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AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

THE FIRST FIFTY YEARS

Peer Interviews

Volume Seven: Special Areas

Copyright © 2011 ACNP

Thomas A. Ban (series editor)

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

Barry Blackwell (volume editor)

VOLUME 7: Special Areas

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, Barry Blackwell (eds):

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

Includes bibliographical references and index

ISBN-

ISBN-

1. Neuropsychopharmacology 2.Pharmacotherapy with psychotropic drugs

3. Psychiatric diagnosis 4. Child psychiatry 5. Geriatric psychiatry

6. Pharmacokinetics

Publisher: ACNP

ACNP Executive Office

5034A Thoroughbred Lane

Brentwood, Tennessee 37027

U.S.A.

Email: acnp@

Website:

Cover design by Jessie Blackwell; JBlackwell Design

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 7

SPECIAL AREAS

VOLUME 7

Barry Blacwell

SPECIAL AREAS

“Desiderata”

Preface

Thomas A. Ban

Dedicated to the Memory of Louis Lasagna, President ACNP, 1980

PREFACE

Thomas A. Ban

Volume Seven, Special Areas, is dedicated to contributions to child psychiatry, gerontopsychiatry, psychiatric diagnosis and pharmacokinetics. The volume also accommodates transcripts which could not be included in the other volumes. Hence it received the subtitle Desidarata from the volume editor. (See, Introduction.)

In Volume Seven, as in all other volumes in this series, interviewees reflect on their contributions to research in their respective field of inquiry. But unlike the first six volumes, some of the contributions presented in this volume are only indirectly related to neuropsychopharmacological research.

Child Psychiatry

In the early years of the 20th century a wide variety of disciplines from pediatrics to psychiatry, including education, criminology, psychology, psychoanalysis, and child guidance, were concerned with the health, and welfare of children.i It was only the mid-1920s that August Homburgerii set the foundation of a subspecialty of psychiatry that was to become known as Child Psychiatry.

The term Child Psychiatry (“Kinder Psychiatrie”) was first used in the early 1930s by Moritz Tramer in the name of his journal, Zeitschrift fűr Kinderpsychiatrie. The term was widely diffused in the English speaking world through the title of Leo Kanner’s Child Psychiatry, published in 1935.iii It was about the same time that the first psychiatric units for children, founded by Eugen Bleuler in Zurich, August Homburger in Heidelberg and Adolf Meyer in Baltimore, were opened.iv

Developments which lead to Child Psychiatry began in the 1860s and ’70s with the separation of three genetically-distinct diagnostic populations within mental deficiency: (1) the Laurence-Moon-Biedl syndrome;v (2) the Langdon- Down syndrome or mongolism;vi,vii,viiiand (3) Tay-Sachs disease, or familial amaurotic idiocy.ix,x Then, in 1934, the same year as the term “child psychiatry” was introduced, Fölling discovered, “phenylketonuria,” an inborn error of metabolism,xi by detecting phenylpyruvic acid in the urine in a group of children with severe mental deficiency.xii Three years later, in 1937, Penrose and Quastel demonstrated the absence of enzymes splitting phenylalanine, in phenylketonuric children.xiii By the end of the 1930s Jervis had shown that phenylketonuria runs in families; he implicated an autosomal recessive gene in the pathogenesis of the disease.xiv The first report on successful treatment of phenylketonuria with a diet low in phenylalanine was published over 15 years later, in 1955, by Woolf, Griffiths and Moncrieff.xv

A major impetus for the development of child psychiatry was the encephalitis lethargica epidemic between 1917 and the late 1920sxvi with the subsequent identification of three mental syndromes (diseases) of childhood. The first, “hyperkinetic disease” (“hyperkinetische Erkrankung”) was described by Kramer and Polnow in 1932xvii; the second, “elective mutism” was discovered in 1934 by Tramerxviii; and the third, “infantile autism” was introduced by Kanner in 1943.xix,xx

Interest in pharmacotherapy in child psychiatry was triggered by the publication of Charles Bradley’s paper in 1938 on the behavior of children receiving Benzedrine (amphetamins slfate)xxi and his subsequent report with Bowen on improvement in school performance of children receiving amphetamine sulfate in 1940.xxii In the same year Cutler, Little and Straussxxiii published the findings of their controlled study with Benzedrine in mentally deficient children. By the early 1950s the amphetamines found their place in the treatment of hyperkinetic children. xxiv,xxvThere were also other drugs, e.g., diphenylhydantoin, an anticonvulsant,xxvi,xxvii,xxviii diphenhydramine, an antihistamine,xxix used in child psychiatry in the 1940s.

The first reports on chlorpromazine in child psychiatry in the United States were published in 1955 by Bein and Herold,xxx and Gatski.xxxi It was also in 1955 that the first papers appeared on the use of myanesinxxxii and glutamic acidxxxiii in children. By the end of the 1950s there were also reports on findings with reserpinexxxiv and meprobamate.xxxv. The first book on research in pediatric psychopharmacology was published in 1959.xxxvi

Geriatric Psychiatry

While individual life span has remained unchanged, average life expectancy has increased at least four-fold over the course of recorded history.xxxvii There was an unprecedented rapid increase in life-expectancy during the first half of the 20th century; from 1900 to 1960 the percentage of old people tripled, reaching 13% of the total population of Europe and 10% of North America.xxxviii The increase in individuals aged 65 years or older has directed attention to gerontology, a term introduced in 1907 by the Russian medical scientist Eli Metschnikoff, the scientific study of the aging process,xxxix and to geriatrics, a term introduced in 1914 by the American pediatrician, Ignatz Nascher, the medical specialty concerned with the study, prevention and treatment of pathologic conditions in the aged.xl Gerontology deals with primary aging or senescence, which is a biologic process rooted in heredity; geriatrics deals with secondary aging or senility, i.e., defects and disabilities resulting from trauma, including disease.xli

Psychiatric morbidity is high in the aged. The three-fold increase in the number of people 65 or over in the United States was associated with a nine-fold increase in admissions to mental hospitals from this age group.xlii A study in Baltimore from the 1960s showed that 12% of the non-institutionalized geriatric population suffered from mental illness.xliii In San Franciso, the figure was 15%.xliv It was the high prevalence of psychiatric morbidity in old people that created the need for the geropsychiatry, or psychogeriatrics.xlv

Developments which lead to psychogeriatrics began in the 1870s with Krafft-Ebing’s introduction of the term “dementia senilis” and with his separation of senile dementia from the other organic dementias.xlvi It continued in the 1880s with the description of what was to become known as the Wernicke – Korsakoff amnestic syndromexlvii,xlviii and the separation of the dysmnesias from the dementias. In 1892 the disease that was to bear his name was described by Pickxlix and separated from senile dementia. In 1899 Binswanger coined the term, “pre-senile dementia”l that was to include Pick’s disease, Alzheimer’s disease, described in 1907,li Jacob – Creutzfeld’s disease,lii,liiidescribed in 1920 and ’21, and several other conditions.

In the mid-1930s, a possible relationship between Alzheimer’s disease and senile conditions was raised by Rothschild and Kasaninliv; and in the mid-1940s Jervis suggested that atrophy of nerve cells and fibers with some glial reaction is the common basic process of the senile and presenile dementias.lv Yet, it was also in the mid 1940s that Rothschild described the differential clinical features of senile and arteriosclerotic (referred to as multi-infarct todaylvi) “psychoses”.lvii

By the 1950s it was recognized that psychiatric diseases in the aged are not restricted to the dementias and dysmnesias A survey in the UK indicated that the in 30 to and 50 percent of patients admitted to mental hospitals over 60 years of age, the clinical picture was dominated by depressive clinical features.lviii Martin Roth and his associates found little overlap in symptomatology between these patients and patients with organic degenerative diseases. They also demonstrated that only about three percent of them developed dementia in two to three years.lix

In Kraepelin’s estimation about 6 to 7 percent of the first episode of manic-depressive psychosis occurs at age 60 or later.lx A similar figure was reported in 1952 by Stenstedt.lxi.

“Late paraphrenia”, another distinct diagnostic population in the aged, was identified in 1957 by Roth.lxii It differs from “late schizophrenia” by firmly systematized delusions.

Late schizophrenia was first recognized in 1911 by Eugen Bleuler.lxiii In 1943, Manfred Bleuler found that in 15 to 17 percent of patients, schizophrenia, starts at age 40 or later. He referred to this population as “late onset schizophrenia”. In Bleuler’s estimation in 4 percent of patients with late schizophrenia the onset of the disease starts at age 60 or later.lxiv Frank Fish, in the early 1960, found that in 1 percent of patients with schizophrenia the disease starts at age 69 or later.lxv

In the late 1940s deWardener and Lennox found that Vitamin B1 insufficiency induced loss of memory for recent events, disorientation, and confabulations, a clinical picture similar to that seen in the Wernicke-Korsakoff syndrome. They also demonstrated that thiamine administration reversed the memory disturbance.lxvi

In the 1950s, V. A. Kral separated “benign senescent forgetfulness” from “malignant senescent forgetfulness”.lxvii,lxviii,lxix,lxxHe also reported on favorable effects with fluoxymesterone, in “benign senescent forgetfulness”.lxxi,lxxii

Stimulated by Holger Hyden’s discovery of the role of ribonucleic acid (RNA) in learninglxxiii Ewen Cameron, administered yeast RNA to patients with senile and arteriosclerotic dementia in the late 1950s.lxxiv In spite of his initial favorable impressionlxxv and of the supportive findings of Leonard Cook in animal pharmacological research,lxxvi later studies by Cameron and his assiociates with labeled RNA revealed that RNA molecules don’t enter the cerebral neurons. (See, Cook Volume 1.) They could only be found in the cells of the ependyma and plexus choroideus.lxxvii

During the 1950s a wide variety of drugs - including gonadal hormones, i.e., estrogen and testosterone alone and in various combinations,lxxviii,lxxix,lxxx,lxxxipsychostimulants, such as pentylenetetrazol,lxxxii,lxxxiiipipradrol,lxxxiv,lxxxv,lxxxvi,lxxxviiand methylphenidate,lxxxviii,lxxxix,xc,xcivasodilators, e.g., isoxsuprine,xcii;xciiiand drugs with an effect on cerebral metabolism, e.g., Hydergine, a hydrogenetaed alkaloid of ergotxciv,xcv,xcvi- were employed in the treatment of psychiatric diseases in the aged. Prescription practices in elderly patients began to shift in the middle of the decade with the introduction of psychotropic drugs. The first reports on the effects of chlorpromazine in geropsychiatric patients were published in 1955 by Kurland,xcvii Seagerxcviii and Terman;xcix on reserpine alone and in combination with psychostimulants and/or vitamins in 1956c and ’58;ci .on prochlorperazine in 1957;cii on meprobamate in 1957ciii and ’58;civ on imipramine in 1958cv,cviand ’59;cvii,cviii and on perphenazine,cix thioridazine,cx and trifluoperazine in 1959.cxi

Psychiatric Diagnosis

The origin of most current diagnostic end-points in neuropsychopharmacological research is in the clinically distinct sub-populations separated from “unitary psychosis” (“Einheitpsychose”)cxii,cxiii,cxiv during the second part of the 19th century. In order of chronology they are as follows: Lasègue’s “délire de persecution” (1852);cxv Falret’s “folie circulaire” (1854);cxvi Briquet’s “hysteria” (1859);cxvii Morel’s “démence precoce” (1860)cxviii & “délire emotiff” (1867);cxix Beard’s “neurasthenia” (1869);cxx Benedict’s “Platztschwindel” (agoraphobia) (1870);cxxi Hecker’s “Hebephrenie” (1871);cxxii Westphal’s “Agoraphobie” (1871cxxiii & 1872cxxiv); Lasègue’s “l’anorexie hystérique” (1873)cxxv & Gall’s “anorexia nervosa” (1873);cxxvi Kahlbaum’s “Katatonie” (1874);cxxvii and Westphal’s “Zwangsvorstellungen“ (obsessive-compulsive disorder) (1978).cxxviii,cxxix At present, hysteria (referred to as “somatization disorder” in some of the current classificationscxxx), neurasthenia, agoraphobia, anorexia nervosa, and obsessive-compulsive states have remained valid diagnostic concepts; délire de persecution developed in the early 1890s into Magnan and Sérieux’s diagnostic concept of “chronic delusional state of systematic evolution”;cxxxi folie circulaire provided the core for Kraepelin’s diagnostic concept of manic-depressive insanity; and démence precoce served as the starting point for Kraepelin to develop his diagnostic concept of dementia praecox.

The origin of some of the other current diagnostic end-points are in Karl Kahlbaum’s classification which distinguishes five classes of disease, i.e., neophrenias, paraphrenias, vecordia, vesanias and dysphrenias,cxxxii and in Emil Kraepelin’s different classifications presented in nine editions of his textbook (the first published in 1883 and the last in 1927). cxxxiii,cxxxiv,cxxxv,cxxxvi,cxxxvii,cxxxviii Diagnostic concepts, like presbyophrenia, dysthymia and cyclothymia, were first introduced in Kahlbaum’s classification, and the unifying diagnostic concepts of dementia praecox and manic depressive insanity first appeared in the sixth edition of Kreapelin’s classification.cxxxix By the time of the eighth edition (1908-1914) of Kraepelin’s text,cxl,cxliEugen Bleuler replaced the name dementia praecox with schizophrenia (1908).cxlii,cxliii,cxliv, cxlv

Adoption of Kraepelin’s classification in the 1950s by the St.Louis School of Psychiatry in the United States was instrumental to the development of the third edition of the diagnostic and statistical manual of mental disorders of the American Psychiatric Association, published in 1980. The DSM-III and its successors were to provide to-date the diagnostic end-points of neuropsychopharmacological research. (See, Preface to Volume 4.)

Pharmacokinetics

Pharmacodynamics deals with action of a substance on the body, whereas pharmacokinetics deals with the action of the body on the substance. Pharmacodynamic properties are responsible for the differential effect of a psychotropic drug in different psychiatric diagnoses, whereas pharmacokinetic properties for the differential effect of the same drug within a particular diagnosis. .

The term pharmacokinetics was introduced by F.H. Dott in 1953.cxlvi,cxlvii Couple of years later Bernard Brodie and his associates revealed that the main pathways used by the organism for metabolizing drugs are: (1) oxidation by microsomal enzymes in the liver, (2) other oxidative reactions, such as dehydrogenation, oxidative deamination, (3) reduction reactions, (4) O-methylation, (5) hydrolysis (of esters and amides), and (6) conjugation.cxlviii,cxlixBy the end of the 1950s it was shown that oxidation by microsomal enzymescl,cliwas the main pathway in the metabolism of LSD, and N-demethylation, partial oxidation of the sulfur atom, and glucuronide formation in the metabolism of chlorpromazine. It was also recognized that the metabolic degradation of imipramine is similar to that of chlorpromazine.clii,cliii,cliv

Introduction of flame photometry by Victor Wynn rendered the measurement of plasma lithium levels feasible.clv,clviThe first clinical studies with lithium plasma level monitoring were conducted in the 1950s by Treutner and his associates,clvii,clviiiand by Schou and his associates.clix,clxIt was in those early studies that the “therapeutic window” of lithium was detected by Treutner and his group. (See, Gershon Volume 1.)

The first plasma level determination of chlorpromazine was reported by Curry and Brodie in 1967,clxi and of imipramine by Moody and his associates in the same year.clxii

Interviewees & Interviewers

The preceding information provides orientation points in the development of the four major areas of research interviewees contributed to.

From the 29 interviewees included in Volume Seven, 3 (Costa, Eichelman, George) are MD/PhDs; 17 (Akiskal, Alexopoulos, Blazer, Chase, Clayton, Dunner, Fish, Glassman, Halbreich, Halmi, Jeste, Kupfer, Lisanby, McKinney, Reisberg, Rapoport and Wender) are MDs; 8 (Arango, Conners, Dahl, Endicott, Kaufman, Klein, Shooter and Weissman) are PhDs and 1 (Cooper) is an MA. From the 17 MDs, 16 are psychiatrists - 1 of the psychiatrists (Halmi) is also a qualified pediatrician - and 1 (Chase) is a neurologist. From the 8 PhDs, 3 (Conners, Endicott and Klein) are psychologists, and from the other 5 each is qualified in a different discipline: Arango in neuroanatomy, Dahl in pharmacology, Kaufman in biochemistry, Shooter in chemistry and Weissman in epidemiology.

All interviewees are affiliated with ACNP; two, Kupfer and Rapoport, are past presidents of the organization.

The interviews were conducted from 1996 to 2008 and with the exception of one, Lisanby, who was interviewed at the CINP Congress in Paris, all were interviewed at ACNP’s annual meetings. .

The 29 interviewees were interviewed by 12 interviewers; 1 interviewee (Fish) was interviewed by 2 interviewers (Meldrum and Bromley). Nine of the interviewers are peers of the interviewees, knowledgeable in the same field and 3 (Bromley, Meldrum and Tone) are medical historians. Eight of the interviewers (Angrist, Clayton, Koslow, Meldrum, Post, Regier, Schatzberg and Van Kammen) conducted one interview, 2 (Bromley and Healy,) conducted two, and from the remaining two, one (Tone) conducted five, and the other (Ban) conducted 13.

By the time the editing of Volume Seven was completed, one of the interviewees (Schuster) passed away.

Contributions of Interviewees

The 29 interviewees contributed to eleven areas of research. Six of the interviewees (Conners, Fish, Kaufman, Klein, Rapoport and Wender) were engaged in research related to child psychiatry. In the 1960s Seymour Kaufman described the structure of the phenylalanine cofactor,clxiii the physical properties of 3,4 dihydroxyphenylalanine-β-hydroxylase. He also defined the role of copper in the catalytic activity of the enzyme.clxiv In the 1970s, Kaufman identfied two new forms of phenylketonuria: one (1975) due to deficiency of dihydropteridine release,clxv and the other (1978), due to biopterin deficiency.clxvi

In the 1960s and’70s Barbara Fish, contributed to the introduction of several psychotropic drugs, including e.g., trifluoperazine,clxvii thothixene,clxviii chlordiazepoxide,.clxix in child psychiatry. She also contributed to the development of a methodology for the detection of drug-induced changes in “an organism that is in the process of changing”.clxx.

C.Keith Conners contributed to the characterization of minimal brain dysfunction,clxxi and to the development of rating scales for use in drug studies with children.clxxii In a series of clinical investigations carried out in the 1960s he also contributed supportive information on the effectiveness of methylphenidate in disturbed children,clxxiii and of dextroamphetamnine on the school behaviour of children with learning disabilities.clxxiv In 1980 Conners was among the first to discuss a possible relationship between food additives and hyperactivity in children.clxxv

Paul H. Wender extended the diagnostic concept of “minimal brain dysfunction from chldren to adults. He was first to explore systematically the pharmacology of minimal brain dysfunction (attention deficit hyperactivity disorder) in both, children and adults He presented his findings in his monographs on Minimal Brain Dysfunction in Children, published in 1971clxxvi and on Minimal Brain Dysfunction in Adults, published in 1995.clxxvii, clxxviii In the 1960s, Wender, in collaboration with Seymour Kety and David Rosenthal, introduced a new methodology in epidemiologic genetic research by studying mental illness in the biological and adoptive families of adopted children with schizophrenia.clxxix They also introduced the concept of ”schizophrenia spectrum disorders”.clxxx,clxxxi

In the 1970s Judith Rapoport contributed to knowledge on the use of methylphenidate in attention deficit hyperactivity disorder.clxxxii,clxxxiiiShe was first to demonstrate that dextroamphetamine produced a marked decrease in reaction time and motor activity in normal pre-pubertal boys.clxxxiv In the 1980s Rapoport‘s research shifted to the study of the pharmacology of obsessive-compulsive disorder (OCD) in children/.clxxxv,clxxxvi In the early 1990s she was a member of the team which showed the differential effect of desipramine and clomipramine in children and adolescents with OCD.clxxxvii

Rachel Gittelman Klein was first in the 1990s to show the effectiveness of imipramine in the treatment of separation anxiety disorder.clxxxviii She was also among the first to extend the use of methylphenidate to conduct disorders.clxxxix Klein was member of the team which explored the use of pemoline in conduct disorders.cxc In 1997 in collaboration with Abikoff, Klein had shown that behaviour therapy gives no added benefit to treatment with methylphenidate in attention deficit hyperactivity disorder.cxci

Five of the interviewees (Alexopoulos, Blazer, Chase, Jeste and Reisberg) were engaged in research related to geriatric psychiatry. Dan G. Blazer was involved in studying the epidemiology and genetics of melancholia in the aged. He was among the first to report on a decrease of depressive illness in old people.cxcii,cxciii,cxciv,cxcv

In the early 1980s Barry Reisberg developed assessment instruments which were to be used extensively in clinical studies with psychotropic drugs in the aged,e.g., Global Deterioration Scale, Brief Cogitive Rating Scale:cxcvi,cxcvii,cxcviii,cxcixReisberg was among the first to study memantine, a substance synthesized in 1963 that blocks glutametergic NMDA receptors, in elderly patients. He led the team which reported in 2003 on favourable effects of meantine in moderate to severe AD.cc

In the 1980s, Thomas N. Chase studied cortical abnormalities in Alzheimer’s disease (AD) with the employment of glucose utilization.cci,cciiHe was among the first to explore GABA agonist therapy for AD.cciii Shifting the focus of his research from AD to Parkinson’s disease (PD) in the 1990s, Chase with his associates demonstrated the significance of continuous dopaminergic stimulation treatment of PD.cciv,ccv,ccviIn 2003 Chase waas first to report on the use of an A2A receptor agonist in the treatment of PD.ccvii

In the 1990s Dilip V. Jeste contributed to knowledge on late onset schizophrenia.ccviii,ccixIn a prospective study he also demonstrated the difference in the risk factor for tardive dyskinesia in old and young patients with schzophreniaccx Jeste was a member of the team which reported in 2000 on the incidence and risk factors for hallucinations and delusions in probable Alzheimer’s disease.ccxi

George S. Alexopoulos contributed to knowledge on late onset depression.ccxii,ccxiii He studied the relationship between: (1) brain changes and depression in geriatric patients;ccxiv (2) late-life depression and neurological disease;ccxv and (3) depressive symptoms, vascular disease and cognitive impairment.ccxvi In the early years of the 21st century, Alexopoulos extended his research to the study of the difference in placebo response between old and young patients.ccxvii In 2008 he reported on a negative correlation between micro-structural white matter abnormalities and remission in geriatric depression.ccxviii

Seven of the interviewees (Akiskal, Clayton, Dunner, Eichelman, Endicott, Halbreich and Halmi) were engaged research related to diagnostic end-points in psychopharmacologic research.. In the late 1960 Paula J Clayton was instrumental in introducing Karl Leonhard’s diagnostic concept of “bipolar disorder” in the United States,ccxix and in the early 1980, in perpetuating Kasanin’s diagnostic concept of “schizoaffective disorder”.ccxx,ccxxiOne of the recurring themes in Clayton’s research was the separation of symptoms of bereavement from symptoms of depression.ccxxii, ccxxiii;ccxxiv In the 1970s Clayton was a member of a team which studied the relationship between nortriptyline plasma levels and therapeutic response.ccxxv In the 1990s she co-authored paper with Jules Angst and his associates in Zurich on mortality of patients with mood disorders.ccxxvi

In the mid 1970s Jean Endicott, in collaboration with Robert Spitzer and Eli Robins developed Research Diagnostic Criteria (RDC) for a Selected Group of Functional Psychoses.ccxxvii,ccxxviii In collaboration with Spitzer she also developed the Schedule of Affective Disorder and Schizophrenia (SADS).ccxxix The RDC and SADS together with Feighner’s Research Diagnostic Crteria ccxxx provided the bridge between the DSM-II,ccxxxi and the DSM-III.ccxxxii During the 1980s and ’90s, Endicott contributed with his research to the recognition of “premenstrual dysphoric disorder” as a distinct diagnostic entity.ccxxxiii

Searching for a unifying hypothesis of affective disorders,ccxxxivHagop Akiskal, studied sub-affective disorders, such as dysthymia, cyclothymia, bipolar II disorder, in the “borderline realm”.ccxxxv In 1983, he critically reviewed te relationship between personality and affective disorder,ccxxxvi and presented his findings on the psychopathology of chronic depressive subtypes.ccxxxvii In the 1990s, pursuing the same line of research further, he introduced the concept of “bipolar spectrum disorders”;ccxxxviii provided evidence for switching from unipolar to bipolar II disorderccxxxix and described prototypes of bipolar I, II, III and IV disorders.ccxl

Studying the genetics of manic-depressive illness in collabortaion with Elliot Gershon, David Dunner, in the late 1960s identified what was to become knoown as “bipolar II disorder.”ccxli Subsequently, studying factors which might be related to failure in responding to lithium, in collaboration with Ronald Fieve,ccxlii,ccxliii,ccxliv,ccxlv,ccxlviDunner was among the first to describe “rapid cycling” patients.ccxlvii They also proposed a classification of bipolar affective disorder.ccxlviii During the 1980s and ’90s Dunner was involved in the clinical evaluation of several psychotropic drugs, including adinazolam,ccxlix alprazolam,ccl fluoxetine,ccli citalopram,cclii paroxetine,ccliii etc.

Using a specially devised assessment form for the detection of premenstrual symptoms in the mid-1980s, Uriel Halbreich, in collaboration with Jean Endicott, found a diversity of premenstrual changesccliv and linked these changes to gonadal hormone secretion.cclv They also revealed a relationship between premenstrual dysphoric changes and depression.cclvi In the 1990s Halbreich suggested that “menstrually related disorders” are valid diagnostic end pointscclvii and embarked on studies on the relationship between gonadal hormones and these disorders.cclviii He also explored the use of progesterone antagonists,cclix and sertralinecclx in the treatment of the premenstrual dysphoric syndrome. In his early research Halbreich found a difference in growth hormone response to dextroamphetmine between depressed patients and normal subjects,cclxi and between postmenopausal women and normal young men.cclxii In 1990 he reported on the effects of oestrogen replacement in the treatment of postmenopausal disorders.cclxiii

Focusing on eating disorders in her research, Katherine A Halmi, in the late 1970s reported on the effectiveness of cyproheptadine, a serotonin antagonist, in the treatment of “anorexia nervosa”.cclxiv She followed up her findings with a comparative study of cyproheptadine and amitriptyline,cclxv and by comparing the effectiveness of cyproheptadine in bulimic and non-bulimic anorexia nervosa patients.cclxvi With the employment of biological measures during the 1980s Halmi found similarities between anorexia nervosa and depression. cclxvii, cclxviii Halmi was a member of the team which identified in 2002 a susceptibility gene for anorexia nervosa on chromosome 1.cclxix

In a series of experiments conducted in the rat in the early 1970s, Burt Eichelman found that social setting influenced physiological response to electric shock.cclxx Focusing on the pharmacology of aggression in his research he revealed the effect of sub-cortical lesions on shock-induced aggression.cclxxi Then, he demonstrated that 6-hydroxydopamine administration facilitated aggressive behaviour.cclxxii In the mid-1980s, Eichelman reported that combined treatment with tryptophan and trazodone has a favourable effect on aggressive behaviour.cclxxiii In 1990, in recognition of the pharmacological heterogeneity of the population displaying aggressive and violent behaviour,cclxxiv Eichelman developed The Carolina Nosology of Destructive Behaviour.cclxxv

Three of the interviewees (Cooper, Dahl and Glassman) were engaged in pharmacokinetic research. Thomas B. Cooper contributed to the determination of plasma and tissue levels of various antipsychotics (including butaperazinecclxxvi, loxapinecclxxvii clozapine,cclxxviii fluphenazinecclxxix), antidepressants (including mianserincclxxx and nortriptylinecclxxxi), and benzodiazepines.cclxxxii In 1973, in collaboration with Bergner and Simpson, Cooper demonstrated that 24-hour serum lithium level is a good “prognosticator” of dose requirement in patients.cclxxxiii Cooper was member of the team which reported in 1980 on the effect of antiparkinson medication on plasma levels of chlorpromazine.cclxxxiv He was also a member of the team which compared (in 2004) the pharmacodynamc and pharmacokinetic effects of d and dl threo-methylphenidate hydrochloride in children with attention deficit disorder.cclxxxv

While studying the relationship between plasma levels and therapeutic effect of imipramine, in the 1970s, Alexander H. Glassman and his associates, found that patients with delusions (psychotic depression) did not respond to the drug.cclxxxvi,cclxxxvii,cclxxxviii,cclxxxix They also revealed cardiac conductance changes, similar to those seen with quinidine.ccxc,ccxci During the 1980s the focus of Glassman’s research shifted to smoking. He was among the first to demonstrate that clonidine, an α-2 adrenergic agonist, reduced the severity of symptoms after “smoking cessation.”ccxcii,ccxciiiHe had also shown the effects of smoking cessation on major depression. ccxciv,ccxcv

Svejn G. Dahl was among the first in the mid-1970s to study the pharmacokinetics of chlorpromazineccxcvi and methotrimeprazineccxcvii after the administration of single and multiple doses. Ten years later, in the mid-1980s he was again among the first to introduce plasma level monitoring of antipsychotic drugs.ccxcviii During the 1990s the focus of Dahl’s research shifted to the study of structure-activity relationships,ccxcix and to the modeling of neurotransmitter receptors.ccc

Two of the interviewees (George and Lisanby) were involved in research with biophysical approaches to treatment, Mark S. George was first in the 1990s to employ transcranial magnetic stimulation in the treatment of depression.ccci,cccii,ccciiiHe was also first to explore the utility of vagus nerve stimulation in the treatment of psychiatric disorders.ccciv

In the early years of the 21st century Sarah Hollingsworth Lisanby was instrumental in developing magnetic seizure therapy,cccv,cccviand repetitive transcranial magnetic stimulationcccvii,cccviiiin the treatment of depression. She also explored the possible augmentation of sertraline treatment with transcranial magnetic stimulation.cccix

Each of the remaining six interviewees (Arango, Costa, Kupfer, McKinney, Shooter and Weissman) was involved in a different are of research. Victoria Arango with her associates demonstrated an increase in serotonin 5HT2 and β-adrenergic receptor binding sites in the brains of suicide victimscccx in the 1990s. They localized the increase of serotonin receptor binding sites to the ventrolateral prefrontal cortex.cccxi In 2002 Arrango was member of the team which reported on altered editing of serotonin 5HT2c receptor pre-mRNA in the prefrontal cortex in suicide,cccxii and in 2006, she was member of the team which demonstrated lower serotonin transporter binding during major depressive episode.cccxiii

Erminio Costa was first to demonstrate the differential expression of serotonin in various areas of the human brain in the late 1950s.cccxiv His findings indicated multiple serotonin receptors with different sensitivity to inhibition by LSD.cccxv,cccxvi In the 1970s Costa and his associates demonstrated that potentiation of gabaminergic activity plays an important role in the mode of action of benzodiazepines.cccxvii,cccxviii. They also contributed to the characterization of benzodiazepine receptors.cccxix In the mid-1980s Costa was member of the team that discovered metabotropic glutamate receptors.cccxx In the early years of the 21st century Costa and his associates found that reelin protein and mRNA was reduced in several brain areas in schizophrenia and manic-depressive disease and suggested that dendritic spine hypoplasticity with downregulation of reelin and gabaergic tone is a vulnerability factor for schizophrenia.cccxxi (See also John Davis Volume 5.) In 2002 they postulated that schizophrenia is a disease at the interface of the genome and the epigenome.cccxxii .

In the 1970s David J Kupfer reported on changed interval between the onset of sleep and rapid eye-movement sleep in depressed patients and suggested that shortened REM latency was an indicator (“biological marker”) of primary depressive disease.cccxxiii,cccxxiv Kupfer found a statistically significant relationship between the changes in the tonic component of rapid eye movement (REM) sleep and therapeutic response to antidepressants. He also demonstrated that an increase in REM latency and REM suppression after a loading dose of 50 mg of amitriptyline was a predictor of favourable treatment outcome with the drug.cccxxv,cccxxvi. In other areas of research Kupfer contributed to knowledge on maintenance treatment in recurrent depression,cccxxvii and on the management of insomnia.cccxxviii

Working with rhesus monkeys, William T, McKinney was first in the 1970s to report on the effect of reserpine on social behaviourcccxxix and on the effect of chlorpromazine on disturbed behaviour.cccxxx In the 1980s he studied the effects of several drugs on the response to social isolation,cccxxxi and published his monograph on Animal Models of Mental Disorders.cccxxxii

In 1976, Eric M. Shooter, in collaboration with Mobley and Schenker, succeeded with the isolation and characterization of “proteolytically modified nerve growth factor”.cccxxxiii Twenty-six years later, in 2002, Shooter, in collaboration with Cosgaya and Chan reported that the neurotrophin receptor p75NTR is a positive modulator of myelinization.cccxxxiv

Myrna M Weissman was among the first to use psychiatric research diagnostic criteria in epidemiological studies.cccxxxv In the late 1970s she published her findings on affective disorder in an urban community of the United States,cccxxxvi and in 1980, she presented epidemiological findings on depression in New Haven.cccxxxvii During the 1970s and ‘80s, Weissman in collaboration with Gerald Klerman studied the interaction between drugs and psychotherapy in the treatment of depression,cccxxxviii and developed short-term interpersonal psychotherapy (IPT).cccxxxix Subsequently, she became involved in molcular genetic research in psychiatry.cccxl.cccxli,cccxlii,cccxliii

The background of interviewees in Volume Seven varies widely. Their only common feature is that all 29 interviewees are members of ACNP.

Interviewees entered the field at different stages in the development of neiropsychopharmacology. Hence the volume covers fifty years of history.

Barry Blackwell, the editor of Volume Seven is a distinguished researcher in the field. He also contributed the Dramatis Personae to Volume 4, and the editing of Volume 9 to this series. In his Introduction, Blackwell describes the characteristic features of the group of interviewees included in Volume 7, and focus attention on some of the issues they raised. In his Dramatis Personae he integrates interviewees personal story and contributions.

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