Dopamine in the pathophysiology and treatment of schizophrenia : new findings PDF
Preview Dopamine in the pathophysiology and treatment of schizophrenia : new findings
Dopamine in the Pathophysiology and Treatment of Schizophrenia New Findings http://avaxhome.ws/blogs/ChrisRedfield Dopamine in the Pathophysiology and Treatment of Schizophrenia New Findings Edited by Shitij Kapur, MD PhD FRCPC Schizophrenia Program and PET Centre Centre for Addiction and Mental Health Toronto Canada Yves Lecrubier, MD PhD INSERM Unite 302, Hopital de la Pitie-Salpetriere Pavillon Clérambault Paris France LONDON AND NEW YORK © 2003 Martin Dunitz, an imprint of the Taylor & Francis Group plc First published in the United Kingdom in 2003 by Martin Dunitz, an imprint of the Taylor & Francis Group plc, 11 New Fetter Lane, London EC4P 4EE Tel: +44 (0)20 7583 9855 Fax: +44 (0)20 7842 2298 E-mail: [email protected] Website: http://www.dunitz.co.uk/ This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. ISBN 0-203-42734-3 Master e-book ISBN ISBN 0-203-44199-0 (Adobe e-Reader Format) ISBN 1 84184 304 0 (Print Edition) Distributed in the USA by Fulfilment Center Taylor & Francis 10650 Toebben Drive Independence, KY 41051 USA Toll Free Tel: 1–800–634–7064 E-mail: [email protected] Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel: +1–877 226 2237 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House, North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0)1264 332424 E-mail: [email protected] Composition by Wearset Ltd, Boldon, Tyne & Wear Contents Contributors v Preface viii 1. Historical aspects and future directions 1 Arvid Carlsson 2. Evidence from brain imaging studies for dopaminergic alterations in 13 schizophrenia Anissa Abi-Dargham 3. Modulation of dopamine D receptors as a basis of antipsychotic effect 42 2 Shitij Kapur 4. Amisulpride as a model: clinical effects of a pure dopaminergic agent 57 Yves Lecrubier 5. A meta-analysis of studies with the atypical antipsychotic amisulpride 76 Stefan Leucht, Gabi Pitschel-Walz, Werner Kissling and Rolf R Engel 6. Evidence from brain imaging for regional monoaminergic specificity in 92 schizophrenia Jean-Luc Martinot and Marie-Laure Paillère-Martinot 7. Dopamine, the prefrontal cortex, and a genetic mechanism of schizophrenia 110 Daniel Weinberger 8. Models of schizophrenia: from neuroplasticity and dopamine to 133 psychopathology and clinical management Manfred Spitzer 9. Multiple neurotransmitters involved in antipsychotic drug action 153 Herbert Meltzer 10. Dopaminergic and glutamatergic influences in the systems biology of 178 schizophrenia Carol Tamminga and Deborah Medoff 11. Pharmacogenomics of antipsychotic drugs 192 Robert Kerwin, Maria Arranz and Dalu Mancama 12. Key issues and unmet needs in schizophrenia 206 Stephen Stahl Index 223 Contributors Anissa Abi-Dargham Departments of Psychiatry and Radiology Columbia University New York State Psychiatric Institute New York USA Maria Arranz Clinical Neuropharmacology Institute of Psychiatry London UK Arvid Carlsson Department of Pharmacology University of Goteborg Sweden Rolf R Engel Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Shitij Kapur Schizophrenia Program and PET Centre Centre for Addiction and Mental Health Toronto Canada Robert Kerwin Clinical Neuropharmacology Institute of Psychiatry London UK Werner Kissling Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Marie-Laure Paillère-Martinot ERM Team INSERM—CEA Frederic Joliot Hospital Orsay France Yves Lecrubier Unite 302, Hopital de la Pitié-Salpêtrière Pavilion Clérambault 47 Boulevard de L’Hôpital 75651 Paris Cedex 13 France Stefan Leucht Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Jean-Luc Martinot ERM Team INSERM—CEA Frederic Joliot Hospital Orsay France Dalu Mancama Clinical Neuropharmacology Institute of Psychiatry London UK Deborah Medoff Maryland Psychiatric Research Center University of Maryland School of Medicine Department of Psychiatry Baltimore MD USA Herbert Meltzer Dept of Psychiatry and Pharmacology Vanderbilt University School of Medicine Nashville TN USA Gabi Pitschel-Walz Clinic for Psychiatry and Psychotherapy Munich University of Technology Klinikum rechts der Isar Munich Germany Manfred Spitzer Department of Psychiatry University of Ulm Ulm Germany Stephen M Stahl Neuroscience Education Institute Dept of Psychiatry, UCSD San Diego USA Carol Tamminga Maryland Psychiatric Research Center University of Maryland School of Medicine Department of Psychiatry Baltimore MD USA Daniel Weinberger Clinical Brain Disorders Branch Intramural Research Program National Institute of Mental Health Bethesda MD USA Preface This book grew, as many good things do, from a casual conversation between the two of us about the state of schizophrenia and antipsychotics, and how things had changed in many ways, whereas in other ways they had remained unchanged. Both of us felt that dopamine was a ‘comeback kid’ of neurotransmitters. With 2002 being the fiftieth anniversary of the introduction of antipsychotics, and with the recent recognition of dopamine researchers as Nobel laureates, we thought this would be a good occasion to get together some of the leaders in the field of dopamine and schizophrenia for a meeting to discuss where we were, and, based on this event, to produce a book aimed at updating current knowledge and theories. We approached Sanofi-Synthelabo and secured from them an unrestricted grant to hold this meeting in Montreal in the summer of 2002. An effort was made to seek a representative spectrum of ideas from across the world. This book serves as a record of the proceedings of that meeting. We begin with a chapter by Professor Arvid Carlsson who has personally watched and shaped much of the history related to dopamine, schizophrenia and antipsychotics. The chapter provides a good historical background and also looks into the future of dopamine therapeutics with the exciting new idea of ‘dopamine stabilizers’. The next chapter by Abi-Dargham provides a broad overview of the dopamine system, including some of the latest concepts about the different dopamine receptors and their specific roles in different brain regions. The chapter reviews findings of Abi-Dargham’s group which has been pivotal in putting dopamine back into the centre stage of the pathophysiology of schizophrenia. This is followed by a chapter by one of us (SK), which highlights the critical role of the action at the dopamine D receptor in atypical antipsychotic action and 2 puts forward a psychological mechanism—salience—to tie together pharmacology and phenomenology. The importance of appropriate modulation of dopamine D -like 2 receptors is uniquely important in the context of amisulpride, as this drug is not known to bind to any other receptor type; the chapter by the other editor (YL) shows how, through action on this one target, the drug is able to affect multiple domains of positive, negative and long-term consequences in schizophrenia. This is further buttressed by the arguments of Leucht et al who, through a meta-analytic approach, show that drugs acting at a single dopamine receptor are able to obtain equivalent clinical effects in multiple domains, compared to drugs that act on multiple receptors. The chapter by Weinberger ties these threads to genetics and shows how a genetic alteration, by virtue of changing dopamine metabolism in the prefrontal cortex, might be a paradigm for schizophrenia and similar illnesses. This idea is picked up by Spitzer who casts this into an even wider context and links together, dopamine, cognition, large-scale networks and how psychological and social influences may all come together in a real world therapeutic intervention. Everything should be made as simple as possible, but not simpler. (Albert Einstein) While there has been a lot of new evidence, new interest and new ideas regarding dopamine in the context of schizophrenia and antipsychotics even its most ardent supporters would admit that an exclusive focus on it may be myopic. In the very opening chapter Carlsson puts it bluntly; ‘we have moved in the direction of drugs of narrow specificity to treat schizophrenia—I believe that this has taken us in the wrong direction’. While dopamine may have a central role in the expression of some symptoms in schizophrenia, there is still no convincing proof that it is the primary point of aetiology or that it can claim exclusivity with any domain of schizophrenia. This point is meticulously made by Meltzer who shows that, when considering the action of antipsychotics, one cannot ignore the very prominent effects on the serotonergic, adrenergic, cholinergic and other brain transmitter systems—and hints at the possibility of some non-D 2 antipsychotics. The point is also made by Tamminga, who suggests that the role of dopamine may be only secondary to alterations in the glutamate system and that it may be this latter neurotransmitter pathway which holds the reins of schizophrenia. This complexity is also underscored in pharmacogenetic studies, as described by Kerwin et al, where a broad range of neurotransmitter gene predict antipsy-chotic response. The book ends with the chapter by Steve Stahl which points out the many areas of unmet needs in schizophrenia and how our patients receive some relief in symptoms but not remission from them, how primary negative symptoms remain largely uncontrolled, and how cognitive symptoms are barely touched. Thus, while this volume attempts to bring under one umbrella some of the recent highlights of dopamine research, it also cautions against a monotheistic view of schizophrenia while anticipating the complex challenges for the next generation of pharmacotherapy. The meeting in Montreal was exciting; the process of editing this book gratifying, and we hope that you, the reader, will find the contents of it to your liking. Shitij Kapur and Yves Lecrubier February 2003
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