64, 65, 95in pediatric schizophrenia

patients, 358–359, 367prevalence of, 27–28, 41, 43, 118and sexual dysfunction, 309treatment for, 65, 193, 382

effect on sexual function, 310–311

undertreatment for, 118untreated, 399

Hyperthermia, benign, 186Hypertriglyceridemia, 50, 63, 64, 102

alcohol abuse and, 288atypical antipsychotics and, 125–

129, 155and cardiovascular disease risk,

383fasting versus nonfasting, 122–123insulin resistance and, 121–122,

156–157in pediatric schizophrenia

patients, 350prevalence of, 118typical antipsychotic medication

and, 124–125Hypogonadism, 354

hypogonadotropic, 389Hyponatremia, 388–389Hypotension, orthostatic, 189–190


Immune dysfunctionin aging patients with

schizophrenia, 385–386human immunodeficiency virus

(HIV) infection and, 253–254Immunosuppression, 254, 261Impulsivity, 281Infectious diseases, 17, 24, 25, 25, 386Inflammatory markers, of

cardiometabolic risk, 49Insulin resistance, 92–93, 94–95, 97,

100, 102–103, 105, 204homeostatic model assessment

(HOMA) of, 360–361, 365hypertriglyceridemia and, 121–

122, 156–157obesity and risk of, 64in pediatric schizophrenia

patients, 350, 352, 360–361,365

Integrated-care clinics, 8–10Intercontinental Schizophrenia

Outpatient Health Outcomes, 316

Interferon, neuropsychiatric side effects of, 262–263

Internal medicine, psychiatrists’ training in, 9–10

International Physical Activity Questionnaire, 74

Intravenous drug abuse, 44, 250, 252, 259, 264, 279–280

Ion channels, 172“Is There a Stethoscope in the House

(and Is It Used?)” (McIntyre and Romano), 6–7

Kraepelin, Emil, 17

Leptin, 67, 72, 102–103Libido, decrease in, 305, 306, 309,

312–313, 314, 316, 317Life expectancy, 18, 44, 64, 169, 203,

355–356, 390Lifestyle

and obesity, 68–69sedentary, 30, 68, 69, 93, 169unhealthful, 30

Lifestyle interventionsfor coronary heart disease

management, 192–193for obesity management, 6, 74,

208–215with pediatric schizophrenia

patients, 356, 362–364, 366–368Limbic system, role in sexual

function, 309Lipid-lowering drugs, 65, 382 See also

StatinsLipid monitoring, in pediatric

schizophrenia patients, 357, 358–359, 365

Lipoproteins, 63, 122, 352, 361Lithium, renal clearance of, 396Lithium carbonate, effect on weight, 76Liver, as drug metabolism site, 268,

394Liver disease, alcohol abuse and,

287, 288Lovastatin, 120Low-density lipoprotein (LDL), 119,

120–121Lung cancer, 24, 25

in aging persons with schizophrenia, 386–387

smoking and, 233Luteinizing hormone (LH), 312

Marijuana. See Cannabis (marijuana)Maudsley Prescribing Guidelines,

183Medicaid, 397–398, 400Medical care. See Health careMedical conditions, untreated, 398Medicare, 397–398, 399, 400

drug coverage benefits of, 399, 400–401

Menstrual irregularities, 306–307, 312–313, 316–317, 318–319, 328–329

Index 447

treatment for, 330, 331–332Mental health care. See Psychiatric

careMetabolic disorders. See also Clinical

Antipsychotic Trials of Intervention Effectiveness (CATIE); specific metabolic disorders

atypical antipsychotics and, 29and cardiovascular disease, 169,

170and depression, 44in pediatric schizophrenia

patients, 346, 350, 352, 353, 366–367

prevention and management of, 77

Metabolic monitoring, 171in obese patients, 73–74, 75

Metabolic syndrome, 63–64, 66, 94–95, 98

CATIE data on, 40, 41, 42–43, 48–49

diagnostic criteria for, 37–38in pediatric schizophrenia

patients, 353, 357, 360–361,370

prevalence of, 40, 42–43Metformin

in combination with quetiapine, 138

as weight loss medication, 6, 79, 80–81, 212, 214–215, 368

Methadone, 268Methamphetamine(s), 283–284d-Methamphetamine, 2883,4-Methylenedioxymeth-

amphetamine (“ecstasy”), 283–284

Mirtazapineeffect on sexual function, 321effect on weight, 76

Molindone, 345–346, 349–350Mood-stabilizing agents

effect on sexual function, 321

effect on weight, 61, 76Morbidity, in persons with

schizophrenia, 27–29cardiovascular, 118–119substance abuse and, 28–29

Mortality/mortality rates, in persons with schizophrenia, 17–20, 23, 25

in aging persons with schizophrenia, 390–391

antipsychotics and, 29–30cancer and, 3, 23, 24, 25, 25, 387–

388cardiovascular disease and, 18,

23, 24, 25, 25, 26–27, 100, 118–119, 169, 181, 190, 269, 384

causes of, 391historical background to, 17–18natural causes of, 19, 22, 23, 23–

27, 25premature, 17relationship to health care

quality, 384substance abuse and, 28–29unnatural causes of, 19, 20–22, 23

Motor effects, of antipsychotic medications, 395

Multiple Risk Factor Intervention Trial (MRFIT), 119–120

Musculoskeletal disorders, 28, 389–390Myocardial infarction

antipsychotics and, 5, 191, 383cannabis and, 290diabetes mellitus and risk of, 94inadequacy of care for, 31, 384as mortality cause, 4, 170, 180painless, 196–197statins and, 120

Myocarditis, 185–186, 189

National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATPIII), 43, 95, 120–121


National Comorbidity Survey, 276National Health and Nutrition

Examination Survey (NHANES) III, 40, 41, 41, 43, 66

National Health Interview Schedule, 66

National Health Interview Survey, 27–28

National Heart, Lung, and Blood Institute, 63

National Institute of Mental Health (NIMH), 6, 8, 37

National Institutes of Health, 204National Patient Care Database, 379Negativism, 17Nephropathy, diabetic, 94Neurocognitive deficits. See

Cognitive deficitsNeuroleptics. See also

Antipsychotics; Atypical antipsychotics; names of specific antipsychotics

anticarcinogenic activity of, 387–388

atypical, 382overdose, as suicide method, 21smoking and, 282teratogenicity of, 421

Neurological disordersdiabetes mellitus and, 94as mortality cause, 24, 25

Neuropathy, as sexual dysfunction cause, 309

Neuropeptide Y, 67Neurotransmitters, effect of nicotine

on, 224–226Nevirapine, neuropsychiatric side

effects of, 267NHANES. See National Health and

Nutrition Examination SurveyNicotine. See also Smoking

cognition-enhancing effects of, 229–230

pharmacological effects of, 224–226

use by persons with schizophrenia, 277

Nicotine addiction/dependencecomorbidity with schizophrenia,

224treatment for, 295

Nicotine replacement therapy, 234–236

Nicotine transdermal patch (NTP), 228, 230, 233, 234–236, 237

Nicotinic acetylcholine receptors, 224–226, 228, 229

Nizatidine, as weight loss medication, 80–81

Non-nucleoside reverse transcriptase inhibitors, 260

North American Association for the Study of Obesity, 39

Nucleoside/nucleotide reverse transcriptase inhibitors, 260

Obesity, 61–90antipsychotics and, 61–62, 69–72,

74–78, 309atypical antipsychotics and, 3and cardiovascular disease risk,

383during childhood, 344definition of, 62determinants and mechanisms of,

66–72and diabetes mellitus risk, 93, 95,

96, 103duration of, 96economic cost of, 65epidemiology of, 65–66general and evolutionary factors

in, 66–67genetic factors in, 68, 72health consequences of, 64–65and hypertension risk, 95lifestyle factors in, 68–69measurement of, 62–64, 72–73metabolic monitoring in, 73–74,

75

Index 449

neurophysiological factors in, 68 “obesogenic” environment and, 69in pediatric schizophrenia patients,

347, 360–361, 366–368prevalence of, 30, 61, 65–66, 118,

170–171prevention and management of,

72–73, 76–83, 206behavioral treatment, 203–222,

206, 209–212combined behavioral/

pharmacological treatment, 216

diet, 206, 208, 209–212, 213–215exercise, 205, 206, 209–212lifestyle interventions, 74pharmacological treatment,

76–82, 216, 368surgical treatment, 82

“thrifty phenotype hypothesis” of, 67

Olanzapineand cardiovascular disease risk,

98CATIE data on, 44–53and diabetes mellitus risk, 3–4, 39,

101, 109as diabetes monitoring indication,

106–107and diabetic ketoacidosis, 99,

101–102effect on cholesterol levels, 46, 51,

53effect on cognitive function, 98effect on C-reactive protein levels,

49, 53, 55effect on diet, 95–96effect on heart rate variability, 180effect on metabolic syndrome

status, 48, 49effect on prolactin levels, 328, 354effect on QTc interval, 45, 52effect on serum lipids, 101, 124,

127–129, 131, 135–151, 153,154, 155, 159

effect on smoking cessation, 230, 236

effect on triglyceride levels, 48–49, 50

effect on weight, 44–45, 46, 47, 54,76–78, 79, 80–81, 98, 101, 102–103, 104, 105, 156, 204, 209–212, 213

fetal/neonatal risks associated with, 422–423, 425

and glucose intolerance, 381and hyperprolactinemia, 316and hypertension, 192and insulin resistance, 102–103,

157metabolic profile of, 39, 44–53secretion in breast milk, 428sexual function effects of, 316–317as substance abuse treatment, 294,

295use in aging schizophrenia

patients, 3–4use in pediatric schizophrenia

patients, 345–346, 354Older adults. See Aging persons;

Aging persons with schizophrenia

Older Americans Resources Survey, 392

Oligomenorrhea, 312–313Ophthalmic disorders, diabetes

mellitus and, 94Opiates, 277Oregon Health and Science

University, 7Orlistat, as weight loss medication,

78Osteoporosis, 313, 354Overdose, as suicide method, 21Oxford Record Linkage Study, 383

Pain sensitivity, 196–197Paliperidone, 294–295

and hyperprolactinemia, 319–320sexual function effects of, 320


Parkinsonism, 28, 29, 278–279Patient Outcomes Research Team

(PORT) program, 27–28, 379, 381, 382, 392

Peony-Glycyrrhiza Decoction (PGD), 330, 332

Peptic ulcers, 19Pericarditis, 185–186Peripheral nervous system, role in

sexual function, 309, 311–312Perphenazine

CATIE data on, 44–53, 98effect on cholesterol levels, 51effect on C-reactive protein levels,

49, 53, 55effect on metabolic syndrome

status, 48, 49effect on QTc interval, 45, 52effect on serum lipids, 124, 153,

154effect on total cholesterol levels,

46, 51, 53effect on triglyceride levels, 48–

49, 50effect on weight, 44–45, 46, 47, 78metabolic profile of, 44–53, 98reproductive safety of, 421sexual function effects of, 331

Pharmacodynamicsin aging persons, 394–395in pediatric schizophrenia

patients, 344Pharmacogenetics, 395–396Pharmacokinetics

in aging persons, 392–394effect of smoking cessation on,

226–227Phenothiazines, 23

anticarcinogenic activity of, 25, 388

and diabetes mellitus risk, 97effect on serum lipids, 123, 132,

133, 155, 159effect on sexual function, 315teratogenicity of, 422

Phenotyping, 253Phenylpropanolamine, as weight

loss medication, 81Phosphodiesterase type 5 inhibitors,

329–330, 332–333Physical activity, 74. See also Exercise

for weight loss, 367Physical health care, for patients

with mental illness, 3–15Physical inactivity. See Sedentary

lifestylePimozide, 184Pituitary tumors, 313, 354Placenta, drug diffusion across, 419–

420Pneumonia, 19, 384–385Polycystic ovarian disease, 64Polydipsia, 92, 109, 388–389Polypharmacy, 29, 417Polyuria, 92, 109Positive and Negative Syndrome

Scale (PANSS), 281, 345Postpartum period, 415, 417–418, 427Pravastatin, 120Prediabetes, 365Pregnancy, in women with

schizophrenia, 415–427antipsychotic therapy

discontinuation during, 415–416, 418–419, 415–427

maternal outcomes in, 417–419obstetric complications risk in, 419treatment for schizophrenia

during, 415–416, 418–419, 425–427

unplanned/unwanted, 326, 416Priapism, 306, 311, 315, 318–319Primary care

integration with mental health treatment, 1, 3, 8<150>10, 12

referrals to, 7, 8, 12Primary care physicians

behavior toward older patients, 399–400

psychiatrists as, 401

Index 451

Primary care training, for psychiatrists, 6–7, 8–10, 12

Procainamide, renal clearance of, 396Prolactin. See also

Hyperprolactinemiafunction of, 312

Prostate cancer, 24, 387Protease inhibitors, 155, 260Proxy, for health care, 401Psychiatric care

integration with primary care, 8–10, 12

lack of health insurance coverage for, 398

Psychiatrists, as primary care physicians, 6–7, 8–10, 12, 401

Psychological Well-Being Index, 64Psychomimetic agents, 283Psychosis

cannabis and exacerbation of, 285–286

cocaine and, 289drug and, 282–283, 284postpartum, 418, 427substance abuse and, 285in suicidal persons, 21

Psychotropic medications, teratogenicity of, 419–421

QRS complex, 171–172QTc interval, estimation of, 179–180QTc interval prolongation, 169–170,

173, 175–179antipsychotics and, 45, 52, 55,

180–184, 181, 189CATIE data on, 45, 52, 55clozapine and, 189estimation of, 176–179, 178, 183–

184nonclozapine antipsychotic

medication and, 189–190in pediatric schizophrenia

patients, 354–355, 369QT dispersion, 179Quality of life, 64, 95, 308

Quetiapineand cataract risk, 45CATIE data on, 44–53and diabetes mellitus risk, 3–4, 101effect on cholesterol levels, 46, 51,



status, 48, 49effect on prolactin levels, 317, 328effect on QTc interval, 45, 52effect on serum lipids, 129–131,

137–141, 153, 154, 156–157, 159

effect on sexual function, 317–318, 328

effect on triglyceride levels, 48–49, 50

effect on weight, 44–45, 46, 47, 54, 70, 78, 98, 105, 348–349, 352


and glucose intolerance risk, 101metabolic profile of, 39, 40, 44–53as substance abuse treatment, 294use in pediatric schizophrenia

patients, 348–349, 350Quinidine, 172

Reboxetine, as weight loss medication, 78–79, 81

Rectal cancer, 24Referrals, to primary care, 7, 8, 12Relapse, during postpartum period,

417–418Renal disorders, diabetes mellitus

and, 94Residency programs, 7, 10Respiratory disorders

in aging patients with schizophrenia, 378–379, 384–385


Respiratory disorders (continued)cannabis and, 290cocaine and, 289hospitalization for, 383–384as mortality cause, 24, 25

“Reward pathway,” 225, 289Rheumatoid arthritis, 28, 385–386Ribavarin, neuropsychiatric side

effects of, 262–263Rimonabant, as weight loss

medication, 79Risperidone

and cancer risk, 313CATIE data on, 44–53and diabetes mellitus risk, 3–4, 101effect on cholesterol levels, 46, 51,



status, 48, 49effect on prolactin levels, 315, 330,

354effect on QTc interval, 45, 52effect on serum lipids, 98, 128,

129, 130, 136–150, 151, 153,154, 156, 157, 159

effect on smoking cessation, 230effect on triglyceride levels, 48–

49,50effect on weight, 44–45, 46, 47, 54,

70, 76, 77, 78, 98, 101, 105, 210, 213, 348–350, 351, 352


and glucose intolerance risk, 101metabolic profile of, 39, 40, 44–53and pituitary tumor, 313sexual function effects of, 315–

316, 317–318, 328as substance abuse treatment, 294use in pediatric schizophrenia

patients, 343–344, 345–346, 348–350, 351, 354

Scandinavian Simvastatin Survival Study, 120

Schizophrenia. See also specific disorders and conditions associated with schizophrenia

prevalence of, 377, 378Sedation, 309, 312Sedatives/hypnotics, 277Sedentary lifestyle, 30, 68, 69, 93, 169Selective serotonin reuptake

inhibitors (SSRIs)effect on sexual function, 311–312,

321effect on weight, 76, 80–81

Selegiline, 331“Self-medication” hypothesis

of smoking, 229of substance abuse, 280–281, 282,

296Seroquel. See QuetiapineSerotonin (5-HT), 289Serotonin agonists, and sexual

dysfunction, 311–312Serotonin antagonism, 125Serotonin receptors, 102, 103Serotonin syndrome, 368Sertindole, cardiac effects of, 176,

182, 184Sex exchange behaviors, 248–249, 326Sexual development, 353–354Sexual dysfunction, 303–342

adjunctive treatment for, 329–332in adolescent schizophrenia

patients, 353–354antipsychotics and, 304–305, 306–

309, 310–311, 311–323assessment of, 322–323, 324–325effect on patient outcomes, 307–

308etiology of, 308–313first-generation antipsychotics

and, 314–315gender differences in, 306–308, 333management of, 326–333neurobiology of, 309, 311, 312

Index 453

patient-physician discussions of, 304

prevalence of, 303–305, 333risk factors for, 333second-generation antipsychotics

and, 315–321types of, 305–306underestimation of, 303–304, 305

Sexual function, physiology of, 309, 311–312

Sexually transmitted diseases (STDs), 249, 252

Sexual risk behaviors, 248–249, 264–265

Sibutramine, 104, 105use in pediatric schizophrenia

patients, 368as weight loss medication, 78, 79,

80–81, 104Sildenafil (Viagra), 329Sinus tachycardia, 188Skin cancer, 24Smoking, 223–243, 277

and calcium deficiency risk, 389of cannabis, 290and cardiovascular disease risk,

120–121, 169, 190–191, 312, 383of cocaine, 288, 289cognitive function effects of, 229–

230effect on antidiuretic hormone

release, 389effect on auditory information

processing defects, 228–229effect on mortality rate, 391effect on schizophrenia

symptoms, 227–230and erectile dysfunction risk, 312harm reduction approach to, 232and lung cancer risk, 24, 387neuroleptic medication and, 282during pregnancy, 416prevalence of, 30, 41, 118, 170–

171, 223–243, 312as “self-medication,” 229

Smoking cessation, 223–224, 227effect of typical versus atypical

antipsychotics on, 230–231effect on schizophrenia

symptoms, 228pharmacokinetic effects of, 226–227pharmacotherapy for, 233–237,

235, 236strategies for, 231–237, 234–236

Statins, 119cardioprotective effects of, 120

Stimulant abuse, 283, 285–286, 289Stroke, 94Substance abuse disorders, in

persons with schizophrenia, 275–302. See also Alcohol abuse; Drug abuse

biological basis for, 280–281, 296comorbidity with human

immunodeficiency virus (HIV) infection, 249–250, 252

demographics of, 275–280, 285effect on course of schizophrenia,

283–287effect on development of

schizophrenia, 282–287in homeless persons, 287medical consequences of, 29, 287–

290and mortality, 29patterns of, 280–283prevalence of, 44, 171, 296screening for, 290–291, 296“self-medication” hypothesis of,

280–281, 282, 296social functioning and, 275suicide and, 22treatment for, 291–296in urban versus rural

populations, 275–280Sudden cardiac death, 169, 170–171,

175–176, 173, 182, 184–186, 383. See also Mortality

Suicide, 17–18, 19, 20–22, 23, 32, 287, 289, 417


Survival curve, 20Sympathetic nervous system, role in

obesity, 68Syndrome X. See Metabolic

syndrome

Tardive dyskinesia, 44, 278–279, 281, 309


Testosterone, 309, 312, 389Tetratogenicity, of psychotropic

medications, 419–425, 421Thioridazine

effect on heart rate variability, 180effect on serum lipids, 133effect on sexual function, 315and QTc interval prolongation, 184quinidine-like properties of, 172reproductive safety of, 421use in pediatric schizophrenia

patients, 343–344Thiorixene, use in pediatric

schizophrenia patients, 345–346Thioxanthenes, teratogenicity of, 422Topiramate, as weight loss

medication, 79, 81Torsade de pointes, 171, 173–175,

174, 182QTc interval prolongation and,

169–170, 174, 175–176, 178risk factors for, 175surrogate risk markers for, 175–

176, 179–180Trazodone, effect on sexual function,

321Treatment. See Health careTricyclic antidepressants, effect on

sexual function, 321Trifluoperazine, reproductive safety

of, 421Triglyceride to high-density

lipoprotein ratio, 121–122Triglycerides, 43, 50, 63. See also

Hypertriglyceridemia

fasting versus nonfasting levels of, 48–49

Tuberculosis, 17Tumors. See also Cancer

prevalence of, 28T-waves

clozapine and changes in, 188–189measurement of, 177, 179–180

Ulcers, diabetic foot, 94Unemployment, 285University of California at San

Diego, 7

Valproate/valproic acideffect on weight, 76, 105sexual function effects of, 321

Vardenafil, 329–330Varenicline, 226, 235, 236, 237Venlafaxine, 321Verapamil, 176Veterans Affairs (VA), 7, 9, 382

National Patient Care Database, 379

Viagra (sildenafil), 329Violence

as mortality cause, 19toward pregnant women, 416

Virtual phenotyping, 253Visual impairment, in aging persons

with schizophrenia, 390

Waist circumference, as obesity measure, 43, 62–63, 64, 72–73

in pediatric schizophrenia patients, 357, 360–361,

Weight gain. See also Obesityantipsychotics and, 61–62, 95, 100,

101, 102–103atypical antipsychotics and, 3, 66,

98, 196CATIE data on, 38–39, 44–47, 46,

47, 53, 54determinants and mechanisms of,

66–67

Index 455

effect on QTc interval, 178–179in pediatric schizophrenia

patients, 347–350, 362–364Weight loss, 6

cocaine and, 289unexplained, 92

Weight loss medications, 78–83, 80–81

Weight measurement, 218in pediatric schizophrenia

patients, 356–357, 358–359West of Scotland Coronary

Prevention Study, 120Women. See also Breastfeeding;

Pregnancybody fat in, 63metabolic syndrome in, 66obesity in, 66schizophrenia prevalence in, 415sexual dysfunction prevalence in,

304, 305substance abuse in, 277–278

Women’s Health Study, 122World Health Organization (WHO),

63, 170

Ziprasidone, 3–4cardiac effects of, 183, 184, 355CATIE data on, 38–39, 44–53effect on cholesterol levels, 46, 51,



status, 48, 49effect on prolactin levels, 318, 320,

354effect on QTc interval, 45, 52, 176effect on serum lipids, 101, 124,

130, 131, 144, 147–149, 151,153, 154, 159

effect on sexual function, 318–319effect on triglyceride levels, 48–

49, 50

effect on weight, 44–45, 46, 47, 54,76, 101, 107

metabolic profile of, 38–39, 44–53as substance abuse treatment, 295use in pediatric schizophrenia

patients, 354, 355, 359Zotepine

effect on serum lipids, 129, 130effect on weight, 70, 130

Zyprexa. See Olanzapine

Documents

Medical-Schizophr