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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): 4b. Contributions of Interviewees)
(Bulletin 52)

 

           Twelve interviewees (Bunney, Davis, Fawcett, de Montigny, Halaris, Janowsky, Oxenkrug, Potter, Richelson, Schildkraut, Shopsin and Van Praag) were engaged in research- related to the neuropsychopharmacology of depression.

           In 1964 Joseph J. Schildkrautre ported that urinary out put of catecholamine metabolites, such as vanyl mandelic acid (VMA) was decreased and normetanephrine increased in imipramine treated patients (Schidkraut 1965; Schildkraut, Klerman, Hammond and Friend 1964). He also demonstrated that the increase of normetanephrine in the urine was temporarily related to the clinical effects of antidepressants. On the basis of his findings, in 1965, Schildkraut put forward the “catecholamine hypothesis of affective disorders” (Schildkraut 1965). Schildkraut was a member of Irwin Kopin’s team at the National Institute of Mental Health (NIMH) which identified 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine and showed that it was the major metabolite of normetanephrine (Schanberg, Schildkraut, Breese and Kopin 198). He also demonstrated that urinary MHPG levels are significantly lower in bipolar than unipolar depression (Schildkraut, Orsulak, Schatzberg et al. 1978).

           William E. Bunney’s review with John Davis, Norepinephrine in depressive reactions, was in print within a month after Schildkraut published his catecholamine hypothesis of affective disorder (Bunney and Davis 1965). In the late 1960s Bunney led the team which found high 17-hydroxycorticosteroid levels in suicidal patients (Bunney, Fawcett, Davis and Gifford 1968). He was also the leader of the team in the early 1970s that documented the relationship between sequential behavioural changes, catecholamine metabolism and rapid eye movement (REM) sleep in manic-depressive patients (Bunney, Goodwin, Murphy, House and Gordon 1972; Bunney, Murphy, Goodwin and Borge 1972). Bunney and his team in the late 1970s corroborated the therapeutic effectiveness of lithium in both unipolar and bipolar depression (Goodwin, Murphy, Dunner and Bunney 1972). In his research in schizophrenia, in the mid-1990s, Bunney with his associates found that gene expression for glutamic acid decarboxylase was reduced in schizophrenic brains without loss of neurons in the prefrontal cortex (Akbarim, Kim, Potkin et al. 1995). Pursuing further his molecular genetic research, Bunney reported on molecular “clock genes” in man and lower animals (Bunney and Bunney 2000).

           John M Davis co-authored the review with Bunney which implicated norepinephrine (NE) in the etiology of depression. He was also a member of Bunney’s team that showed high 17-hydroxycorticosteroid levels in suicidal patients. Davis collaborated with Stephen Curry in studying the relationship between chlorpromazine plasma levels and therapeutic response in schizophrenia. He also collaborated with David Janowsky in studies which led to a cholinergic-adrenergic hypothesis of mania and depression, the use of methylphenidate as a challenge test in schizophrenia and the recognition that chlorpromazine blocks guanethidine’s antihypertensive effects (Curry, Davis, Marshall and Janowsky 1970). In the early 1970s Davis introduced meta-analysis in psychopharmacology and reported the findings of first meta-analyses on the effectiveness of maintenance treatment with neuroleptics in schizophreniaand with antidepressants in depression (Davis 1975, 1978; Davis, Chen and Glick 2003; Davis, Wang and Janicak 1993).

           Jan A. Fawcett was also a member of Bunney’s team which showed adrenal hyperactivity, as measured by increased urinary 17-hydroxycorticosteroid levels, preceding suicide. He introduced the amphetamine load test in predicting response to antidepressants and found that “feeling better” after an “amphetamine challenge” as well as low urinary MHPG levels were predictors of a favourable response to desipramine (Fawcett and Maas 1972; Fawcett and Simopoulos 1971).  Fawcett was among the first to show that amphetamines and monoamine oxidase inhibitors (MAOIs could potentiate the therapeutic effect of tricyclic antidepressants (Fawcett, Kravits, Zajecka and Schaff 1991).

           In the early 1970s David S. Janowsky reviewed findings which indicated that the ovarian hormones, estrogen andprogesterone, have an effect on sexual and emotional behaviour by altering monoamine release and uptake (Janowsky, Fann and Davis 1971). He demonstrated a correlation between mood, weight and electrolytes during the menstrual cycle and put forward a renin-angiotensin–aldosterone hypothesis of premenstrual tension (Janowsky, Berens and Davis1973). Based on his findings that physostigmine, a cholinesterase inhibitor, could control mania and aggravate depression, he also put forward a “cholinergic-adrenergic” hypothesis of affective disorders (Janowsky, El-Yousef, Davis and Sekerke 1972a). During the 1970s Janowsky had shown that methylphenidate, a dopamine agonist, could activate pre-existing psychotic symptoms in some schizophrenic patients (Janowsky, El-Yousef, Davis and Sekerke 1972b). In collaboration with Edmund Fann and Khalid E-Yousef he also showed that the antihypertensive effect of guanathidine was antagonized by chlorpromazine (Janowsky, El-Yousef and Fann 1972).

           In the late 1960s Gregory F. Oxenkrug and Izyaslav Lapin found that antidepressants intensified central serotonergic processes in the frog and suggested that the cause of the antidepressant effect of imipramine-type drugs was their serotonergic property (Lapin and Oxenkrug 1969). In the mid-1980s Oxenkrug demonstrated that selective inhibition of MAO-A activity increased melatonin synthesis in the pineal gland of rats (Oxenkrug, McCauley, McIntyre and Filipowitcz (1985).

           In the late 1970s Claude de Montignyin collaboration with George Aghajanian reported that long-term treatment with tricyclic antidepressants increased the responsiveness of rat forebrain neurons to serotonin (de Montigny and Aghajanian 1978). In the 1980s with Pierre Blier, he tracked the electrophysiological change affected by antidepressants on serotonin mediated neurotransmission (Blier and de Montigny 1988; de Montigny and Blier 1990). They had also shown that serotonin mediated transmission was augmented by lithium (Blier and de Montigny 1985, 1988; de Montigny and Blier 1990, 1992). In 1994, de Montigny demonstrated that in treatment resistant depression lithium potentiated the effect of antidepressants (de Montigny 1994).

           Herman M. Van Praag was among the first to use the probenecid (augmentation) technique for measuring monoamine metabolites in the CSF (Van Praag, Korf and Puite 1970; Van Praag, Korf and Schut 1973). In the early 1970s he divided endogenous depression into two groups, one with and one without a disturbance of serotonin metabolism (Van Praag 1970; Van Praag and Korf 1971a). He had also shown changes in dopamine metabolism in retarded depression (Van Praag and Korf 1971b). In 1980, Van Praag postulated that central serotonin deficiency increases vulnerability for depression (Van Praag and De Haan 1980).

           Baron Shopsin was first to show, in the mid-1970s, that blocking the synthesis of serotonin by para-chlorophenylalanine reversed the therapeutic effect of imipramine and tranylcypromine, where as blocking the synthesis of NE by α-methylparatyrosine did not (Shopsin Freedman and Gershon 1976; Shopsin, Gershon, Goldstein et al. 1975). He was also among the first to show the therapeutic effect of dopamine receptor stimulation by piribedil in depression (Shopsin and Gershon 1978). Shops in contributed to the clinical development of lithium, bupropion, clozapine, and several other drugs (Gershon and Shopsin 1973; Shopsin 1975, 1983; Shopsin, Gershon, Thompson and Collins 1975; Shopsin Kim and Gershon 1971; Shopsin, Klein, Aronson et al. 1979).

           In the mid-1980s William Z. Potter demonstrated that both the selective NE inhibitor desipramine and the selective serotonin reuptake inhibitor zimelidinedecreased both the serotonin metabolite 5-hydroxyindole acetic acid (5HIAA) and the norepinephrine metabolite MHPG in the cerebrospinal fluid (CSF) (Calil, Lesier, Gold, Brown, Zavadil and Potter 1984; Linnoila, Karoum, Calil, Kopin and Potter 1982; Potter, Scheinin, Golden et al. 1985). He also contributed to the clinical development of clorgyline (Potter, Murphy, Wehr et al. 1982).

           Elliott Richelson demonstrated in the late 1970s that tricyclic antidepressants (TCAs) block muscarinic acetylcholineand histamine receptors (Petersen and Richelson 1982; Richelson 1978; Richelson and Divinetz-Romero 1977).He had also shown that the histamine receptor blocking potency of TCAs is greater than their muscarinic acetylcholine receptor blocking potency and that the histamine receptor blocking potency of tertiary amine TCAs is greater than of secondary amine TCAs (Figge, Leonard and Richelson 1979).  In the 1980s Richelson spearheaded research in studying receptor affinities in normal human brainand reported on the receptor binding profiles of clinically used antidepressantsandantipsychotics (Cussack, Nelson and Richelson  1994; Richelson and Nelson 1984;  Richelson and Souder  2000; Tutsumi, Groshan, Blakely  and Richelson 1997; Tutsumi, Jansen,  Blakely  and Richelson 1999).   Richelson also contributed to the development of neurotensin peptide analogs (Cussack, Bouler, Tyler, Fauq, Cormick and Richelson 1999).

           In the mid-1990s Angelos E. Halaris and associates found that platelet 1-imidazoline receptor binding sites are elevated only in depressive and not in anxiety states and that the elevated 1-imidazoline binding sites are down-regulated by treatment with antidepressants (Halaris and Piletz 2001; Piletz, Halaris, Chikkala and Qu 1996; Piletz, Halaris, Nelson et al. 1996). Halaris also contributed to the clinical development of bupropion; he demonstrated that elevated 1-imidazoline receptor binding sites are down-regulated after bupropion treatment (Halaris, Stein, Van Wyck et al. 1983; Halaris, Zhu, Ali et al. 2002; Zhu, Halaris, Madakasira et al. 1999).

 

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January 10, 2019