DRUGS AFFECTING 5-HT SYSTEMS The transcript of a Witness Seminar held by the History of Modern Biomedicine Research Group, Queen Mary, University of London, on 20 November 2012 Edited by C Overy and E M Tansey Volume 47 2013 ©The Trustee of the Wellcome Trust, London, 2013 First published by Queen Mary, University of London, 2013 The History of Modern Biomedicine Research Group is funded by the Wellcome Trust, which is a registered charity, no. 210183. ISBN 978 0 90223 887 9 All volumes are freely available online at www.history.qmul.ac.uk/research/modbiomed/ wellcome_witnesses/ Please cite as: Overy C, Tansey E M. (eds) (2013) Drugs Affecting 5-HT Systems. Wellcome Witnesses to Contemporary Medicine, vol. 47. London: Queen Mary, University of London. CONTENTS What is a Witness Seminar v Acknowledgements E M Tansey and C Overy vii Illustrations and credits ix Abbreviations xi Ancillary guides xiii Introduction E M Tansey xv Transcript Edited by C Overy and E M Tansey 1 Appendix 1 Pioneering research by SmithKline Beecham: 5-HT3 receptor antagonism and anti-emetic activity Professor Gareth Sanger 139 Biographical notes 141 References 159 Index 187 Witness Seminars: Meetings and Publications 203 WHAT IS A WITNESS SEMINAR? The Witness Seminar is a specialized form of oral history, where several individuals associated with a particular set of circumstances or events are invited to meet together to discuss, debate, and agree or disagree about their memories. The meeting is recorded, transcribed and edited for publication. This format was first devised and used by the Wellcome Trust’s History of Twentieth Century Medicine Group in 1993 to address issues associated with the discovery of monoclonal antibodies. We developed this approach after holding a conventional seminar, given by a medical historian, on the discovery of interferon. Many members of the invited audience were scientists or others involved in that work, and the detailed and revealing discussion session afterwards alerted us to the importance of recording ‘communal’ eyewitness testimonies. We learned that the Institute for Contemporary British History held meetings to examine modern political, diplomatic and economic history, which they called Witness Seminars, and this seemed a suitable title for us to use also. The unexpected success of our first Witness Seminar, as assessed by the willingness of the participants to attend, speak frankly, agree and disagree, and also by many requests for its transcript, encouraged us to develop the Witness Seminar model into a full programme, and since then more than 50 meetings have been held and published on a wide array of biomedical topics.1 These seminars have proved an ideal way to bring together clinicians, scientists, and others interested in contemporary medical history to share their memories. We are not seeking a consensus, but are providing the opportunity to hear an array of voices, many little known, of individuals who were ‘there at the time’ and thus able to question, ratify or disagree with others’ accounts – a form of open peer-review. The material records of the meeting also create archival sources for present and future use. The History of Twentieth Century Medicine Group became a part of the Wellcome Trust’s Centre for the History of Medicine at UCL in October 2000 until September 2010. It has been part of the School of History, Queen Mary, University of London, since October 2010, as the History of Modern Biomedicine Research Group, which the Wellcome Trust funds principally 1 See pages 203–208 for a full list of Witness Seminars held, details of the published volumes and other related publications. v under a Strategic Award entitled ‘The Makers of Modern Biomedicine’. The Witness Seminar format continues to be a major part of that programme, although now the subjects are largely focused on areas of strategic importance to the Wellcome Trust, including the neurosciences, clinical genetics, and medical technology.2 Once an appropriate topic has been agreed, usually after discussion with a specialist adviser, suitable participants are identified and invited. As the organization of the seminar progresses and the participants’ list is compiled, a flexible outline plan for the meeting is devised, with assistance from the meeting’s designated chairman/moderator. Each participant is sent an attendance list and a copy of this programme before the meeting. Seminars last for about four hours; occasionally full-day meetings have been held. After each meeting the raw transcript is sent to every participant, each of whom is asked to check his or her own contribution and to provide brief biographical details for an appendix. The editors incorporate participants’ minor corrections and turn the transcript into readable text, with footnotes, appendices and a bibliography. Extensive research and liaison with the participants is conducted to produce the final script, which is then sent to every contributor for approval and to assign copyright to the Wellcome Trust. Copies of the original, and edited, transcripts and additional correspondence generated by the editorial process are all deposited with the records of each meeting in the Wellcome Library, London (archival reference GC/253) and are available for study. For all our volumes, we hope that, even if the precise details of the more technical sections are not clear to the non-specialist, the sense and significance of the events will be understandable to all readers. Our aim is that the volumes inform those with a general interest in the history of modern medicine and medical science; provide historians with new insights, fresh material for study, and further themes for research; and emphasize to the participants that their own working lives are of proper and necessary concern to historians. 2 See our Group’s website at http://www.history.qmul.ac.uk/research/modbiomed (visited 13 August 2013). vi ACKNowlEDGEMENTS The topic of ‘Drugs affecting 5-HT systems’ was suggested as a Witness Seminar by Professor Paul Andrews and Professor Gareth Sanger and we are grateful for their assistance over several months in planning the meeting. Our thanks also go to Professor Rod Flower for his excellent chairing of the occasion, and to Dr Patrick Humphrey for providing images and documents to illustrate the volume. As with all our meetings, we depend a great deal on Wellcome Trust staff to ensure their smooth running: the Audiovisual Department, Catering, Reception, Security and Wellcome Images. We are also grateful to Mr Akio Morishima for the design and production of this volume; the indexer Ms Liza Furnival; Mrs Lois Reynolds and Ms Fiona Plowman for proof reading; Mrs Deborah Gee for transcribing the seminar; Mr Adam Wilkinson for assisting in the organization of the meeting and also Ms Emma Jones and Mr Alan Yabsley for help with running the seminar. Finally, we thank the Wellcome Trust for supporting this programme. Tilli Tansey Caroline Overy School of History, Queen Mary, University of London vii ILLUSTRATIONS AND CREDITS* Figure 1 Professor Rod Flower and Professor Tilli Tansey 3 Figure 2 Dr Mick Bakhle 6 Figure 3 Professor David Wallis 9 Figure 4 Dr Patrick Humphrey 14 Figure 5 Professor David Clarke, Professor Daniel Hoyer, Professor Richard Green and Dr Tom Blackburn 16 Figure 6 Professor Gareth Sanger 19 Figure 7 Professor Merton Sandler and Professor Charles Marsden 21 Figure 8 Dr Tom Blackburn 23 Figure 9 Professor David Clarke 35 Figure 10 Some members of the 5-HT meeting held on Heron Island, Australia, indicating the number of 5-HT receptor subtypes they believed existed. Photograph provided by Dr Patrick Humphrey 36 Figure 11 Professor Gavin Reynolds 40 Figure 12 Classification of peripheral 5-HT (serotonin-S) receptors. Glaxo Group Research Report, 1983, authored by Dr Patrick Humphrey 42 Figure 13 Poster advertising the 5-HT meeting held on Heron Island, Queensland, Australia, in September 1987. Poster provided by Dr Patrick Humphrey 44 Figure 14 Professor Gavin Reynolds and Professor Charles Marsden 54 Figure 15 Mr Wesley Miner 60 * Unless otherwise stated, all photographs were taken by David Sayer, Wellcome Trust, and reproduced courtesy of the Wellcome Library, London. ix Figure 16 Professor Paul Andrews 62 Figure 17 Professor Paul Andrews and Dr Mike Tyers 66 Figure 18 Professor David Clarke and Professor Alberto Kaumann 69 Figure 19 Dr Colin Dourish 75 Figure 20 Dr Jackie Hunter 76 Figure 21 Professor Gerald Curzon 78 Figure 22 Dr Jeffrey Aronson 92 Figure 23 Professor Helen Cox 98 Figure 24 Professor Phillip Cowen 116 Figure 25 Participants at the Witness Seminar 137 Table 1 Outline programme for ‘Drugs affecting 5-HT Systems’ Witness Seminar 5 Table 2 A summary of the organization of clinical trials. Adapted from: www.clinicaltrials.gov/ct2/info/ glossary (visited 5 June 2013), and reprinted from Reynolds and Tansey (eds) (2008), page 10. 111 Table 3 The top psychiatric medicines prescribed in 2011 using information from the British National Formulary and 2011 prescription data from Lindsley (2012), page 631. 126 ABBREVIATIONS 5-H1AA 5-Hydroxyindoleacetic acid 5-HT 5-hydroxytryptamine 5-HTP 5-Hydroxytryptophan BDNF Brain-derived neurotrophic factor BPS British Pharmacological Society cAMP Cyclic adenosine monophosphate / cyclic AMP CNS Central Nervous System COPD Chronic obstructive pulmonary disease DHE Dihydroergotamine EEG Electroencephalography FDA Food and Drug Administration, US GABA Gamma-aminobutyric acid GI Gastrointestinal GPCR G protein-coupled receptor