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Friday, 21.02.2020

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): 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).  



Ayd FJ, Blackwell B. Discoveries in Biological Psychiatry. Philadelphia: Lippincott; 1970.

Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG, et al.Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 1994; 271: 918-24.

Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC, Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ.A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of out patients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000; 57:481-9.

Freedman RA, Markowitz JC, Pardes M, Kocsis JH. Acute response of social functioning in dysthymic patients with desipramine. J Affective Disorder 1995; 34: 85-8.

Garyl KA, Sevarinol KA, Kocsis JH, Frances AJ. A critical discussion of DSM-III dysthymic disorder. Am J. Psychiatry 1987; 144: 1534-42.

Hensley PL, Slonimski CK, Uhlenhuth EH, Clayton PJ. Escitalopram: an open label study of bereavement related to depression and grief. J Affect Disord 2000; 113: 142-9.

Hollifield M, Thompson PM, Ruiz JE, Uhlenhuth EH. Potential effectiveness and safety of olanzapine in refractory panic disorder.  Depress Anxiety 2005; 21: 33-40.

Janowsky DS, el-Yousel MK, Davis JM, Sekerke HJ. Provocation of schizophrenic symptoms by intravenous administration of methylphenidate. Archives of General Psychiatry  1973; 28: 185-91.

Kane J, Honigfeld G, Singer J, Meltzer H.Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 1988; 45: 789-96.

Kane JM, Marder SR, Schooler NR, Wirshing WC, Umbricht D, Baker RW, Wirshing DA, Safferman A, Ganguli R, Bronstein M, McMenniman M. Clozapine and haloperidol in moderately refractory schizophrenia: a six months randomized and double-blind comparison. Arch Gen Psychiatry 2001; 58: 965-72.

Kane JM, Quitkin F, Rifkin A, Ramos–Lorenzi JR, Nayak D. Fluphenazine versus placebo in patients with remitted acute first episode schizophrenia. Arch Gen Psychiatry 1982; 39: 70-3.

Klein DF. Delineation of two drug-responsive anxiety syndromes. Psychophramacologia 1964; 5: 397-408.

Klein DF. Anxiety re-conceptualized Comprehensive Psychiatry 1980; 21: 411-27.

Klein DF. Drug therapy a means of syndromal identification and nosological revision. In: Cole JO, Freedman AM, Friedhoff AJ, editors. Psychopathology and Psychopharmacology. Baltimore and London: The Johns Hopkins University Press; 1973. p. 143-60. 

Klein DF. The pharmacological validation of diagnoses. In: Robins LN, Barret JE, editors. The Validity of Psychiatric Diagnoses. New York: Raven Press:1989. p. 203-217.

Klein DF. False suffocation alarms, spontaneous panics, and related conditions: an integrative approach. Ach Gen Psychiatry 1993; 50: 306-17. 

Klein DF. The loss of serendipity in psychopharmacology. JAMA 2008; 299: 1063-5.

Klein DF, Fink M. Behavioral reaction patterns with phenothiazines. Archives of General Psychiatry 1962; 24: 449-59.

Kocsis JH, Frances AJ. A critical discussion of DSM-III dysthymic disorder. Am J. Psychiatry 1987; 144: 1534 – 42.

Kocsis JH, Zisook S, Davidson J, Shelton R, Yonkers K, Hellerstein DJ, Rosenbaum J, Halbreich U. Double-blind comparison of sertraline, imipramine and placebo  in the  treatment of dysthymia. Psychosocial outcome measures. Am J Psychiatry 1997; 154: 390-5.

Lieberman JA, Kane JM, Gadaleta D, Brenner R, Lesser MS, Kinon B. Methylphenidate challenge as predictor of relapse in schizophrenia. Am J Psychiatry 1984; 141: 633-8.

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators.Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.N Engl J Med2005; 353:1209-23.

Papp LA, Klein DF, Gorman JM. Carbon dioxide hypersensitivity, hyperventilation and panic disorder. Am J Psychiatry 1993; 150: 1149-57.

Papp LA, Martinez JM, Klein DF, Liebowitz MR, Fyer AJ, Hollander I, Gorman JM. Arterial blood changes in panic disorder and lactate-induced panic. Psychiatry Research 1989; 28: 171-80.

Quitkin FM, Harrison W, Stewart JW, McGrath PJ, Tricamo E, Ocepek-Welikson K, Rabkin JG, Wager SG, Nunes E, Klein DF. Response to phenelzine and imipramine in placebo non-responders with atypical depression: a new application of the crossover design. Arch Gen Psychiatry 1991; 48:319-32.

Quitkin FM, McGrath PJ, Stewart JW, Harrison W, Tricamo E, Wager SG, Ocepek-Welikson K, Nunes E, Rabkin JG, Klein DF. Atypical depression, panic attacks, and response to imipramine and phenelzine: a replication. Arch Gen Psychiatry 1990; 47 935-41. 

Quitkin FM, McGrath PJ, Stewart JW, Harrison W, Wager SG, Nunes E, Rabkin JG, Tricamo E, Markowitz J, Klein DF: Phenelzine and imipramine in mood reactive depressives: further delineation of the syndrome of atypical depression. Arch Gen Psychiatry 1989; 46:787-93.

Quitkin FM, Stewart JW, McGrath PJ, Liebowitz MR, Harrison WM, Tricamo E, Klein DF, Rabkin JG, Markowitz JS, Wager SG: Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders. Am J Psychiatry 1988; 145:306-11. 

Quitkin FM, Stewart JW, McGrath PJ, Nunes EV, Klein DF: The identification and validation of distinct depressive syndromes in a population-based sample of female twins. Arch Gen Psychiatry 1997; 54: 970-2.

Ross DC, Klein DF, Uhlenhuth EH. Improved statistical analysis of moclobemide dose effects on panic disorder treatment. Eur Arch Psychiatry Clin Neurosci 2010; 260: 243-8.

Rotschild AJ, Schatzberg AF. Diagnosis an and treatment of psychotic depression. In: Grunhaus L, Greden JF, editors. Severe Depressive Disorders. Washington: American Psychiatric Press; 1994.  p. 195-207.

Schatzberg AF, Rothschild AJ, Langlais PJ, Bird ED, Cole JO A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 1985; 19:57–64.

Szuba MP, Amsterdam JD, Fernando AT, Whybrow PC, Winokur A Rapid antidepressant response after nocturnal TRH administration in patients with bipolar I and bipolar II patients with major depression. J Clin Psychopharmacol 2005; 25: 325-3.0

Uhlenhuth EH, Balter MB, Ban TA, Yang K. International study of expert judgment on therapeutic use of benzodiazepines and other therapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders. J Clin Psychopharmacol 1999; 19: 2S-29S.

Uhlenhuth EH, Balter MB, Ban TA, Yang K. Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel. 1992-1997. European Psychopharmacology 1999; 9 (Supplement 6): S393-S8.

UhlenhuthEH, Balter MB, Mellinger GD. Clinical variables in pharmacoepidemiology.  J Psychiatr Res 1993; 27 (Supplement.1): 89–95.

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Wheatley D. Adrenergic drugs in depression. Arch Gen Psychiatry 1975; 32: 653-55.

Wheatley D. Psychopharmacology of Sleep. London: Heinemann & Appleton Century Croft; 1981.

Wheatley D New hypnotic agents: clinical study in general practice Pharmacology, Biochemistry and Behavior 1988; 29: 811-3.

Wheatley D. The Anxiolytic Jungle. Chichester: Wiley; 1990.

Wheatley D. Psychopharmacology of Cognitive and Psychiatric Disorders in the Elderly. London: Chapman & Hall; 1997.

Wheatley D. Research in general practice. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacolog and the Story of CINP. Budapest: Animula; 1998. p. 281-4.

Wheatley D. Insomnia in general practice: the role of temazepam in comparison with zopiclone.  Acta PsychiatrScandinavica 2007; 74: 142-8.

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Yarborough GG, Prange JJ, Winokur A. The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. The Journal of Pharmacology 2003; 305: 410-6.


December 6, 2018