Schizophrenia

This Third Edition of Schizophrenia is dedicated to the founding editor, Steven R. Hirsch, M.D., whose vision and devotion to schizophrenia research launched the fi rst edition of this book and was instrumental in the success of the

second, and whose legendary persistence and commitment to this fi eld, to his students and his colleagues, nurtured a generation of researchers and clinicians interested in understanding patients with schizophrenia and in helping them.

Dedication

Schizophrenia

Daniel R. Weinberger MDDirector, Genes, Cognition and Psychosis Program,Clinical Studies Section,Clinical Brain Disorders Branch,National Institute of Health,Bethesda,MD, USA

Paul J. Harrison MA, BM, BCh, DM(Oxon), FRCPsychDepartment of Psychiatry,University of Oxford,Warneford Hospital,Oxford, UK

THIRD EDITION

A John Wiley & Sons, Ltd., Publication

This edition fi rst published 2011, © 1995, 2003, 2011 by Blackwell Publishing Ltd

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Library of Congress Cataloging-in-Publication Data

Schizophrenia / [edited by] Daniel R. Weinberger, Paul J. Harrison. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-7697-21. Schizophrenia. I. Weinberger, Daniel R. (Daniel Roy) II. Harrison, P. J. (Paul J.), 1960– [DNLM: 1. Schizophrenia. WM 203 S33721 2010] RC514.S33413 2010 616.89’8--dc22 2010015115

A catalogue record for this book is available from the British Library.

This book is published in the following electronic formats: ePDF 9781444327304; Wiley Online Library 9781444327298

Set in 9.25 on 12 pt Palatino by Toppan Best-set Premedia Limited

2011

Contributors, vii

Editor’s note, xi

Preface to the 3rd Edition, xii

Preface to the First Edition, xiii

Part 1 Descriptive Aspects, 1

1 Concept of schizophrenia: past, present, and future, 3Nancy C. Andreasen

2 The schizophrenia construct: symptomatic presentation, 9Celso Arango and William T. Carpenter

3 Child and adolescent schizophrenia, 24Chris Hollis and Judith Rapoport

4 Late-onset schizophrenia, 47Robert Howard and Dilip Jeste

5 The schizophrenia spectrum personality disorders, 62Eran Chemerinski and Larry J. Siever

6 The prodrome of schizophrenia, 91Jean Addington and Shôn W. Lewis

7 Course and outcome, 104Wolfram an der Heiden and Heinz Häfner

8 Neurocognitive impairments in schizophrenia: their character and role in symptom formation, 142Terry E. Goldberg, Anthony David, and James. M. Gold

Part 2 Biological Aspects, 163

9 The secondary schizophrenias, 165Thomas M. Hyde and Maria A. Ron

10 Schizophrenia: the epidemiological horizon, 185Assen Jablensky, James B. Kirkbride, and Peter B. Jones

11 Environmental risk factors for schizophrenia, 226John J. McGrath and Robin M. Murray

12 Classical genetic studies of schizophrenia, 245Brien Riley and Kenneth S. Kendler

13 Genetic associations in schizophrenia, 269Michael C. O’Donovan and Michael J. Owen

14 Intermediate phenotypes in genetic studies of schizophrenia, 289Michael F. Egan and Tyrone D. Cannon

15 Electrophysiology of schizophrenia, 311Georg Winterer and Robert W. McCarley

16 Structural brain imaging in schizophrenia and related populations, 334Stephen M. Lawrie and Christos Pantelis

17 Functional brain imaging in schizophrenia, 353Andreas Meyer-Lindenberg and Edward T. Bullmore

18 Neuropathology of schizophrenia, 372Paul J. Harrison, David A. Lewis, and Joel E. Kleinman

19 Neurodevelopmental origins of schizophrenia, 393Daniel R. Weinberger and Pat Levitt

20 Dopamine and schizophrenia, 413Anissa Abi-Dargham and Anthony A. Grace

21 Contributions of glutamate and GABA systems to the neurobiology and treatment of schizophrenia, 433John H. Krystal and Bita Moghaddam

22 Animal models of schizophrenia, 462Barbara K. Lipska and Joseph A. Gogos

Part 3 Physical Treatments, 483

23 Pharmacology and neuroscience of antipsychotic drugs, 485John L. Waddington, Colm M.P. O’Tuathaigh, and Gary J. Remington

Contents

v

vi Contents

24 Principles of pharmacological treatment in schizophrenia, 515Thomas R.E. Barnes and Stephen R. Marder

25 Comparative effi cacy and effectiveness in the drug treatment of schizophrenia, 525John R. Geddes, T. Scott Stroup, and Jeffrey A. Lieberman

26 Approaches to treatment-resistant patients, 540Stephan Leucht, Christoph U. Correll, and John M. Kane

27 Neurological complications of antipsychotic drugs, 561Peter M. Haddad and Venkata S. Mattay

28 Metabolic adverse effects associated with antipsychotic medications, 577John W. Newcomer and Stefan Leucht

Part 4 Psychosocial Aspects, 599

29 Schizophrenia and psychosocial stresses, 601Paul E. Bebbington and Elizabeth Kuipers

30 Mental health services for patients with schizophrenia, 625Tom Burns and Bob Drake

31 Societal outcomes in schizophrenia, 644Iain Kooyman and Elizabeth Walsh

32 Psychological treatment of psychosis, 666Gillian Haddock and Will Spaulding

33 Economics of the treatment of schizophrenia, 687Nancy H. Covell, Susan M. Essock, and Linda K. Frisman

Index, 701

Colour plates are found facing page 338

A. Abi - Dargham, MD Professor of Clinical Psychiatry and Radiology, Chief, Division of Translational Imaging, Chief of Clinical and Imaging Research, Lieber Center, Department of Psychiatry, Columbia University & New York State Psychiatric Institute, New York, NY, USA

J. Addington, PhD Professor, Department of Psychiatry, Alberta Mental Health Centennial Research Chair, Novartis Chair in Schizophrenia Research, University of Calgary, Canada

W. an der Heiden, DIPL - PSYCH PhD Deputy Head, Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany

N.C. Andreasen, MD PhD Andrew H. Woods Chair of Psychiatry, Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA

C. Arango, MD PhD Head, Adolescent Unit, Department of Psychiatry, Hospital General Universitario Gregorio Mara ñ on, Cibersam, Madrid, Spain

T.R.E. Barnes, MD FRCPsych DSc Professor of Clinical Psychiatry, Centre for Mental Health, Imperial College, Charing Cross Campus, London, UK

P.E. Bebbington, MA PhD FRCP FRCPsych Professor of Social and Community Psychiatry, UCL, London, UK

E.T. Bullmore, PhD FRCP FRCPsych FMedSci Professor, Department of Psychiatry, University of Cambridge, Cambridge, UK

T. Burns, DSc FRCPsych Professor of Social Psychiatry, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

T.D. Cannon, PhD Staglin Family Professor, Departments of Psychology and Psychiatry and Biobehavioral Sciences Director, Staglin Center for Cognitive Neuroscience Associate Director, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA

W.T. Carpenter, MD Professor of Psychiatry & Pharmacology, University of Maryland School of Medicine, Director, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA

E. Chemerinski, MD Assistant Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY, and James J. Peter Veterans Affairs Medical Center, Bronx, NY, USA

C.U. Correll, MD Medical Director, Recognition and Prevention (RAP) Program, The Zucker Hillside Hospital, Glen Oaks, NY; Associate Professor of Psychiatry, Albert Einstein College of Medicine; and The Feinstein Institute for Medical Research, Manhasset, NY, USA

N.H. Covell, PhD Assistant Professor, Division of Mental Health Services & Policy Research, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York, NY, USA; Connecticut Department of Mental Health and Addiction Services, Hartford, CT, USA

A.S. David, MD FRCP FRCPsych MSc Professor of Cognitive Neuropsychiatry, Institute of Psychiatry, King ’ s College, London, London, UK

B. Drake, MD, PhD Professor of Psychiatry and of Community and Family Medicine, Director, Dartmouth Psychiatric Research Center, Lebanon, New Hampshire, USA

M.F. Egan, MD Senior Director, Clinical Neurosciences, Merck & Co Inc, North Wales, PA, USA

Contributors

vii

viii Contributors

S.M. Essock, PhD Edna L. Edison Professor of Psychiatry, Director, Division of Mental Health Services & Policy Research, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, New York, NY, USA

L.K. Frisman, PhD Director of Research, Connecticut Department of Mental Health and Addiction Services, University of Connecticut School of Social Work, Hartford, CT, USA

J.R. Geddes, MD FRCPsych Professor of Epidemiological Psychiatry, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

J.A. Gogos, MD PhD Professor, Department of Physiology and Department of Neuroscience, Columbia University Medical School, New York, NY USA

J.M. Gold, PhD Associate Professor, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Crownsville, MD, USA

T.E. Goldberg, PhD Professor, Psychiatry and Behavioral Science, Albert Einstein College of Medicine Zucker Hillside Hospital/Litwin Zucker Alzheimer’s Disease Research Center Feinstein Institute for Medical Research Manhasset, NY, USA

A.A. Grace, PhD Professor of Neuroscience, Psychiatry and Psychology, Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

P.M. Haddad, MD FRCPsych Consultant Psychiatrist and Honorary Senior Lecturer, Neuroscience and Psychiatry Unit, School of Psychiatry and Behavioral Sciences, University of Manchester, Manchester, UK

G. Haddock, BSc MClinPPsychol PhD Professor of Clinical Psychology, School of Psychological Sciences, University of Manchester, Manchester, UK

H. H ä fner, MD PhD Dres.h.c. Professor of Psychiatry, Head, Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany

P.J. Harrison, MA BM BCh DM(Oxon) FRCPsych Professor of Psychiatry, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

C. Hollis, MBBS, BSc PhD DCH MRCPsych Professor of Child and Adolescent Psychiatry, Division of Psychiatry, University of Nottingham, Queen ’ s Medical Centre, Nottingham, UK

R. Howard, MD MRCPsych Professor of Old Age Psychiatry and Psychopathology, Department of Old Age Psychiatry, Institute of Psychiatry, King ’ s College London, London, UK

T.M. Hyde, MD PhD Chief Operating Offi cer, Lieber Institute for Brain Development, Baltimore, Maryland MD, USA

A. Jablensky, MD DMSc FRCPsych FRANZCP Professor of Psychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia

D.V. Jeste, MD Estelle and Edgar Levi Chair in Aging, Professor of Psychiatry and Neurosciences, Chief, Division of Geriatric Psychiatry, University of California; VA San Diego Healthcare System, San Diego, CA, USA

P.B. Jones, MD FRCPsych Head, Department of Psychiatry, University of Cambridge, Cambridge, UK

J.M. Kane, MD Chairman, Department of Psychiatry, The Zucker Hillside Hospital, Psychiatry Research, North Shore — Long Island Jewish Health System, Glen Oaks, NY, Albert Einstein College of Medicine, Bronx, NY, and The Feinstein Institute for Medical Research, Manhasset, NY, USA

K.S. Kendler, MD Rachel Brown Banks Distinguished Professor of Psychiatry, Professor of Human Genetics, Departments of Psychiatry and Human and Molecular Genetics, and Director, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

J.B. Kirkbride, PhD Postdoctoral Research Fellow, Department of Psychiatry, University of Cambridge, Cambridge, UK

J.E. Kleinman, MD PhD Chief, Section on Neuropathology, Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute for Mental Health, National Institute for Health, Bethesda, MD, USA

I. Kooyman, MBBS, MA, MRCPsych Specialist Registrar in Forensic Psychiatry, North London Forensic Service, and Department of Forensic Mental Health Science, Institute of Psychiatry, London, UK

Contributors ix

J.H. Krystal, MD Robert L. McNeil, Jr. Professor of Clinical Pharmacology and Deputy Chairman for Research, Department of Psychiatry, Yale University School of Medicine, New Haven, CT; Schizophrenia Biological Research Center (151 - D), VA Connecticut Healthcare System, West Haven, CT, USA

E. Kuipers, BSc MSc PhD FBPsS Professor of Clinical Psychology, Head of Department of Psychology, Institute of Psychiatry, King ’ s College London, London, UK

S.M. Lawrie, MD FRCPsych Hon.FRCP(Edin) Professor of Psychiatry and Head of Psychiatry, University of Edinburgh Division of Psychiatry, Royal Edinburgh Hospital, Edinburgh, UK

S. Leucht, MD Vice - Chairman, Department of Psychiatry and Psychotherapy, Technische Universit ä t M ü nchen, Klinikum rechts der Isar, Munich, Germany

P. Levitt, PhD Director, Zilkha Neurogenetic Institute, Chair, Department of Cell & Neurobiology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA

D.A. Lewis, MD UPMC Professor in Translational Neuroscience and Chair, Department of Psychiatry, University of Pittsburgh, Medical Director and Director of Research, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA

S. Lewis, MD FMedSci Professor of Adult Psychiatry, University of Manchester, Manchester, UK

J.A. Lieberman, MD Chairman, Department of Psychiatry, College of Physicians & Surgeons, Columbia University; Director, New York State Psychiatric Institute; Director, Lieber Center for Schizophrenia Research; Psychiatrist - in - Chief at New York Presbyterian Hospital & Columbia University Medical Center, New York, NY, USA

B.K. Lipska, PhD Staff Scientist, Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

S.R. Marder, MD Professor and Director, Section on Psychosis Semel Institute for Neuroscience at UCLA, Veterans Affairs Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, USA

V.S. Mattay, MD Director, Neuroimaging Core, Genes, Cognition and Psychosis Program, National Institutes of Mental Health, National Institutes of Health, Bethesda, MD, USA

R.W. McCarley, MD Professor and Head, Harvard Department of Psychiatry; and Associate Director, Mental Health Service, VA Boston Healthcare System, Brockton, MA, USA

J.J. McGrath, AM MBBS MD PhD FRANZCP Professor and Director, Queensland Centre for Mental Health Research and Department of Psychiatry, Queensland Brain Institute, University of Queensland, Australia

A. Meyer - Lindenberg, MD PhD MSc Director, Central Institute of Mental Health, Mannheim, Professor and Chair of Psychiatry and Psychotherapy, University of Heidelberg, Medical Faculty, Mannheim, and Chairman, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany

B. Moghaddam, PhD Professor of Neuroscience, Psychiatry and Pharmacy, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

R.M. Murray, MD M Phil MRCP MRC Psych FRS Professor of Psychiatric Research, Institute of Psychiatry at the Maudsley, King ’ s College, University of London; Honorary Consultant Psychiatrist, Maudsley Hospital, London, UK

J.W. Newcomer, MD Gregory B. Couch Professor of Psychiatry, Psychology and Medicine; Medical Director, Center for Clinical Studies at Washington University School of Medicine, St. Louis, MO, USA

M.C. O ’ Donovan, FRCPsych PhD Professor of Psychiatric Genetics, UKMRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK

C.M.P. O ’ Tuathaigh, PhD Senior Research Fellow, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

M.J. Owen, FRCPsych PhD Head, Department of Psychological Medicine, UKMRC Centre for Neuropsychiatric Genetics and Genomics, Department, of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK

C. Pantelis, MB BS MD MRCPsych FRANZCP Associate Professor and Head, Cognitive Neuropsychiatry Research and Academic Unit, Department of Psychiatry; Co - ordinator, Applied Schizophrenia Division, Mental Health Research Institute; Principal Fellow, Centre for Neuroscience, The University of Melbourne, Melbourne, Australia

J. Rapoport Chief, Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

x Contributors

G.J. Remington, MD PhD FRCPC Director, Medication Assessment Program for Schizophrenia (MAPS) Clinic and Professor of Psychiatry, Schizophrenia Division, Centre for Addiction and Mental Health, Faculty of Medicine, University of Toronto, Toronto, Canada

B. Riley, PhD Director of Molecular Genetics, Departments of Psychiatry and Human and Molecular Genetics, and Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

M.A. Ron, MD PhD FRCP FRCPsych Professor of Neuropsychiatry, Institute of Neurology, University College London, London, UK

L.J. Siever, MD Professor of Psychiatry, Department of Psychiatry, Mount Sinai School of Medicine New York, NY, and James J. Peter Veterans Affairs Medical Center, New York, NY, USA

W. Spaulding, PhD Professor of Psychology, University of Nebraska, Lincoln, USA

T.S. Stroup, MD Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA

J.L. Waddington, PhD DSc Professor of Neuroscience, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

E. Walsh, MB BCh BAO MSc MRCPsych MD Consultant in General Adult and Forensic Psychiatry, South London and Maudsley NHS Trust, London, UK

D.R. Weinberger, MD Director, Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, MD, USA

G. Winterer, MD PhD Head, Translational Neurogenetics Group, Cologne Center for Genomics (CCG), University of Cologne, Germany

The Third Edition of Schizophrenia represents a milestone in the evolution of this textbook. It is an extensive revision and update on dramatic new developments in research about schizophrenia and its therapeutics. But it also marks the end of Steven Hirsch ’ s tenure as a founding editor. Professor Hirsch was the visionary fi gure behind the crea-tion of this volume. His idea was that we would assemble a team of prominent basic and clinical scientists and schol-ars at the leading edge of schizophrenia research from both sides of the Atlantic — and beyond — to collaborate in pro-ducing this comprehensive review of the fi eld. His retire-ment has not compromised this vision or its implementation, but his participation has been missed. In keeping with the

Editor ’ s Note

xi

goal of trans - Atlantic cooperation in assembling the faculty for this new volume, and in seeking a translational scientist in the tradition of Professor Hirsch to co - edit this project with me, I invited Professor Paul Harrison of the Univer-sity of Oxford to pick up the mantle and step into Professor Hirsh ’ s shoes. Professor Harrison brings a unique back-ground in basic molecular neuroscience and extensive clinical experience to serve in this capacity. I could not have done this without his help, dedication, and insight. I look forward to the next volume and the ones after that in part-nership with Professor Harrison.

Daniel. R. Weinberger, M.D.

In the eight years since the previous edition of this book, the pace and breadth of research into schizophrenia has increased dramatically, generating much light but also heat. There have been dramatic new fi ndings, concepts, and interpretations across the whole spectrum — from bio-logical to social, and from aetiology to therapeutics: the prodrome, genes, cannabis, cognition, brain oscillations, and metabolic syndrome, to name but a few. And older debates continue, not least concerning the relative merits of atypical versus typical antipsychotics — and how schizo-phrenia should be classifi ed.

We have attempted to capture the progress, the excite-ment, and the controversies in the fi eld. Refl ecting the developments, as well as the retirement of some experts and the emergence of others, substantial revisions have been made to the content and authorship of this edition; in reality, this is not a revision but a new volume. Seven new chapters have been introduced, eleven chapters dropped, and many of the surviving chapters have new authors or co - authors. The new chapters focus on areas that are par-ticularly topical, or where there has been signifi cant research developments since the last edition; equally, chap-ters were not retained if there had been little new research fi ndings, or if their key elements were better subsumed within another chapter. Overall this has led to signifi cant changes to all four parts of the book. In Part 1, there is a new chapter on the prodrome (Chapter 6 ). In Part 2, the

Preface to the 3 rd e dition

xii

dramatic increase in genetic research is refl ected in a second genetics chapter (Chapter 13 ), and the chapter on brain imaging has been divided into separate chapters on struc-tural (Chapter 16 ) and functional (Chapter 17 ) modalities. Part 3, covering physical treatments, has been reorganised, with chapters now focusing on psychopharmacological principles (Chapter 24 ), typical versus atypical antipsy-chotics (Chapter 25 ) and on their metabolic effects (Chapter 28 ). Part 4 has also been updated and reorganised, in line with the increasing focus on psychosocial treatments and societal outcomes.

We are fortunate that so many leading experts have again contributed to this volume, ensuring that every chapter is an authoritative, up - to - date, and cutting edge review. Chapters are comprehensively referenced, and a detailed index is provided, allowing the book to be used as a stand-ard reference text and also to serve as an entr é e to the primary literature. We worked with the authors to remove unnecessary redundancy between chapters, but some overlap has been retained where it allows for complemen-tary perspectives. We thank our colleagues for their impor-tant and authoritative contributions and our families for their extraordinary patience and support.

Daniel R. Weinberger Paul J. Harrison

January 2011

For Sandra, Rosie, Charlie and Grace Paul J Harrison

For Leslie and Collin Daniel R Weinberger

Schizophrenia has been a controversial topic since the term was fi rst proposed by Eugen Bleuler to describe a uniquely human syndrome of profoundly disturbed behaviour. In the years following Bleuler ’ s original work the controver-sies have continued at least as vigorously, but their content has changed. The debate is no longer about the nature of intra - psychic mechanisms, or whether schizophrenia really exists, or whether it is an illness as opposed to a life choice, or whether it is an important public health concern. Indeed, a recent editorial in Nature reifi ed the current status of schizophrenia in the biomedical research establishment by declaring, ‘ Schizophrenia is arguably the worst disease affecting mankind, even AIDS not excepted ’ ( Nature Editorial, 1988 ). In the United States alone it is estimated to cost over $40 billion each year in economic terms: the price that is paid by affected individuals and their families is inestimable.

The debate has shifted away from the view that schizo-phrenia is caused by a fault in the infant – mother psycho-logical relationship. This had gained the status of orthodoxy during the late/middle part of this century and has been radically revised. Early parenting as a aetiologic factor never stood up to scientifi c scrutiny (Hirsch & Leff, 1975 ). The evidence that schizophrenia is associated with objec-tive changes in the anatomy and function of the brain and has a genetic predisposition is incorporated in a major revi-sion of the concept of schizophrenia encompassed in this book.

Schizophrenia has assumed an increasingly important place in neuroscience and molecular biological research programs around the world. Provocative evidence has sug-gested that aberrations of complex molecular processes responsible for the development of the human brain may be responsible for this illness. The possibility of fi nding a specifi c genetic defect that may participate in the liability to develop this disease has never seemed brighter. At the same time, the pharmaceutical industry has revitalized the search for effective new medical treatments. Where it was believed for almost three decades that all antipsychotic drugs were equally effective, it has now been shown that

Preface to the First Edition

this is not the case. Moreover, it is clear that more effective drugs can be developed which are safer and have fewer side effects.

This textbook of schizophrenia represents a major shift of thinking infl uenced by the recent changes in our under-standing of the brain, the developments in methodology which have infl uenced scientifi cally informed notions of our clinical practice, and the changes in our culture which have led to new concepts of management and treatment and a new understanding of the factors which are likely to affect relapse.

While we have asked the authors to make their chapters up to date and comprehensive, we have also worked with them to maintain a “ textbook ” orientation so that students and researchers from other disciplines, as well as clinical and research specialists in the fi eld, may be intelligibly informed about schizophrenia.

Promising as some of the basic science may seem, schizo-phrenia is still a disease whose diagnosis depends on clini-cal acumen and careful assessment. Therefore all the traditional subject areas are covered. This includes a series of chapters that discuss current issues in the phenomeno-logical characterization of the illness, from its history to the ongoing debate about clinical subtypes, modifying factors, spectrum disorders, and the very nature and prognostic implications of the fundamental symptoms. The increased recognition of the importance of neuropsychological defi -cits in the chronic disability and outcome of this illness is highlighted by several contributors.

The series of chapters focused around the theme of aetio-logical factors emphasizes the dramatic shift in thinking on the medical aspects of schizophrenia. The application of new methods for studying the brain during life and at post - mortem examination has provided compelling data that subtle abnormalities are associated with the illness. The precise nature of the fundamental pathological process is unknown, and many uncertainties about it need to be answered. Is brain development disturbed in a character-istic way? Is there a common aetiology, or can schizophre-nia arise from a myriad of causes, any of which affect a

xiii

xiv Preface to the First Edition

fi nal common path of brain disturbance? Could the devel-opmental abnormality result solely from environmental causes, or is a genetic factor essential? What is the corre-spondence between pathological changes and clinical man-ifestations? Does everyone with the pathological change manifest the illness, or is it possible to have the defect but compensate for it? What makes decompensation happen? What factors encourage clinical recovery?

The application of recombinant DNA technology involves a new language in asking the old question of how and what genetic factors play a role in the illness. While it is widely believed that a simple Mendelian genetic defect does not account for schizophrenia, what does it take in genetic terms? How many genes could be involved in lia-bility? Are the genes likely to be recognizable as having anything to do with the phenotype as we have traditionally perceived it? What should relatives of a patient be advised about genetic risk? The straightforward dopamine hypoth-esis that had guided most researchers for the seventies and eighties has become much more sophisticated and enlightened. It is still important in understanding how the illness is treated, but it clearly has much less explanatory power than it seemed to have in the past. Is dopamine really involved in schizophrenia, or is it simply a way of modulating symptoms by affecting neurotransmission in a relatively unimportant but peripherally connected brain

system? Can the illness be treated with drugs that do not touch the dopamine system?

Intensive, insight oriented psychotherapy on an indi-vidual basis is no longer used to treat patients with schizo-phrenia. Indeed, controlled outcome studies indicate that doing so is potentially harmful. However, more rationally based cognitive behavioural methods have shown real gains in symptom control and are becoming increasingly important in modern management. There is solid evidence that therapy aimed at altering the family environment sig-nifi cantly reduces the risk of relapse. The value of com-munity rather than hospital based treatment is a modern trend, but the evidence from carefully controlled research leaves many questions unanswered: yet, a consensus is beginning to emerge on several of the basic issues.

We have invited leading experts to review established knowledge of the major fi elds of study in schizophrenia. This inevitably leads us to include new topical areas of interest including homelessness, the risk of violence and the relationship of depression to schizophrenia, as well as brain imaging studies and the treatment of refractory states which would not have appeared in texts a decade ago. The result is a radical revision of our con-cepts and understanding which we believe justifi es the effort of our authors whom we gratefully thank for their contribution.

Steven R. Hirsch Daniel R. Weinberger

1995

References

Editorial ( 1988 ) Where next with psychiatric illness? Nature 336 , 95 – 96 .

Hirsch , S.R. & Leff , J. ( 1975 ) Abnormalities in Parents of Schizophrenics: Review of the Literature and an Investigation of Communication Defects and Deviances . Maudsley Monograph Services, No. 22. Oxford : Oxford University Press .

PART 1 Descriptive Aspects

3

Schizophrenia, 3rd edition. Edited by Daniel R. Weinberger and Paul J Harrison © 2011 Blackwell Publishing Ltd.

Schizophrenia is one of the most important public health problems in the world. A survey by the World Health Organization ranks schizophrenia among the top ten ill-nesses that contribute to the global burden of disease (Murray, 1996 ). Because of its early age of onset and its subsequent tendency to persist chronically, often at signifi -cant levels of severity, it produces great suffering for patients and also for their family members. It is also a rela-tively common illness. Although estimates of rates in the general population vary, it appears to affect from 0.5% to 1% of people worldwide. Furthermore, it is an illness that affects the essence of a person ’ s identity — the brain and the most complex functions that the brain mediates. It affects the ability to think clearly, to experience and express emo-tions, to read social situations and to have normal interper-sonal relationships, and to interpret past experiences and plan for the future. Some of its symptoms, such as delu-sions and hallucinations, produce great subjective psycho-logical pain. Other facets of the illness produce great pain as well, such as the person ’ s recognition that they are liter-ally “ losing their mind ” or being controlled or tormented by forces beyond personal control. Consequently, it can be fatal — a substantial number of its victims either attempt or complete suicide.

It is also an illness that is conceptually challenging, because its manifestations are so diverse. Over the past several centuries various attempts have been made to for-

mulate a consensus about the defi nition and essence of schizophrenia. This introduction will review this concep-tual history in order to provide a foundation for the later chapters in this book. Even at present, creating a consensus about how best to defi ne the phenotype(s) of schizophrenia is a task that has not yet been successfully achieved. And yet the defi nition of the concept and its phenotype must provide a foundation for both the study of disease mecha-nisms and for the development of improved approaches to treatment and prevention.

The p ast: e arly c oncepts of p sychosis

The term “ schizophrenia ” was only coined in the last century, and therefore it is sometimes assumed that it is a “ new disease ” , perhaps a consequence of the development of a complex highly - industrialized world and resultant stresses in lifestyle. Although the name for this illness is relatively new, the concept of psychosis is very old. Based on portrayals of similar psychotic states in early history and literature and on early medical descriptions, we know that schizophrenia - like psychoses have been recognized since at least the fi rst millenium bc .

One of the earliest descriptions of a psychotic condition occurs in the book of Samuel in the Old Testament. After David successfully defends the Israelites against the Philistines by killing Goliath and then wins several subse-quent battles, King Saul becomes increasingly paranoid about David ’ s military prowess, to the point of repeatedly making plans to murder David, and even attempting to do it himself:

CHAPTER 1 Concept of s chizophrenia: p ast, p resent, and f uture Nancy C. Andreasen Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA

The past: early concepts of psychosis, 3 The past: further delineation of psychoses and early

defi nitions of schizophrenia, 4 The present: Schneiderian symptoms, psychosis, and

the dominance of diagnostic criteria, 6

The future: beyond diagnostic criteria and the search for fundamental mechanisms, 7

References, 8

4 Chapter 1

in origin, deriving either from an imbalance of humors (yellow bile, black bile, phlegm, and blood) or to an imbal-ance in the brain. In general, fi ve groups of illnesses were described: melancholia, phrenitis, mania, hysteria, and epi-lepsy. Mania was essentially equivalent to our concept of psychosis. Psychotic disorders were not, however, further subdivided until the late 19th century.

The p ast: f urther d elineation of p sychoses and e arly d efi nitions of s chizophrenia

Kraepelin (1919) gave us the conceptual framework that created the modern concept of schizophrenia. One of Kraepelin ’ s many great contributions was to take the general concept of psychosis and to subdivide it into two major groups, based on his observation of differences in course and outcome. One group of patients who were psy-chotic had an episodic course, typically with a full remis-sion of symptoms. A second group of psychotic patients had a chronic course and typically progressed to a deterio-rated state. He named these two groups “ manic - depression ” and “ dementia praecox ” . Although this distinction is so familiar today that we scarcely think about it, it was a major intellectual achievement at the time, and it has infl u-enced psychiatric classifi cation and the concept of schizo-phrenia for more than a century.

Kraepelin did not, however, consider psychotic symp-toms to be the most important features of dementia praecox. When he spoke of symptoms, those that he considered to be most fundamental were what we today would call nega-tive symptoms. Negative symptoms include abnormalities in cognition and emotion: alogia, avolition, anhedonia, affective blunting, and (in some conceptualizations) atten-tional impairment. Kraepelin said:

There are apparently two principal groups of disorders that characterize the malady. On the one hand we observe a weakening of those emotional activities which permanently form the mainsprings of volition. … Mental activity and instinct for occupation become mute. The result of this highly morbid process is emotional dull-ness, failure of mental activities, loss of mastery over volition, of endeavor, and ability for independent action. … The second group of disorders consists in the loss of the inner unity of activities of intellect, emotion, and voli-tion in themselves and among one another. … The near connection between thinking and feeling, between delib-eration and emotional activity on the one hand, and practical work on the other is more or less lost. Emotions do not correspond to ideas. The patient laughs and weeps without recognisable cause, without any relation to their circumstances and their experiences, smile as they narrate a tale of their attempted suicide.

(Kraepelin, 1919 , pp. 74 – 75)

… the evil spirit from God came upon Saul, and he prophesied in the midst of the house: and David played [music] with his hand, as at other times; and there was a javelin in Saul ’ s hand. And Saul cast the javelin; for he said, I will smite David even to the wall with it. And David avoided out of his presence twice. And Saul was afraid of David, because the Lord was with him, and was departed from Saul.

(1 Samuel 10 – 12) In fact, Saul eventually begins to have hallucinatory - like

experiences, seeking help from the witch of Endor, and also having visions of his former advisor, the deceased prophet Samuel.

If we move on to the classical era in Greece and Rome, there are many descriptions of paranoid schizophrenia - like psychotic states. Greek tragedy is fi lled with portrayals of individuals who are tormented by psychosis, and are often driven to committing horrendous acts while insane. In The Bacchae , Agave murders her son Pentheus with her own hands, driven by the delusional belief that he is a lion. In Medea , after Jason abandons his wife Medea, she falls into a psychotic rage that drives her to murder their two chil-dren with a sword, also murdering King Creon and his daughter by giving them a poisoned robe and chaplet that consumes them in a fi ery painful death. In The Oresteia , Orestes is pursued by the Furies until he fi nally loses his reason and lapses into madness. And there are many more examples.

In the 16th and 17th centuries Elizabethan and Jacobean drama are similarly fi lled with portrayals of individuals who experience schizophrenia - like psychotic states. Some of the best known are in the plays of Shakespeare. Hamlet, Lear, Othello, and Lady Macbeth all experience psychosis. King Lear is a vivid and powerful example. Three main characters are all “ mad ” : Lear himself, Gloucester, and Edgar (pretending to be a “ bedlam beggar ” — an escapee from the Bethleham Hospital for the insane in London). As Gloucester says of Lear:

Thou say ’ st the King grows mad; I ’ ll tell thee, friend, I am almost mad myself. I had a son, Now outlaw ’ d from my blood; he sought my life. … The grief hath craz ’ d my wits

(King Lear III.iv.169 – 174) In addition to these historical and literary portrayals,

which document that schizophrenia - like illnesses have been present for at least three millennia, the “ medical ” lit-erature of these early times provides parallel evidence that psychotic disorders similar to schizophrenia were recog-nized as important medical illnesses. They are described in the writings of our early medical forefathers, such as Hippocrates, Galen, or Soranus of Ephesus. The disorders described by these forefathers do not map perfectly on to modern classifi cation systems, but they have surprising similarities. Mental illnesses were clearly seen as “ physical ”

Concept of schizophrenia 5

name “ schizophrenia ” (schiz = fragmenting, splitting; phren = mind, Gk). Bleuler ’ s name eventually prevailed over Kraepelin ’ s. Today many feel that either is an unfor-tunate choice, because each leads to misunderstanding about the nature of the illness by the general public. Too often people assume that the name refers to a “ split per-sonality ” . However, to date no good substitute has been identifi ed.

Since Bleuler ’ s fundamental symptoms involve cogni-tion and emotion, since negative symptoms (a related but also slightly different concept) also involve cognition and emotion, and since “ cognitive dysfunction ” in schizophre-nia is currently a topic of considerable interest, some clini-cians and investigators fi nd the interface between cognition and negative symptoms confusing. The word “ cognition ” has multiple meanings in cognitive psychology and clinical usage (Andreasen, 1997 ). Sometimes it refers to all activi-ties of “ mind ” , including emotion and language. Sometimes it refers to “ rational ” as opposed to “ emotional ” processes. Sometimes it is used very narrowly to refer to performance on objective neuropsychological tests or experimental cog-nitive psychology tests. Heuristically, the term “ cognition ” is probably most useful in the context of schizophrenia when it is used to refer to the broadest meaning (activities of mind). Since negative symptoms are closely tied to defects in basic cognitive processes (e.g., volition, ability to think abstractly, initiation of thoughts and language, attrib-uting affects to experiences), assessing them at the clinical level may provide a relatively direct “ window ” into cogni-tive impairments in schizophrenia. While Kraepelin and Bleuler did not refer to their clusters of fundamental symp-toms by calling them “ negative ” , this appears to be the point that they were making. In a sense, therefore, negative symptoms may be the most fundamental and clinically important symptoms of schizophrenia.

Neither Kraepelin nor Bleuler actually used the terms “ positive symptoms ” or “ negative symptoms ” . While various sources for these terms can be cited (Berrios, 1985 ), one of the earliest and most prominent was Hughlings - Jackson (1931) . Although Hughlings - Jackson ’ s work was not published until much later, in the late 19th century Jackson speculated about the mechanisms that might underlie psychotic symptoms:

Disease is said to “ cause ” the symptoms of insanity. I submit that disease only produces negative mental symptoms, answering to the dissolution, and that all elaborate positive mental symptoms (illusions, halluci-nations, delusions, and extravagant conduct) are the outcome of activity of nervous elements untouched by any pathological process; that they arise during activity on the lower level of evolution remaining.

(Hughlings - Jackson, 1931 ) Thus Hughlings - Jackson believed that some symptoms

represented a relatively pure loss of function (negative

Such passages in Kraepelin ’ s textbook indicate that he perceived negative symptoms to be the most important symptoms of schizophrenia. Nevertheless, his comprehen-sive description of schizophrenia covered a broad range of symptoms, including delusions and hallucinations.

Bleuler (1950) , on the other hand, tried to clarify the group of schizophrenias by very explicitly attempting to identify what he considered to be the underlying fundamental abnormality. Consequently, he divided the symptoms of schizophrenia into two broad categories: fun-damental and accessory symptoms. Bleuler believed that the fundamental symptoms were present in all patients, tended to occur only in schizophrenia, and therefore were pathognomonic. The accessory symptoms, on the other hand, could occur in a variety of different disorders. Depending how one interprets and summarizes his writ-ings, one can argue that Bleuler identifi ed four, fi ve, or six fundamental symptoms of schizophrenia. These included the loss of the continuity of associations, loss of affective responsiveness, loss of attention, loss of volition, ambiva-lence, and autism. These symptoms correspond relatively closely to those we currently refer to as negative symp-toms. They refl ect abnormalities in basic cognitive and emotional processes, which (in Bleuler ’ s thinking) pro-vided the basis for other types of symptoms observed in the illness. Accessory symptoms, on the other hand, include phenomena such as delusions and auditory hallucinations. Bleuler wrote:

Certain symptoms of schizophrenia are present in every case and in every period of the illness even though, as with every other disease symptom, they must have attained a certain degree of intensity before they can be recognized with any certainty. … Besides the specifi c permanent or fundamental symptoms, we can fi nd a host of other, more accessory manifestations such as delusions, hallucinations, or catatonic symptoms. … As far as we know, the fundamental symptoms are charac-teristic of schizophrenia, while the accessory symptoms may also appear in other types of illness.

(Bleuler, 1950 , p. 13) When Kraepelin called the disorder “ dementia praecox ” ,

he intended to highlight the fact that it had an early ( “ praecox ” ) onset and therefore differed from another type of dementia described by his friend and colleague, Alois Alzheimer. However, in choosing the term “ dementia ” , he wished to highlight the fact that the illness had a chronic and deteriorating course. His contemporary Swiss col-league, Eugen Bleuler, admired many of Kraepelin ’ s ideas, but he took exception to the fact that chronicity and dete-rioration were inevitable. Therefore, he chose to rename the illness in order to highlight his own view that a fragment-ing of thinking, sometimes referred to as “ thought disor-der ” , was the most important feature, and also to eliminate the concept that deterioration was inevitable. He chose the

6 Chapter 1

pretation of his thinking by infl uential British psychiatrists. Schneider was greatly infl uenced by the work of Karl Jaspers, who explored phenomenology and created a bridge between psychiatry and philosophy. Jaspers believed that the essence of psychosis was the experience of phenomena that were “ non - understandable ” , i.e., symp-toms that a “ normal ” person could not readily imagine experiencing. Schneider, like Bleuler, wished to identify symptoms that were fundamental. He concluded that one critical component was an inability to fi nd the boundaries between self and not - self and a loss of the sense of personal autonomy. This led him to discuss various “ fi rst - rank ” symptoms that were characterized by this loss of auton-omy, such as thought insertion or delusions of being con-trolled by outside forces (Schneider, 1959 ; Fish, 1962 ; Mellor, 1970 ).

Schneiderian ideas were introduced to the English - speaking world by British investigators and began to exert a powerful infl uence on the concept of schizophrenia. An emphasis on Schneiderian fi rst - rank symptoms satisfi ed the fundamental need to fi nd an anchor in the perplexing fl ux of the phenomenology of schizophrenia. Schneiderian symptoms were incorporated into the fi rst major struc-tured interview developed for use in the International Pilot Study of Schizophrenia (IPSS), the Present State Examination (PSE) (Wing et al ., 1974 ). From this major base, they were thereafter introduced into other standard diagnostic instru-ments such as the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott & Spitzer, 1978 ), Research Diagnostic Criteria (RDC) (Spitzer et al ., 1978 ), and the Diagnostic and Statistical Manual (DSM - III) (American Psychiatric Association, 1980 ).

The emphasis on positive symptoms, and especially Schneiderian symptoms, derived from several concerns. The fi rst was that Bleulerian symptoms were diffi cult to defi ne and rate reliably. They are often continuous with normality, while positive symptoms are clearly abnormal. In addition to concerns about reliability, work with the IPSS and the US/UK Study also indicated that in the US the concept of schizophrenia had broadened to an exces-sive degree, particularly in the North - eastern parts of the US (Kendell et al ., 1971 ; Wing et al ., 1974 ). Thus, in the US there was clearly a need to narrow the concept of schizo-phrenia. Stressing fl orid psychotic symptoms, particularly Schneiderian symptoms, was a useful way to achieve this end, since it appeared that schizophrenia was often being diagnosed on the basis of mild Bleulerian negative symp-toms. When diagnostic criteria such as the RDC and later DSM - III were written, these placed a substantial emphasis on positive symptoms and essentially ignored negative symptoms.

While there have been many good consequences of this progression and of the interest in Schneider ’ s work, there have also been problems.

symptoms answer to the dissolution), while positive symp-toms such as delusions and hallucinations represented an exaggeration of normal function and might represent release phenomena. Hughlings - Jackson presented these ideas at a time when Darwinian evolutionary theories were achieving ascendance, and his concepts concerning the mechanisms that produced the various symptoms were clearly shaped by a Darwinian view that the brain is organ-ized in hierarchical evolutionary layers. Positive symptoms represent aberrations in a primitive (perhaps limbic) sub-strate that is for some reason no longer monitored by higher cortical functions. Thus Huglings - Jackson ’ s concept of negative and positive symptoms rather closely resem-bles those which are currently discussed. Although most investigators do not necessarily embrace the specifi c mech-anism that he proposed, they accept his view that they must be understood in terms of brain mechanisms, as well as his basic descriptive psychopathology.

The writings of Kraepelin, Bleuler, and Huglings - Jackson laid down a descriptive and conceptual foundation for con-temporary thinking about the symptoms and defi nition of schizophrenia. Both Kraepelin and Hughlings - Jackson attempted to understand symptoms in terms of their underlying neural mechanisms. While Hughlings - Jackson stressed the importance of the interplay between brain regions that were hierarchically organized, Kraepelin dis-cussed the possible localization of the various symptoms in the prefrontal, motor, and temporal cortex. Kraepelin and Bleuler both stressed the importance of a loss of cogni-tive, affective, volitional, and attentional function in schizo-phrenia. Kraepelin clearly believed that these could be the most debilitating and central symptoms of the disorder, while Bleuler stated that they were pathognomonic. Throughout most of the 20th century, Bleuler ’ s perspective predominated. Clinicians all over the world were taught to defi ne and diagnose schizophrenia based on the symptoms Bleuler saw as fundamental, such as associative loosening and affective blunting.

The p resent: Schneiderian s ymptoms, p sychosis, and the d ominance of d iagnostic c riteria

For a variety of historical reasons, this emphasis shifted in the 1960s and 1970s. This change in emphasis arose prima-rily from an interest in improving diagnostic precision and reliability. Because they are essentially “ all or none ” phenomena, which are relatively easy to recognize and defi ne, fl orid psychotic symptoms such as delusions and hallucinations were steadily given greater prominence and indeed even placed at the forefront of the defi nition of schizophrenia.

The emphasis on fl orid psychotic symptoms arose because of the infl uence of Kurt Schneider and the inter-

Concept of schizophrenia 7

toms than the older “ typicals ” , has been helpful in effecting this change (Green et al ., 1997 ; Tollefson & Sanger, 1997 ).

The interest in negative symptoms has been comple-mented by a return to an interest in cognitive aspects of schizophrenia. Many negative symptoms are cognitive in nature — alogia (poverty of thought and speech), avolition (inability to formulate plans and pursue them), and atten-tional impairment. While their assessment may emphasize objective aspects of behavior in order to achieve reliability, their underlying essence is in the domains of thought and emotion. Increasingly, therefore, investigators are return-ing to the original insights of Kraepelin and Bleuler that the core symptoms of schizophrenia represent a funda-mental defi cit in cognition and emotion. This in turn has led to recent initiatives to incorporate assessments of cogni-tive function into clinical drug trials (Green & Neuchterlein, 2004 ).

Several prominent investigators have turned from a focus on explaining and “ localizing ” the specifi c symptoms of schizophrenia to a search for more fundamental under-lying cognitive mechanisms (Andreasen, 1997 ). Examples include Frith ’ s (1992) hypotheses concerning an inability to think in “ metarepresentations ” , Goldman - Rakic ’ s (1994) studies of working memory, our descriptions of cognitive dysmetria (Andreasen et al ., 1996 ), or the work of Holzman et al . (1976) , Braff (1993) , Swerdlow and Geyer (1993) , and Freedman et al . (1991) on information processing and atten-tion. These cognitive models provide a general theory of the disease that is consistent with its diversity of symp-toms, permit testing in human beings with a variety of convergent techniques (e.g., imaging, neurophysiology), and even permit modeling in animals. This effi cient and parsimonious approach offers considerable hope for the future because it facilitates the search both for improved treatments and for molecular mechanisms.

Finally, the growing maturation of the fi eld of complex genetics offers many potential opportunities for under-standing the mechanisms of schizophrenia at the molecular level and hope for improved pre - emption, prevention, and personalization of care. The most pressing need facing those engaged in this work is to identify more meaningful ways to defi ne the phenotype of schizophrenia. The success of the Human Genome Project has conceptually revolu-tionalized our thinking about the ways in which the search for phenotypes must be guided. It has created a new disci-pline that is sometimes referred to as “ phenomics ” (Freimer & Sabatti, 2003 ). The primary task of this new discipline is to delineate the various phenotypic components that com-prise the phenome — in this case the phenome of a disease, schizophrenia. Phenomics takes a broad approach to defi n-ing the concept of the phenotype. That is, the phenotype includes not just clinical symptoms and other “ behavioral ” measures, but also morphological, biochemical, and physi-ological characteristics. What will eventually emerge from

From a Schneiderian perspective, Schneider ’ s work and point of view have been oversimplifi ed and even misun-derstood. As a Jasperian phenomenologist, Schneider was in fact deeply interested in the subjective experience of schizophrenia — in understanding the internal psychologi-cal processes that troubled his patients. For him, the fun-damental core of the illness was not the specifi c fi rst - rank symptoms themselves, but rather the internal cognitive and emotional state that they refl ected. It is somewhat ironic that he has become the symbol of objective quantifi -cation and reductionism. He himself was a complex thinker who was concerned about individual patients.

The development of diagnostic criteria has also had both advantages and disadvantages. When DSM - III was origi-nally developed, it was intended only as a “ provisional consensus agreement ” based on clinical judgment. The cri-teria were created by a small group of individuals who reached a decision about what to include based on a mixture of clinical experience and research data available up to that point. The criteria were chosen to serve as a gate - keeper that would include or exclude individual cases, and they were not intended to be a full description of the illness. Unfortunately, they are now sometimes treated as a text-book of psychiatry. Further, the criteria have become reifi ed and given a power that they originally were never intended to have.

Diagnostic criteria have substantial and undeniable advantages: they improve reliability, provide a basis for cross - center standardization both nationally and interna-tionally, improve clinical communication, and facilitate research. However, they may also have potential disadvan-tages and even abuses: they provide an oversimplifi ed and incomplete view of the clinical picture, discourage clinical sensitivity to individual patients and comprehensive history - taking, lead students and even clinicians to believe that “ knowing the criteria is enough ” , reify an agreement that was only intended to be provisional , and discourage creative or innovative thinking about the psychological and neural mechanisms of schizophrenia.

The f uture: b eyond d iagnostic c riteria and the s earch for f undamental m echanisms

As the present moves toward the future, corrective read-justments are already beginning to occur. Paradoxically, these often occur by returning to the past and coming back full circle to the work of Kraepelin, Bleuler, Jackson, and Schneider.

Clinically, the emphasis on negative as well as psychotic symptoms is leading to increased interest in the full range of symptoms of schizophrenia and in developing methods for treating that full range. The development of atypical antipsychotics, which may affect a broader range of symp-

8 Chapter 1

Goldman - Rakic , P.S. ( 1994 ) Working memory dysfunction in schizophrenia . J. Journal of Neuropsychiatry and Clinical Neurosciences 6 , 348 – 357 .

Green , M.F. & Neuchterlein , K.H. ( 2004 ) The MATRICS initia-tive: developing a consensus cognitive battery for clinical trials . Schizophrenia Research 72 , 1 – 3 .

Green , M.F. , Marshall Jr , B.D. , Wirshing , W.C. et al. ( 1997 ) Does risperidone improve verbal working memory in treatment - resistant schizophrenia? American Journal of Psychiatry 154 , 799 – 804 .

Holzman , P.S. , Levy , D.L. & Proctor , L.R. ( 1976 ) Smooth pursuit eye movements, attention, and schizophrenia . Archives of General Psychiatry 45 , 641 – 647 .

Kendell , R.E. , Cooper , J.R. , Gourlay , A.J. et al . ( 1971 ) Diagnostic criteria of American and British psychiatrists . Archives of General Psychiatry 25 , 123 – 130 .

Kraepelin , E. ( 1919 ) Dementia Praecox and Paraphrenia (tranlstated by Barclaym, R.M. & Robertson, G.M). Edinburgh : ES Livingstone .

Mellor , C.S. ( 1970 ) First - rank symptoms of schizophrenia . British Journal of Psychiatry 117 , 15 – 23 .

Murray , C.J.L. ( 1996 ) The global burden of disease: a compre-hensive assessment 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 Organization and the World Bank; dis-tributed by Harvard University Press.

Schneider , K. (translated by Hamilton, M.W.) ( 1959 ) Clinical Psychopathology . New York : Grune & Stratton, Inc .

Spitzer , R.L. , Endicott , J. & Robins , E. ( 1978 ) Research diagnostic criteria: Rationale and reliability . Archives of General Psychiatry 35 , 773 – 782 .

Swerdlow , N.R. & Geyer , M.A. ( 1993 ) Clozapine and haloperi-dol in an animal model of sensorimotor gating defi cits in schizophrenia . Pharmacology, Biochemistry, and Behaviour 44 , 741 – 744 .

Taylor , J. ed. ( 1931 ) Selected writings of J.Hughlings - Jackson . London : Hodder & Stoughton, Ltd .

Tollefson , G.D. & Sanger , T.M. ( 1997 ) Negative symptoms: A path - analytic approach to the double - blind, placebo - and haloperidol - controlled clinical trial experience with olanzap-ine . American Journal of Psychiatry 154 , 457 – 465 .

Wing , J.K. , Cooper , J.E. & Sartorius , N. ( 1974 ) The Measurement and Classifi cation of Psychiatric Symptoms . Cambridge : Cambridge University Press .

a phenomic approach is a more valid and etiologically - based defi nition of disease phenotypes that may be quite different from those created by using the clinical level alone, as has been the tradition in psychiatry and the rest of medicine for the past century. These improved pheno-types will advance the fi eld in several ways. One is to assist in the identifi cation of individualized treatment strategies that are more rationally based and data - driven. A second is to improve our knowledge of disease mechanisms at the neural and genomic levels so that more targeted treatment strategies can be developed.

References

American Psychiatric Association Committee on Nomenclature and Statistics ( 1980 ) Diagnostic and Statistical Manual of Mental Disorders ; 3rd edn . Washington, DC : American Psychiatric Association .

Andreasen , N.C. ( 1997 ) Linking mind and brain in the study of mental illnesses: A project for scientifi c psychopathology . Science 275 , 1586 – 1593 .

Andreasen , N.C. , O ’ Leary , D.S. , Cizadlo , T. et al . ( 1996 ) Schizophrenia and cognitive dysmetria: A positron - emission tomography study of dysfunctional prefrontal - thalamic - cere-bellar circuitry . Proceedings of the National Academy of Sciences USA 93 , 9985 – 9990 .

Berrios , G.E. ( 1985 ) Positive and negative symptoms and Jackson . Archives of General Psychiatry 42 , 95 – 97 .

Bleuler , E.P. ( 1950 ) Dementia Praecox of the Group of Schizophrenias (translated by Zinkin, J.). New York : International Universities Press .

Braff , D.L. ( 1993 ) Information processing and attention dysfunc-tions in schizophrenia . Schizophrenia Bulletin 19 , 233 – 259 .

Endicott , J. & Spitzer , R.L. ( 1978 ) A diagnostic interview: The schedule for affective disorders and schizophrenia (SADS) . Archives of General Psychiatry 35 , 837 – 844 .

Fish , F.J. ( 1962 ) Schizophrenia . Bristol : John Wright & Sons, Ltd . Freedman , R. , Waldo , M. , Bickford - Wimer , P. & Nagamoto , H.

( 1991 ) Elementary neuronal dysfunctions in schizophrenia . Schizophrenia Research 4 , 233 – 243 .

Freimer , N. & Sabatti , C. ( 2003 ). “ The human phenome project ” . Nature Genetics 34 , 15 – 21 .

Frith , C.D. ( 1992 ). The Cognitive Neuropsychology of Schizophrenia . East Sussex : Lawrence Erlbaum .

9

CHAPTER 2 The s chizophrenia c onstruct: s ymptomatic p resentation Celso Arango 1 and William T. Carpenter 2 1 Hospital General Universitario Gregorio Mara ñ on, Cibersam, Madrid, Spain 2 University of Maryland School of Medicine, Baltimore, MD, USA

Introduction, 9 Description of pathological manifestations associated

with the diagnosis of schizophrenia, 10 Reality distortion: delusions and hallucinations, 10 Disorganization: thought and behavior, 11 Negative symptoms, 12 Cognition, 12 Motor/neurological signs, 13 Phenotypes, 14

Other aspects critical to clinical evaluation and treatment, 14 Developmental history and prognostic indicators, 14 Emotion and suicide, 14 Substance abuse, 15 Physical health, 15

Other critical issues, including sexual dysfunction, sleep problems, and eating disorders, 16

Social and occupational role performance, 16 Quality of life, 16

Paradigm shift, 17 Disease entity versus domains of pathology, 17 Onset of illness in each paradigm, 18 Therapeutic implications of the paradigm shift, 18

Anticipating DSM - V and ICD - 11, 18 Nosological classes for DSM - V and ICD - 11, 19 Spectrum concepts, 19 Introduction of dimensions, 20

Conclusions, 20 References, 20

Introduction

The syndrome schizophrenia is composed of a broad col-lection of symptoms from all domains of mental function. Most persons who have this diagnosis experience delu-sions and hallucinations. Many, but not all, manifest disor-ganization of thought. These psychotic experiences are most commonly associated with the syndrome, but other pathological features are critical to the concept. These include avolitional and restricted affect pathologies, motor signs, and impaired basic cognitive functions. There is considerable variation between cases. Heterogeneity is a hallmark of schizophrenia.

The concept of schizophrenia as a disease entity as described by Kraepelin and Bleuler has been badly com-promised by evidence that schizophrenia syndrome may comprise a number of specifi c disease entities (Kendell,

1987 ; Carpenter, 2007 ). The diagnostic criteria currently used (ICD - 10 and DSM - IV - TR) can be considered provi-sional and arbitrary constructs with some face validity that meet the objective of facilitating international communica-tion and research. A good example of this is the classical subtypes of schizophrenia (paranoid, catatonic, disorgan-ized or hebephrenic in ICD - 10, residual and undifferenti-ated) that have been shown to have low validity. Dividing patients into mutually exclusive categorical subgroups is the classical procedure in the disease model in medicine and may help to reduce heterogeneity and enhance research. However, for clinical purposes and based on epi-demiological data, many authors support the clinical use-fulness of psychopathological dimensions. There are some studies showing a continuous distribution of psychosis - like symptoms (R ö ssler et al ., 2007 ) and even of dimensions of positive, negative, and depressive symptoms (Stefanis et al ., 2002 ) in the general population. Diagnostic models using both categorical and dimensional representations of psychosis may have better predictive validity than either model independently (Allardyce et al ., 2007 ).

Schizophrenia, 3rd edition. Edited by Daniel R. Weinberger and Paul J Harrison © 2011 Blackwell Publishing Ltd.

10 Chapter 2

Delusions are extremely variable in content. The most common delusions with respect to type of content are shown in Table 2.2 . The most common content of delusion in schizophrenia is persecution. Unlike the form of the delusion, the content is determined by the maturational, emotional, social, educational, and cultural background of the patient.

Kretschmer (1927) stressed the importance of the under-lying personality for the explanation of some delusional

Description of p athological m anifestations a ssociated with the d iagnosis of s chizophrenia

Reality d istortion: d elusions and h allucinations

A delusion is an unshakable, false idea or belief that cannot be attributed to the patient ’ s educational, social, or cultural background, which is held with extraordinary conviction and subjective certainty, and is not amenable to logic. Delusions have been divided into primary and secondary delusions. Primary delusions, which are more characteris-tic of schizophrenia, do not occur in response to another psychopathological form, such as mood disorder or hal-lucinations. Jaspers (1946/1963) considered that the per-ception of reality is a primary event not determined by the sense organs. Secondary delusions can be understood in terms of a person ’ s background culture or emotional state. Kurt Schneider (1959) posited that “ fi rst - rank symptoms ” , which refl ect an inability to defi ne boundaries between the self and non - self and which mainly include delusions and hallucinations (see below), were the defi ning characteris-tics of schizophrenia. As a result of this infl uential view, diagnostic criteria mainly used those symptoms for the diagnosis of schizophrenia. In fact, it was not until DSM - IV that negative symptoms have been included among the symptoms for diagnosing schizophrenia.

Primary delusions include delusional perceptions and delusional intuitions. Delusional perceptions are normal perceptions that are interpreted with a delusional meaning, usually with personal signifi cance. They were described by Kurt Schneider as one of the fi rst - rank symptoms in schizo-phrenia (see Table 2.1 ).

Table 2.1 First - rank symptoms of schizophrenia as defi ned by K . Schneider.

Delusions Delusional perception

Auditory hallucinations Audible thoughts Voices arguing or discussing Voices commenting on the patient ′ s action

Thought disorder: passivity of thought Thought withdrawal Thought insertion Thought broadcasting (diffusion of thought)

Passivity experiences Passivity of affect Passivity of impulse Passivity of volition Somatic passivity

Table 2.2 Content of delusion.

Content Example

Delusions of persecution “ No matter wherever I go, there are cameras fi lming me to know what I do ”

Delusions of infl uence/control

“ My brain has no bricks and my feelings are controlled from the outside because they are accessible to everyone ”

Thought withdrawal “ My thoughts are removed from my mind by strangers when I pass them in the street ”

Thought insertion “ They put thoughts in my mind that are not mine ”

Thought broadcasting “ Everyone knows what I am thinking because my brain is transparent ”

Morbid jealousy “ My wife cheats on me with everyone, even our neighbors and friends ”

Delusions of love (erotomania) *

“ I would give my life for my loved one who, although he makes others believe he does not know me, is truly and deeply in love with me ”

Delusional misidentifi cation

Capgras syndrome “ My sister has been replaced by a double ”

Fregoli syndrome “ You [to an stranger] are my sister, do not try to pretend you are not ”

Grandiose delusions “ I have the mission to save this world ”

Religious delusions “ I am the Virgin Mary and cannot have contact with men ”

* de Clerambault described a variant of erotomania in which a woman believes that a man, who is usually older and of higher social status that she, is in love with her. The person who is supposed to be in love has done nothing to deserve her attention and is usually quite unaware of her existence, and sometimes is even a famous person.

The schizophrenia construct: symptomatic presentation 11

The different mechanisms used by patients with schizo-phrenia to cope with hallucinations are related to changes in behavior (e.g., seeking someone to talk to or change in environment), changes in sensory/affective state (e.g., exercise, thinking about pleasurable moments) or changes in cognition (e.g., control of attention) (Falloon & Talbot, 1981 ).

Disorganization: t hought and b ehavior

Most patients with schizophrenia have different degrees of impairment in the thought process. Formal thought disor-ders can be assessed from manifestations present in speech and from the patient ’ s subjective awareness of disturbed thought patterns.

The most prominent formal thought disorders in schizo-phrenia are retardation, circumstantiality, tangentiality, derailment, thought blocking, and perseveration. Patients with retardation take a long time before answering ques-tions, showing a delay before producing any speech. Mutism would be the extreme form of retardation. In cir-cumstantiality, patients give unnecessary details, obscur-ing and decorating the answers before getting to the point. Unlike tangentiality, where the patient never gets to the point, in circumstantiality, the question is eventually answered. In derailment, there is a breakdown in associa-tion with no logical connection in the chain of thoughts. The patient is unable to link the fl ow of ideas, and there are illogical and unconnected changes in the direction of thinking. In thought blocking, the patient experiences a sudden breaking of the train of thought, without an expla-nation for this. Illogicality is the tendency to offer bizarre explanations for things and events. It is present where there are erroneous conclusions or internal contradictions in thinking. Illogicality is a diffi cult category that survives in disputed territory between disorders of thought form and content. Neologism is the creation of new words. Some patients also distort words or use real words in an idiosyn-cratic manner. Paraphasia is the use of a word with a new meaning. A remarkable feature of neologism and parapha-sia is that patients with schizophrenia usually seem unaware that they lack meaning for the listener. Finally, in perseveration, the patient repeats an idea or an answer that has become inappropriate.

Abnormal thought processes in schizophrenia usually result in concrete thinking with literalness of expression and understanding. Concrete thinking is a tendency to select one aspect of a concept or thing at the expense of the overall meaning. It is usually tested with interpretation of proverbs and similitudes between things or categories. These patients also have problems with abstraction and symbolism.

Andreasen (1979) studied the incidence of 18 varieties of thought disorders in patients with diagnoses of mania,

experiences. He described the sensitive personality in people who retain affect - laden complexes and have a limited capacity for emotional self - expressions. This type of person is usually rigid and paranoid, and has sensitive ideas of reference. A trigger experience may happen in life circumstances and the ideas are structured as delusions of reference.

Patients with schizophrenia experience abnormal per-ceptions, mainly in the form of sensory distortions, where real objects are perceived to be distorted, and false per-ceptions, where a new perception occurs that may or may not be in response to an external stimulus. In false per ceptions, we have illusions and hallucinations, which were separated phenomenologically by Esquirol (1838) . Illusions are transformations of perceptions, with a mixing of the reproduced perceptions of the subject ’ s fantasy with the real perceptions. An hallucination is a perception without object and the most common, although not at all specifi c, hallucinations in schizophrenia are auditory. Kandinsky (1890) described pseudohallucinations as a separate form of perception, as they are recognized by the subject as having no external correlate. Another abnor-mality of perception experienced by patients with schizo-phrenia is autoscopy, the experience of seeing oneself and knowing that it is oneself (also called phantom mirror image).

Hallucinations can occur in any sensory modality (audi-tory, visual, olfactory, gustatory and tactile, somatic or kinesthetic). Around 50% of patients with schizophrenia experience auditory hallucinations, 15% visual, and 5% tactile (DeLeon et al ., 1993 ). These anomalous experiences are usually present at the time of the fi rst psychotic episode. The most common hallucinatory experiences are voices talking to the patient or among themselves. On many occa-sions, the voice, which can be identifi ed as male or female, is not associated with anyone known by the patient. The voice is usually clear, objective, and defi nite, and experi-enced as coming from the outside. Sometimes these experi-ences are pleasurable and patients feel comfort when hearing reassuring comments by the voices. Occasionally, patients experience command hallucinations that, in most instances, are not obeyed. Particularly characteristic of schizophrenia are voices that repeat the patient ’ s thoughts aloud, give commentaries on the patient ’ s actions or thoughts, or argue with one another and talk to the patient in the third person. The three types of auditory hallucina-tions described as fi rst - rank symptoms by Kurt Schneider are given in Table 2.1 .

The neural correlates of auditory hallucinations have been studied with functional imaging showing activations associated with auditory hallucinations in a network of cortical and subcortical areas, some of which match those activated during normal hearing (Silbersweig et al ., 1995 ; Shergill et al ., 2000 ).

12 Chapter 2

assess them. The most commonly used assessment scales have been the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1983 ), the Positive and Negative Syndrome Scale (PANSS; Kay et al ., 1987 ), Negative Symptom Assessment (NSA; Alphs et al ., 1989 ), and the Schedule for the Defi cit Syndrome (SDS) (Kirkpatrick et al ., 1989 ). The generally accepted negative symptoms are shown in Table 2.3 .

Negative symptoms are more important for prognosis than positive symptoms. It is important to distinguish between primary and secondary negative symptoms, as these may be due to positive symptoms (e.g., not wanting to go into the street for fear of being killed), medication (e.g., parkinsonism), depression (e.g., anhedonia) or insti-tutionalization. If negative symptoms are to be useful in the etiopathophysiology of schizophrenia, they should be direct expressions of such processes (Carpenter et al ., 1988 ). Enduring, primary negative symptoms have been distin-guished from negative symptoms in general and are used to defi ne defi cit syndrome in schizophrenia (Carpenter et al ., 1988 ). The validity of defi cit syndrome has been dem-onstrated using brain imaging, neuropsychological, neuro-logical, illness outcome, and developmental history data, temporal stability, and treatment response (Kirkpatrick et al ., 2001 ). The distinction between primary and negative symptoms is also important at the level of drug treatment and drug discovery, and novel approaches such as antip-sychotics have not proven effective in primary negative symptoms (Arango et al ., 2004 , Kirkpatrick et al ., 2006 ).

Cognition

Cognitive defi cits, discussed in detail in Chapter 8 , have been considered core features of schizophrenia since the original descriptions by Kraepelin (1919) and Bleuler (1911) . It has been consistently shown that patients with schizophrenia have cognitive defi cits right from the onset of psychotic symptoms (Good et al ., 2004 ) and even in the prodromal period (Simon et al ., 2007 ) or well before showing any kind of symptomatology (Reichenberg et al ., 2006 ).

depression, and schizophrenia. She argued against the pathognomonic characteristic that Eugen Bleuler had given to these symptoms in schizophrenia. In the study, derail-ment was the most common variety in patients with schizo-phrenia (56%), but it did not discriminate between patients with mania and schizophrenia. Other symptoms, such as neologism or blocking, were very rare.

Negative s ymptoms

In general, negative symptoms are conceptualized as dis-orders of omission, or things patients do not do. In schizo-phrenia, disturbances of volition are more at the level of motivation or will than at the level of need.

The distinction between positive and negative symp-toms was originally introduced by Reynolds (1828 – 1896) and Jackson (1834 – 1911) (see Berrios, 1985 ). Jackson de-scribed positive symptoms as an exaggeration of normal brain processes, whereas negative symptoms were concep-tualized as a diminution or negation of normal processes. Jackson ’ s concept of hierarchical organization of the brain was that negative symptoms were secondary to tissue destruction and that positive symptoms were disinhibiting consequences for that tissue destruction. Kraepelin (1919) provided a compelling framework to distinguish between positive and negative symptoms, referring to two groups of maladies within dementia praecox:

There are apparently two principal groups of disorders which characterize the malady. On one hand we observe a weakening of those emotional activities which perma-nently form the mainsprings of volition. The results of this part of the morbid process is emotional dullness, failure of mental activities, loss of mastery over volition, of endeavour, and ability for independent action. The essence of personality is thereby destroyed, the best and most precious part of its being, as Griesinger once expressed it, torn from her. Strauss et al . (1974) reintroduced negative symptom ter-

minology, supporting the advantages of using three differ-ent types of psychopathological manifestations: positive symptoms, negative symptoms, and disorders of relating. Subsequently, Crow (1985) described Type I and Type II schizophrenia, with various criteria, one being the presence of negative symptoms in Type II schizophrenia. Andreasen and Olsen (1982) conceptualized positive and negative symptoms as different ends of the same continuum and described patients as either predominantly positive or neg-ative, and subsequently introducing a third mixed group.

In many instances, negative symptoms are present before the onset of positive symptomatology. They are present through the psychotic phase, when they are usually obscured by fl orid positive symptoms, and usually persist to varying degrees once the positive symptoms remit. Negative symptoms vary depending on the scale used to

Table 2.3 Most common negative symptoms and defi nitions.

Alogia Marked poverty of speech, or poverty of content of speech

Affective fl attening or blunted affect

Reduction in emotional expressiveness

Anhedonia Inability to experience pleasure

Asociality Lack of interest in social contacts

Avolition Lack of motivation

Apathy General lack of interest

The schizophrenia construct: symptomatic presentation 13

presence of two prominent signs is suffi cient for the patient to meet the current DSM criteria (Table 2.4 ).

The two most common abnormal movements in schizo-phrenia are mannerisms and stereotypy. Mannerisms are idiosyncratic voluntary movements that are odd and stilted, although they seem to have a purpose. Grimacing, for instance, is a common feature in schizophrenia. Stereotypy is a constant repetition of certain meaningless gestures or movements that are not goal - directed. The posture may be retained for a long time.

Patients may be stuporous with a virtual absence of movements and speech while fully conscious. Some patients with schizophrenia show abnormalities in the execution of movements. This can take the form of negativ-ism, automatic obedience, or ambitendency in which there is an alternation of cooperation and opposition. Other abnormal movements are mitgehen (the patient ’ s limbs can be moved by slight pressure, despite being told to resist the pressure) and echopraxia (imitating the movements of another person). Finally, waxy fl exibility, now rarely seen, describes a posture maintained indefi nitely after being manipulated into that attitude by the observer.

Patients with schizophrenia, healthy relatives, and patients at risk of developing schizophrenia also show neu-rological soft signs. These signs have been described as non - localizing neurological abnormalities that cannot be related to impairment of a specifi c brain region or are not believed to be part of a well - defi ned neurological syn-drome (signs elicited through graphesthesia, stereoagnosis, motor coordination assessment, go/no go test, or primitive refl exes). Their occurrence is independent of demographic variables and most medication variables. Neurological

Post - psychotic deterioration does not seem to occur as duration of illness has not been signifi cantly related to cognitive level (Gold et al ., 1999 ) and most longitudinal studies do not show further deterioration (Nopoulos et al ., 1994 ; Hoff et al ., 2005 ). However, deterioration or a devel-opmental arrest may account for reduced cognitive capac-ity during childhood and early adolescence.

One problem in the assessment of cognition in schizo-phrenia has been the lack of standard assessment scales. The assessment scales used differ in domains assessed, time requirements, repeatability, ease of administration, face validity, and availability of co - normative data (Kraus & Keefe, 2007 ). Under the name of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), a consensus cognitive battery has been devel-oped for clinical trials of cognition - enhancing treatments for schizophrenia through a broadly based scientifi c evalu-ation of measurements. MATRICS has recently been vali-dated (Nuechterlein et al ., 2008 ; Kern et al ., 2008 ). Seven separable cognitive factors were replicable across studies and represent fundamental dimensions of cognitive defi cit in schizophrenia that may be amenable to change (Verbal Comprehension was not included, as it was thought to be resistant to change): Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning and Memory, Visual Learning and Memory, Reasoning and Problem Solving, and Social Cognition.

Cognitive impairment is associated with poorer progno-sis and functional outcome (Bowie et al ., 2008 ), negative symptoms (O ’ Leary et al ., 2000 ); more specifi cally to defi cit syndrome (Buchanan et al ., 1994 ), and disorganized symp-toms (Bilder et al ., 1985 ; Cuesta & Peralta, 1995 ), but not with positive symptoms (Cuesta & Peralta, 1995 ; O ’ Leary et al ., 2000 ). Patients with defi cit syndrome seem to do more poorly in social cognition, global cognition, and language (Cohen et al ., 2007 ).

Motor/ n eurological s igns

Movement disorders are characteristic of catatonia, in which the patient may become immobilized in a retarded – stuporous way or, on the contrary, with hyperactivity in an excited – delirious variety of catatonia. Karl Ludwig Kahlbaum (1973) characterized catatonia as a specifi c dis-turbance in motor functioning that represents a phase in a progressive illness that typically ends in dementia. Later, Emil Kraepelin incorporated the features of catatonia into his concept of dementia praecox. Bleuler followed Kraepelin ’ s conceptual model for catatonia and, although numerous authors have argued against this view (Taylor & Fink, 2003 ), catatonia has been considered a subtype of schizophrenia in all DSM and ICD editions.

The most common signs are posturing, mutism, stupor, negativism, staring, rigidity, and echophenomena, but the

Table 2.4 Diagnostic criteria for schizophrenia, catatonic type [ DSM - IV 295.20) (from Diagnostic and Statistical Manual of Mental Disorders , 4th edn. American Psychiatric Association, 1994.) .

A type of schizophrenia in which the clinical picture is dominated by at least two of the following:

1. Motoric immobility as evidenced by catalepsy (including waxy fl exibility) or stupor

2. Excessive motor activity (that is apparently purposeless and not infl uenced by external stimuli)

3. Extreme negativism (an apparently motiveless resistance to all instructions or maintenance of rigid posture against attempts to be moved) or mutism

4. Peculiarities of voluntary movement as evidenced by posturing (voluntary assumption of inappropriate or bizarre postures), stereotyped movements, prominent mannerisms or prominent grimaces

5. Echolalia or echopraxia

14 Chapter 2

Emotion and s uicide

Emotion is a non - specifi c term covering feeling, affect and mood. Different languages have different descriptions that are not equal when translated. Feeling is used to describe a positive or negative reaction to an experience, in Jaspers ’ words, “ an individual unique and radical commotion of the psyche ” (Jaspers, 1946/1963 ). Affect is used to describe a momentary differentiated specifi c emotional process directed towards objects; in Jaspers words, “ a momentary and complex emotional process of great intensity with con-spicuous bodily accompaniment and sequelae ” (Jaspers, 1946/1963 ). Mood is a more pervasive state or disposition describing the state of the self in relation to its environ-ment; in Jaspers ’ words, “ states of feeling of frames of mind that come about with prolonged emotion ” (Jaspers, 1946/1963 ).

All feelings, affect, mood, and motivation have different phenomenological varieties and can be abnormal in schizo-phrenia (Table 2.5 ). Some of those symptoms are regarded as part of the dimensions of disorganization (inappropriate affect) or negative symptoms (blunted affect, apathy, or loss of motivation). Some of the affective symptoms may in turn be reactive to the stress of the primary schizophre-nia experiences.

The rate of depression in schizophrenia varies greatly in the published studies (Koreen et al ., 1993 ; Bressan et al ., 2003 ). Depression has been found to be more prevalent in women and patients with fi rst - episode schizophrenia (Emsley et al ., 1999 ). People with comorbid schizophrenia and depressive symptoms have poorer long - term func-tional outcomes in terms of poorer quality of life, greater use of mental health services, higher risk of problems with the law, and higher risk of suicide (Siris et al ., 2001 ; Conley et al ., 2007 ). Post - schizophrenic depression is defi ned as depression occurring following or in conjunction with psy-

signs are strongly associated with negative symptoms and cognitive impairment, and have been used in some studies as prognostic markers (Bombin et al ., 2005 ).

Phenotypes

In addition to symptomatic manifestations, schizophrenia is associated with a number of information processing and neuroanatomic variables that distinguish the syndrome from normal control cohorts. These include electrophysi-ological measures related to sensory gating phenomena (e.g., P50 and PPI; Braff & Light, 2005 ; Javitt et al ., 2008 ), to early and late components of evoked response potentials, and to differences in functional anatomy measured with neuroimaging techniques during task performance.

Considered intermediate between symptomatic manifes-tations and pathophysiology, such measures may reduce heterogeneity, provide more decisive assessment of genetic associations, and contribute to the understanding of patho-physiology. The use of endophenotypes is an alternative method for measuring phenotypic variation that may facil-itate the identifi cation of susceptibility genes for complexly inherited traits, rather than the use of more heterogeneous diagnostic groups, such as the schizophrenia phenotype (Braff et al ., 2007 ). Endophenotypes are now hypothesized to be treatment targets for drug development (Thaker, 2007 ).

Other a spects c ritical to c linical e valuation and t reatment

Developmental h istory and p rognostic i ndicators

Accurate diagnosis of psychotic disorders at early stages of the disease has critical clinical relevance, since the impor-tance of early treatment implementation has been demon-strated using different measures of outcome (Keshavan & Amirsadri, 2007 ).

This variable has been conceptualized mainly as the level of social functioning prior to the onset of illness, and it has been suggested that it may be an important factor related to diagnosis, disease progression, and outcome (Addington et al ., 2007 ). It has also been reported that there is an asso-ciation between premorbid adjustment and certain aspects of illness. Negative symptoms have been related to poorer premorbid adjustment in patients with fi rst - episode schizophrenia (Buchanan et al ., 1990 ). Poor premorbid adjustment in schizophrenia has been associated with male sex, earlier age at onset, illness severity, negative symptoms, worse response, poor outcome (Schmael et al ., 2007 ), and worse response to treatment after a fi rst episode (Rabinowitz et al ., 2006 ).

Table 2.5 Disturbances of emotion [reproduced with permission from Cutting, J. (2003) Descriptive psychopathology. In: Hirsch, S.R. & Weinberger, D., eds. Schizophrenia , 2nd edn. Oxford: Blackwell Science] .

Normal aspects Main psychopathological varieties

Feeling Loss of feeling — anhedonia Heightened feeling

Affect Inappropriate affect Flattened, blunted affect

Mood Depression Elation Anxiety

Motivation Apathy