CLINICAL HANDBOOK OF SCHIZOPHRENIA - PART 1 pps

Donald Addington, MD, Department of Psychiatry, Foothills Hospital, Calgary, Alberta, Canada Jean Addington, PhD, Department of Psychiatry, University of Toronto, and PRIME Clinic, Centr

CLINICAL HANDBOOK OF SCHIZOPHRENIA

CLINICAL HANDBOOK OF SCHIZOPHRENIA

Edited by KIM T MUESER DILIP V JESTE

© 2008 The Guilford Press

A Division of Guilford Publications, Inc.

72 Spring Street, New York, NY 10012

www.guilford.com

All rights reserved

No part of this book may be reproduced, translated, stored in

a retrieval system, or transmitted, in any form or by any means,

electronic, mechanical, photocopying, microfilming, recording,

or otherwise, without written permission from the Publisher.

Printed in the United States of America

This book is printed on acid-free paper.

Last digit is print number: 9 8 7 6 5 4 3 2 1

The authors have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards of practice that are accepted at the time of publication However, in view of the possibility of human error or changes in medical sciences, neither the authors, nor the editor and publisher, nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or the results obtained from the use of such information Readers are encouraged to confirm the information contained in this book with other sources.

Library of Congress Cataloging-in-Publication Data

Clinical handbook of schizophrenia / edited by Kim T Mueser, Dilip V Jeste.

p ; cm.

Includes bibliographical references and index.

ISBN 978-1-59385-652-6 (hardcover : alk paper)

1 Schizophrenia—Handbooks, manuals, etc I Mueser, Kim Tornvall.

II Jeste, Dilip V III Title.

[DNLM: 1 Schizophrenia WM 203 C641153 2008]

RC514.C564 2008

616.89 ′ 8—dc22

2007033713

ABOUT THE EDITORS

Kim T Mueser, PhD, is a licensed clinical psychologist and a Professor in the

Depart-ments of Psychiatry and Community and Family Medicine at the Dartmouth MedicalSchool in Hanover, New Hampshire He was on the faculty of the Psychiatry Department

at the Medical College of Pennsylvania in Philadelphia until 1994, when he moved toDartmouth Medical School and joined the Dartmouth Psychiatric Research Center Dr.Mueser’s clinical and research interests include psychiatric rehabilitation for persons withsevere mental illnesses, intervention for co-occurring psychiatric and substance use disor-ders, and the treatment of posttraumatic stress disorder His research has been supported

by the National Institute of Mental Health (NIMH), the National Institute on DrugAbuse, the Substance Abuse and Mental Health Services Administration, and the NationalAlliance for Research on Schizophrenia and Depression (NARSAD) He has served on nu-merous editorial boards, has published many journal articles and book chapters, and has

coauthored 10 books In 2007 his book The Complete Family Guide to Schizophrenia

(with Susan Gingerich) received the National Alliance on Mental Illness NYC Metro KenBook Award for outstanding contributions to better understanding of mental illness

Dilip V Jeste, MD, is the Estelle and Edgar Levi Chair in Aging, Director of the Sam and

Rose Stein Institute for Research on Aging, and Distinguished Professor of Psychiatry andNeurosciences, University of California, San Diego (UCSD) and VA San Diego HealthcareSystem He is also the Director of the NIMH-funded Advanced Center for Interventionsand Services Research at UCSD focusing on psychosis in late life, and of the John A.Hartford Center of Excellence in Geriatric Psychiatry Dr Jeste was a research fellow, andlater, Chief of the Units on Movement Disorders and Dementias at NIMH before moving

to San Diego He is the Principal Investigator on several research and training grants; haspublished 8 books and over 500 articles in peer-reviewed journals and books; and is the

Editor-in-Chief of the American Journal of Geriatric Psychiatry He is a member of the

Institute of Medicine of the National Academy of Sciences, and of the National AdvisoryMental Health Council of the National Institutes of Health Dr Jeste is a past President

of the American Association for Geriatric Psychiatry (AAGP) and the West Coast College

of Biological Psychiatry, and Founding President of the International College of GeriatricPsychoneuropharmacology His numerous awards include NIMH’s MERIT Award; theSociety of Biological Psychiatry’s A E Bennett Neuropsychiatric Research Award; AAGP’sSenior Investigator Award; the American Psychiatric Association’s Research Award; MostDistinguished Physician Teacher/Researcher Award from the American Association ofPhysicians of Indian Origin; Asian Heritage Award for Excellence in Science, Technology,and Research; American College of Psychiatrists’ Geriatric Research Award; and Distin-guished Investigator Award from NARSAD

v

Donald Addington, MD, Department of Psychiatry, Foothills Hospital, Calgary,

Alberta, Canada

Jean Addington, PhD, Department of Psychiatry, University of Toronto, and PRIME Clinic,

Centre for Addiction and Mental Health, Toronto, Ontario, Canada

Britton Ashley Arey, MD, private practice, Costa Mesa, California

Christine Barrowclough, PhD, Academic Division of Clinical Psychology, School

of Psychiatry and Behavioural Sciences, Wythenshawe Hospital, Manchester,

United Kingdom

Stephen J Bartels, MD, Department of Psychiatry, New Hampshire–Dartmouth Psychiatric

Research Center, Dartmouth Medical School, Concord, New Hampshire

Paul Bebbington, MD, Department of Mental Health Sciences, Royal Free and University

College Medical School, London, United Kingdom

Deborah R Becker, MEd, Department of Psychiatry, New Hampshire–Dartmouth

Psychiatric Research Center, Dartmouth Medical School, Concord, New Hampshire

Alan S Bellack, PhD, Department of Psychiatry, University of Maryland School

of Medicine, Baltimore, Maryland

Jonathan Bindman, MD, PhD, Lambeth Hospital, London, United Kingdom

Gary R Bond, PhD, Department of Psychology, Indiana University–Purdue University

Indianapolis, Indianapolis, Indiana

Catherine Briand, PhD, Faculty of Medicine, University of Montreal,

Montreal, Quebec, Canada

Tyrone D Cannon, PhD, Departments of Psychology and Psychiatry and Biobehavioral

Sciences, University of California, Los Angeles, Los Angeles, California

William T Carpenter, Jr., MD, Departments of Psychiatry and Pharmacology

and Maryland Psychiatric Research Center, University of Maryland School

of Medicine, Baltimore, Maryland

David J Castle, MD, Mental Health Research Institute, University of Melbourne,

Parkville, Victoria, Australia

Robin E Clark, PhD, Center for Health Policy and Research, University of Massachusetts

Medical School, Shrewsbury, Massachusetts

vii

Carl I Cohen, MD, Division of Geriatric Psychiatry, State University of New York

Downstate Medical Center, Brooklyn, New York

Marc Corbière, PhD, Institute of Health Promotion Research, University of British

Columbia, Vancouver, British Columbia, Canada

Patrick W Corrigan, PsyD, Institute of Psychology, Illinois Institute of Technology,

Chicago, Illinois

John G Cottone, PhD, Stony Brook Psychotherapy and Wellness, Stony Brook, New York Gary S Cuddeback, PhD, Department of Social Work, Cecil G Sheps Center for Health

Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Larry Davidson, PhD, Program on Recovery and Community Health, School of Medicine

and Institution for Social and Policy Studies, Yale University, New Haven, Connecticut

Kenneth L Davis, MD, Department of Psychiatry, Mount Sinai School of Medicine,

New York, New York

Natalie L DeLuca, PhD, National Center for Organizational Development, VA Healthcare

System of Ohio, Cincinnati, Ohio

Lisa Dixon, MD, MPH, Division of Health Services Research, University of Maryland

School of Medicine, Baltimore, Maryland

Christian R Dolder, PharmD, Wingate University School of Pharmacy, Wingate,

North Carolina

Jonathan Downar, MD, PhD, Department of Psychiatry, University of Toronto,

Toronto, Ontario, Canada

Robert E Drake, MD, PhD, Department of Psychiatry, New Hampshire–Dartmouth

Psychiatric Research Center, Dartmouth Medical School, Concord, New Hampshire

Lauren M Ellman, PhD, New York State Psychiatric Institute, Columbia University,

New York, New York

Lisa T Eyler, PhD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Walid K H Fakhoury, PhD, Unit for Social and Community Psychiatry, Newham Centre

for Mental Health, London, United Kingdom

Roger D Fallot, PhD, Community Connections, Washington, DC

Alan Felix, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia

University, New York, New York

Richard B Ferrell, MD, Department of Psychiatry, Dartmouth–Hitchcock Medical Center,

Dartmouth Medical School, Lebanon, New Hampshire

Bernard A Fischer IV, MD, Department of Psychiatry, University of Maryland School

of Medicine, Baltimore, Maryland

Frederick J Frese III, PhD, Summit County Recovery Project, Akron, Ohio

Matthew A Fuller, PharmD, Pharmacy Service, Louis Stokes Cleveland Department

of Veterans Affairs Medical Center, Brecksville, Ohio

Susan Gingerich, MSW, private practice, Philadelphia, Pennsylvania

Stephen J Glatt, PhD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Richard J Goscha, MSW, School of Social Welfare, University of Kansas,

Lawrence, Kansas

Gillian Haddock, PhD, Academic Division of Clinical Psychology, University of

Manchester, Manchester, United Kingdom

Heinz Häfner, PhD, Schizophrenia Research Unit, Central Institute of Mental Health,

Mannheim, Germany

Wolfram an der Heiden, DiplPsych, Schizophrenia Research Unit, Central Institute of

Mental Health, Mannheim, Germany

Marnin J Heisel, PhD, Departments of Psychiatry and Epidemiology and Biostatistics,

Schulich School of Medicine and Dentistry, University of Western Ontario, London,Ontario, Canada

Dan Herman, DSW, Department of Clinical Epidemiology, Mailman School of Public

Health, Columbia University, New York, New York

Mustafa M Husain, MD, Department of Psychiatry, University of Texas Southwestern

Medical Center at Dallas, Dallas, Texas

Dilip V Jeste, MD, Institute for Research on Aging and Departments of Psychiatry

and Neurosciences, University of California, San Diego, and VA San Diego HealthcareSystem, La Jolla, California

Shitij Kapur, MD, PhD, Centre for Addiction and Mental Health and Department of

Psychiatry, University of Toronto, Toronto, Ontario, Canada

David J Kavanagh, PhD, Department of Psychiatry, University of Queensland,

Brisbane, Australia

Alex Kopelowicz, MD, San Fernando Mental Health Center, Granada Hills, California Elizabeth Kuipers, PhD, Department of Psychology, Institute of Psychiatry, Kings College

London, London, United Kingdom

Sanjiv Kumra, MD, Department of Psychiatry, University of Minnesota,

Minneapolis, Minnesota

Eric C Kutscher, PharmD, Department of Pharmacy Practice, South Dakota State

University College of Pharmacy, Brookings, South Dakota; Department of Psychiatry,Sanford School of Medicine, University of South Dakota School of Medicine,

Vermillion, South Dakota; Department of Psychiatry, Avera Behavioral Health Center,Sioux Falls, South Dakota

Jonathan E Larson, PhD, Rehabilitation Psychology Faculty, Institute of Psychology,

Illinois Institute of Technology, Chicago, Illinois

Helen Lavretsky, MD, MS, Department of Psychiatry and Behavioral Sciences, University

of California, Los Angeles, Los Angeles, California

William B Lawson, MD, PhD, Department of Psychiatry, Howard University Hospital,

Washington, DC

Tania Lecomte, PhD, Department of Psychology, University of Montreal,

Montreal, Quebec, Canada

Robert Paul Liberman, MD, Department of Psychiatry and Behavioral Sciences, University

of California, Los Angeles, Los Angeles, California

Fiona Lobban, PhD, Academic Division of Clinical Psychology, School of Psychiatry

and Behavioural Sciences, University of Manchester, Manchester, United Kingdom

James B Lohr, MD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Subramoniam Madhusoodanan, MD, St John’s Episcopal Hospital, Far Rockaway,

New York; Department of Psychiatry, State University of New York DownstateMedical Center, Brooklyn, New York

Stephen R Marder, MD, Semel Institute for Neuroscience and Human Behavior and

Department of Psychiatry, David Geffen School of Medicine, University of California,Los Angeles, Los Angeles, California

Thomas W McAllister, MD, Department of Psychiatry, Dartmouth–Hitchcock Medical

Center, Dartmouth Medical School, Lebanon, New Hampshire

Shawn M McClintock, PhD, Department of Psychiatry, University of Texas Southwestern

Medical Center at Dallas, Dallas, Texas

John R McQuaid, PhD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Thomas W Meeks, MD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Matthew R Merrens, PhD, New Hampshire–Dartmouth Psychiatric Research Center,

Dartmouth Medical School, Lebanon, New Hampshire

Alexander L Miller, MD, Department of Psychiatry, University of Texas Health Science

Center at San Antonio, San Antonio, Texas

Laura Miller, MD, Department of Psychiatry, University of Illinois at Chicago,

Chicago, Illinois

David J Moore, PhD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Vera Morgan, MA, School of Psychiatry and Clinical Neurosciences, University of Western

Australia, Perth, Australia

Anthony P Morrison, PhD, Department of Clinical Psychology, Mental Health Services,

Manchester, United Kingdom

Joseph P Morrissey, PhD, Departments of Health Policy and Administration and

Psychiatry and Cecil G Sheps Center for Health Services Research, University ofNorth Carolina at Chapel Hill, Chapel Hill, North Carolina

Lorna L Moser, MS, Department of Psychology, Indiana University–Purdue University

Indianapolis, Indianapolis, Indiana

Kim T Mueser, PhD, Department of Psychiatry, New Hampshire–Dartmouth Psychiatric

Research Center, Dartmouth Medical School, Concord, New Hampshire

Barnaby Nelson, PhD, The PACE Clinic, ORYGEN Youth Health, Parkville, Victoria,

Australia

Joanne Nicholson, PhD, Department of Psychiatry and Community Health Center for

Mental Health Services Research, University of Massachusetts Medical School,Worcester, Massachusetts

Thomas O’Hare, MSW, PhD, Graduate School of Social Work, Boston College,

Boston, Massachusetts

Fred C Osher, MD, Health Systems and Services Policy Justice Center, Council of State

Governments, Bethesda, Maryland

Barton W Palmer, PhD, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Roger H Peters, PhD, Department of Mental Health Law and Policy, Louis de la Parte

Florida Mental Health Institute, University of South Florida, Tampa, Florida

Stefan Priebe, PhD, Unit for Social and Community Psychiatry, Newham Centre

for Mental Health, London, United Kingdom

Najeeb Ranginwala, MD, Department of Psychiatry, University of Texas Southwestern

Medical Center at Dallas, Dallas, Texas

Charles A Rapp, MSW, PhD, School of Social Welfare, University of Kansas,

Lawrence, Kansas

Priscilla Ridgway, PhD, Connecticut Mental Health Center, Yale University, New Haven,

Connecticut

David Roe, PhD, Department of Community Mental Health, Faculty of Social Welfare

and Health Studies, University of Haifa, Haifa, Israel

Stanley D Rosenberg, PhD, Department of Psychiatry and Dartmouth Trauma Intervention

Research Center, Dartmouth Medical School, Lebanon, New Hampshire

Abraham Rudnick, MD, PhD, Departments of Psychiatry and Philosophy, University

of Western Ontario, London, Ontario, Canada

Ingrid B Rystedt, MD, PhD, Department of Community and Family Medicine, New

Hampshire–Dartmouth Psychiatric Research Center, Dartmouth Medical School,Lebanon, New Hampshire

Martha Sajatovic, MD, Department of Psychiatry, Case Western Reserve University School

of Medicine, Cleveland, Ohio

Mihail Samnaliev, PhD, Center for Health Policy and Research, University

of Massachusetts Medical School, Shrewsbury, Massachusetts

Antonio M Santos, PhD, private practice, La Jolla, California

Gauri N Savla, MA, MS, Department of Psychiatry, University of California, San Diego,

La Jolla, California

Mary V Seeman, MD, Centre for Addiction and Mental Health, University of Toronto,

Toronto, Ontario, Canada

Jennifer J Shaw, MD, Guild Lodge Medium Secure Unit, Lancashire, United Kingdom Pattie B Sherman, BA, Department of Psychology, University of South Florida,

Daniel G Stewart, MD, Department of Psychiatry, Mount Sinai School of Medicine,

New York, New York

Donald Stolar, PhD, Department of Psychiatry, University of California, Los Angeles,

Los Angeles, California

Ezra Susser, MD, Department of Epidemiology, Mailman School of Public Health,

Columbia University, New York, New York

Wendy N Tenhula, PhD, Department of Psychiatry, University of Maryland School

of Medicine, Baltimore, Maryland

Graham Thornicroft, MD, PhD, Institute of Psychiatry, King’s College London,

London, United Kingdom

Ipsit V Vahia, MD, Sam and Rose Stein Institute of Research for Aging, University of

California, San Diego, La Jolla, California

Vihang N Vahia, MD, Department of Psychiatry, Dr R N Cooper Hospital and Seth

G S Medical College, Mumbai, India

Dawn I Velligan, PhD, Department of Psychiatry, University of Texas Health Science

Center at San Antonio, San Antonio, Texas

Charles Weijer, MD, PhD, Department of Philosophy, Talbot College, University of

Western Ontario, London, Ontario, Canada

Karen Wohlheiter, PhD, Department of Psychiatry, University of Maryland School of

Medicine, Baltimore, Maryland

Til Wykes, PhD, Institute of Psychiatry, King’s College London, London, United Kingdom Alison Yung, MD, Department of Psychiatry, University of Melbourne, Parkville, Victoria,

Australia

Schizophrenia is arguably the most serious major psychiatric disorder, usually ing in late adolescence or early adulthood, and often having a profound effect over thelifetime on daily functioning People with schizophrenia frequently have difficulties livingindependently and caring for themselves, working or attending school, fulfilling parental

develop-or other role obligations, and enjoying close relationships and rewarding leisure activities(American Psychiatric Association, 2000) Although schizophrenia develops in about 1 in

100 individuals, it accounts for a disproportionate share of treatment costs and, ing to the World Health Organization, is ranked as the second highest contributor tooverall burden of diseases, behind cardiovascular disease (Murray & Lopez, 1996).Despite the severity of schizophrenia, in recent years there has been enormous prog-ress in our understanding of the illness, and the treatment for it is a rapidly evolving field.Two to three decades ago only a few treatments had been shown to be effective forschizophrenia, and most people with the illness continued to be substantially disabledthroughout their lives Although no “cure” for schizophrenia is currently known, a grow-ing number of treatments, both pharmacological and psychosocial, have been shown to

accord-be effective Of equal or greater importance, there has accord-been a sea change in how the ment, course, and outcome of schizophrenia are conceptualized Whereas treatment used

treat-to focus primarily on a reduction or containment of psychopathology, traditional cepts of medical recovery have been challenged and recently have given way to new andmore meaningful definitions of recovery that emphasize improved functioning, client self-direction, empowerment, and hope (Anthony, 1993; Bellack, 2006; Deegan, 1988) Thereare now solid grounds for optimism in the treatment of schizophrenia, and the potential

con-to help individuals with this disorder lead rewarding and productive lives The change inthe perception about schizophrenia (although still quite limited in the public mind) may

be exemplified by two films that won the Oscar for the best film of the year: One Flew

over the Cuckoo’s Nest in 1976 versus A Beautiful Mind in 2002 The former depicted

prevalent treatment of serious mental illnesses within a rigid, authoritarian, impersonalchronic mental institution, whereas the latter focused on a person with schizophreniawho not only had a remission of his illness, but also received a Nobel Prize for his earlierscientific work

Because knowledge about schizophrenia and its treatment has grown at an tial rate in recent years, clinicians have a critical need to keep abreast of the latest devel-opments, within the constraints of limited time, resources, and their own expertise.Specifically, clinicians require access to authoritative information and recommended

exponen-xiii

resources, written in nontechnical language and covering a broad range of topics related

to schizophrenia and its treatment The Clinical Handbook of Schizophrenia is designed

to meet these practical needs of clinicians working with individuals with schizophreniaand their families

Each chapter in the Handbook has been written by a world authority on the topic, in

plain language with minimal (or no) references in the text, and a resource list of ences and recommended readings at the end All of the chapters on treatment are aimed

refer-at providing not only guidelines to clinicians about implementing specific trerefer-atment proaches or working with particular populations but also succinct reviews of the researchliterature supporting these methods The major “take-home” messages on each topic aresummarized in a series of “Key Points” at the end of each chapter The selection of topics,the writing style, the emphasis on briefly summarizing research findings rather thanexhaustively reviewing the scientific literature, and the focus on providing practical clini-

ap-cal recommendations are intended to make the Handbook an interesting and useful

re-source for clinicians In addition, the comprehensive yet accessible nature of this bookwill be of interest to students in the health professions (e.g., clinical psychology, psychia-try, general medical practice or family medical practice, psychiatric rehabilitation, socialwork, nursing, occupational therapy, family and marital counselors), mental health ad-ministrators and policymakers, relatives and other support persons, and individuals withschizophrenia themselves

The Handbook is divided into eight different sections, each covering a variety of topic areas Part I focuses on Core Science and Background Information on schizophre-

nia The section begins with a chapter on the history of the concept of schizophrenia, lowed by chapters on epidemiology, biological theories, brain imaging, neuropathology,genetics, and pre- and perinatal influences on the development of the illness This sectionalso includes chapters on psychosocial factors in schizophrenia, psychopathology, cogni-tive functioning, and the course and outcome of the disease

fol-Part II addresses practical issues related to Assessment and Diagnosis of

schizophre-nia The first chapter in this section addresses clinical methods for the diagnosis of phrenia and related schizophrenia spectrum disorders (e.g., schizoaffective disorder andschizophreniform disorder), which are of critical importance considering symptom over-lap in schizophrenia and major mood disorders The second chapter addresses the assess-ment of medical comorbidity, which is now recognized as the most important factor con-tributing to premature mortality for individuals with schizophrenia (Jeste, Gladsjo,Lindamer, & Lacro, 1996) A third chapter addresses the assessment of psychosocialfunctioning—a crucial topic considering that impaired social functioning is a hallmark ofschizophrenia The final chapter in this section provides a framework for treatment plan-ning and ongoing monitoring of outcomes

schizo-Part III addresses the Somatic Treatment of schizophrenia The primary focus of this

section is on pharmacological approaches, which are widely accepted as the “mainstay”

in the treatment of schizophrenia Although not everyone with schizophrenia benefitsfrom medication, the vast majority do, and effective pharmacological treatment makes itpossible for many individuals to participate in psychosocial treatment This section alsoincludes a chapter on the use of electroconvulsive therapy for schizophrenia, a frequentlymisunderstood but potentially useful treatment approach for a small proportion of indi-viduals with intractable symptoms

Part IV addresses the Psychosocial Treatment of schizophrenia Extensive research in

recent years has demonstrated the effectiveness of a variety of different approaches topsychosocial treatment and self-help for schizophrenia The chapters in this sectionreflect the broad range of psychosocial interventions for schizophrenia, including the in-

corporation of environmental supports into individuals’ lives to facilitate medication herence and improve daily functioning, family intervention to educate relatives aboutschizophrenia and the principles of its management, cognitive-behavioral therapy for psy-chosis, social skills training, cognitive rehabilitation, vocational rehabilitation, and train-ing in illness self-management skills In addition, the specific application of psychosocialtreatments in a group format is covered in one chapter, whereas another describes theprinciples of supported housing The final chapter in this section addresses the role ofself-help in promoting coping and recovery from schizophrenia.

ad-Part V focuses on Systems of Care for delivering treatment to people with

schizo-phrenia The initial chapter in this section is devoted to the role of clinical case ment in coordinating mental health treatment, followed by chapters on strengths-basedcase management and the assertive community treatment (ACT) model In addition, onechapter addresses treatment in emergency room, inpatient, and residential settings,whereas another describes the treatment of schizophrenia in jails and prisons, a topic ofmajor interest considering the dramatic and distressing growth in recent years of individ-uals with severe mental illness in the criminal justice system (Torrey, 1995)

manage-Part VI addresses a range of Special Populations and Problems among the broad

group of individuals with schizophrenia The first chapter describes the treatment of thefirst episode of schizophrenia, a topic that has garnered a great deal of interest over thepast decade The second addresses the treatment of the prodromal phase of schizophre-nia, a new and promising area of research The third chapter describes the treatment ofschizophrenia in older individuals, also a growing topic of interest considering the rapidlygrowing population of people over age 50 with the illness This section also containschapters on common problems experienced by individuals with schizophrenia, includingaggression and violence, housing instability and homelessness, medical comorbidity, intel-lectual disability, trauma and posttraumatic stress disorder, and substance abuse Finally,one chapter describes the treatment of individuals with schizophrenia who are parents,and strategies for ensuring that their children’s needs are met This is a topic of consider-able importance, especially for women with schizophrenia who have children, butfrequently have difficulty fulfilling their parental obligations (Apfel & Handler, 1993).Another chapter describes the treatment of schizophrenia in children and adolescents.This section concludes with a chapter on suicide

Part VII addresses Policy, Legal, and Social Issues related to the treatment of

schizo-phrenia One chapter in this section discusses the economics of schizophrenia, includingestimates of the direct and indirect costs of the illness Two chapters deal with legal as-pects of the care of people with schizophrenia, including involuntary commitment totreatment and treatment in jail and prison settings One chapter in this section addressesthe vexing problem of stigma, including both social rejection and fear of people with theillness, and the dispiriting effects of self-stigma, or the integration of social beliefs aboutthe illness into one’s self-concept Another chapter addresses implementation of evidence-based practices for the treatment of schizophrenia This topic is of particular importance,because research has shown that a wide range of treatments are effective for schizophre-nia, but there has been an unacceptably long delay between the discovery of effectivetreatments and access to them in public mental health care settings (Drake et al., 2001;Lehman & Steinwachs, 1998) The final chapter in this section addresses schizophrenia indeveloping nations, a topic that has been the focus of increasing attention in recent years

Part VIII is devoted to Special Topics related to the treatment of schizophrenia The

sec-tion begins with a chapter defining criteria for remission of schizophrenia, followed by achapter on growth and recovery that addresses the paradigm shift from approaching schizo-phrenia mainly in terms of psychopathology and impairment to exploring the potential of

individuals with the illness to achieve personally meaningful recovery and to continue togrow as people The next chapter in this section addresses issues related to gender, followed

by a chapter that considers the topic of quality of life, including both subjective and tive approaches to the issue Two chapters in this section address the topics of religion (andspirituality) and sexuality, both of paramount importance in the lives of many people withand without mental illness, but frequently neglected in books and guidelines describing thetreatment of schizophrenia One chapter addresses the topic of schizophrenia in AfricanAmericans; the extensive research by this chapter’s author and his group may have impor-tant and useful implications for understanding the complex interrelationships betweenschizophrenia and race/ethnicity This section concludes with a chapter on ethics, an in-creasingly complex topic in both research and clinical practice as treatment options multi-ply, and the importance of engaging and empowering individuals with schizophrenia inmaking decisions about their own treatment is now recognized

objec-The treatment of schizophrenia has now evolved to the point that clinicians, uals with the illness, and their loved ones have numerous choices, and a more hopefulfuture However, to take advantage of the latest developments in the causes and the treat-ment of schizophrenia, the people interested in this topic need an authoritative yet acces-

individ-sible guide We hope that our readers will find the Clinical Handbook of Schizophrenia a

valuable resource in furthering their understanding of schizophrenia, and in guiding theirtreatment decisions Ultimately, broad dissemination of scientifically accurate and clini-cally relevant information is the best means of reducing social stigma against seriousmental illnesses such as schizophrenia

KIMT MUESER

DILIPV JESTE

REFERENCES

American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (4th

ed., text rev.) Washington, DC: Author

Anthony, W A (1993) Recovery from mental illness: The guiding vision of the mental health service

system in the 1990s Psychosocial Rehabilitation Journal, 16, 11–23.

Apfel, R J., & Handler, M E (1993) Madness and the loss of motherhood: Sexuality, reproduction,

and long-term mental illness Washington, DC: American Psychiatric Press.

Bellack, A S (2006) Scientific and consumer models of recovery in schizophrenia: Concordance,

contrasts, and implications Schizophrenia Bulletin, 32, 432–442.

Deegan, P E (1988) Recovery: The lived experience of rehabilitation Psychosocial Rehabilitation

Journal, 11, 11–19.

Drake, R E., Goldman, H H., Leff, H S., Lehman, A F., Dixon, L., Mueser, K T., et al (2001)

Imple-menting evidence-based practices in routine mental health service settings Psychiatric Services,

52, 179–182.

Jeste, D V., Gladsjo, J A., Lindamer, L A., & Lacro, J P (1996) Medical comorbidity in

schizophre-nia Schizophrenia Bulletin, 22(3), 413–430.

Lehman, A F., & Steinwachs, D M (1998) Patterns of usual care for schizophrenia: Initial results

from the Schizophrenia Patient Outcomes Research Team (PORT) client survey Schizophrenia

Bulletin, 24, 11–20.

Murray, C J L., & Lopez, A D (Eds.) (1996) The global burden of disease: A comprehensive

assess-ment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to

2020 Cambridge, MA: Harvard School of Public Health, on behalf of the World Health

Organi-zation and the World Bank, Harvard University Press

Torrey, E F (1995) Jails and prisons: American’s new mental hospitals [Editorial] American Journal

of Public Health, 85, 1611–1613.

I CORE SCIENCE AND BACKGROUND INFORMATION

CHAPTER 1 History of Schizophrenia as a Psychiatric Disorder 3

Helen Lavretsky

David J Castle and Vera Morgan

Jonathan Downar and Shitij Kapur

CHAPTER 7 Environmental Pre- and Perinatal Influences in Etiology 65

Lauren M Ellman and Tyrone D Cannon

Paul Bebbington and Elizabeth Kuipers

Ipsit V Vahia and Carl I Cohen

Gauri N Savla, David J Moore, and Barton W Palmer

Heinz Häfner and Wolfram an der Heiden

xvii

II ASSESSMENT AND DIAGNOSIS

Abraham Rudnick and David Roe

Karen Wohlheiter and Lisa Dixon

Tania Lecomte, Marc Corbière, and Catherine Briand

Alexander L Miller and Dawn I Velligan

III SOMATIC TREATMENT

Britton Ashley Arey and Stephen R Marder

Shawn M McClintock, Najeeb Ranginwala, and Mustafa M Husain

IV PSYCHOSOCIAL TREATMENT

Dawn I Velligan and Alexander L Miller

Christine Barrowclough and Fiona Lobban

Anthony P Morrison

Wendy N Tenhula and Alan S Bellack

Til Wykes

Deborah R Becker

CHAPTER27 Illness Self-Management Training 268

Kim T Mueser and Susan Gingerich

John R McQuaid

Priscilla Ridgway

Frederick J Frese III

V SYSTEMS OF CARE

Margaret V Sherrer and Thomas O’Hare

Charles A Rapp and Richard J Goscha

Natalie L DeLuca, Lorna L Moser, and Gary R Bond

CHAPTER34 Emergency, Inpatient, and Residential Treatment 339

Mounir Soliman, Antonio M Santos, and James B Lohr

Roger H Peters, Pattie B Sherman, and Fred C Osher

VI SPECIAL POPULATIONS AND PROBLEMS

Donald Addington and Jean Addington

CHAPTER37 Treatment of the Schizophrenia Prodrome 380

Barnaby Nelson and Alison Yung

Thomas W Meeks and Dilip V Jeste

CHAPTER39 Understanding and Working with Aggression, Violence,

and Psychosis

398

Gillian Haddock and Jennifer J Shaw

Alan Felix, Dan Herman, and Ezra Susser

Ingrid B Rystedt and Stephen J Bartels

CHAPTER42 Intellectual Disability and Other Neuropsychiatric Populations 437

Richard B Ferrell and Thomas W McAllister

CHAPTER43 Trauma and Posttraumatic Stress Syndromes 447

Stanley D Rosenberg and Kim T Mueser

CHAPTER44 Management of Co-Occurring Substance Use Disorders 459

David J Kavanagh

Joanne Nicholson and Laura Miller

John G Cottone and Sanjiv Kumra

Marnin J Heisel

VII POLICY, LEGAL, AND SOCIAL ISSUES

Mihail Samnaliev and Robin E Clark

Jonathan Bindman and Graham Thornicroft

Joseph P Morrissey and Gary S Cuddeback

Patrick W Corrigan and Jonathon E Larson

Matthew R Merrens and Robert E Drake

Vihang N Vahia and Ipsit V Vahia

VIII SPECIAL TOPICS

Stefan Priebe and Walid K H Fakhoury

Roger D Fallot

CHAPTER59 Sexuality 604

Alex Kopelowicz, Robert Paul Liberman, and Donald Stolar

PA RT I

CORE SCIENCE AND

BACKGROUND INFORMATION

C H A P T E R 1

HISTORY OF SCHIZOPHRENIA

AS A PSYCHIATRIC DISORDER

HELEN LAVRETSKY

HISTORY OF CLINICAL DIAGNOSIS OF SCHIZOPHRENIA

Schizophrenia is one of the most serious psychiatric disorders It carries a lifetime risk ofapproximately 1% The symptoms of schizophrenia remain perhaps the most mysteriousform of human psychological experience The early onset of the disease, most often oc-curring between ages 15 and 30 years, and its chronic course make this a particularly dis-abling disorder for patients and their families Chronic disability results primarily fromthe negative and cognitive symptoms, whereas acute relapses result from exacerbations ofthe positive psychotic symptoms, such as delusions and hallucinations The social andeconomic impact of the disorder on society and families is enormous

Despite extensive research, the international psychiatric community still lacks nostic precision, clarity of etiology, and knowledge of underlying pathophysiology ofschizophrenia Disputes over concepts and appropriate models of mental illness extendback to classical times Reports of schizophrenia-like illness can be found even in ancientliterature However, the first comprehensive description dates to the beginning of the18th century Schizophrenia was defined as an early dementia in the 19th century French

diag-psychiatrist, Benedict Augustine Morel (1809–1873), coined the term dementia praecox,

para-“hallucinations of hearing.” Although Kraepelin defined dementia praecox on the basis

of the characteristic course and outcome of a cluster of symptoms and signs, he also

3

stated that it was a disorder with a specific neuroanatomical pathology and etiology Thisstatement generated an early and continuing interest in the anatomy of the central ner-

vous system underlying schizophrenic process The sixth edition of Kraepelin’s Textbook

of Psychiatry (1899/1990) distinguished between dementia praecox and manic–depressive

disorder He described one group of patients whose clinical picture was dominated by ordered mood and who followed a cyclical pattern of relapse and relative remission; for

dis-this condition, Kraepelin coined the term manic depressive insanity Another group of

patients had a deteriorating illness characterized by an acute onset of psychosis in cence, with a prolonged course marked by profound social and functional disability; this

adoles-he called dementia praecox

Kraepelinian concepts profoundly influenced European and American psychiatry.These diagnostic categories continue to guide our clinical practice and research in the21st century, despite the fact that Kraepelin himself recognized their limitations, such asthe existence of late-onset disorders and the possibility of reasonable functional remission

in some individuals

Kraepelin’s (1899/1990) diagnostic concept of dementia praecox was expanded with

the inclusion of Magnan and Legrain’s (1895) notion of délire chronique By the time of

the seventh edition of Kraepelin’s (1904) textbook, his concept embraced all disorderswith a course leading to psychic invalidism of varying severity Subsequently, however, heseparated paranoid deteriorations (paraphrenias) with prevalent delusions, but withoutemotional and volitional psychopathology, from the paranoid form of dementia praecox.Then, he identified 10 different forms of dementia praecox: dementia simplex, silly dete-

rioration (replacing the term hebephrenia), depressive deterioration, depressive

deteriora-tion with delusional manifestadeteriora-tions, circular, agitated, periodic, catatonic, paranoid, andschizophasia Finally, in the eighth edition of his textbook, Kraepelin (1913) described 10different end states of the disease: cure; cure with defect; simple deterioration; imbecilitywith confusion of speech; hallucinatory deterioration; hallucinatory insanity; paranoiddeterioration; flighty, silly deterioration; and dull, apathetic dementia In the same edi-

tion, he defined dementia praecox as a series of clinical states that have as their common

characteristic a peculiar destruction of the internal connections of the psychic personality,with the most marked damage to the emotional and volitional life In 1959, Kurt Schnei-der further defined a list of relatively easily and reliably identified first-rank symptomsthat were considered to be most consistent with the diagnosis of schizophrenia: audiblethoughts; arguing or commenting voices; feeling controlled or influenced by an externalforce; thought withdrawal; diffusion of thought; and delusions

The Swiss psychiatrist Eugen Bleuler coined the term schizophrenia in 1911, and that

term rapidly replaced dementia praecox Although Bleuler subtitled his book on dementia

praecox The Group of Schizophrenias, his major argument was that the concept of

schizophrenia was unified by a single defining phenotype that was present in all patientswith the illness Bleuler thought of schizophrenia in psychological rather than in

neuropathological terms He chose the name schizophrenia because it meant literally “a

mind that is torn asunder.” He developed a hierarchy that distinguished between

funda-mental and accessory symptoms Fundafunda-mental symptoms were shared by all

schizophre-nia subtypes as a common endophenotype, and included “fragmented” disturbed

associa-tions, or what we now term cognitive disturbances Psychic schisis or split, ambivalence,

cognitive features of “loose associations,” avolition, inattention, autism, and incongruentfeatures signified primary deficits for Bleuler, whereas florid psychotic symptoms of delu-

sions and hallucinations were conceptualized as secondary or accessory to the core

cogni-tive disturbances Bleuler’s advanced cognicogni-tive theory of schizophrenia was ahead of itstime, and difficult to prove and define reliably due to a lack of measurement tools, partic-

4 I CORE SCIENCE AND BACKGROUND INFORMATION

ularly for the “softer” concepts of “simple” or” latent” types of schizophrenia that dressed personality characteristics of “odd individuals.” It required another 100 years ofneurocognitive research to narrow down the fundamental schizophrenic deficit of cogni-tive dysmetria, which Bleuler hypothesized as a disruption of the fluid, coordinated se-quences of thought and action that are the hallmark of normal cognition (Andreasen,1999).

ad-The conceptual confusion at the beginning of the 20th century was compounded byclinical heterogeneity of schizophrenia, lack of clear prognostic features, and failure todiscover any definitive pathological abnormalities Bleuler’s approach led to an expansion

of the diagnostic concept of schizophrenia that incorporated many other neuropsychiatric

disorders, particularly, in the United States during the early development of the

Diagnos-tic and StatisDiagnos-tical Manual of Mental Disorders (DSM-I and II) through the 1970s, and in

the former Soviet Union

Another prominent influence on the concept of schizophrenia in the United Stateswas provided by the theories of Adolph Meyer, who emphasized the impact of the indi-vidual history of each particular patient on the schizophrenia syndrome (Peteres, 1991).Other important broad diagnostic concepts included schizoaffective psychosis (Kasanin,1933), ambulatory schizophrenia (Zilboorg, 1956), and “pseudoneurotic schizophrenia”(Hoch & Polatin, 1949) DSM-II (American Psychiatric Association, 1968) presentedschizophrenia in its broadest interpretation In 1966, the World Health Organizationsponsored the International Pilot Study of Schizophrenia (IPSS; 1973), which investigatedthe illness in several centers around the world and found a high degree of consistency inthe clinical features of schizophrenia when using strict diagnostic criteria This finding led

to the critical revision of diagnostic categories during the 1970s in the United States, withnarrowing of its definitions and development of the core symptoms criteria DSM-IIIbecame a turning point for U.S psychiatry, reintroducing a neo-Kraepelinian approachtoward the diagnosis of mental disorders that brought U.S and European concepts closer

Further revisions of both DSM (III-R and IV) and the International Classification of

Dis-eases (ICD-10) brought these systems even closer Both systems identify a number of

sub-types of schizophrenia, and both use only cross-sectional disease status for diagnosticpurposes These diagnostic systems differ only in the affective categorization of psychosis,with mood-incongruent features subsumed under affective psychosis in DSM-IV, and un-der schizophrenias in the ICD-10

In addition to the improved clinical diagnostic boundaries, major advances havebeen made in the psychopharmacological and psychosocial treatments of schizophrenia,providing new hope for improved outcomes of this disabling disease

HISTORY OF TREATMENT OF SCHIZOPHRENIA

For decades following Kraepelin’s seminal description of schizophrenia there was no fective medical treatment Unfortunate patients were treated with some “desperate”methods, such as prolonged barbiturate-induced sleep therapy, insulin coma, or psycho-surgery (Valenstein, 1986) Insulin coma involved creating a hypoglycemic state throughadministration of large doses of insulin that resulted in loss of consciousness and seizures

ef-A few reports suggested that a series of such insulin shocks might reduce patients’ chotic episodes However, the technique was never carefully evaluated, and posed risks ofheart attack and stroke

psy-Frontal lobotomies, or leukotomies, involved neurosurgery that cut the nerve tracts

of the frontal lobes, thereby reducing agitation and impulsive behavior, but causing

addi-1 History of Schizophrenia 5

tional cognitive impairment Large numbers of patients underwent the operation, withlittle demonstrable benefit and little concern for ethical requirements such as informedconsent for treatment.

Limited therapeutic options and prospects during the first half of the 20th centurymeant that thousands of patients with schizophrenia were warehoused in huge psychiat-ric hospitals By the mid-1950s, the United States and Canada alone had over 500,000psychotic inpatients who were hospitalized indefinitely Despite the efforts of the pioneers

of psychiatry to address treatment of schizophrenia, patients’ quality of life did not prove Modern psychopharmacology was started serendipitously A French naval sur-geon, Henry Laborit, was testing a new drug, promethazine, to determine its effect on au-tonomic nervous system He was looking for a treatment for circulatory shock aftersurgeries However, the secondary properties of the drug included drowsiness, reducedpain, and feelings of euphoria Laborit published observations of the psychotropic effects

im-of promethazine that stimulated interest im-of researchers at the laboratories im-of the firmRhone-Poulenc They, in turn, modified the promethazine formula, resulting in the cre-ation of the first effective antipsychotic drug, chlorpromazine The initial observations ofpromethazine and chlorpromazine in psychiatric patients reflected the drugs’ short-termantipsychotic and sedating effects Later, a number of clinical trials, especially those byDelay, Deniker, and Harl (1952), and Sigwald and Bouttier (1953) in Europe, Lehmannand Hanrahan (1954) in Canada, and finally, the large, collaborative National Institute

of Mental Health (NIMH; Cole, Goldberg, & Klerman, 1964) study in the United States,demonstrated the efficacy of new medications Chlorpromazine reduced agitation andmood disturbance, as well as positive psychotic symptoms of delusions, hallucinations,and thought disorder, and even some negative symptoms Patients who received this med-ication spent less time in the hospital, had fewer relapses, and showed enhanced life func-tioning compared to untreated patients

Although psychopharmacological interventions revolutionized care for patientswith chronic schizophrenia and changed the cost of care for society, they did not pro-vide a cure A minority of patients responded poorly to antipsychotic drugs, and evenresponsive patients had to deal with unpleasant and occasionally disabling side effects.Many patients relapsed, if the drug was discontinued In addition, even in improvedpatients, a lack of occupational and daily living skills or social support underminedsuccessful functioning after discharge from the hospital Such services were not avail-able to a vast majority of chronically mentally ill patients Deinstitualization of patientswith severe mental illness, beginning in the mid-1950s, without adequate follow-upcare resulted in a social drift to poverty and stigma despite improvement in treatmentoutcomes

The main form of psychotherapy used for schizophrenia in the United States and theUnited Kingdom until the early 1960s was psychoanalysis or dynamically oriented psy-chotherapy The NIMH-sponsored 1964 study showed that such psychotherapy (as well

as electroconvulsive therapy) was significantly less effective than antipsychotic drugs Atthe same time, it became clear that the medications were only useful for reducing severity

of symptoms and for preventing relapse Supportive psychotherapy was therefore ered an essential adjunct to pharmacotherapy Subsequently, other forms of psychosocialinterventions, such as cognitive-behavioral therapy (CBT), social skills training, supportedemployment, and family intervention programs, were developed and tested for usefulness

consid-in people with schizophrenia It is now well accepted that medications alone are consid-quate for management of schizophrenia, and that a combined psychopharmacological–psychosocial approach is a must for improving long-term outcome in persons withschizophrenia

inade-6 I CORE SCIENCE AND BACKGROUND INFORMATION

PSYCHOPHARMACOLOGY AND NEUROSCIENCE OF SCHIZOPHRENIA

The revolution in psychopharmacology and biological psychiatry started by the tion of chlorpromazine provided the first effective treatment for schizophrenia, as well asideas and evidence about the pathophysiology of the illness There is evidence for a vari-ety of neurochemical abnormalities, ranging from excessive to deficient concentrations ofdopamine, serotonin, and glutamate, in studies comparing patients with schizophreniaand controls

introduc-Dopamine

The early 1960s implicated monoamines in the effects of the antipsychotic drugs and inthe pathophysiology of schizophrenia and related drug side effects Dopamine was one ofthe approximately 10 neurotransmitters distributed diffusely throughout the brain con-sidered for pathophysiology of schizophrenia The strongest support for a connection be-tween dopamine function and schizophrenia came from studies showing that the clinicalefficacy of drugs depends on their ability to block dopamine receptors, especially the do-pamine D2receptor subtype These studies, carried out in the 1970s, used postmortembrain tissue samples The studies of dopamine metabolites in the cerebrospinal fluid and

dopamine receptor binding that used in vivo functional neuroimaging provided

addi-tional evidence for dopamine abnormalities in schizophrenia

Serotonin

In 1943, Swiss chemist Albert Hoffman ingested a new chemical compound—an ergotderivative called lysergic acid diethylamide (LSD) He experienced psychotic delusionsand vivid hallucinations That experience led him to the studies of drugs that producepsychotic symptoms LSD seemed to enhance and potentiate the effects of serotonin inthe brain This finding initiated interest in the role of serotonin in schizophrenia, whichwas rekindled in the late 1980s and early 1990s with the development of atypicalantipsychotic drugs, starting with clozapine and risperidone These compounds appeared

to work by blocking both dopamine D2and serotonin S2receptors This dual activity tinguished these newer, atypical antipsychotics from the older, typical antipsychotics thatonly blocked dopamine receptors The serotonin-blocking action seemed to be an impor-tant part of the demonstrated efficacy for positive and, to some extent, negative symp-toms of schizophrenia, as well as a reduction in the risk of tardive dyskinesia with atypi-cal compared with typical antispychotics Other, newer atypical antipsychotic agentsdeveloped since then, such as olanzapine, quetiapine, ziprasidone, and aripiprazole, sharethis dual neurotransmitter action However, direct evidence for a primary role of seroto-nin in the pathophysiology of schizophrenia remains less convincing compared to that fordopamine

hippocam-1 History of Schizophrenia 7

effects of a drug of abuse, phencyclidine (PCP), which serves as one of the putative chemical models for schizophrenia (Kornhuber, 1990) PCP binds to a specific site on the

neuro-N-methyl-D-aspartate (NMDA) receptor and blocks the action of glutamate, which isconsidered to be responsible for its analgesic, anesthetic, and physiological effects Sup-portive evidence comes from postmortem neuropathological studies reporting reduction

in the glutamate transmitter binding in brains of people with schizophrenia Deficientglutamate neurotransmission may be a primary or secondary, underlying mechanism inschizophrenia

Other candidate neurotransmitters include aspartate, glycine, and gamma-aminobutyricacid (GABA), collectively dominating excitatory and inhibitory neurotransmission Even-tually, we might discover that dysregulation of several neurotransmitter systems is theunifying underlying mechanism of the disease Brain imaging studies of receptor densities

in young adults and children, or in patients with first-episode schizophrenia may be ful in identifying early vulnerability factors

help-HISTORY OF THE NEUROSCIENCE OF SCHIZOPHRENIA

Over the last two decades, with the rapid development of the neurosciences, new hopeand confidence have arisen that schizophrenia will soon be cured or, at least, that its out-come will be dramatically improved It is our hope that knowledge of the structure andfunction of the brain yields breakthroughs in science and treatment

In 1989, the U.S Congress declared the coming “Decade of the Brain,” in tion of a major victory in conquering serious mental illness by the new millennium Theresulting “explosion” of neuroscience and drug development research did lead to im-proved schizophrenia treatment portfolios, but unfortunately failed to lead to dramaticchanges in the disease course and long-term outcomes The failure to achieve this goal re-flects the complexity of schizophrenia and the limitations of our conceptual understand-ing of its pathophysiology and diagnostic classification, as well as the limitations of newtechnologies and research methodology

expecta-For these reasons, in the recent years, schizophrenia research has expanded thesearch for markers to include behavior, neuroanatomy, neuropathology, and most re-cently, genetics to define vulnerability to the disease A genuine marker must be prevalentand occur at high frequency in patients with the disease, and at very low frequencies inpeople with other disorders or in healthy controls Next, we review the major historicalmilestones in schizophrenia research that have led toward identification of biologicalmarkers

Neuroanatomy and Structural Neuroimaging

Since the time of Émil Kraepelin and Alois Alzheimer (who first described what is nowconsidered the most common form of dementia), many investigators have examinedneuropathological and neuroanatomical brain changes in schizophrenia The initial work

in this area concerned coarse brain structure, and reported lower brain weight, frontalatrophy, lacunae, pyknotic neuronal atrophy, focal demyelination, and metachromaticbodies However, the relative lack of gliosis in patients’ brains has generated considerableinterest, supporting the idea of the neurodevelopmental origin of schizophrenia Abnor-malities in neuronal distribution, cell size, and laminar density in schizophrenic brain tis-sue have been reported At the same time, a frequent absence of consistency in findingsand small effect sizes have diminished enthusiasm about histopathological findings

8 I CORE SCIENCE AND BACKGROUND INFORMATION

The next technological development, pneumoencephalography, an early precursor ofthe modern structural neuroimaging techniques, by the American neurosurgeon Dandy in

1919 was applied to the studies of neuroanatomical brain changes in schizophrenia Themain findings were cortical atrophy and ventricular enlargement in patients compared tocontrols Pneumoencephalography is a complex, invasive procedure with enormous vari-ations in technical details and potentially serious adverse effects due to the draining of thedifferent amounts of cerebrospinal fluid, and volume-for-volume exchange with air Thistechnique was replaced with noninvasive computerized axial tomography (CAT) devel-oped in the early 1970s

CAT findings have supported those of pneumoencephalography, reporting increasedcortical atrophy and lateral ventricular enlargement, as well as increased ventricle-to-brain ratio The effects of medications and other somatic treatments were not examined.Although CAT was a great improvement in neuroimaging tools, with its gradual enhance-ment of resolution, it did not allow for distinction between gray and white matter, thusprecluding precision in localizing pathology and standardization of procedures duringrescanning

In 1984, the first magnetic resonance imaging (MRI) scan study in schizophreniawas published The images were much clearer than those with CAT, and allowed differen-tiation of the white and gray matter MRI studies of schizophrenia consistently reportedventricular enlargement, decreased cortical volume, and disproportionate volume loss inthe temporal lobe

Neuroimaging studies of schizophrenia are limited by their use of convenience cal samples that are generally small and a lack of specificity of findings (compared tothose of other serious mental illnesses) Despite these limitations, the MRI techniquesbrought an understanding of the neuroanatomical substrates of schizophrenia in sight.Newer MRI techniques, such as magnetic resonance proton spectroscopy, or magnetiza-tion transfer and diffusion tensor imaging (DTI) continue to improve the range of investi-gation from white matter tract connectivity to biochemical changes in the brain, ap-

clini-proaching the goals of in vivo functional imaging Enhanced by the new computational

brain atlases and statistical algorithms, the morphometric methods offer an advantage ofmapping structural abnormalities and correlating them with any other functional, meta-bolic, spectroscopic, and architectonic data Furthermore, cortical mapping can also iden-tify deficit patterns associated with genetic risk for schizophrenia, which may provide re-searchers with the neuroimaging-defined rather then pure clinical endophenotypes

Functional Neuroimaging

Functional MRI

The first report by Belliveau and colleagues (1991) of localized changes in cerebral bloodoxygenation in the occipital cortex following visual stimulation in humans was of semi-nal importance to neuropsychiatric research This technological development enabled

noninvasive visualization of in vivo human brain function (based on investigation of

changes in oxyhemoglobin) in response to specific cognitive tasks in patients with phrenia compared to age-matched controls The techniques have the advantage of opti-mal spatial resolution, and (in comparison to the functional imaging techniques describedbelow) lower cost

schizo-Functional MRI (fMRI) research in schizophrenia has explored a broad range ofcognitive functioning, especially executive function, attention, working memory, psycho-motor function, and basic sensory processing fMRI studies further define the hypothe-

1 History of Schizophrenia 9

sized hypofrontality in the activation studies of schizophrenia, evaluating the subject formance on the executive cognitive tasks The fMRI approach is well suited for use inthe within-subject longitudinal design evaluating changes over time and the effects oftreatment and for developing more disease-specific cognitive probes.

per-Single Photon Emission Computed Tomography and Positron

pat-of positive symptoms, such as hallucinations and delusions

PET and SPECT are powerful techniques that enable exploration of the chemistry of the living brain They have been instrumental in testing the hyperdopa-minergic theory of schizophrenia, as well as the dopaminergic occupancy theory ofantipsychotic drugs PET and SPECT have also proven to be invaluable tools for measur-ing drug occupancy at D2 and other receptors in vivo, and exploring relationships be-

neuro-tween occupancy and clinical measures This observation presents a clear opportunity fordrug development and for further understanding of the psychopharmacological effects ofantipsychotic medications and the pathophysiology of schizophrenia

The development of new and exciting technologies of neuroimaging advances ourunderstanding of the pathophysiological substrates of schizophrenia, generally support-ing earlier clinical–neuropathological observations However, a pattern of brain dysfunc-tion that would serve as a biological trait marker or predict treatment response has notemerged to date A combination of genetics, cognitive neuropsychology, and multimodalstructural–functional neuroimaging can further elucidate vulnerability factors and helpdefine endophenotypes Despite great advances in technology, neuroimaging remains aresearch tool for schizophrenia, with no utility for clinical practice at the present time

Cognitive Neuroscience

While psychoanalysts theorized about psychological causes of schizophrenia, suggestingpsychotherapy to resolve infantile traumas and early rejection experiences believed to causethe disease, the search continued for behavioral vulnerability markers Stemming from theideas of Bleuler and Kraepelin, it is increasingly believed that impaired cognitive processingmay be a marker of vulnerability to schizophrenia, including deficits in attention and con-centration, in sustained mental effort, and in selecting and processing information Physio-logical indicators can be used as objective markers of cognitive disturbances

10 I CORE SCIENCE AND BACKGROUND INFORMATION

Since the turn of the 20th century, theories of frontal dysfunction have provided aframework that may be helpful in understanding the consequences of injury to the brain.Neuropsychological tests serve as probes of brain dysfunction The extent to whichschizophrenia is a disorder of executive dysfunction remains an object of extensive inves-tigation Structural and functional imaging, combined with neuropsychological testing,can improve the precision of the search for markers.

Genetics

The first theory about the role of heredity in mental illness was proposed by Morel(1857) He postulated that insanity was the result of an innate biological defect, and thatthe severity of mental syndromes increased in lineal descents Morel’s theory of hereditarybrain degeneration remained in mainstream psychiatry for several decades Its propo-nents included Krafft-Ebing (1868) in Austria, Maudsley (1870) in England, Magnan andLegrain (1895) in France, and many others In the eighth edition of his textbook,Kraepelin (1919/1971) noted that about 70% of his patients with dementia praecox atthe Heidelberg Clinic (1891–1899) had family histories of psychosis His findings set thestage for research in the genetics of the disease Findings in family studies are consistentwith a genetic etiology of schizophrenia The risk of developing schizophrenia was found

to be consistently higher in the relatives of patients with schizophrenia than in the generalpopulation, with greater risk for first-degree relatives than for second-degree relatives InZerbin-Rudin’s (1967) pooled data, the risk for children with one parent with schizo-phrenia was nearly 15 times greater (12.3%) than that in the general population (0.85%);with siblings and parents, about 10 times greater (8.5% and 8.2%, respectively); and withuncles and aunts (2%), nephews and nieces (2.2%), grandchildren (2.8%), and half-siblings (3.2%), roughly three times greater than the general population rate

Recent research has identified genetic variations associated with schizophrenia Theprimary goal of modern genetic research is first to characterize how genes associated withschizophrenia affect brain development and function, and second, to see how this trans-lates into the clinical manifestation of the disorder This will ultimately have implicationsfor the prevention and treatment of the disease The goal has become more immediate as

we witness a shift in psychiatric genetics from mapping illness loci to identifying gene fects on information processing in the brain

ef-Genomic approaches to schizophrenia are also becoming increasingly feasible asdata from the Human Genome Project accumulate However, studies aiming to identifysusceptibility genes for schizophrenia and other complex psychiatric disorders are facedwith confounds of subjective clinical criteria, commonly occurring phenocopies, signifi-cant between-subject variability of candidate traits, and a likelihood of allelic and locusheterogeneity

Over the past couple of years, several specific genes have been shown to be ated with schizophrenia risk in a number of populations around the world Some of the

associ-genes that have been studied more extensively include catechol-O-methyltransferase (COMT; chromosome 22q), dysbindin-1 (chromosome 6p), neuregulin 1 (chromosome 8p), metabotropic glutamate receptor 3 (GRM-3; chromosome 7q), glutamate decarbox-

ylase 1 (chromosome 2q), and disrupted-in-schizophrenia 1 (DISC1; chromosome 1q) A

functional polymorphism in the COMT gene, which affects prefrontal cortical function

by changing dopamine signaling in the prefrontal cortex, has probably been studied mostextensively Data suggest that these susceptibility genes influence the cortical informationprocessing that characterizes the schizophrenic phenotype

Taken together, the new and improved methods of neuroscience are dazzling in theirability to display the biology of the brain They offer new avenues for developing trans-

1 History of Schizophrenia 11