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Wednesday, 01.04.2020

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): 2c. Contributions of Interviewees
Bulletin 47           

 

            Two of the interviewees, Kane and Lieberman were intensively involved in research with atypical antipsychotic drugs in the treatment of schizophrenia. John M. Kane led the multicenter clinical investigations in which clozapine was found effective in some schizophrenic patients refractory to treatment with chlorpromazine and haloperidol (Kane, Hoenigsfeld, Singer et al. 1988; Kane, Marder, Schooler et al. 2001). He was instrumental in the registration of clozapine in the United States. Kane also contributed to verification of the therapeutic efficacy of maintenance treatment with neuroleptics in schizophrenia (Kane, Quitkin, Rifkin et al. 1982).

            Jeffrey A. Lieberman, a collaborator of Kane in the 1980s, led the team which showed that response to a methylphenidate challenge could predict early relapse in maintenance treatment of schizophrenic patients (Janowsky, El-Yousef, Davis et al. 1973; Lieberman, Kane, Gadaleta et al. 1984). Lieberman was also principal investigator of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), which conclusively demonstrated that “atypical neuroleptics” offered a different side effect profile from typical neuroleptics but no advantages in terms of efficacy and therapeutic profile in the treatment of schizophrenia (Lieberman, Stroup, McEvoy et al. 2005).

            Five of the interviewees, Bowden, Uhlenhuth, Kocsis, Winokur and Wheatley, were involved in research related to the therapeutic profile of drugs already in clinical use.  Charles C. Bowden in the 1990s demonstrated that valproate semisodium (divalproex) an anticonvulsant, had comparable efficacy to lithium, the standard mood stabilizer, in the treatment of mania and bipolar disorder (Bowden, Brugger, Swann et al. 1994; Bowden, Calabrese, McElroy et al. 2000). He was instrumental in the registration of divalproex for the treatment of bipolar disorder in the United States.

            Eberhard H Uhlenhuth contributed to research which showed that olanzapine, an atypical neuroleptic for the treatment of schizophrenia, and moclobemide, a monoamine  oxidase (MAO)-A inhibitor for the treatment of depression, might have a place in the treatment of panic disorder (Hollifield, Thompson, Ruiz and Uhlenhuth 2005; Ross, Klein and Uhlenhuth 2010). He also contributed to research which showed that escitalopram, a selective serotonin re-uptake inhibitor for the treatment of major depression, might be useful in the treatment of depressive symptoms of bereavement(Hensly, Slonimski, Uhlenhuth and Clayton 2000). Uhlenhuth was first, in the late 1950s, to conduct a placebo- and standard-controlled clinical trial with meprobamate in patients with anxiety symptoms (Uhlenhuth, Canter, Neustadt and Payson 1959). During the 1980s and 1990s, in collaboration with Mitchell Balter, he extended the scope of epidemiological research by surveying experts’ judgments about the use of psychotropic drugs including benzodiazepines (Uhlenhuth, Balter, Ban and Yang 1987, 1999; Uhlenhuth, Balter and Mellinger 1993).

            James H. Kocsis was first to demonstrate that some of the antidepressants used in the treatment of major depression, e.g., imipramine, desipramine and sertraline, had a favorable effect on social functioning in patients with “dysthymia”(Freedman, Markowitz, Pardes and Kocsis 1995; Kocsis and Frances 1987; Kocsis, Zisook, Davidson et al. 1997). 

            Andrew Winokur’s discovery in the 1970s that the thyrotropine releasing hormone (TRH) is widely distributed in the brain,coupled with Davidson et al.’s demonstration of TRH’s activating effect, led to the hypothesis that TRH regulates arousal, like a “thermostat” (Garyl, Sevarinol, Yarborough, Prange and Winokur 2003; Winokur and Utiger 1974). Thisled also to the possible extension of the therapeutic indications for the substance (Szuba, Amsterdam, Fernando, Whybrow and Winokur 2005).  Winokur was a member of the team which demonstrated the therapeutic effectiveness of modafinil in narcolepsy (US Modafinil Multicenter Study Group 2000). 

            David Wheatley was first to organize a general practice network for clinical investigations with psychotropic drugs (Wheatley 1998). He contributed to the clinical characterization of the effects of antidepressants, hypnotics, anxiolytics and cognitive enhancers in primary care (Wheatley 1964, 1975a,b, 1981, 1988, 1990, 1997, 2007).

            At the heart of psychopharmacological research is the identification of psychiatric populations which are sufficiently homogeneous for studying the pathophysiology and neurochemical underpinning of the condition. Three of the interviewees, Klein, Quitkin and Schatzberg, were involved in such research.

            Based on responsiveness to imipramine (“pharmacological dissection”), Donald F. Klein identified a population within anxiety disorders in the early 1960s that was characterized by recurrent anxiety attacks (Klein 1964, 1973, 1980, 1989, 2008; Klein and Fink 1963). He used the term “panic disorder” as a label for this population and the term was adopted in 1980 into the Third Diagnostic and Statistical Manual (DSM - III) of the American Psychiatric Association as an Axis I diagnosis.  In the 1980s Klein and his associates found that panic attacks could be triggered by increase of carbon dioxide in arterial blood flow. Based on this finding Klein’s postulated that “panic disorder” is a “false suffocation alarm” (Klein 1993; Papp, Klein and Gorman 1993; Papp, Martinez, Klein et al. 1989).

            Frederic Quitkin, a disciple of Klein, corroborated in the late 1980s and early 1990s the diagnostic concept of “atypical depression” (Quitkin, McGrath, Stewart et al. 1989a,b; Quitkin, Stewart, McGrath et al. 1988).He also verified the advantages of phenelzine over imipramine in the treatment of “atypical depression” (Quitkin, Harrison, Stewart et al. 1991; Quitkin, Stewart, Mc Grath et al. 1993, 1997).

            Based on findings which indicated an upregulated hypothalamic-pituitary-adrenal axis with excessive glucocorticoid production in depressed patients with delusions, Alan F. Schatzberg in the mid-1980s advanced a corticosteroid/dopamine hypothesis for psychotic depression. He also demonstrated that administration of glucocorticoids produced “cognitive changes” similar to those seen in depression (Schatzberg, Rothschild, Langlais et al. 1985). To block the effect of glucocorticoids Schatzberg suggested the administration of mifepristone, an antagonist, in high doses of low affinity glucocorticoid receptors (Rotschild and Schatzberg 1994).

            Interviewees included in Volume 4 entered the field at different stages in the development of psychopharmacology. Hence the transcripts cover 50 years of history, from uncontrolled single center clinical studies to multicenter clinical investigations using power statistics. With the development of clinical methodology, evidence-based findings replaced testimonials about the clinical effects of psychotropic drugs. As the armamentarium of psychotropic drugs with demonstrated efficacy grew, it came to include first antipsychotics, antidepressants and anxiolytics, then mood stabilizers and ultimately cognitive enhancers.

            Jerome Levine, the editor of volume four was one of the architects of the methodology used in clinical investigations with psychotropic drugs. Barry Blackwell, who contributed the Dramatis Personae, is a distinguished researcher in the field. He was first in 1970 to record, in collaboration with Frank Ayd, the story of the pioneers in the development of new psychotropic drugs (Ayd and Blackwell 1970).  

 

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December 6, 2018