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
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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Chouinard G, Lehmann HE, Ban TA, Ananth JV. Fluspiriline in the treatment of chronic schizophrenic patients. Current Therapeutic Research 1970; 12: 604-8.
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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.
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Friedhoff AJ, Van Winkle E. Isolation and characterization of a compound from the urine of the schizophrenic. Nature. 1962; 194: 897-8.
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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.
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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
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January 3, 2019