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The Psychopharmacologists Interviews by Dr David Healy A member of the Hodder Headline Group LONDON· NEW YORK· NEW DELHI First published in Great Britain in 1996 by Chapman & Hall. This impression published by Arnold, a member of the Hodder Headline Group, 338 Euston Road, London NW1 3BH http://www.arnoldpublishers.com Distributed in the USA by Oxford University Press Inc., 198 Madison Avenue, New York, NY10016 Oxford is a registered trademark of Oxford University Press © 200 1 Arnold All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenharn Court Road, London W1P OLP. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however, it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly urged to consult the drug companies' printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library ofC ongress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 1 8603 6008 4 What do you think about this book? Or any other Arnold title? Please send your comments to [email protected] Contents Contributors vu Preface 1X Acknowledgements XVll Glossary X1X Dramatis personae XXV Chronology of interviews XXXlll 1 Pierre Pichot (Paris) 1 The discovery of chlorpromazine and the place of psychopharmacology in the history of psychiatry 2 ]ulius Axelrod (NIMH) 29 The discovery of amine reuptake 3 Arvid Carlsson (Gothenburg) 51 The rise of Neuropsychopharmacology: impact on basic and clinical neuroscience 4 Frank Ayd (Baltimore) 81 The discovery of antidepressants 5 Alan Broadhurst (Cambridge) 111 Before and after imipramine 6 Silvio Garattini (Milan) 135 The role of independent science in psychopharmacology 7 Heinz Lehmann (Montreal) 159 Psychopharmacotherapy 8 Hanns Hippius (Munich) 187 The founding of the CINP and the discovery of clozapine 9 Hannah Steinberg (London) 215 Bridging the gap: psychology, pharmacology and after 10 ]onathan Cole (Harvard) 239 The evaluation of psychotropic drugs 11 Alex Coppen (Epsom) 265 Biological psychiatry in Britain 12 ]ules Angst (Zurich) 287 The myths of psychopharmacology VI The Psychopharmacologists 13 George Beaumont (Cheshire) 309 The place of clomipramine in psychopharmacology 14 Donald Klein (New York) 329 Reaction patterns to psychotropic drugs and the discovery of panic disorder 15 Herman van Praag (Maastricht) 353 Psychiatry and the march of folly 16 Merton Sandler (London) 381 The place of chemical pathology in psychopharmacology 17 Floyd Bloom (Scripps) 401 Neurophysiology and the psychopharmacology of the addictions 18 Alexandra Delini-Stula (Basle) 425 The changing face of psychotropic drug development - from 1965 to 1995. 19 Gordon Claridge (Oxford) 441 The role of individual differences in psychopharmacology 20 Malcolm Lader (London) 463 Psychopharmacology: clinical and social 21 Herbert Meltzer (Ohio) 483 A career in biological psychiatry 22 Brian Leonard (Galway) 509 The role of behavioural pharmacology in drug development 23 John Hughes (Cambridge) 539 The discovery of the opioid peptides 24 Peter Waldmeier (Basle) 565 From mental illness to neurodegeneration 25 Tom Ban (Toronto) 587 They used to call it psychiatry Index 621 Contributors ]ules Augst Department of Psychiatry, Psychiatrische Universiteats Klinik Zurich, Postfach 68, CH-8029, Zurich 8, Switzerland. Julius Axelrod Laboratory of Cell Biology, National Institute of Mental Health, Building 36, 9000 Rockville Pyke, Bethesda, Maryland 20892, USA Frank Ayd 1130 East Cold Spring Lane, Baltimore, Maryland 21239-3931, USA Thomas A. Ban 1177 Yonge Street, Toronto, Ontario M4T 2Y4 , Canada George Beaumont 11 Dorchester Road, Hazel Grove, Stockport, Cheshire SK7 SHE, UK Floyd Bloom Department of Neuropharmacology, The Scripps Research Institute, 10666 North Terney Pines Road, La Hella, California 92037, USA Alan Broadhurst Vicarage Grove, The Park, Great Barton, near Bury St Edmonds, Suffolk IP31 2SU, UK Arvid Carlsson Department of Pharmacology, University of Gothenburg, Mediconarega tan 7, S-41390 Gothenburg, Sweden Gordon Claridge Magdalen College, Oxford OX1 4AU, UK Jonathan Cote 57 Ellery Street, Cambridge, Massachusetts 02138, USA Alec Coppen 5 Walnut Close, Downs Road, Epsom, Surrey, UK viii The Psychopharmacologists Alex Delini-Stula Roche International Clinical Research Center, Pare Club des Tanneries, BP 83, F-673 82 Lingoisheim, France Silvio Garattini Director, Institue de Ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, 20157 Milan, Italy Hanns Hippius Am Forst 4-A, 82166 Grafelfing, Germany John Hughes Director, Park-Davies Neuroscience Centre, Addenbrooke's Hospital, Hill Road, Cambridge CB2 2QB, UK Donald R Klein 1016 Fifth Avenue, New York NY 10028, USA Malcolm Lader Institute of Psychiatry, Clinical Psychopharmacology Section, De Cres pigny Park, Denmark Hill, London SE5 8AF, UK Heinz Lehmann 1212 Pine Avenue, Montreal, Quebec H39 1A9, Canada Brian Leonard Department of Pharmacology, University College, Galway, Republic of Ireland Herbert Meltzer Department of Psychiatry, Hanna Pavilion, 2040 Abingden Road, Cleve land, Ohio 44104, USA Pierre Pichot 24 rue de Fosses, Saint Jacques 75005 Paris, France Merton Sandler Department of Chemical Pathology, Queen Charlotte's Maternity Hospi tal, Goldhawk Road, London W6 OXG, UK Hannah Steinberg Health Research Centre, School of Psychiatry, Middlesex University, Queensway, Enfield EN3 4SF, UK Herman van Praag Professor and Chairman, Academic Psychiatric Centre, University ofLim burg, PO Box 616, 6200 MD Maastricht, The Netherlands Peter Waldmeier K-125,607, Ciba-Geigy Limited, Basle, Switzerland Preface The impetus to put this book together came from a number of sources. One was a need to do some research for a history of the period (see References). During the course of this, it became clear that others might also be interested in the raw material of the interviews and might have quite differing interpretations. The precipitating event was a train ride with George Beaumont from London to Guildford. This only takes an hour or so; just as the train pulled out, for whatever reason, I told George I'd been thinking about doing this and his story about how he targeted clomipramine for OCD was one of the ones I'd be interested to have. We looked at each other, I whipped out a tape recorder and we began the first interview. There are a number of interviews in the book that are almost verbatim as they were first recorded. George's is one of these. Another was Silvio Garattini's, which was done in the dark in the back of a taxi while travelling from Heathrow into London. Once a few had been done, the project just grew. There were a few things I was keen to chase, which didn't come out. One of these was an idea that science operates more often because of clashes of personality than anyone suspects. A good example involved the race for absolute zero, which happened between groups in England and Holland at the turn of the century. The English lost out because the two people who needed to cooperate with each other in order to produce a result, Ramsay and Dewar, weren't prepared to talk to each other. The psychoanalytic story, similarly, is a story of people coming to particular viewpoints almost to spite someone else rather than because of the intrinsic merits of their position. Now this may have to do with ambition and priority issues but you also have to check and see that things are not happening because of who stole whose wife, for instance. Indeed one of the wives put it to me that I might find out more about the history of psychopharmacology by interviewing the wives rather than the 'great men' themselves. There's something to be said for this. You can often gauge the real reaction to a person or an event from a spouse where the participant in the event has to inhibit their feelings because the game is ongomg. Part of the reason this kind of material didn't actually emerge may have x The Psychopharmacologists been that the people I've interviewed came out on top, so they have less need to recall these things. There was a reluctance or at least a caution about speaking ill of others. Nevertheless there are clashes buried in the interviews that can be traced by looking at who fails to cite whom, even when they worked in the same institution. And there have been very visible clashes, as in the discovery of the opioid peptides, recounted by John Hughes, and the story of the evaluation of lithium, which got fairly personalized. There have also been clashes around the foundation of ECNP, BAP and CINP, which seem to have involved the clash of person ality styles. Personality styles - or historical forces as expressed through personal ities? Another motive to do these interviews was that at the time I was the Secretary for the British Association for Psychopharmacology and I thought it would be a good idea to chase the origins of the BAP. Now at just this time, the Presidency of the BAP had become a hot political issue. For 20 years the question of who was going to be the next President had been a fix but in 1994, it was bitterly contested, with all sorts of personalized comments flying around and skullduggery that came close to being actionable. On one level, the issues were pitched as a battle between the fixers, who wanted to stitch things up behind the scenes, and those who wanted a transparent democracy. To my surprise, I found myself on the fixer side of the argument. This I think was because these things never come as single issues. Open democracy as I saw it was being linked to a particular view of how science operates, the classical idea that we should be system atically testing models, as opposed to a pragmatic 'let's fish' model. On this level the fishing model is much more open and democratic while the purist model can be something of a stitch-up - at least as I saw it then. Historically, psychopharmacology has been a pragmatic exercise, whereas neuroscience, which is springing forth, Athena-like from it, is classically principled. Add in the personality end of it and you have the historical dilemma of trying to decide how much of history is down to personalities - would we have had the Second World War without Hitler; would the Northern Ireland problem have been as bad without Paisley? Given that I was arguing for a position that in many respects was alien to me, I was left wondering how much we become the pawns of historical forces, which produce a situation in which people who would otherwise have a lot in common end up divided by deep animosities. I took these issues with me into many of the interviews - where are societies like the British Association and the American College for Neuropsychopharmacology situated today? What's going to happen them? The ACNP has thrown off a Society for Clinical Psychopharmacology and it's not clear how the BAP will evolve. In some ways, societies like the ACNP and BAP can act as the miner's canary for changes in the scientific atmosphere because they are relatively pure scientific societies, Preface XI rather than semi-trade unions like the American Psychiatric Association or the Royal College ofPsychiatrists. ACNP/BAP are shaped by completely different dynamics to the APA/RCP. Committee behaviour anywhere in my experience involves illusory intimacies between people who when the going gets difficult are usually more concerned to ensure that no one shouts too loud in case the neighbours are listening than they are about anything else. But because the preserve of professional turf is not on the agenda for BAP, in practice what happens is much less likely to be dictated by the actions of people who may be almost openly referred to as blustering bullies but whose behaviour cannot be or is not contained. Another reason for trying to put a history together can be to try to make sense of what has happened in one's own life. Having trained in medicine, I got involved in psychopharmacology research, partly for the not-very-elevated reason that it seemed a good idea in order to be able to get some control over the kind ofj obs I might want. The only research happening in Ireland in 1980 that seemed in any way relevant was with Brian Leonard- looking at what psychotropic drugs did to 5-HT reup take. At the time, it seemed that working on these drugs was one of the few serious ways into the brain and the mind and the inter-relationships between brain and behaviour. In my case, however, this led away from the now highly topical area of amine reuptake to work on circadian rhythms in affective disorders. I happen to think that a circadian model is much more persuasive than the amine theories ever were. There are coherent competing hypotheses to choose between - so it should be of interest to the purists but on the contrary the whole area has remained a backwater. The other area I've been involved in has been giving drugs to healthy human volunteers to test what effects these have on mental functioning with a view to working backwards from that to how the brain works - but the whole area is closing down it seems. It's difficult to get ethical committees or funding agencies to agree to projects even though the agents in question may have little more effect than, say, coffee. This seems to represent an important 'loss of nerve' and trying to trace the origins of this has been another reason to examine the history. To paraphrase Oscar Wilde, if one area of research you're involved in gets eclipsed, that's bad luck but if two do, you have to wonder what's going on. Fairly early in my 5-HT uptake career, it seemed to me that far from being descriptions of any reality, the amine theories were simply a case of the politically correct language - the language that had triumphed because you've got to have some view about what the drugs are doing. The psychodynamic theories were at a major disadvantage even though they were much more complex and subtle theories because they couldn't account for one of the obvious features of modern practice, which is that psychotropic drugs work. Even simplistic biological theories were better placed from that point of view. There have been tremendous advances

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