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This book is dedicated to
HELGA INGRID HEIDE
Preface to Third Edition ix
Preface to Second Edition xi
Preface to First Edition xiii
1 Functional Neuroanatomy of the Brain 1
2 Basic Aspects of Neurotransmitter Function 15
3 Pharmacokinetic Aspects of Psychopharmacology 79
4 Clinical Trials and their Importance in Assessing the Efficacy and Safety of Psychotropic Drugs 101
5 Molecular Genetics and Psychopharmacology 113
6 Psychotropic Drugs that Modify the Serotonergic System 133
7 Drug Treatment of Depression 153
8 Drug Treatment of Mania 193
10 Drug Treatment of Insomnia 241
12 Drug Treatment of the Epilepsies 295
13 Drug Treatment of Parkinson's Disease 319
14 Alzheimer's Disease and Stroke: Possible Biochemical Causes and Treatment Strategies 341
15 Psychopharmacology of Drugs of Abuse 375
16 Paediatric Psychopharmacology 417
17 Geriatric Psychopharmacology 425
18 The Inter-relationship Between Psychopharmacology and Psychoneuroimmunology 431
19 Endocoids and their Importance in Psychopharmacology 445
Appendix 1 Some Important Psychotropic Drug Interactions 459
Appendix 2 Glossary of some Common Terms Used in Psychopharmacology 463
Appendix 3 Generic and Proprietary Names of Some
Common Psychotropic Drugs 483
Appendix 4 Key References for Further Reading 489
The second edition of Fundamentals of Psycho/pharmacology was published in 1996 and therefore a thorough revision of the text became essential. This revision has taken me much longer than originally anticipated because I soon came to realize that every chapter would require a thorough reassessment. Retrospectively it would have been easier to have written a completely new book, but hopefully this edition will be a compromise between the style of the previous editions and the requirement to include increasingly complex concepts with the inclusion of molecular neuro-biology and molecular genetics. In attempting to make such areas accessible to the non-specialist neuroscientist and clinical psychiatrist, I hope I have managed to accurately interpret the areas in which I have no specialist knowledge.
Besides thoroughly revising every chapter contained in the second edition, I have added a new short chapter on clinical trials of psychotropic drugs. The methods used to determine the efficacy and safety of new psychotropic drugs are becoming of major importance and now have an impact on all areas of medicine. I hope that this chapter will help to fill the gap that occurred in the earlier editions of the text. I have also broadened the final chapter to discuss the role of endogenous factors (the endocoids) that might play a crucial role in psychiatric disorders. Besides the endogenous opioids, it is now apparent that cannabinoids, benzodiazepine ligands and various neuropeptides (such as the sleep factor) may play a fundamental role not only in the psychopathology of the various disorders but also in the mechanisms whereby psychotropic drugs act.
As in the previous editions, I have been guided by the need to integrate the various areas of psychopharmacology. It is my belief that the neurosciences, like most branches of medicine, have become too fragmented into their specialist areas so that their important impact in our understanding of the whole organism (whether animal or man) is lost. The brain is not just a collection of cells that function in a tissue culture and genes are not independent, deterministic entities that function independently of their environment. Neither is it sufficient to classify psychiatric disorders by diagnostic criteria, quantified by esoteric rating scales, without seriously considering the biological components that contribute to the nature of the behavioural disorder. Perhaps it is time to return to a more integrated and dialectical approach to the basic and clinical neurosciences.
The revision of the third edition largely occurred between January 2002 and January 2003. Despite my early retirement as Head of the Pharmacology Department in 1999, I have found even less time to devote to writing a textbook than I did during my years as a full-time academic. Nevertheless, I am eternally grateful to the numerous students and colleagues who, over the past 4 years, have continued to stimulate my interest and excitement in the neurosciences and helped me to expand, and hopefully improve, this textbook. Special thanks must go to CNS forum (which has been supported by the Lundbeck Foundation, Skodsborg, Denmark), for permission to use several of the figures used to illustrate this edition.
I wish to give thanks in particular to Dr Brian O'Shea of Newcastle Hospital, Co. Wicklow, for the care and attention he gave in pointing out some of the errors in the second edition of the text. My thanks are also due to Charlotte Brabants of John Wiley and Sons Ltd, for her encouragement and regular e-mails to ensure that, though overdue, the third edition did materialize. Lastly, I again thank my wife for her support and understanding of my obsession with the brain, behaviour and the psycho-pathology of mental illness.
Brian E. Leonard
Emeritus Professor of Pharmacology National University of Ireland, Galway
The first edition of Fundamentals of Psychopharmacology was completed five years ago and, due to the major advances which have been made in the subject in the intervening years, a thorough revision of the text was necessary. Unfortunately, I did not have the privilege of a sabbatical leave on this occasion to rewrite all the chapters that would ideally be necessary. However, I have tried to compromise by adding several new chapters (on molecular genetics and functional neuroanatomy for example) and to revise intensively those areas (such as the antidepressants, antipsychotics and the importance of serotonin in psychiatric illness) that have undergone major advances in the intervening five years. In addition, I have added two chapters that hopefully will give a flavour to the development of psychopharmacology in the 21st century. One of these deals with the growing area of psychoimmunology and its importance in integrating the immune, endocrine and neurotransmitter systems with behaviour. The second area concerns the role of the enigmatic sigma receptors that appear to play a role in modulating the immune, endocrine and neurotransmitter systems.
Despite my best intentions, I am aware of the deficiencies and limitations that still exist in this volume. I have tried to correct the numerous minor errors in the first edition which undoubtedly reflected my lax proof reading. In this respect I wish to express my sincere thanks to the numerous friends and colleagues who took the time to comment on the strengths and deficiencies of the first edition. Hopefully, the second edition has remedied the more glaring errors and omissions. In producing the second edition, my intention has been to keep the volume as concise as possible without compromising on the accuracy of the contents.
The last five years have seen the publication of numerous excellent texts and monographs in psychopharmacology, many of which are mentioned in the bibliography. Hopefully, the second edition of Fundamentals of Psychopharmacology will generate sufficient enthusiasm for the reader to be encouraged to delve more deeply into the subject.
The revision of the second edition largely occurred between April and October 1996. As with the first edition, I am particularly indebted to the staff and postgraduate students of the Department of Pharmacology for their help and encouragement for this venture. In particular, I wish to express sincere thanks to my secretary Marie Morrissey for her help in processing some of the new text, to Ambrose O'Halloran for his assistance with all the technical aspects of my word processing, diagrams, etc. and to Dr John Kelly who enabled me to dedicate time and energy to writing by taking over the organization of the research group and many of my departmental activities. Several of the post-doctoral students from the department have also indirectly contributed to the ideas which have been incorporated into the second edition. In particular I wish to thank Maeve Caldwell, Bernadette Earley, Mairead McNamara, Anna Redmond, Cai Song, Alan O'Connell and Michael O'Neill. Michael Davis and Hilary Rowe of John Wiley and Sons have been a constant source of encouragement and monthly faxes to ensure that the second edition materialized. Lastly, I thank my long-suffering wife for having endured yet another period of physical and mental absence from our domestic life while I remained obsessed with the fascination of receptors, ion channels and the biochemistry of the brain.
Department of Pharmacology
This textbook started life some ten years ago as a collection of lecture notes in neuro- and psychopharmacology. These notes were produced in response to the needs of the undergraduate medical students and postgraduates studying for membership examinations at University College Galway and at the Muhibili Medical Centre, University of Dar es Salaam, where I was involved for several years in teaching under the auspices of an Irish Development Aid programme. Clearly the time had come to completely rewrite the lecture notes or to produce a proper textbook.
The problem was partly solved by my election as a visiting Fellow at Magdalen College, Oxford, during my sabbatical year 1990-1991, and I am particularly grateful to the Fellows of Magdalen College for having given me this opportunity. The access to the Radcliffe Science Library and the tranquillity of life in Magdalen College provided the ideal setting for this undertaking. Whether the pleasure I achieved in writing this text is reflected in the quality of its content is for the reader to judge. One thing is certain, without the support of Dr Jim O'Donnell and the postgraduates and staff of my department in Galway, who undertook many of the vital teaching and administrative duties during my year of absence, the completion of the textbook would have been impossible.
I am particularly grateful to my secretary, Marie Morrissey, for her dedication and determination to ensure that my appallingly bad word-processing was made intelligible to the reader. Ambrose O'Halloran not only taught me what little I know about word-processing but also had the patience and creativity to convert my illiterate sketches of chemical formulae and anatomical drawings into comprehensible figures. Without his enthusiastic support for this project, I am certain that the text would have been even more mediocre!
My colleagues Drs Ted Dinan and Veronica O'Keane of the Department of Psychiatry, Trinity College, Dublin, kindly offered to read critically the penultimate draft of the text. Their contribution was crucial in highlighting the errors, inconsistencies and lack of clarity in the draft. Their time and energy in helping to improve the text is gratefully acknowledged. Any errors and omissions that remain are, of course, entirely the responsibility of the author!
Michael Davis of John Wiley and Sons has also given invaluable support during the gestation of the text and made many useful suggestions regarding its content.
Finally I express my thanks to my long-suffering wife for having endured my obsessional preoccupation with this enterprise and with my physical and mental absence from our domestic life for the past year.
My sincere wish is that you, the reader, will look upon this modest contribution as merely an introduction to the exciting world of psychopharmacology. Your comments and criticisms will be particularly welcome.
Department of Pharmacology
The pain and suffering of those with major psychiatric illness has been appreciated since the dawn of civilization. For over 5000 years, drugs have been used in an attempt to alleviate the suffering of such patients. There is evidence that the Sumerians in the Tigris-Euphrates valley were aware of the mood-elevating effects of the juice of the opium poppy and cultivated these plants for that purpose. The potent analgesic effect of opium was well known to the inhabitants of Asia Minor, Cyprus, Mycenae and Egypt 2000 years BC. Indeed it should not be forgotten that opiates were still being used in the 19th century to relieve depression.
Other plants known to contain psychoactive compounds include hellebore, which was used for centuries in Europe to treat mania, violent temper, mental retardation and epilepsy. However, a drug of major importance in modern psychopharmacology arose from the discovery by medicinal chemists of the alkaloids of Rauwolfia serpentina, a root which had been used in the Indian subcontinent for centuries, not only for the treatment of snake bite but also for alleviating ''insanity''. Understandably, the mechanism of action of reserpine, the alkaloid purified from Rauwolfia serpentina, helped to lay the basis to psychopharmacology by demonstrating how the depletion of central and peripheral stores of biogenic amines was correlated with a reduction in blood pressure and tranquillization.
An unexpected discovery also arose during the therapeutic use of reserpine in the treatment of hypotension when it was found that approximately 15% of patients became clinically depressed. As it has been shown that reserpine depletes both the central and peripheral nervous system of noradrenaline, it was postulated that depression would be a consequence of the defective synthesis of noradrenaline and possibly serotonin. This helped to form the basis of the amine therapy of depression.
It is interesting to note that one of the founders of modern psychiatry, Kraepelin, listed only nine substances that were available for the treatment of psychiatric illness in the 1890s. These were: opium, morphine, scopolamine, hashish, chloral hydrate, a barbiturate, alcohol, chloroform and various bromides. Later Bleuler, another founder of modern psychiatry, added paraldehyde and sodium barbitone to the list. Thus psychopharmacology is a very recent area of medicine which largely arose from the chance discovery of chlorpromazine by Delay and Deniker in France in 1952, and of imipramine by Kuhn in Switzerland in 1957.
Although the chemical structure of the benzodiazepines was first described by Sternbach in the 1930s, the clinical efficacy of these anxiolytics was only fully realized following a clinical trial of chlordiazepoxide by Harris in the USA in 1960.
The purpose of this book is to give the basic neuroscientist and the psychiatrist an overview of psychopharmacology, that branch of pharmacology which is concerned with the study of drugs used to treat mental illness. The scope of the subject also covers the use of drugs and other chemical agents as tools that enable the researcher to investigate how the brain functions. This is one of the most rapidly advancing fields of medicine and therefore any short textbook on the subject is bound to omit many aspects which are fundamentally important.
Nevertheless, based on several years of experience teaching psychophar-macology to undergraduates and to postgraduate clinicians studying for their membership examination for the Royal College of Psychiatrists, I have tried to emphasize the practical advantages of understanding how psychotropic drugs work, not only because this may lead to an improvement in their therapeutic use but also that their side effects may be predicted. A brief glance through this book will persuade the reader that this is not a ''cook-book'' containing proprietary drug names, doses and a list of side effects. Neither have I attempted to give anything but a brief synopsis of the clinical features of the psychiatric illnesses for which the psychotropic drugs are used. There are many good texts available that cover clinical aspects of psychiatry and most countries have produced excellent formularies to provide practising clinicians with a summary of the therapeutic uses and side effects of the psychotropic drugs in common use. I hope that the reader will not only gain some insight into psychopharma-cology as a result of this text but, more importantly, that it will enable the basic and clinical neuroscientist to better understand how the brain works in health and disease.
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