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).

References:

Akbarim S, Kim JJ, Potkin SG, Hagman JO, Taffazzoli A, Bunney WE, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in the prefrontal cortex in schizophrenia. Arch Gen Psychiatry 1995; 52: 258-66.

Blier P, de Montigny C. Short term lithium administration enhances serotonergic neurotransmission: electrophysiological evidence. European Journal of Pharmacology 1985; 113: 69-77.

Blier P, de Montigny C. Electrophysiological assessment of the effects of antidepressant treatment on the efficacy of 5HT neurotransmission. Clinical Neuropharmacology 1988; 11 (supplement): 51-60.

Bunney WE, BunneyBG. Molecular clock genes in man and lower animals: Possible implications for circadian abnormalities in depression. Neuropsychopharmacology 2000; 22: 335-45.

Bunney WE, Davis JM. Norepinephrine in depressive reactions. Arch Gen Psychiatry. 1965; 3: 483-494.

Bunney WE, Fawcett JA, Davis JM, Gifford S. Further analysis of urinary 17-hydroxycorticosteroids in suicidal patients. Arch Gen Psychiatry 1868; 2: 138-50

Bunney WE, Goodwin FK, Murphy DL, House KM, Gordon EK.The “switch process” in manic–depressive illness. II. Relationship to catecholamines, REM sleep and drugs. Arch Gen Psychiatry 1972; 27: 304-9.

Bunney WE, Murphy DL, Goodwin DK, Borge GF. The “switch process” in manic-depressive illness. I. A systematic study of sequential behavioral changes. Arch Gen Psyciatry 1972; 27: 304-9.

Calil M, Lesier P, Gold PW, Brown GM,Zavadil AP, Potter WZ. Humoral responses to zimelidine and desipramine in depressed patients. Psychiatric Research 1984; 13: 231-42. 

Curry SH, Marshall JH, Davis JM, Janowsky DS. Chlorpromazine plasma levels and effects. Arch Gen Psychiatry.1970; 22: 289–96.

Cusack B, Boules M, Tyler BQ, Fauq A, McCormick DJ, Richelson E.  Effects of novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol.  Brain Res 2000; 856: 48-54.

Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors.  Focus on newer generation compounds. Psychopharmacol 1994; 114: 559-65. 

Davis JM. Overview: Maintenance therapy in psychiatry. I Schizophrenia. Am J Psychiatry 1975; 132: 1237-45.

Davis JM. Overview: Maintenance therapy in psychiatry. II. Affective disorders. Am J Psychiat 1976; 133: 1- 13.

Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second generation of antipsychotics. Archives of General Psychiatry 2003; 60: 553-64.

Davis JM, Wang Z, JanicakPG. A Quantitative analysis of clinical drug trials for the treatment of affective disorders. Psychopharmacol Bull 1993; 175-81.

de Montigny C. Lithium addition in treatment resistant depression. International Clinical Psychopharmacology 1994; 9 (supplement): 31-5.

de Montigny C, AghajanianGK. Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science 1978; 20: 1302-6.

de Montigny C, Blier C.  The role of the serotonin system in the mechanism of antidepressant action of antidepressant treatment: preclinical evidence. The Journal of Clinical Psychiatry 1990; 51 (supplement): 14-20.

de Montigny C, Blier P. Potentiation of 5-HT neurotransmission by short-term lithium: in vivo electrophysiological studies. Clinical Neuropharmacology 1992; 15 (supplement): 610-11.

Fawcett JA, Maas JW, Dekermenjian H. Depression and MHPG excretion.  Arch Gen Psychiatry 1972; 25: 247-55.

Fawcett JA, Kravits HM, Zajecka JM, Schaff MR. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment refractory depression. J ClinPsychopharmacol 1991; 11: 127-32. 

Fawcett JA, Simopoulos V. Dextroamphetamine. Response as possible predictor of improvement with tricyclic antidepressants in depression. Arch Gen Psychiatry 1971; 25: 247-55.

Figge J, Leonard P, Richelson E. Tricyclic antidepressants: potent blockade of histamine-H₁ receptors of guinea pig ileum. Eur J Pharmacol. 1979; 58: 479–83

Gershon S, Shopsin B, editors. Lithium:  Its Role in Psychiatric Research and Treatment. New York: Plenum Press; 1973

Goodwin FK, Murphy DL, Dunner DL, Bunney WE. Lithium response in unipolar versus bipolar depression. Am J Psychiatry 1972; 129: 44-7.

Halaris A, Piletz JE. Imidazoline receptors: possible involvement in the pathophysiology and treatment of depression. Human Psychopharmacol 2001; 16: 65-9.

Halaris AE, Stern W, Van Wyck Fleet J, Reno RM. Evaluation of the safety and efficacy of bupropion in depression. J Clin Psychiatry 1983; 44: 101-3.

Halaris A, Zhu H, Ali J, Nasrallah A, De Vane CL, Piletz JE. Down-regulation of platelet imidazoline-1-binding sites after bupropion treatment. Int J Neuropsychopharmacol 2002;5(1):37-46.

Janowsky DS, Berens SC, Davis JM. Correlations between mood, weight, and electrolytes during the menstrual cycle: A renin-angiotensin-aldosterone hypothesis of premenstrual tension. Psychosom Med 1973; 35: 143-54.

Janowsky DS, Fann WE, Davis JM. Monoamines and ovarian hormone-linked sexual and emotional changes: A review. Arch Sex Behav 1971; 1: 205-18.

Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ.  A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972a; 2: 632-635.

Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ. Provocation of schizophrenic symptoms by intravenous administration of methylphenidate. Arch Gen Psychiatry 1972b; 28: 185-191

Janowsky DS, El-Yousef MK, FannEW. Antagonism of guanathidine by chlorpromazine. Am J Psychiatr 1973; 103: 808-12.

Lapin JP, Oxenkrug GF. Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. Lancet 1969; 1: 32-9.

Linnoila M, Karoum F, Calil HM, Kopin IJ, Potter WZ. Alteration of norepinephrine metabolites with desipramine and  zimelidine in depressed patients. Archives of General Psychiatr 1982; 39: 1025-8.

Oxenkrug GF, McCauley RB, McIntyre IM, Filipowitcz C. Selective inhibition of MAO-A but not MAO-B activity increases rat pineal melatonin. J Neural Transm 1985; 61: 265-70.

Petersen RC, Richelson E. Anticholinergic activity of imipramine analogs at muscarinic receptors of cultured mouse neuroblastoma cells. Psychopharmacology (Berl) 1982; 76: 26–8.

Piletz JE, Halaris AE, Chikkala D, Qu Y. Platelet 1-imidazoline binding sites are decreased by two dissimilar antidepressant agents in depressed patients. J Psychiatr Res 1996; 30: 169-80..

Piletz JE, Halaris A, Nelson J, Qu Y, Bari M. Platelet 1-imidazoline binding sites are elevated in depression but not generalized anxiety disorder. J Psychiatr Res 1996; 30: 147-68.

Potter WZ, Murphy DL, Wehr TA, Linnoila M, Goodwin FK. Clorgyline: a new treatment of refractory rapid cycling disorder. Arch Gen Psychiatry 1982; 39: 505-10.

Potter WZ, Scheinin M, Golden RN, Rudorfer MV,Cowdry RW, Calil HM, Ross RJ, Linnoila M. Selective antidepressants and cerebrospinal fluid: Lack of specificity on norepinephrine and serotonin metabolites.Arch Gen Psychiatry 1985; 47: 1171-77.

Richelson E. Tricyclic antidepressants block histamine H₁ receptors of mouse neuroblastoma cells. Nature1978; 274:176–7.

Richelson E, Divinetz-Romero S. Blockade by psychotropic drugs of the muscarinic acetylcholine receptor in cultured nerve cells. Biol Psychiatry1977; 12::771–85.

Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J PharmacolExpTher. 1984; 230: 94-102.

Richelson  E, Souder T. Binding of antipsychotc drugs to human brain receptors: focus on new generation  compounds.  Life Sci 2000;  68: 29-39.

Schanberg SM, Schildkaut JJ, Breese DR, Kopin IJ. Metabolsm of noermetanephrne (³H) in rat brain: identification of conjugated 3-methoxy-4-hydroxy-phenyl glycol as the major metabolite. BiochemPharmacol 1968; 17: 247-54.

Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965; 122: 509-22.

Schildkraut JJ, Gordon EK, Durell J. Catecholamine metabolites in affective disorders: I.  Normetanephrine and VMA excretion in depressed patients  treated with imipramine . J Psychiat Res 1965; 3: 213-28

Schildkraut JJ, Klerman GL, Hammond R, Friend DG. Excretion of 3-methoxy-4-hydroxymandelic acid (VMA) in depressed patients treated with antidepressant drugs. Br J Psychiatr Res. 1964; 2: 251-66.

Schildkraut JJ, Orsulak PJ, Schatzberg AF, Gudeman JE, Cole JO, Rohde WA, Larie RA. Toward a biochemical classification of depressive disorders I: Differences in urinary MHPG and other catecholamine metabolites  in clinically defined subtypes of  depressions. Arch Gen Psychiatry 1978; 35: 1427-33.

Shopsin B. Bupropion’s prophylactic effect in bipolar affective illness. J Clin Psychiatry  1983; 44: 163-9.

Shopsin B, Friedman E, Gershon S. Parachlorophenylalanine reversal of tranylcypromine  effects in depressed patients. Arch Gen Psychiatry  1976; 33: 811-9.

Shopsin B, Gershon S. Cogwheel rigidity related to lithium maintenance Am J Psychiatr  1975; 132: 526-8.

Shopsin B, Gershon S. Dopamine receptor stimulation in the treatment of depression : Piribedil (ET-495.) Neuropsychobiology  1978; 4: 1-14.

Shopsin B, Gershon S, Goldstein M, Friedman E, Wilk S.Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacology Communications 1975; 1: 238-49.   

Shopsin B, Gershon S, Thompson S, Collins P. Psychoactive drugs in mania.  A controlled comparison of lithium carbonate, chlorpromazine and haloperidol. Archives of General Psychiatry 1975; 32: 34-42.

Shopsin B, Kim SS, Gershon S. A controlled study of lithium vs chlorpromazine in acute schizophrenia. The British Journal of Psychiatry 1971; 119: 435-40.

Shopsin B, Klein H, Aaronsom M, Collora M. Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison.Arch Gen Psychiatry. 1979;36:657-64.

Tutsumi M,  Groshan K, Blakely RD,  Richelson E.  Pharmacological profile of antidepressants  and related compounds  at human monamine transporters.  Eur J Phramacol   1997; 340:  248-58.

Tutsumi M, Jansen K, Blakely RD, Richelson E. Pharmacological profile of neuroleptics at human monomainetansporters.  Eur J Pharmacol  1999;  368:  277-83.

Van Praag. Towards a biochemical typologyof depression. Pharmacopsychiat 1974; 7: 281-92. 

Van Praag, HM, De Haan S. Central serotonin deficiency. A factor which increases depression vulnerability. Acta PsychiatScandinavica 1980; 61: 89-95. 

Van Praag HM, Korf J. Endogenous depression with and without disturbances of 5-hydroxytryptamine metabolism.: A biochemical classification? Psychopharmacol 1971a; 19: 148-52.

Van Praag HM, Korf J. Retarded depression and dopamine netabolism. Psychopharmacol 1971b; 19: 199-203.

Van Praag HM, Korf J, Puite J. 5-Hydroxyindoleacetic acid levels in the cerebrospinal fluid of depressive patients treated with probenecid. Nature. 1970; 225: 1259-60.

Van Praag HM, Korf J, Schut T. Cerebral monoamines and depression. An investigation with the probenecid technique Arch Gen Psychiatry1973; 28:827-31.

Zhu H, Halaris A, Madakasira S, Pazzaglia P, Goldman N, DeVane CL, Andrew M, Reis D, Piletz JE. Effect of bupropion on immunodensity of putative imidazoline receptors on platelets of depressed patients. J Psychiatr Res. 1999;33:323-33.

January 10, 2019