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Monday, 24.02.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years
Psychopharmacology (Volume Four): 2a. Contributions of Interviewees
Bulletin 45


            The information in Bulletin 44 provided the necessary orientation points for identifying the place of the contributions of the 30 interviewees whose transcripts in Volume 4 record the development of psychopharmacology. All transcripts are based on videotaped interviews.

            From the 30 interviewees of Volume Four, 23 are MDs (Autry, Ban, Blackwell, Bowden, Cole, Gallant, Gardos, Goldstein, Kane, Klein D, Kocsis, Lecrubier, Levine, Lieberman, Paykel, Quitkin, Rickels, Schatzberg, Simpson, Uhlenhuth, Vinar, Wheatley and Winokur),  and seven  PhDs (Hogarty, Katz, Klett, McNair, Overall, Raskin and Schooler)  All but one of the MDs, David Wheatley, a general practitioner,  are psychiatrists; and all but one of the PhDs, Gerard Hogarty, a social worker, are psychologists. All, but two of the interviewees, Lecrubier and Wheatley, are ACNP members; one of the interviewees, Autry, was, at the time of the interview, an administrative member. Four of the interviewees, Cole, Klett, Rickels and Uhlenhuth, are founders, and five, Cole, Klein D, Schatzberg, Simpson and Uhlenhuth, are past presidents.

            All interviews were done in a period from 1994 to 2007 and with the exception of two interviews, Autry’s and Klett’s, they were done at annual meetings. Autry and Klett were interviewed in Washington, DC, between meetings.

            The 30 interviews were done by 10 interviewers with seven interviewers, Braslow, Endicott, Gershon, Healy, Kapur, Levine and Robinson, conducting one interview and from the other three interviewers Tone conducting four, Ban nine, and Hollister 10.

            By the time Volume Four was published five of the interviewees, Cole, Hogarty, Lecrubier, Quitkin and Wheatley, and one of the interviewers, Hollister, had passed away (Ban 2011; Levine 2011).


Contributions of Interviewees


             In Bulletin 45 some of the contributions of 12 of the 30 interviewees of Volume Four to the development of psychopharmacology are reviewed.

             Two interviewees, Cole and Levine, were instrumental in developing the Biometric Laboratory Information Processing System(BLIPS)and implementing the clinical methodology that was to be used in efficacy studies with psychotropic drugs.  Jonathan O. Cole, the founding director of Psychopharmacology Service Center (PSC), lead the team that designed and organized the NIMH Collaborative Studies in which the effectiveness of the phenothiazine neuroleptics in the treatment of acute and chronic schizophrenia was conclusively demonstrated (Goldberg, Klerman and Cole 1965; National Institute of Mental Health 1964, 1967). Cole was also first, in collaboration with Gerald (Jerry) Klerman, to demonstrate the efficacy of imipramine and related antidepressants in depressive disorders (Klerman and Cole 1965).

            Jerome Levine, the successor of Jonathan Cole as director of PSC, developed in collaboration with Nina Schooler, the Abnormal Involuntary Movement Scale (AIMS) for rating the severity of tardive dyskinesia, and an instrument for recording side effects in clinical trials with psychotropic drugs, (Systematic Assessment for Treatment Emergent Events - SAFTEE) (Levine and Schooler 1986). Levine was a member of the team which demonstrated that LSD offers no benefit in chronic alcoholism, a treatment advocated by Hoffer and Osmond in the 1960s (Hoffer and Osmond 1968; Ludwig, Levine and Stark 1970; Ludwig, Levine, Stark and Lazar 1969).

            Numerous NIMH programs from the late 1950s to the end of the 1980s addressed issues relevant to the clinical use of psychotropic drugs. Joseph H. Autry helped set up the collaborative research program in the treatment of depression in the early 1980s which indicated that only in “severe depression” was pharmacotherapy the primary choice of treatment (Elkin, Perloff, Hadley and Autry 1985).

            Findings in clinical investigations are based on the assessment instruments employed; five of the interviewees, McNair, Klett, Overall, Raskin and Vinar, were involved in the development of rating scales for the assessment of change in the course of treatment. John E. Overall with Donald Gorham developed the Brief Psychiatric Rating Scale (BPRS) from Maurice Lorr’s Multi-dimensional Scale for Rating Psychiatric Patient (MSRPP) (Lorr, Jenkins and Holsopple 1953; Overall and Gorham 1962). The BPRS, introduced in 1962, was to become one of the most extensively used rating scales in clinical studies with psychotropic drugs (Overall and Gorham 1962).Overall was first to apply “least squares analysis” for natural data with psychotropic drugs (Overall and Spiegel 1969). He also spearheaded the application of other statistical techniques in clinical research by publishing, with Klett in 1972, Applied Multivariate Analysis (Overall and Klett 1971).

            James C. Klett, in collaboration with Gilbert Honigfeld, developed the Nurses Observation Scale for Inpatient Evaluation (NOSIE.) The NOSIE, introduced in 1965, was to become one of the standard assessment instruments in clinical trials with hospitalized psychiatric patients (Honigfeld and Klett 1965). Klett was a member of the US Veterans Administration (VA) team which demonstrated the efficacy of phenothiazines in the treatment of schizophrenia in 1960 (Casey, Lasky, Klett and Hollister 1960). He was also member of Lorr’s team which developed the Inpatients Multi-dimensional Rating Scale (IMPS) from the MSRPP (Lorr and Klett 1975).

            Douglas McNair was also a member of Lorr’s team converting the MSRPP into the IMPS (Lorr and Klett.1962).In collaboration with Lorr and Droppleman, McNair introduced in 1971 the Profile of Mood States (POMS) that was to be used for the assessment of change in outpatient clinical trials (McNair, Lorr and Droppleman 1971).

            Allen Raskin, an associate of Jerome Levine at PRC who set up NIMH’s nine-hospital antidepressant study, developed in the late 1960s, the Raskin Depression Rating Scale (RDRS) (Raskin 1972; Raskin, Schulterbrandt, Reatig and McKeon 1969). With the employment of “reverse factor analysis,” Raskin separated four distinct groups within the depressive population: “agitated,” “neurotic,” “endogenous” and “poor pre-morbid personality” depressions (Raskin and Crook 1976).

            Oldrich Vinar developed, in the early 1960s, scales referred to by their Czech acronyms as FKP (Farmacologicka Kvantífikace Deprese)and FKD (Farmacologicka Kvantífikace Psychos)Scales, for measuring changes in psychotic and depressive symptomatology in clinical studies (Vinar 1975; Vinar, Vinar and Grof 1966).Vinar also introduced the “continuous controlled clinical trial  in his research unit in Czechoslovakia (Vinar1976). He was instrumental in the development of several psychotropic drugs for the Czechoslovakian pharmaceutical industry, e.g., dosulepine, a chlorinated amitriptyline, dichlorpromazine, a minor tranquilizer and isofloxythepine, a clozapine-like drug (Vinar 1998).

            Not all changes in rating scale scores could be attributed to the pharmacological action of psychotropic drugs; three of the interviewees, Rickels, Hogarty, and Schooler, were involved in research to determine the contribution of other factorsKarl Rickels led clinical research in the 1960s studying the effect of non-specific factors on drug treatment (Rickels 196?).He was also first in the United States, to organize a network of practitioners to collaborate in clinical investigations with these drugs (Rickels, Cattell, Weise et al. 1966). Rickels contributed to the clinical development of some of the early anxiolytic drugs, e.g., meprobamate, chlordiazepoxide and diazepam; he also contributed to delineating the differential effect of antidepressants and anxiolytics in the first phase of treatment of generalized anxiety disorder (Rickels 1966; Rickels, Downing, Schweizer and Hassman 1993).

            Gerard E. Hogarty, a member of Jonathan Cole’s team in the NIMH Collaborative Studies in schizophrenia, explored systematically the interaction between social and pharmacological treatments in schizophrenia including personal therapy, major role therapy and cognitive enhancement training (Hogarty, Goldberg and Schooler 1964; Hogarty, Goldberg, Schooler and Ulrich 1974).He was the first to show that social therapies alone, without neuroleptics, might have a negative effect, whereas social therapies combined with neuroleptics could help patients in social adjustment (Hogarty 2002).

            Nina R. Schooler, a member of the Cole/Levine group, was involved with Hogarty’s team studying the interaction between drugs and social therapies in the treatment of schizophrenia. In collaboration with Hogarty and Weissman, she developed a Social Adjustment Scale (SAS II), introduced in 1979 (Schooler, Hogarty and Weissman 1970). Schooler participated in research on the clinical development of several “atypical antipsychotics” including aripiprazole, clozapine, risperidone, sertindole and ziprasidone (Schooler 1997; Schooler, Ralsinawitz, Davidson et al. 2005).

            Four of the interviewees, Katz, Paykel, Blackwell and Lecrubier, were involved in the development of assessment instruments other than the rating scales used in the assessment of change in clinical trials. Martin M. Katz, one of the first members of Cole’s team at the PSC, introduced the Katz Adjustment Scales in 1963 for measuring adjustment of social behavior in the community of patients discharged from hospital after successful pharmacological treatment (Katz and Lyerly 1963). He also developed a “video methodology” for research in psychopathology and psychopharmacology in the 1970s (Katz and Itil 1974; Katz, Wetzler, Kastor and Secunda 1989). In a NIMH sponsored multi-center clinical investigation in depression, Katz and his associates demonstrated clinical changes within a week of commencement of treatment with SSRIs and TCAsand challenged the theory about delayed onset of anti-depressant effects (Katz, Houston, Brannan et al. 2004; Katz, Koslow, Maas et al. 1987). The changes with paroxetine within the first week were in anxiety and hostility whereas the changes with desipramine were in retardation and depression (Katz, Tekell, Bowden et al. 2004).

            Eugene S. Paykel developed a “life events” scale in the late 1960s and was the first to verify the commonly held view that recent life events might play a role in the pathogenesis of some depression (Paykel 1969).In the early 1970s, with the employment of cluster analysis, Paykel divided depressed patients into four groups: psychotic, anxious, hostile and depressives with personality disorder (Paykel 1971). Paykel also corroborated evidence for the differential effect of the tricyclic antidepressant amitriptyline and the MAOI phenelzine in the treatment of neurotic depressionand for the efficacy of continuation and maintenance treatment with antidepressants in unipolar depression (Paykel 2001; Rowas, Paykel and Parker 1982).

            The first validated screening instrument for the identification of psychiatric disorders in a primary care setting, the General Health Questionnaire (GHQ,) was developed by David Goldberg in collaboration with Barry Blackwell.  With the employment of the GHQ they found psychiatric morbidity in one out of every five patients seen by general practitioners (Goldberg and Blackwell 1970).Blackwell was one of the first to report on hypertensive crisis involving tranylcypromine in patients consuming cheese (Blackwell 1963). His discovery of cheese and the role of tyramine and other variables in patients treated with MAOIs has profoundly affected the pharmacological treatment of depression (Blackwell 1998; Blackwell, Marley, Price and Taylor 1967).

            Yves Lecrubier, in collaboration with David Sheehan, developed a brief, about 15-minute, structured interview, the Mini-International Neuropsychiatric Interview (MINI), which yields a DSM-IV and an ICD-10 diagnosis (Sheehan, Lecrubier, Amorim et al. 1998).Lecrubier also developed an instrument for measuring “retardation” that he considered the cardinal symptom of depressive illness (Lecrubier 2006). In his research in schizophrenia, Lecrubier substantiated the notion that low dose neuroleptics affect “deficit,” whereas high dose neuroleptics affect “productive” symptoms (Kapur and Lecrubier 2003).




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November 22, 2018.