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
Neuropsychopharmacology (Volume Five): 4a. Contributions of Interviewees
(Bulletin 51)


            The information in Bulletins 48, 49 and 50 provides orientation points in the development of neuropsychopharmacology, placing in perspective historical contributions of the interviewees in Bulletins 51, 52 and 53. 

            All 30 interviewees of Volume Five are psychiatrists and ACNP members. One of the interviewees, Arnold Friedhoff, is founder and past president, and four, William Bunney, William Carpenter, Herbert Meltzer and Arthur Prange, are past presidents.

            All interviews were done in a period from 1995 to 2007 and, with the exception of one, at annual meetings. Claude de Mintigny was interviewed in Paris between meetings. 

            The 30 interviews were done by 15 interviewers with one interviewee (Carroll) interviewed by two interviewers (Hollister and Ban); 10 interviewers (Belmaker, Braslow, Bromley, Bunney, Calabrese, Davis, Detre, Goodwin, Greden, and Koslow) conducted one interview; one interviewer (Hollister) three; two interviewers (Healy and Tone) four; and one (Ban) nine.

            By the time Volume Five was published in 2011, two of the interviewees (Friedhoff and Schildkraut) and two of the interviewers (Detre and Hollister) had passed away (Ban 2011; Gershon 2011).


Contributions of Interviewees


            The 30 interviewees were involved in six broadly defined areas of research in neuropsychopharmacology; most of the interviewees were involved in more than one area. Eight interviewees (Angrist, Baldessarini, Carpenter, Chouinard, Friedhoff, Kapur, Meltzer and van Kammen) were engaged in research related to the neuropsychopharmacology of schizophrenia. William T. Carpenter divided schizophrenia into “deficit schizophrenia” and “non-deficit schizophrenia” and demonstrated that “deficit schizophrenia” responds differently to neuroleptics than “non-deficit schizophrenia” (Carpenter, Hanlon, Henrichs et al. 1990; Carpenter, Heinrichs and Wagman 1988; Kirkpatrick, Buchanan, Ross and Carpenter 2001).

            In 1962 Arnold J. Friedhoff detected a “pink spot” in the urine of schizophrenic patients and identified it as 3,4-dimehoxyphenylamine (DMPEA), the endogenous psychotoxic mescaline-like substance that Harley-Mason suggested as the cause of schizophrenia (Friedhoff 1977; Friedhoff and Van Winkle 1962). Ten years later, in 1972, in collaboration with Schweitzer and Miller, he demonstrated the biosynthesis of mescaline and N-acetylmescaline by mammalian liver (Friedhoff, Schweitzer and Miller 1972).

            In the late 1970s Ross J. Baldessarini showed that administration of S-Adenosyl-L-methionine (SAMe), a methyl donor, did not result in an increase in the formation of psychotoxic dimethyltryptamine (DMT) (Stramentolini and Baldessarini (1978). In collaboration with Giorgio Stramentolini, Baldessarini demonstrated that N-methyl transferase, the enzyme involved in the formation of DMT, is saturated under normal conditions (Baldessarini, Stramentolini and Lipinsky 1979). Baldessarini also contributed to the determination of the maintenance dose of neuroleptics in the treatment of schizophrenia (Baldessarini and Davis 1980).

            In the 1970s Burt Angrist, a disciple of Samuel Gershon, reported that not only amphetamine but also other dopamine agonists could induce psychosis in normal subjects and exacerbate symptoms of schizophrenia. He also found a positive correlation between the intensity of psychotic symptoms and homovanillic acid (HVA) levels in the cerebrospinal fluid (CSF) of schizophrenic patients (Angrist, Sathananthan, Wilk and Gershon 1974). Angrist demonstrated that both positive and negative symptoms can be induced by amphetamine and that neuroleptics have a differential effect on the positive and negative symptoms of schizophrenia (Angrist and Gershon 1970; Angrist, Rotrosen and Gershon 1980).

            In the early 1980s Daniel Van Kammen reported on low CSF γ-amino butyric acid (GABA) levels in recently ill schizophrenic patients (Van Kammen, Steinberg, Hare,Waters and Bunney 1982). He also found an inverse relationship between CSF dopamine beta-hydroxylase (DBH) levels and treatment response to neuroleptics (Sternberg, Van Kammen, Lerner and Bunney 1982). Van Kammen demonstrated that elevated CSF-norepinephrine (NE) levels are predictive of relapse after withdrawal of haloperidoland provided further substantiation for the pharmacological heterogeneity of schizophrenia to a d-amphetamine challenge (Van Kammen, Peters, Van Kammen, Nugent et al. 1989; Van Kammens, Peter, Van Kammen, Rosen et al 1989). Van Kammen contributed to the clinical development of clonidineand several atypical neuroleptic drugs, including quetiapine, risperidone, sertindol and ziprasidone (Van Kammen 2002; Van Kammen, Bunney, Docherty et al. 1982; Van Kammen, McEvoy, Targum and Kardeijzke 1986).

            Guy Chouinard was first, in the late 1970s, to describe the clinical and pharmacologic characteristics of a super-sensitivity psychosis to neuroleptics (Chouinard and Jones 1979, 1980a; b; Chouinard, Jones and Annable 1978). He was also among the first to propose that schizophrenia is a dopamine deficiency disease (Choinard and Jones 1979, 1980b). Chouinard contributed to the clinical development of numerous psychotropic drugs including  alprazolam, bupropion, clonazepam, clozapine, fluoxetine, fluspirilene, gabapentine, Mogedon, nitrazepam, pimozide, risperidone, sertraline, tomoxetine, tryptophan and zimelidine (Bordoleau, Chouinard and Tetrault 1966; Chouinard 1983, 1985; Chouinard and Annable 1976; Chouinard, Annable and Bradwejn 1984; Chouinard, Annable, Fontain et al. 1982; Chouinard, Beauclair and Belanger 1998; Chouinard, Bouchard and Belanger 1990; Chouinard, Goodman, Greis et al. 1990; Chouiard, Jones, Remington et al. 1993; Chouinard, Lehmann and Ban 1970; Chouinard, Lehmann, Ban and Ananth 1970;  Chouinard. Young and Annable 1983; Chouinard, Young, Bradwejn et al. 1983; Fontaine, Chouinard and Ivy 1985).

            Shitij Kapur studied the relationship between dopamine-D2 receptor occupancy, clinical response and side effects of neuroleptics with the employment of positron emission tomography (PET) (Kapur, Zipursky, Jones et al. 2000). He found high levels of dopamine-D2 receptor occupancy with relatively low doses of haloperidol (Kapur, Remington, Jones et al. 1996). Together with Philip Seeman, Kapur demonstrated that atypical neuroleptics dissociate more rapidly from the dopamine-D2 receptor than typical neuroleptics (Kapur and Remington 2001; Kapur and Seeman 2001).

            Herbert H. Meltzer was among the first to demonstrate that atypical neuroleptics have a reversed affinity to dopamine-D2 and serotonin-5HT2 receptors compared to typical neuroleptics (Meltzer, Matsubara and Lee 1989). He was a member of the team that demonstrated the efficacy of clozapine in treatment refractory schizophrenia and also the team which showed its favourable effect on “cognitive function” in schizophrenia (Kane, Honigfeld, Meltzer and Singer 1988). Meltzer contributed to the clinical development of several “atypical neuroleptics,” including olanzepine, risperidone, melperone (Hagger, Buckley, Kenny et al. 1993; Meltzer and McGurk 1999; Meltzer, Park and Kessler 1999; Meltzer, Samiyoshi and Yawathilake 1999).

            The research of one interviewee, Donald Robinson, focused on the relationship between monoamine oxidase (MAO) inhibition and therapeutic effects. With the employment of a modification of the assay developed by Wurtman and Axelrod, Robinson revealed an association between the dose of phenelzine, platelet MAO inhibition and urinary tryptamine excretion (Robinson, Lovenberg, Kaiser and Sjoersdma 1969; Wurtman and Axelrod 1961). In the early 1970s he reported on the therapeutic effects of phenelzine in depression and anxiety states, established that 80% or higher inhibition of MAO was a prerequisite for effective treatment with monoamine oxidase inhibitors (MAOIs) and demonstrated the therapeutic efficacy of phenelzine in the continuation and maintenance therapy of major depression (Ravaris, Nies, Robinson et al 1976; Robinson, Lerfold, Bennett et al. 1991; Robinson, Nies, Ravaris and Lamborn 1973)..




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Angrist B, Rotrosen J, Gershon S. Differential effects of amphetamine and neuroleptics on negative vs. positive symptoms in schizophrenia. Psychopharmacology. 1980; 72: 17-9.

Angrist B, Sathananthan G, Wilk S, Gershon S. Amphetamine psychosis: Behavioral and biochemical aspects. J Psychiatr Res 1974; 11: 13-23.

Baldessarini RJ, Davis JM. What is the best maintenance dose of neuroleptics. Psychiatry Research 1980; 3: 115-22.

Baldessarini RJ, Stramentolini G, Lipinski JF. Methionine hypothesis. Arch Gen Psychiatry  1979; 36: 303-7.

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Bordoleau JM, Chouinard G, Tetreault L. Study of the hypnotic properties of a new benzodiazepine preparation (Mogedon). Comparative evaluation. Union Med 1966; 95: 50-3.

Carpenter WT, Hanlon TE, Heinrichs DW, Summerfelt A, Kirkpatrick B, Levine J, Buchanan RW. Continuous vs. targeted medication in schizophrenic outpatients: Outcome results. Am J Psychiatry 1990; 147: 1138-48.

Carpenter WT, Heinrichs DW, Wagman AM.  Deficit and non-deficit forms of schizophrenia: The concept. Am J Psychiatry. 1988; 145: 578-83.

Chouinard G. Bupropion and amitriptyline in the treatment of depressed patients. J Clin Psychiatry 1983; 44: 121–9.

Chouinard G, Annable L. Clozapine in the treatment of newly admitted schizophrenic patients. A pilot study. J Clin Pharmacol 1976; 16: 289-97.

Chouinard G, Annable L, Bradwejn J. An early phase II clinical trial of tomoxetine (LY139603) in the treatment of newly admitted depressed patients. Psychopharmacology (Berl) 1984; 83: 126–8.

Chouinard G, Annable L, Fontaine R, et al. Alprazolam in the treatment of generalized anxiety and panic disorders: a double-blind placebo-controlled study. Psychopharmacology (Berl) 1982; 77: 229–33.

Chouinard G, Beauclair L, Belanger MC. Gabapentin: long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders. Can J Psychiatry 1998; 43: 305-9.

Chouinard G, Goodman W, Greist J, Jenike M, Rasmussen S, White K, Hackett E, Gaffney M, Bick PA. Results of a double-blind placebo-controlled trial of a new serotonin uptake inhibitor, sertraline, in the treatment of obsessive-compulsive disorder. Psychopharmacol Bull. 1990; 26: 279-84.

Chouinard G, Jones BD. Evidence of brain dopamine deficiency in schizophrenia. Can J Psychiatry 1979; 24: 661-7.

Chouinard G, Jones BD. Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 1980a;137: 16–21

Chouinard G, Jones BD. Schizophrenia; a dopamine deficiency disease. Lancet 1980b; 2: 99-100

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Chouinard G, Lehmann HE, Ban TA. Pimozide in the treatment of chronic schizophrenic patients. Current Therapeutic Research 1970; 12: 598-603.

Chouinard G, Lehmann  HE, Ban TA, Ananth JV. Fluspiriline in the treatment of  chronic schizophrenic patients. Current Therapeutic Research  1970; 12: 604-8.

Chouinard G, Young SN, Annable L. Antimanic effect of clonazepam. Biol Psychiatry 1983; 18: 451–66.

Chouinard G, Young SN, Bradwejn J et al. Tryptophan in the treatment of depression and mania. In: van Praag HM, Mendlewicz J, editors. Advances in Biological Psychiatry. Volume. 10. Basel: Karger; 1983. p. 47–66.

Fontaine R, Chouinard G, Ivy L. An open clinical trial of zimelidine in the treatment of obsessive compulsive disorder. Curr Ther Res 1985; 37: 326–32. 

Friedhoff AJ. Biosynthesis of endogenous hallucinogens: In Usdin E, Hamburg DA, Barchas JD, editors. Neuro-Regulators and Psychiatric Disorders. New York: Oxford University Press; 1977. p. 557-64.

Friedhoff AJ, Schweitzer JW, Miller JC. Biosynthesis of mescaline and N-acetylmescaline by mammalian liver. Nature. 1972; 237: 454-55.

Friedhoff AJ, Van Winkle E. Isolation and characterization of a compound from the urine of the schizophrenic. Nature. 1962; 194: 897-8.

Gershon S, editor. Neuropsychopharmacology. Volume 5. (In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews). Budapest: Animula; 2011.

Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY. Improvement in cognitive functions and psychiatric symptoms in treatment refractory schizophrenic patients receiving clozapine. Biol Psychiatry 1993; 34: 702-12.

Kane J, Honigfeld G, Singer J, Meltzer HY, The Clozaril Collaborative Study Group. Clozapine for treatment resistant schizophrenia: A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-98.

Kapur S, Remington G: Dopamine-D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 2001; 50: 873-83

Kapur S, Remington G, Jones C, Wilson A, DaSilva J, Houle S, Zipursky R. High level of dopamine-D2 occupancy with low doses of haloperidol a PET study. Am J Psychiatry 1996; 153: 942-50

Kapur S, Seeman P: Does fast dissociation from the dopamine-D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. Am J Psychiatry 2001; 158:360-9

Kapur SJ, Zipursky R, Jones C, Remington G, Houle S: Relationship between dopamine-D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157: 514-52

Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 2001; 58: 165-71.

Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin2 pk1 values. J Exp Ther 1989; 251: 238-48.

Meltzer HY, McGurk SR. The effect of clozapine, risperidone, and olanzepine on cognitive functions in schizophrenia. Schizophrenia Bulletin 1999; 25: 233-5.

Meltzer HY, Park S, Kessler R. Cognition, schizophrenia and atypical antipsychotic drugs. Proc Natl Acad Sci USA 1999; 96: 13591-3.

Meltzer HY, Sumiyoshi T, Yavathilake K. Melperone in the treatment of neuroleptic-resistant schizophrenia. Psychiatr Res 2001; 96: 201-9.

Ravaris CL, Nies A, Robinson DS, Ives JO, Lamborn KR, Korson L. A multiple-dose controlled study of phenelzine in depression and anxiety states. Arch Gen Psychiatry 1976; 33: 347-50.

Robinson DS, Lerfold SC, Bennett B, Laux D, Devereaux E, Kayser A, Corcella J, Albright D. Continuation and maintenance treatment of major depression with the monoamine oxidase inhibitor phenelzine: A double-blind placebo-controlled discontinuation study. Psychopharm Bull. 1991; 27: 31-9.

Robinson DS, Lovenberg W, Keiser H, Sjoersma A. Effects of drugs on human blood platelet and plasma amine oxidase activity in vitro and in vivo. Biochem Pharmacol. 1969; 17: 109-19.

Robinson DS, Nies A, Ravaris CL, Lamborn KR. The monoamine oxidase inhibitor, phenelzine, in the treatment of depressive-anxiety states; a controlled clinical trial. Arch Gen Psychiatry. 1973; 29: 407-13.

Sternberg DE, van Kammen DP, Lerner P, Bunney WE Jr. Schizophrenia: Dopamine-ß –hydroxylase activity and treatment response. Science. 1982; 216: 1423-5.

Stramentolini G, Baldessarini RJ. Lack of enhancement of dimethyltryptamine formation in rat brain and rabbit lung in vivo by methionine and S-adenosylmethionine. Journal of Neurochemistry 1978; 31: 1015-20.

Van Kammen D. Pursuing the demons of schizophrenia. In: Ban TA, Healy D, Shorter E, editors. From Psychopharmacology to Neuropsychopharmacology and The Story of CINP. Budapest: Animula; 2002, p. 252-9.

Van Kammen, DP, Bunney WE, Docherty JP, Marder S, Ebert MH, Goodwin FK,  Rosenblatt JE, Rayner  JN. D-amphetamine  induced  heterogeneous  changes in psychotic behaviour in  schizophrenia.  Am J Psychiatry  1982;  139:  991-7.

Van Kammen DP, McEvoy JP, Targum SD, Kardayzke T. A randomized, controlled dose ranging trial of sertindole in patients  with schizophrenia. Psychopharmacology 1996; 124: 168-75. 

Van Kammen DP, Peters JC, Van Kammen WB, Nugent A, Goetz KL, Yao J, Linnoila M. CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal. Biological Psychiatry 1989; 2: 175-88.

Van Kammen DP, Peters JL, Van Kammen WB, Rosen J, Yao JK, McAdam D, Linnoila M. Clonidine treatment of schizophrenia: can we predict treatment response?  Psychiatry Research 1989; 27: 297- 11.

Van Kammen DP, Sternberg WA, Hare TA, Waters RN, Bunney WE. CSF levels of γ-aminobutyric acid  in schizophrenia. Low values in recently ill patients. Arh Gen Psychiatry  1982; 39: 91-7.

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January 3, 2019