Schizophrenia -  - ebook

Schizophrenia ebook

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Schizophrenia is one of the most complex and disabling diseases toaffect mankind. Relatively little is known about its natureand its origins, and available treatments are inadequate for mostpatients. As a result, there are inevitable controversies aboutwhat causes it, how to diagnose it, and how best to treat it. However, in the past decade, there has been an explosion ofnew research, with dramatic discoveries involving genetic etiologyand epidemiological risk factors. There has also been acatalog of new drugs coming to market, and controversy about therelative advantages and disadvantages of newer compared with oldertherapies. In addition, developing technologies in genomics,molecular biology and neuroimaging provide streams of newinformation. This book represents a definitive, essential, and up-to-datereference text on Schizophrenia. It extensively and criticallydigests and clarifies recent advances and places them within aclinical context. The Editors (one American and one British),highly respected clinical psychiatrists and researchers andacknowledged experts on Schizophrenia, have again assembled anoutstanding group of contributors from the USA, UK, Europe andAustralia, It will be of value to practising psychiatrists and totrainees, as well as to clinical and neuroscience researchersinterested in keeping up with this field or coming into it. The book consists of four sections: descriptive aspects,biological aspects, physical treatments, and psychological andsocial aspects. It reviews the theoretical controversiesover symptomatology, classification and aetiology (particularlypertinent as DSM-V is being developed), the relationship ofschizophrenia to the other psychoses, the significance of positiveand negative symptoms and pre-morbid personality. It describes avariety of approaches to integrating the vast research data aboutschizophrenia, including neurodevelopmental, genetic,pharmacological, brain imaging and psychological findings. Thebiological treatment section reviews the comparative efficacy ofvarious drugs, the management of drug-resistant patients and bothneurological and metabolic complications. The final section looksat psychological therapies, social outcomes, and the economics ofschizophrenia. Highly Commended in the Psychiatry section of the 2012BMA Book Awards.

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Editor’s note

Preface to the 3rd Edition

Preface to the First Edition, xiii

Part 1 Descriptive Aspects

1 Concept of schizophrenia: past, present, and futureNancy C. Andreasen

2 The schizophrenia construct: symptomatic presentationCelso Arango and William T. Carpenter

The past: early concepts of psychosis

The past: further delineation of psychoses and early definitions of schizophrenia

The present: Schneiderian symptoms, psychosis, and the dominance of diagnostic criteria

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

2 The schizophrenia construct: symptomatic presentationCelso Arango and William T. Carpenter


Description of pathological manifestations associated with the diagnosis of schizophrenia

Other aspects critical to clinical evaluation and treatment

Paradigm shift

Anticipating DSM-V and ICD-11


3 Child and adolescent schizophreniaChris Hollis and Judith Rapoport


Clinical phases

Diagnosis in childhood and adolescence

Course and outcome


Etiology and risk factors

Concepts of schizophrenia





Differential diagnosis

Treatment approaches


4 Late-onset schizophreniaRobert Howard and Dilip Jeste

Historical background and approaches to classification

Clinical features





5 The schizophrenia spectrum personality disordersEran Chemerinski and Larry J. Siever



Relationship of schizotypal personality disorder to schizophrenia

Psychometric assessment

Spectrum personality disorders in premorbid clinical prof iles of patients with schizophrenia



Cognitive impairment in the schizophrenia spectrum






6 The prodrome of schizophreniaJean Addington and Shon W. Lewis


What is the prodrome?

Transition to psychosis

Imaging findings

Intervention in the prodrome


7 Course and outcomeWolfram an der Heiden and Heinz Hafner


Methodological aspects of course and outcome research

Study population

Course types of schizophrenia

Positive and negative symptom dimensions

Functional and cognitive impairment

Course of empirical symptom dimensions

Prepsychotic prodromal stage and early psychotic stage

Social course of schizophrenia

Medium- and long-term course of schizophrenia

Long-term clinical course and outcome of schizophrenia

Comorbidity with substance abuse as a predictor of course

Suicide in the course of schizophrenia

Quality of life



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


Course of cognitive impairment

Tradition of clinical neuropyschological studies of schizophrenia

Experimental approaches to the study of specific cognitive functions in schizophrenia

Cognition, functional outcome, and the cognitive effects of antipsychotics

Neuropsychological investigations of psychotic symptoms


Part 2 Biological Aspects

9 The secondary schizophreniasThomas M. Hyde and Maria A. Ron

1010 Schizophrenia: the epidemiological horizonAssen Jablensky, James B. Kirkbride, and Peter B. Jones

Terminology and classification

How common are secondary schizophrenias?

Inferring cause and effect

Co-occurrence of schizophrenia-like symptoms and organic brain disease

Drug-related psychosis

Sex chromosome abnormalities

Associations with Mendelian disorders

Phenomenology of primary versus secondary schizophrenia


1010 Schizophrenia: the epidemiological horizonAssen Jablensky, James B. Kirkbride, and Peter B. Jones


Sources of variation in the epidemiology of schizophrenia related to the method of investigation

Descriptive epidemiology and demography of schizophrenia

Analytical epidemiology of schizophrenia: risk factors, exposures, and antecedents

Prospects for epidemiology in the search for the causes of schizophrenia

11 Environmental risk factors for schizophreniaJohn J. McGrath and Robin M. Murray


Risk factor epidemiology as a clue generator

Exposures to early biological hazards

Exposure to later biological candidate risk factors

Social biology

Risk factors and dopamine dysregulation

Conclusions and future directions


12 Classical genetic studies of schizophreniaBrien Riley and Kenneth S. Kendler


Genetic epidemiology: Why are we looking for genes contributing to schizophrenia?

Methods: Where and how will such genes be found?

Results: Where is the evidence strongest for schizophrenia susceptibility genes?

13 Genetic associations in schizophreniaMichael C. O’Donovan and Michael J. Owen

Basis of genetic association

False positives

Genome-wide association studies

Functional candidate genes

Dopamine genes

Gene–gene i nteraction

Serotonergic genes

Positional candidate genes

Structural genomic variation


14 Intermediate phenotypes in genetic studies of schizophreniaMichael F. Egan and Tyrone D. Cannon


Methodological issues

Eye tracking dysfunction

Electrophysiological/sensorimotor gating phenotypes (see also Chapter 15)

Neuroimaging phenotypes (see also Chapters 16 and 17)

Cognitive phenotypes

Receptors, neurotransmitters, and cell-based phenotypes

Other phenotypes


15 Electrophysiology of schizophreniaGeorg Winterer and Robert W. McCarley


The place of electrophysiology in the neuroimaging spectrum

Electrophysiology in schizophrenia

Magnetoencephalography: a complement to electroencephalography


16 Structural brain imaging in schizophrenia and related populationsStephen M. Lawrie and Christos Pantelis

Historical techniques

Structural magnetic resonance imaging

Magnetic resonance spectroscopy

Diffusion tensor MRI

Overall conclusions and challenges

17 Functional brain imaging in schizophreniaAndreas Meyer-Lindenberg and Edward T. Bullmore


Imaging neurocognitive functions

Imaging treatment effects

Imaging systems: connectivity

Studies in relatives and high-risk populations


18 Neuropathology of schizophreniaPaul J. Harrison, David A. Lewis, and Joel E. Kleinman

Neurodegeneration in schizophrenia

Hippocampal formation

Dorso-lateral prefrontal cortex

Neuropathological interpretations


19 Neurodevelopmental origins of schizophreniaDaniel R. Weinberger and Pat Levitt


What is the evidence that abnormal brain development increases risk?

Clues to a molecular mechanism of developmental deviation

Why do the clinical manifestations of schizophrenia change over time?

Relevant biological events in adolescent brain development

Candidate maturational processes and psychosis onset


20 Dopamine and schizophreniaAnissa Abi-Dargham and Anthony A. Grace


Historical perspective

Dopamine and psychosis: increased striatal phasic dopamine release

Dopamine and cognition: suboptimal cortical dopamine transmission

Preclinical considerations


21 Contributions of glutamate and GABA systems to the neurobiology and treatment of schizophreniaJohn H. Krystal and Bita Moghaddam

Glutamatergic and GABAergic neuropathology in schizophrenia

Psychopharmacology and physiology of glutamate and GABA systems



22 Animal models of schizophreniaBarbara K. Lipska and Joseph A. Gogos

Pharmacological dopamine-based animal models

Novel approaches to modeling schizophrenia

Neurodevelopmental models

Models of disrupted neurogenesis

Perinatal stress models

Neonatal lesion models

Pharmacological models of glutamatergic antagonism

Genetic models


Part 3 Physical Treatments

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

Origins of contemporary concepts and challenges

Evolution of the D2 receptor blockade hypothesis

Reappraisal of the D2 receptor blockade hypothesis by PET and SPECT

Clozapine as the prototype second-generation antipsychotic

Subsequent second-generation antipsychotics

Putative “third-generation” antipsychotics

Interim synthesis

New dopamine-related mechanisms

New non-dopamine-related mechanisms

Neuroprotection and related cellular processes as targets for “fourth-generation” antipsychotics


24 Principles of pharmacological treatment in schizophreniaThomas R.E. Barnes and Stephen R. Marder

Who benefits from these medications?

Prescribing principles

Choice of antipsychotic

Long-term treatment

25 Comparative efficacy and effectiveness in the drug treatment of schizophreniaJohn R. Geddes, T. Scott Stroup, and Jeffrey A. Lieberman


First-generation antipsychotics

Clozapine and atypicality

Second-generation (atypical) antipsychotics

Pragmatic trials comparing first-and second-generation antipsychotics

Antipsychotics: clinical trial design and data interpretation


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


Conceptual issues: definitions of response to treatment, remission, and treatment resistance


Management and treatment

Childhood-onset schizophrenia

27 Neurological complications of antipsychotic drugsPeter M. Haddad and Venkata S. Mattay


Acute extrapyramidal syndromes

Tardive dyskinesia

Neuroleptic malignant syndrome


Cerebrovascular events

28 Metabolic adverse effects associated with antipsychotic medicationsJohn W. Newcomer and Stefan Leucht


Morbidity and mortality in schizophrenia

Weight gain during antipsychotic treatment

Metabolic effects of antipsychotic treatment

Metabolic effects of antipsychotics independent of changes in adiposity

Changes in metabolic risk associated with switching antipsychotic treatment

Recommendations to reduce cardiometabolic risk


Conflict of interest

Part 4 Psychosocial Aspects

29 Schizophrenia and psychosocial stressesPaul E. Bebbington and Elizabeth Kuipers

Psychosocial stress and the definition of psychotic disorders

Setting the agenda for a social etiology

Expressed emotion and schizophrenia

Life events and schizophrenia

Increased sensitivity to stress

Distal social adversity in people who develop schizophrenia

Social defeat and schizophrenia

The trauma/post-traumatic stress disorder/schizophrenia triad



30 Mental health services for patients with schizophreniaTom Burns and Bob Drake


Limitations of mental health services research

Components of mental health services for schizophrenia

Multidisciplinary community teams

Specialized teams

Specialist teams or specialist functions?

Controversies and ethics in schizophrenia care


31 Societal outcomes in schizophreniaIain Kooyman and Elizabeth Walsh


Violence and schizophrenia



Substance misuse




32 Psychological treatment of psychosisGillian Haddock and Will Spaulding


Psychodynamic treatment approaches in schizophrenia

Individual cognitive and behavioral therapies for psychosis

Family interventions for psychosis

Neuropsychological and cognitive remediation approaches

Definition of the approach

Neuropsychological therapy: a description of the approach

Social skills training and integrated approaches

Contingency management

Comorbid disorders

Implementation and skills needed to deliver psychological therapists


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

Economics of mental health and schizophrenia


Cost of the newer antipsychotic medications

Conclusions and additional resources




Colour plates are found facing page


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 first edition of this book and was instrumental in the success of the second, and whose legendary persistence and commitment to this field, to his students and his colleagues, nurtured a generation of researchers and clinicians interested in understanding patients with schizophrenia and in helping them.Schizophrenia

This edition first 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--dc222010015115

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


A. Abi-Dargham, MDProf essor 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, PhDProf essor, Department of Psychiatry, Alberta Mental Health Centennial Research Chair, Novartis Chair in Schizophrenia Research, University of Calgary, Canada

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

N.C. Andreasen, MDPhDAndrew 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, MDPhDHead, Adolescent Unit, Department of Psychiatry, Hospital General Universitario Gregorio Marañon, Cibersam, Madrid, Spain

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

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

E.T. Bullmore, PhD FRCP FRCPsych FMedSciProf essor, Department of Psychiatry, University of Cambridge, Cambridge, UK

T. Burns, DSc FRCPsychProf essor of Social Psychiatry, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

T.D. Cannon, PhDStaglin Family Prof essor, 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, MDProf essor 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, MDAssistant Prof essor of Psychiatry, Mount Sinai School of Medicine, New York, NY, and James J. Peter Veterans Affairs Medical Center, Bronx, NY, USA

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

N.H. Covell, PhDAssistant Prof essor, 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 MScProf essor of Cognitive Neuropsychiatry, Institute of Psychiatry, King’s College, London, London, UK

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

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

S.M. Essock, PhDEdna L. Edison Prof essor 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, PhDDirector of Research, Connecticut Department of Mental Health and Addiction Services, University of Connecticut School of Social Work, Hartford, CT, USA

J.R. Geddes, MD FRCPsychProf essor of Epidemiological Psychiatry, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

J.A. Gogos, MDPhDProf essor, Department of Physiology and Department of Neuroscience, Columbia University Medical School, New York, NY USA

J.M. Gold, PhDAssociate Prof essor, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Crownsville, MD, USA

T.E. Goldberg, PhDProf essor, 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, PhDProf essor of Neuroscience, Psychiatry and Psychology, Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

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

G. Haddock, BSc MClinPPsychol PhDProf essor of Clinical Psychology, School of Psychological Sciences, University of Manchester, Manchester, UK

H. Häfner, MDPhD Dres.h.c.Prof essor of Psychiatry, Head, Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany

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

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

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

T.M. Hyde, MD PhDChief Operating Officer, Lieber Institute for Brain Development, Baltimore, Maryland MD, USA

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

D.V. Jeste, MDEstelle and Edgar Levi Chair in Aging, Prof essor 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 FRCPsychHead, Department of Psychiatry, University of Cambridge, Cambridge, UK

J.M. Kane, MDChairman, 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, MDRachel Brown Banks Distinguished Prof essor of Psychiatry, Prof essor 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, PhDPostdoctoral Research Fellow, Department of Psychiatry, University of Cambridge, Cambridge, UK

J.E. Kleinman, MDPhDChief, 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, MRCPsychSpecialist Registrar in Forensic Psychiatry, North London Forensic Service, and Department of Forensic Mental Health Science, Institute of Psychiatry, London, UK

J.H. Krystal, MDRobert L. McNeil, Jr. Prof essor 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 PhDFBPsSProf essor 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)Prof essor of Psychiatry and Head of Psychiatry, University of Edinburgh Division of Psychiatry, Royal Edinburgh Hospital, Edinburgh, UK

S. Leucht, MDVice-Chairman, Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, Munich, Germany

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

D.A. Lewis, MDUPMC Prof essor 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 FMedSciProf essor of Adult Psychiatry, University of Manchester, Manchester, UK

J.A. Lieberman, MDChairman, 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, PhDStaff Scientist, Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

S.R. Marder, MDProf essor 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, MDDirector, Neuroimaging Core, Genes, Cognition and Psychosis Program, National Institutes of Mental Health, National Institutes of Health, Bethesda, MD, USA

R.W. McCarley, MDProf essor 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 FRANZCPProf essor and Director, Queensland Centre for Mental Health Research and Department of Psychiatry, Queensland Brain Institute, University of Queensland, Australia

A. Meyer-Lindenberg, MD PhD MScDirector, Central Institute of Mental Health, Mannheim, Prof essor 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, PhDProf essor of Neuroscience, Psychiatry and Pharmacy, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

R.M. Murray, MD M Phil MRCP MRC Psych FRSProf essor 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, MDGregory B. Couch Prof essor 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 PhDProf essor 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, PhDSenior Research Fellow, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

M.J. Owen, FRCPsych PhDHead, 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, MBBS MD MRCPsych FRANZCPAssociate Prof essor and Head, Cognitive Neuropsychiatry Research and Academic Unit, Department of Psychiatry; Coordinator, Applied Schizophrenia Division, Mental Health Research Institute; Principal Fellow, Centre for Neuroscience, The University of Melbourne, Melbourne, Australia

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

G.J. Remington, MDPhD FRCPCDirector, Medication Assessment Program for Schizophrenia (MAPS) Clinic and Prof essor of Psychiatry, Schizophrenia Division, Centre for Addiction and Mental Health, Faculty of Medicine, University of Toronto, Toronto, Canada

B. Riley, PhDDirector 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 FRCPsychProf essor of Neuropsychiatry, Institute of Neurology, University College London, London, UK

L.J. Siever, MDProf essor 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, PhDProf essor of Psychology, University of Nebraska, Lincoln, USA

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

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

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

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

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

Editor’s Note

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. Prof essor Hirsch was the visionary figure behind the creation of this volume. His idea was that we would assemble a team of prominent basic and clinical scientists and scholars at the leading edge of schizophrenia research from both sides of the Atlantic—and beyond—to collaborate in producing this comprehensive review of the field. His retirement has not compromised this vision or its implementation, but his participation has been missed. In keeping with the goal of trans-Atlantic cooperation in assembling the faculty for this new volume, and in seeking a translational scientist in the tradition of Prof essor Hirsch to co-edit this project with me, I invited Prof essor Paul Harrison of the University of Oxford to pick up the mantle and step into Prof essor Hirsh’s shoes. Prof essor Harrison brings a unique background 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 partnership with Prof essor Harrison.

Daniel. R. Weinberger, M.D.

Preface to the 3rd edition

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 findings, concepts, and interpretations across the whole spectrum—from biological 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 schizophrenia should be classified.

We have attempted to capture the progress, the excitement, and the controversies in the field. Reflecting 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 particularly topical, or where there has been significant research developments since the last edition; equally, chapters were not retained if there had been little new research findings, or if their key elements were better subsumed within another chapter. Overall this has led to significant 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 dramatic increase in genetic research is reflected in a second genetics chapter (Chapter 13), and the chapter on brain imaging has been divided into separate chapters on structural (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 antipsychotics (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 standard reference text and also to serve as an entrée 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 complementary perspectives. We thank our colleagues for their important and authoritative contributions and our families for their extraordinary patience and support.

Daniel R. WeinbergerPaul J. HarrisonJanuary 2011

For Sandra, Rosie, Charlie and GracePaul J Harrison

For Leslie and CollinDaniel R Weinberger

Preface to the First Edition

Schizophrenia has been a controversial topic since the term was first proposed by Eugen Bleuler to describe a uniquely human syndrome of prof oundly disturbed behaviour. In the years following Bleuler’s original work the controversies 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 inNature reified the current status of schizophrenia in the biomedical research establishment by declaring, ‘Schizophrenia is arguably the worst disease affecting mankind, even AIDS not excepted’ (NatureEditorial, 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 schizophrenia is caused by a fault in the infant-mother psychological 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 scientific scrutiny (Hirsch & Leff, 1975). The evidence that schizophrenia is associated with objective changes in the anatomy and function of the brain and has a genetic predisposition is incorporated in a major revision 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 suggested that aberrations of complex molecular processes responsible for the development of the human brain may be responsible for this illness. The possibility of finding a specific 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 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 influenced by the recent changes in our understanding of the brain, the developments in methodology which have influenced scientifically 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 field, may be intelligibly informed about schizophrenia.

Promising as some of the basic science may seem, schizophrenia is still a disease whose diagnosis depends on clinical 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 deficits 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 postmortem 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 characteristic way? Is there a common aetiology, or can schizophrenia arise from a myriad of causes, any of which affect a final common path of brain disturbance? Could the developmental abnormality result solely from environmental causes, or is a genetic factor essential? What is the correspondence between pathological changes and clinical manifestations? 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 liability? 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 hypothesis 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 individual basis is no longer used to treat patients with schizophrenia. 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 significantly reduces the risk of relapse. The value of community 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 fields 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 concepts and understanding which we believe justifies the effort of our authors whom we gratefully thank for their contribution.

Steven R. HirschDaniel R. Weinberger1995


Editorial (1988) Where next with psychiatric illness? Nature336, 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 1Descriptive Aspects

CHAPTER 1Concept of schizophrenia: past, present, and future

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

The past: further delineation of psychoses and early definitions of schizophrenia

The present: Schneiderian symptoms, psychosis, and the dominance of diagnostic criteria

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


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 illnesses that contribute to the global burden of disease (Murray, 1996). Because of its early age of onset and its subsequent tendency to persist chronically, of ten at significant levels of severity, it produces great suffering for patients and also for their family members. It is also a relatively 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 emotions, to read social situations and to have normal interpersonal relationships, and to interpret past experiences and plan for the future. Some of its symptoms, such as delusions and hallucinations, produce great subjective psychological pain. Other facets of the illness produce great pain as well, such as the person’s recognition that they are literally “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 formulate a consensus about the definition and essence of schizophrenia. This introduction will review this conceptual history in order to provide a foundation for the later chapters in this book. Even at present, creating a consensus about how best to define the phenotype(s) of schizophrenia is a task that has not yet been successfully achieved. And yet the definition of the concept and its phenotype must provide a foundation for both the study of disease mechanisms and for the development of improved approaches to treatment and prevention.

The past: early concepts of psychosis

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 first 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 subsequent 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:

... 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 filled with portrayals of individuals who are tormented by psychosis, and are of ten 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 children with a sword, also murdering King Creon and his daughter by giving them a poisoned robe and chaplet that consumes them in a fiery painful death. In The Oresteia, Orestes is pursued by the Furies until he finally 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 filled 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” literature of these early times provides parallel evidence that psychotic disorders similar to schizophrenia were recognized 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 classification systems, but they have surprising similarities. Mental illnesses were clearly seen as “physical” in origin, deriving either from an imbalance of humors (yellow bile, black bile, phlegm, and blood) or to an imbalance in the brain. In general, five groups of illnesses were described: melancholia, phrenitis, mania, hysteria, and epilepsy. Mania was essentially equivalent to our concept of psychosis. Psychotic disorders were not, however, further subdivided until the late 19 th century.

The past: further delineation of psychoses and early definitions of schizophrenia

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 psychotic had an episodic course, typically with a full remission of symptoms. A second group of psychotic patients had a chronic course and typically progressed to a deteriorated 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 influenced psychiatric classification and the concept of schizophrenia for more than a century.

Kraepelin did not, however, consider psychotic symptoms 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 negative symptoms. Negative symptoms include abnormalities in cognition and emotion: alogia, avolition, anhedonia, affective blunting, and (in some conceptualizations) attentional 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 dullness, 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 volition in themselves and among one another.... The near connection between thinking and feeling, between deliberation 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)

Such passages in Kraepelin’ s textbook indicate that he perceived negative symptoms to be the most important symptoms of schizophrenia. Nevertheless, his comprehensive 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: fundamental 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 writings, one can argue that Bleuler identified four, five, 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, ambivalence, and autism. These symptoms correspond relatively closely to those we currently refer to as negative symptoms. They reflect abnormalities in basic cognitive and emotional processes, which (in Bleuler’s thinking) provided 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 specific permanent or fundamental symptoms, we can find a host of other, more accessory manifestations such as delusions, hallucinations, or catatonic symptoms.... As far as we know, the fundamental symptoms are characteristic 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 colleague, Eugen Bleuler, admired many of Kraepelin’s ideas, but he took exception to the fact that chronicity and deterioration were inevitable. Therefore, he chose to rename the illness in order to highlight his own view that a fragmenting of thinking, sometimes referred to as “thought disorder”, was the most important feature, and also to eliminate the concept that deterioration was inevitable. He chose the name “schizophrenia” (schiz = fragmenting, splitting; phren = mind, Gk). Bleuler’s name eventually prevailed over Kraepelin’s. Today many feel that either is an unfortunate choice, because each leads to misunderstanding about the nature of the illness by the general public. Too of ten people assume that the name refers to a “split personality”. However, to date no good substitute has been identified.

Since Bleuler’ s fundamental symptoms involve cognition and emotion, since negative symptoms (a related but also slightly different concept) also involve cognition and emotion, and since “cognitive dysfunction” in schizophrenia is currently a topic of considerable interest, some clinicians and investigators find 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 activities 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 cognitive 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, attributing affects to experiences), assessing them at the clinical level may provide a relatively direct “window” into cognitive impairments in schizophrenia. While Kraepelin and Bleuler did not refer to their clusters of fundamental symptoms 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, hallucinations, 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 symptoms answer to the dissolution), while positive symptoms 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 organized in hierarchical evolutionary layers. Positive symptoms represent aberrations in a primitive (perhaps limbic) substrate that is for some reason no longer monitored by higher cortical functions. Thus Huglings-Jackson’s concept of negative and positive symptoms rather closely resembles those which are currently discussed. Although most investigators do not necessarily embrace the specific mechanism 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 contemporary thinking about the symptoms and definition 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 discussed 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 cognitive, affective, volitional, and attentional function in schizophrenia. 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 define and diagnose schizophrenia based on the symptoms Bleuler saw as fundamental, such as associative loosening and affective blunting.

The present: Schneiderian symptoms, psychosis, and the dominance of diagnostic criteria

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

The emphasis on florid psychotic symptoms arose because of the influence of Kurt Schneider and the interpretation of his thinking by influential British psychiatrists. Schneider was greatly influenced 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., symptoms 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 find the boundaries between self and not-self and a loss of the sense of personal autonomy. This led him to discuss various “first-rank” symptoms that were characterized by this loss of autonomy, such as thought insertion or delusions of being controlled 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 influence on the concept of schizophrenia. An emphasis on Schneiderian first-rank symptoms satisfied the fundamental need to find an anchor in the perplexing flux of the phenomenology of schizophrenia. Schneiderian symptoms were incorporated into the first major structured 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 instruments 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 first was that Bleulerian symptoms were difficult to define and rate reliably. They are of ten 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 excessive 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 schizophrenia. Stressing florid psychotic symptoms, particularly Schneiderian symptoms, was a useful way to achieve this end, since it appeared that schizophrenia was of ten being diagnosed on the basis of mild Bleulerian negative symptoms. 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.

From a Schneiderian perspective, Schneider’s work and point of view have been oversimplified and even misunderstood. As a Jasperian phenomenologist, Schneider was in fact deeply interested in the subjective experience of schizophrenia—in understanding the internal psychological processes that troubled his patients. For him, the fundamental core of the illness was not the specific first–rank symptoms themselves, but rather the internal cognitive and emotional state that they reflected. It is somewhat ironic that he has become the symbol of objective quantification 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 originally developed, it was intended only as a “provisional consensus agreement” based on clinical judgment. The criteria 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 gatekeeper 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 textbook of psychiatry. Further, the criteria have become reified 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 internationally, improve clinical communication, and facilitate research. However, they may also have potential disadvantages and even abuses: they provide an oversimplified 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 future: beyond diagnostic criteria and the search for fundamental mechanisms

As the present moves toward the future, corrective readjustments are already beginning to occur. Paradoxically, these of ten 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 symptoms 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 complemented 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 attentional 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 returning to the original insights of Kraepelin and Bleuler that the core symptoms of schizophrenia represent a fundamental deficit in cognition and emotion. This in turn has led to recent initiatives to incorporate assessments of cognitive function into clinical drug trials (Green & Neuchterlein, 2004).

Several prominent investigators have turned from a focus on explaining and “localizing” the specific symptoms of schizophrenia to a search for more fundamental underlying 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 attention. These cognitive models provide a general theory of the disease that is consistent with its diversity of symptoms, permit testing in human beings with a variety of convergent techniques (e.g., imaging, neurophysiology), and even permit modeling in animals. This efficient and parsimonious approach of fers considerable hope for the future because it facilitates the search both for improved treatments and for molecular mechanisms.

Finally, the growing maturation of the field of complex genetics of fers many potential opportunities for understanding 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 define the phenotype of schizophrenia. The success of the Human Genome Project has conceptually revolutionalized our thinking about the ways in which the search for phenotypes must be guided. It has created a new discipline 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 comprise the phenome—in this case the phenome of a disease, schizophrenia. Phenomics takes a broad approach to defining the concept of the phenotype. That is, the phenotype includes not just clinical symptoms and other “behavioral” measures, but also morphological, biochemical, and physiological characteristics. What will eventually emerge from a phenomic approach is a more valid and etiologically- based definition 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 field in several ways. One is to assist in the identification 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.


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