American College of Neuropsychopharmacology

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

THE FIRST FIFTY YEARS

Peer Interviews

Volume Nine: Update

Thomas A. Ban (series editor)

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

Barry Blackwell (volume editor)

VOLUME 9 UPDATE

Library of Congress Cataloging-in-Publication Data

Thomas A. Ban, Barry Blackwell (eds):

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

Includes bibliographical references and index

ISBN-

1. Neurospychopharmacology 2. Pharmacogenetics

3. Molecular genetics and neuropsychopharmacology

4. Psychopathology 5. Psychiatric nosology

Publisher: ACNP

ACNP Executive Office

5034A Thoroughbred Lane

Brentwood, Tennessee 37027

U.S.A.

Email:

Website: www.acnp.org

Cover design by Jessie Blackwell; JBlackwell Design www.jblackwelldesign.com

AMERICAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

THE FIRST FIFTY YEARS

Peer Interviews

Edited by

Thomas A. Ban

Co-editors

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

VOLUME 9

UPDATE

ACNP

2011

VOLUME 9

BARRY BLACKWELL

UPDATE

Preface

Thomas A. Ban

Dedicated to the Memory of Nathan S. Kline, President ACNP, 1967.

PREFACE

Thomas A. Ban

In the first eight volumes of this ten-volume series, interviewees reflect on their contributions to the development of neuropsychopharmacology.[(] Volume Nine (Update) differs from all prior volumes in that it includes a second interview that complements and updates the information in the first interviews. These second interviews were not planned. They were done on request of the interviewees or others, most often for adding to the information covered in the first interviews.

In Volume Nine, interviewees contributed to diverse areas of research in neuropsychopharmacology. Hence, in the same way as in Volume Eight (Diverse Topics), the information in the transcripts provides the prime material for an overview of the changes which have taken place in neuropsychoharmacology since the 1950s.

During its first fifty years neuropsychopharnmacology was a rapidly moving field. In the 1960s behavioral pharmacology (see, Volume 1) was replaced by neuropharmacology (see, Volume 3) in the screening and preclinical development of psychotropic drugs. In the 1970s, research in neuropharmacology was extended from cerebral monoamines to neurotransmitter modulators, peptides and prostaglandins; interest shifted from pre-synaptic to post-synaptic mechanisms; and studies of neurotransmitter biochemistry were supplemented with studies on receptor affinities.[1] In the 1980s electrophysiological studies were complemented by studies of brain metabolism with the employment of brain imaging (see, Volume 2) and research studies on the effect of drugs on “wiring transmission” by studies on the effect of drugs on “volume transmission.”[2], [3] (See, Fuxe Volume 3.)

In the 1990s, with the sequencing of the human genome from 1989 to 2004,[4] a molecular genetic (pharmacogenetic) approach emerged and in a decade replaced the “traditional” biochemical approach in the study of the biology of mental illness. By the dawn of the 21st century, the neurotransmitter era, the first epoch in the history of neuropsychopharmacology was succeeded by a molecular genetic era, opening up a new perspective for developing psychotropic drugs.

The subject matter of this volume is the charting of this rapid transformation of the field in the thoughts, writings and research of the interviewees.

As in all prior volumes in this series, the first part of the Preface provides orientation points for placing interviewees’ contributions into a historical context and the last part reviews personal contributions. Although there are some overlaps, the vignettes in this volume on interviewees’ contributions differ from the vignettes in prior volumes In Volume Nine the vignettes are based primarily on what interviewees themselves consider their most important contributions to neuropsychopharmacology, whereas in the other volumes they are based on editor’s judgment about interviewees’ contributions to the particular area of research covered in the volume. Another difference is that in Volume Nine, special attention is paid to early and most recent contributions.

Pharmacogenetics[5]

The term “pharmacogenetics”, was coined by Friedrich Vogel in 1959,[6] about six years after James Watson and Francis Crick proposed (in 1953) the “double helix” as the structure of the human DNA (deoxyribonucleic acid.)[7]

The roots of pharmacogenetics are in Archibald Garrod’s recognition in the first decade of the 20th century[8] that genetic factors “direct” the chemical transformation (metabolism) of drugs in the body.[9],[10] The first systematic account on pharmacogenetics was published in 1962 by Werner Kalow.[11]

Pharmacogenetics studies inter-individual differences in response to drugs. The objective is to identify and characterize genetic factors that underlie differential responsiveness to drugs between groups and between individuals within a group. Accordingly, one area of pharmacogenetic research is focused on the responses of patients with different psychiatric diagnoses to the pharmacodynamic properties of the same drug, whereas another area of research is focused on genetically-based pharmacokinetic differences between members of the same diagnostic group in responding to the same drug.[12]

The genetics of pharmacokinetic differences entered psychiatric pharmacotherapy in 1960 with Evans and associates’ recognition that the rate of acetylation of isoniazid, is under genetic control.[13] In 1964 they reported that patients who metabolize phenelzine[(] at a relatively lower rate, as measured by the ratio of acetylated to free sulfapyridine in urine after sulfamethazine administration,[14] developed more side effects to the drug.[15] These findings were complemented by the work of Johnstone, who reported in 1966 that “slow acetylators” respond more favorably to the drug. Nevertheless, the relationship between acetylator status[16] and response to treatment has remained tenuous; Robinson and associates found no difference between slow and fast acetylators in therapeutic response, side effects and platelet monoamine oxidase inhibition in patients treated with phenelzine.[17] (See, Robinson, Volume 5.)

The genetics of pharmacodynamic differences entered psychiatry in the 1990s in molecular genetic studies of schizophrenia and manic-depressive illness. On the basis of the mode of action of drugs with demonstrated therapeutic efficacy, various genes which encode transporters (e.g., the serotonin tansporter, the dopamine transporter), receptors (e.g., the serotonin-5HT2A receptor, the dopamine-D2 and D3 receptors), and enzymes (e.g., monoamine oxidase, dopamine-β-hydroxylase, catechol-methyl-transferase), have been implicated in the pathophysiology of these diseases. Genetic ”association studies” however, have failed to detect consistent differences in mutations (polymorphism), in the implicated genes, between normal volunteers and patients with either of these diseases.[18],[19]

Genetics and Neuropsychophamacology

The observation that mental illness runs in families has been documented since the mid-18th century[20]; the first genetic theory of mental illness was formulated by Morel in the mid-1850s.[21] It was based on the assumption of “degeneration”, the notion that mental disease is the result of an “innate biological defect” that becomes manifest in increasingly severe mental syndromes in “lineal descents.”[22] Morel’s degeneration theory was replaced by Moebius’ “endogeny theory”, in the 1890s which implicated a “constitutionally determined predisposition” for developing mental illness.[23]

The heredity of mental illness received substantial support in epidemiologic genetic studies. The risk of developing schizophrenia for relatives of patients with schizophrenia and manic-depressive illness was found to be consistently higher than in the general population; and the .risk of developing the respective illness in both diagnostic groups was found to be higher for first, than for second degree relatives.[24],[25] Furthermore, children of schizophrenic biological parents adopted into the families of non-schizophrenic foster parents were found to develop schizophrenia at a much higher rate than adopted away children of normal parents,[26],[27] and mental illness was found to occur also at a much higher rate in the biological than in the adoptive families of adopted schizophrenic and manic-depressive children.[28],[29] (See, Kety, Volume 2, and Wender, Volume 7.)

In spite of evidence, that mental illness runs in families, molecular genetic studies using “linkage analysis”, “positional cloning”, and “genome scanning”, yielded inconsistent findings. Susceptibility loci for schizophrenia and manic-depressive illness were reported on various, chromosomes,[(] the findings in one group of patients, however, could not be replicated in others.[30] Failure to replicate findings in a similar diagnostic population from one study to the next indicates genetic heterogeneity within the diagnostic groups. Thus, the heterogeneity within diagnoses interfered with molecular genetic research in mental illness.[31]

The inconsistent findings in molecular genetic research lead to growing dissatisfaction with consensus-based classifications.[32] The unhappiness was such that in 1999, Steven Hyman, at the time the Director of NIMH in the United States, pointed out that “it would be foolish to think” that diagnostic criteria in classifications like the DSM-IV would “select anything that maps into the genome”.[33] It was also recognized that without a re-evaluation of diagnostic concepts in psychiatry, it would be futile to employ either a pharmacogenetic or a pharmacogenomic approach,[34] in psychotropic drug development.[35]

The problem created by the genetic, pharmacological and psychopathological heterogeneity within diagnoses was compounded by the vanishing from view by the end of the 20th century of the two disciplines of psychiatry, psychopathology and psychiatric nosology that dealt with the delineation and classification of psychiatric diseases. Since both disciplines may offer leads for the identification of pharmacologically more homogeneous psychiatric populations than identified in consensus-based classifications, a subject matter central in the research of several interviewees in this volume, in the following two sections some of the basic tenets of psychopathology and psychiatric nosology are briefly reviewed.

Psychopathology

Psychopathology studies the symptoms and signs of psychiatric disease. The term, psychopathology, first appeared in 1845, in Ernst Feuchtersleben’s textbook on “psychic diseases”.[36] Subsequently, it was used only sporadically, as a generic term for psychiatry in the rest of the 19th century.[37],[38],[39],[40] [(]

Development of modern psychopathology began in the early 20th century with Karl Jaspers’ recognition that patients with different psychiatric disease perceive the same experience differently. His adoption of the Aristotelian distinction between “form” and “content” in the analysis of psychiatric symptoms led in 1910, to the separation of “psychiatric disease” from “abnormal personality development”.[41] In 1913, by distinguishing between “phenomenology” and “performance psychology” in his General Psychopathology, Jaspers opened up a new perspective for studying the pathology of a group of diseases referred to at the time as “functional” or “endogenous” psychoses”.[42]

In phenomenological psychopathology, the distinction between “form” and “content” provides a means for the detection and differentiation of the pathological experiences encountered by patients. In a phenomenological analysis it is not the subject matter, the “content” (e.g., a “somatic hypochondriacal) complaint”), but the “form” in which this content is experienced by the patient, e.g., “bodily hallucinations”, “obsessive ideas”, “hypochondriacal delusions”, that is relevant to patient’s illness and psychiatric diagnosis.[43]

From 1918 to 1933 a group of psychiatrists in Kurt Wilmann’s department of psychiatry at Heidelberg University embarked on “phenomenological analysis” of the psychopathological symptom displayed in psychiatric patients’.[44] Their research yielded a set of symptoms that reflect the pathologies in the processing of signals in the brain from “symbolization” to “psychomotility”.[45] It also provided fine distinctions between manifestations, such as the difference between “dysphoria” and “dysthymia”, “psychomotor retardation” and “psychomotor inhibition”, etc. By linking the pathologies in the processing of signals to psychiatric diagnoses, e.g., “tangential thinking” to the schizophrenias, “circumstantial thinking” to the dementias, “rumination” to the depressions,[46] the Heidelberg school, set the foundation for a language of psychiatry that reflects the ongoing functional pathology in the brain.

The notion that different psychopathologic symptoms reflect different pathologies in the processing of experience in the brain was in keeping with Ramon y Cajal’s contributions in the late 19th and early 20th century. His findings that neural circuits in the brain consist of sensory, motor, and inter-neurons, and his demonstration of the “connection specificity of neurons”,[47],[48],[49] provided the neural underpinning of “structural psychopathology”, spearheaded by Gyula Nyirö in the mid-20th century.[50]

In structural psychopathology, psychopathological symptoms are organized as in Carl Wernicke’s classification[51] into three psychic structures, based on the three phases of reflex mechanism: (1) afferent – cognitive, (2) central – affective and (3) efferent – adaptive. Each structure has several levels[(] and each level is connected with each level within and across structures. For the structural pstchopathologist, psychopathological symptoms are abnormalities in these connections. Operating within a Pavlovian frame of reference (see, Preface, Volume 2, and Postscript, Volume 10), Nyiro opened the path for the study of psychopathological symptoms with conditioned reflex methods.[52]

Nosology

Psychiatric nosology deals with the methodology of synthesizing psychopathological symptoms into diseases and in classifying the diseases synthesized.[53] The term “nosology”, first appeared in 1743 in Robert James’ Medical Dictionary.[54] Development of “nosology”, as a discipline was triggered well over 100 years later, in the mid-18th century, by Francois Boissier de Sauvage’s postulation that a disease should be defined by “the enumeration of symptoms that suffice to recognize it and distinguish it from other diseases”. One of the essential noslogic premises is that a classification should “allow the attribution of each patient to one and only one class.”[55]

The first, nosologic organizing principle of “madness,” was introduced by William Cullen.[56] His division of the “vesanias”, which included all the different forms of madness, on the basis of “totality,” into “mania,” or “universal madness,” and melancholia,” or “partial madness,” dominated classifications in psychiatry during the 19th century.[57],[58][(]

Adoption of Thomas Sydenham’s conceptualization of disease[59] as a “process” with a “natural history of its own” that “runs a regular and predictable course”, led to the identification and classification of psychiatric diseases on the basis of their “temporal characteristics”, including “onset” (sudden or insidious), “course” (episodic or continuous) and “outcome” (recovery or defect). It was Jean Pierre Falret first in 1854 to identify a psychiatric disease, “folie circulaire”,[60] on the basis of its “temporal” characteristics. Karl Kahlbaum in 1863 also proposed temporal course as a principle of classsification without much resonance. (See, Preface, Volume 7.) So, it was onlyw with Emil Kraepelin’s disease-oriented classification, in the 6th edition of his textbook,[61] published in 1899, that “temporal characteristics” firmly entered psychiatry as a classifying principle of mental disease. Kraepelin’s division (“dichotomy”) of the “endogenous psychoses” into “manic depressive insanity”, a disease that follows an episodic course with full remission between episodes, and “dementia praecox”, a disease that follows a continuous deteriorating course, led to a re-evaluation of psychiatric diagnoses and classifications. In the course of this re-evaluation, diseases were divided into three groups. One of these groups, that includes diseases characterized by episodic course with full remission between episodes, becomes manifest in the form of “attacks” that last from minutes to hours (e.g., Martin Roth’s “phobic-anxiety-depersonalization syndrome”[62]), or in the form of “phases” that last from days to years (e.g., Edna Neele’s “phasic psychoses”[63]). Another group that includes diseases characterized by recurring episodes without full remission between episodes, becomes manifest in the form of “thrusts” or “shifts” (e.g., Eugen Bleuler’s “schizophrenias”[64]). The third group, that includes diseases` characterized by continuous course, becomes manifest in the form of highly differentiated “end states” (e.g., Karl Leonhard’s “systematic schizophrenias”[65]), or in the form de-differentiated “dementia” (e.g., Alzheimer’s disease[66]).