An oral history of neuropsychopharmacology

НазваниеAn oral history of neuropsychopharmacology
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Peer Interviews

Volume Eight: Diverse Topics

Copyright © 2011 ACNP

Thomas A. Ban (series editor)


Carl Salzman (volume editor)


All rights reserved. No part of this book may be used or reproduced in any manner without written permission from the American College of Neuropsychopharmacology (ACNP).

Library of Congress Cataloging-in-Publication Data

Thomas A. Ban, Carl Salzman (eds):

An Oral History of Neuropsychopharmacology: The First Fifty Years, Peer Interviews

Includes bibliographical references and index



1. Neurospychopharmacology. 2. Glutamate 3. Neuropeptides.

4. Prostaglandins 5. Psychotropic drug development

6. Education in psychopharmacology

Publisher: ACNP

ACNP Executive Office

5034A Thoroughbred Lane

Brentwood, Tennessee 37027




Cover design by Jessie Blackwell; JBlackwell Design




Peer Interviews

Edited by

Thomas A. Ban


Volume 1: Starting Up - Edward Shorter

Volume 2: Neurophysiology - Max Fink

Volume 3: Neuropharmacology - Fridolin Sulser

Volume 4: Psychopharmacology - Jerome Levine

Volume 5: Neuropsychopharmacology - Samuel Gershon

Volume 6: Addiction - Herbert D. Kleber

Volume 7: Special Areas - Barry Blackwell

Volume 8: Diverse Topics - Carl Salzman

Volume 9: Update - Barry Blackwell

Volume 10: History of the ACNP - Martin M. Katz






Carl Salzman



Thomas A. Ban

Dedicated to the Memory of Milton Greenblatt, President ACNP, 1964.


Thomas A. Ban

In each of the first seven volumes in this series interviewees reflect on their contributions to a particular area of research in neuropsychopharmaclogy.1 Thus, in each volume the story of nneuropsychopharmacology is told from a different perspective. In Volume Eight, interviewees talk about their contributions on diverse topics. Presentation of these many stories does not focus on any particular area of research. Yet, the volume as a whole mirrors the changes which have taken place in the entire field in fifty years.

The Preface to Volume Eight also differs from the Preface to the other volumes. In all other volumes the first part of the Preface provides background information to interviewees’ research contributions, placing the contributions into a historical context. For the interviews` in Volume Eight such background information may be found in prior volumes. Instead, in the first part of the Preface, the larger framework of the development in neuropsychopharmacology that has been the subject of this series is discussed.


One of the essential prerequisites for neuropsychophamacological research is the availability of psychotropic drugs with known therapeutic effects. During the 1950s several drugs were introduced by the pharmaceutical industry for the treatment of schizophrenia, depression, mania and anxiety disorders. Yet, it was not before the 1960s that approval of drugs for specific indications in clinical use, based on demonstrated efficacy, became a requirement in the United States.

The first Pure Food and Drug Act in the United States, was introduced in 1906,1 but until the early sixties all regulations were related to safety requirements, and to the separation of prescription drugs from over the counter medications. The scope of legislation was extended in 1962 with the enactment of the Kefauver-Harris Amendment (KHA),2 which stipulated that: the effectiveness as well as the safety of a new drug has to be established before the drug is released for clinical use.2

Extension of the legislation from proof of safety to efficacy has had a major impact on clinical research with psychotropic drugs. It has also led to the implementation of structured clinical drug development in three successive phases. Phase I, “human pharmacology” starts when the new drug is first given to man, usually to normal subjects. Its purpose is the determination of the drug’s preferred route of administration and safe dose range. Phase II, “clinical pharmacology” includes the initial clinical trials for the treatment of a specific disease, or prophylactic purposes. Phase III, “clinical investigation” provides information on the efficacy, safety, optimum dose range and schedule of administration of the drug.

The single, most important influence on pharmacotherapy is the regulation that defines the requirements for approval of a new drug on prescription. To meet requirements of the US Food and Drug Administration (FDA), a drug must show a statistically significant difference (superiority) to placebo in two pivotal double-blind, randomized clinical trials which are of adequate sample size and statistical power. Furthermore, to meet the requirement that an ineffective or unsafe drug could be removed, the three-phase clinical development was supplemented with drug surveillance (Phase IV).

A resolution of the National Advisory Health Council in 1965 led to the establishment of Institutional Review Boards (IRBs). It also also helped build the clinical framework in which research with psycotropic drugs, operates. IRBs are to approve proposed research.Their primary objective is to ensure the safety of experimental subjects (ES) involved in the research. In 1966, the Surgeon General of the United States issued a policy statement in which various methods were listed to safeguard humans involved in National Insitutes of Health (NIH) or more generally Public Health Service (PHS) supported research. Special policies were formulated for controlled experiments.

In 1966 the FDA amended its regulation with a statement of policy formulated by Goddard. The “Goddard Amendment” stipulated that whenever an investigational drug is used in human beings the investigators should obtain informed consent from the ES.3 At the time the Goddard amendment was introduced it served exclusively the protection of patients but by the time of the 1980s it became a protective shield (from litigation) for studying new drugs developed by drug companies. The amendment has had an impact on breaking the old paternalistic style of doctor–patient relationship. It also opened the path for “medical ethics” to play a steadily increasing role in medical universities.


Human experiments have been instrumental in the development of medical skills. Yet, until the mid-20th century human experiments were not controlled by legislation but by the informal code of approval of the scientific fraternity. In the middle of the19th century, Claude Bernard, in his Introduction to Experimental Medicine, asserted that “it is the duty and the right of the physician to perform an experiment on man whenever it can save his life, cure him, or gain him some personal benefits”. But, Bernard also insisted on “never performing on man an experiment which might be harmful to him to any extent, even though the result might be highly advantageous to science”.4 The first systematic presentation of the ethics on experimentation in humans was drawn up by the Nuremberg Military Tribunal after World War II, and published in 1947, in a legal document, the Nuremberg Code. The gist of the “laws” incorporated in this document are: (1) the ES must give voluntary (informed) consent prior to being included in an experiment; (2) the experiment should yield fruitful results for the good of society, and its results should not be attainable by any other means; (3) the experiment must be based on prior animal studies and knowledge of the natural history of the disease; (4) the degree of risk involved in the experiment should not exceed the potential benefits of the research for society; (5) the ES should be at liberty to bring the experiment to an end.5

The principles of the Nuremberg Code were revived in 1955 by the United Nations Third Committee on Social, Humanitarian and Cultural Questions, and incorporated in 1964 in the Helsinki Declaration (HD), based on the Declaration of Geneva of the World Medical Association, and the International Code of Ethics. The Helsinki Declaration emphasizes that the “responsibility for clinical research always remains with the research worker,” and “it never falls on the (experimental) subject”.6 The Declaration has been endorsed by several nations and numerous medical associations; the Judicial Council of the American Medical Association recommended its adoption in 1966 at the annual convention of the Association. .

During the second half of the 20th century clinical studies with psychotropic drugs have become a large component of research in which human subjects are involved. To meet fully the obligations of ethical conduct, the “fruitful results for the good of society,” must be disseminated, and integrated with the existing body of knowledge. Within our societal structure, it is the task of marketing to disseminate the findings in clinical research, and it is the responsibily of education to integrate the new information with existing knowledge.

Marketing & Education

In the l950s, the pharmaceutical industry was not ready for the dissemination of the rapidly growing body of information on psychotropic drugs. (See, Berger Volumes 3 & 9.) Means of communication were scarce. The first journal in neuropsychopharmacology, Psychopharmacologia,7 was launched n 1958 by Ernst Rothlin, the founding president of CINP, and Abraham Wikler, and the second, International Journal of Neuropharmacology,8 (now, Neuropharmacology), was founded in 1961 by Bernard Brodie, Erminio Costa, Silvio Garattini, and Corneille Radouco-Thomas, one of the founders of CINP, with Costa and Radouco-Thomas, as founding editors-in-chief. (See, Costa Volume 7 and Garattini Volume 3.) In 1966, to overcome the difficulties in communication of information on psychotropic dugs, a World Health Organization Scientific Group on Research in Psychopharmacology recommended the development of an International (Collaborative) Reference Centers Network in Psychopharmacology (IRCNP). The IRCNP was launched in 1968 with regional and national reference centers around the world; its activities were coordinated by Alice Leeds from the Psychopharmacology Research Branch of the NIMH in Rockville.9,10 Supported by NIMH, IRCNP published and distributed its journal, the Psychopharmacology Bulletin, with free copies to Universities. It also compiled an International Directory of Investigators in Psychopharmacology, including their names, addresses, affiliations and field of research, and developed an index card system for the collection of data on the efficacy, safety and mechanism of action of psychotropic drugs.11 In the same year as IRCNP was launched, the first data bank for clinical investigations was established in Washington DC, at George Washington University. (See, Preface Volume 4 and Overall Volume 4.)

As time passed, industry developed the necessary marketing arms required to disseminate the information about their psychotropic drugs. By the 1980s the IRCNP withered away.

The objective of industrial marketing is to capture the largest possible market for a substance, by persuading physicians to prescribe the drug. Industry is free to support research in order to generate findings that would attract attention to a substance or trigger speculations about possible advantages in prescribing it. The only limitation of marketing is that it has to adhere to the labelling and advertising approved by the FDA in the United States. Yet, by sponsoring studies using eletrophysiological, biochemical, neuroimaging, molecular genetics, and other advanced technologies in psychiatry, industrial marketing has had a major impact on the development of neuropsychopharmcology. It was also instrumental in transforming psychiatry, dominated by psychodynamics in the United States, into a medical discipline. Without this support, the replacement of the old cadre of psychoanalysts, with neuropsychopharmacologists, at the helm of psychiatric departments could not have taken place.

Parallel with the changes in Psychiatry, the role of psychiatrists in the drug industry has changed from advisors on issues which required psychiatric knowledge in the 1960s and ‘70s, to leaders of teams that generate the evidence in clinical investigations for regulatory approval of drugs in the 1980s. . By the 1990s, psychiatrists working in the employment of industry were moving back and forth between industry and academy. They had become key players in the generation of information on which both, education in pharmacotherapy and marketing of psychotropic drugs, is based.

The signal difference between marketing and education is that marketing is focused on a drug with the objective of getting a particular product prescribed, whereas education is focused on the patient with the objective of selecting for each individual the optimal treatment by the discriminate use of available drugs. While sophisticated marketing tries to guide physicians to prescribe a particular product or give preference to a group of products in treatment, proper education equips physicians with the know-how to evaluate and integrate new information with the existing body of knowledge. At the core of education is the the translation in information from preclinical research, which sets the stage for the clinical development of a psychotropic drug, and from clinical investigations upon which the prescribing of the drug in clinical practice is based. In the evaluation of pre-clinical information the focus is on the separation of findings from interpretations. Findings are established relationships between research results in different areas of the field usually derived by hypotheses testing, whereas interpretations are assumed relationships prone to the fallacies of formal logic. In the evaluation of clinical information, the focus is on the recognition of the clinically relevant findings hidden behind satistically sigificant results. Without information on the “effect size,” “t” values, response rates, etc., the “p” values 12 of statistical analyses indicate only the level of confidence, the probability that there is a treatment responsive group within the population studied. (See, Preface Volume 4.)

A division of labour has evolved in clinical drug development during the past fifty years. It is based on a model in which it is the task of (governmental) regulatory bodies to ascertain that the drug released for clinical use is effective and safe, relative to the risk of the disease itself; the task of industrial marketing is to disseminate information on the drug and to generate interest in prescribing it; and the task of (academic) education is to provide the necessary teaching so that the drug is prescribed in a discriminative manner. The confounding of roles and functions in this model has led to conflicts of interest and interfered with the optimal use of psychotropic drugs. It also interfered with the development of rational pharmacological treatment for psychiatric disorders.

Conflict of Interest

Prior to the 1980s, little attention was paid to “conflict of interest” in science and medicine.13,14 At present authors, in most medical journals, and speakers, at most medical conferences, are required to disclose their financial involvement with the pharmaceutical industry.15 By focusing on financial motivation current policies have distracted attention that in neuropsychopharmacology, a discipline in which pharmacological homogeneity of psychiatric populations is prerequisite for progress, the conflicting motivations (objectives) of marketing with education has interfered with the development of rational pharmacological treatment.

. Introduction of psychotropic drugs, during the 1950s, focused attention on the pharmacological heterogeneity within psychiatric diagnoses.16 There was a need to resolve this heterogeneity by developing a pharmacologically valid classification of mental illness.17 To date, this has not happened..18 Instead, to meet marketing needs, the randomized clinical trial was adopted for the demonstration of efficacy in pharmacologically heterogeneous diagnostic populations.19 The problem became compounded in the early 1990s, with the replacement of single-center isolated clinical studies by multi-center centrally coordinated clinical investigations. Many of these studies are designed for the purpose of registration by regulatory authorities and for supporting possible advantages of new drugs. Moreover, the data collected in most of these studies are propriety and communication, based on analyses of these data, is controlled by sponsoring drug companies. Since the findings of this research provide the evidence base for both, marketing and education, by the end of the 20th century, information related to the pharmacotherapy of mental illness has become controlled by the drug industry.

Today, most “evidence-based” information is generated in multi-center studies and serves the purpose of guiding physicians to prescribe one or another psychotropic drug, or group of drugs. Treatment guidelines, prepared by opinion leaders and endorsed by professional societies are no exceptions.20 By disqualifying papers from the first thirty years of pharmacotherapy on grounds of methodological shortcomings, and summarizing findings in studies designed to create a market niche for each newly introduced drug , guidelines, task force reports, and experts’ reviews inadvertently justify the preferential prescription and inclusion in national drug formularies the newest and most expensive drugs.21

The blurring of education and marketing in the communication of “evidence-based” information has encouraged educators in pharmacotherapy to pursue activities in conflict with their fiduciary interest. Addressing violations which arise from this confound as ethical, distracts attention from the heart of the issue that until the pharmacological heterogeneity within the diagnostic groups is resolved pharmacotherapy, with psychotropic drugs will remain prone to one sided, marketing input and interests. Furthermore, with pharmacologically heterogeneous diagnoses the pharmacodynamic information generated by neuropharmacological research can be related only to the side effect profile of psychotropic drugs.

It is within this framework that the research and educational activities of interviewees took place in Volume Eight and in all other volumes of this series. .

Interiewees & Interviewers

Volume 8 includes transcripts of 24 videotaped biographic interviews with 19 psychiatrists, 2 basic scientists (Koslow and Maickel), one neurologist (Kleinman), one internist/clinical pharmacologst (Ackenheil), and one clinical psychologist (Frank). All but two of the interviewees (Ceskova and Gaszner) are affiliated with ACNP; and five (Charney, Coyle, Davis, Nemeroff and Shader) are past-presidents of the College.

The interviews were conducted in a period from 1997 to 2008, and with the exception of two, at the annual meeting of the College. One of these two interviews, Ceskova’s was done at CINP’s biennial Congress in Paris (France), and the other, Shader’s was conducted at Tufts University (his work place,) in Medford, Massachusetts.

The 24 interviewees were interviewed by 13 interviewers. Eleven of the interviewers are peers of the interviewees, and 2, Braslow and Tone, are medical historians. (Braslow is also a psychiatrist.) From the 13 interviewers, 4 conducted more than one interview: Tone conducted seven, Ban four, and Hollister and Bunney two each.

By the time the editing of Volume Eight was completed, 3 of the interviewees (Ackenheil, Maickel and Tollefson), and 1 of the interviewers (Hollister) passed away.

Contributions of Interviewees

Four of the interviewees (Ackenheil, Maickel, Cole and Koslow) are first, second and third generation representatives of
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