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Saturday, 22.02.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era

Joseph J. Schildkraut: Autobiography – The catecholamine hypothesis before and thereafter
(Bulletin 14 - 1. Autobiographies 2)




            Developments in the neuropharmacology of imipramine-like antidepressants began in the late 1950s with the demonstration that imipramine, a tricyclic substance, has antihistaminic, anticholinergic, noradrenergic and serotonergic properties without offering any clues which of these actions might be related to its antidepressant effect (Domenjoz and Theobald 1959).  The finding that imipramine antagonized and reversed reserpine - induced sedation, hypothermia, ptosis and diarrhea (Costa, Garattini and Valzelli 1960) did not advance this issue because reserpine, in addition to depleting norepinephrine (NE) and serotonin (5HT) from brain storage sites (Sulser and Watts 1960) also has cholinomimetic effects (Muller et al. 1955). Far from being clearly a mood depressant, reserpine was classified by the World Health Organization as a neuroleptic and was reported to be effective in the treatment of anxious and depressed patients (Davies and Shepherd 1955; World Health Organization 1967).

Imipramine blocks muscarinic acetylcholine receptors and has central and peripheral anticholinergic effects (Sulser and Watts 1960).  In 1961 Helmut Selbach (1909 -1987) attributed the antidepressant effect of imipramine to its action on autonomic regulation, producing an imbalance in which the parasympathetic-trophotropic, acetylcholine system is more strongly inhibited than the sympathetic-ergotropic, adrenaline-epinephrine system (Selbach 1961). He also described three successive stages in the course of treatment: the first characterized by “trophotropic actions,” such as feelings of tiredness and decrease of blood pressure; the second by “lability,” manifest in tremor and fluctuation of blood pressure; and the third by “ergotropic actions” displayed in elation and increased interest (Selbach 1962).

The noradrenergic properties of imipramine were further elaborated in the late 1950s by Ernest Sigg who demonstrated that imipramine enhanced and prolonged physiological responses to exogenous NE and to endogenous NE released by pre- or postganglionic sympathetic nerve stimulation (Sigg 1959).  The only findings which indicated this might translate into an effect on behaviour and psychopathology were Elmadjian and associates’ report of a correlation between urinary excretion of NE and aggression, and Ström-Olsen and Weil-Malherbe’s report of higher urinary excretion of epinephrine and NE in the manic compared to the depressive phase of manic-depressive psychosis (Elmadjian, Hope and Lawson 1957; Ström-Olsen and Weil-Malherbe 1958).

            In 1961 Axelrod, Whitby and Hertting discovered that imipramine and amitriptyline blocked neuronal reuptake of NE and in 1964 Sulser, Bickel and Brodie demonstrated that imipramine’s reserpine reversal was suspended after the depletion of NE in the brain by the administration of α-methyl-metatyrosine, a substance that blocked the activity of the enzyme responsible for its formation (Axelrod, Whitby and Hertting 1961; Sulser, Bickel and Brodie 1964). Since reserpine-reversal with desipramine (DMI), the demethylated metabolite of imipramine, a selective NE re-uptake blocker, was more potent than with imipramine, the possibility was raised that NE is the neurotransmitter involved in the antidepressant effect of these drugs (Brodie et al. 1961; Sulser 1998; Sulser, Bickel and Brodie 1964). Clinical observations and findings with desipramine were less impressive. Its therapeutic effect did not seem to be much different from imipramine, the parent substance (Ban and Lehmann 1962; Kline, Simpson and Brodie 1962; Mann 1962; Oltman and Freedman 1962).

            In 1964 Joseph J. Schildkraut (1934 – 2006), with some of his associates, reported that urinary output of vanylmandelic acid (VMA) was decreased and normetanephrine increased in imipramine treated patients (Schildkraut, Klerman, Hammond and Friend 1964). In 1965, with some other associates, he also demonstrated that the increase of normetanephrine in the urine was temporarily related to the clinical effects of antidepressants (Schildkraut, Gordon and Durell 1965). In the same year (1965), Schildkraut put forward the “catecholamine hypothesis of affective disorders” (Schildkraut 1965).  At the time, Schildkraut was a member of Irwin Kopin’s team at the US National Institute of Mental Health which was to identify 3-methoxy - 4 – hydroxyl - phenyl glycol (MHPG) in urine and show that it was the major metabolite of normetanephrine (Schanberg, Schildkraut, Breese and Kopin 1968).

            Schildkraut continued his research in the biochemistry of affective disorders and in 1978 he demonstrated, with his associates, that urinary MHPG levels are significantly lower in bipolar than unipolar depression (Schildkraut, Orsulak, Schatzberg, Gudeman, Cole, Rohde, LaBrie                                                                    1978).

            Joseph J. Schildkraut’s autobiography was first published, with the title “The catecholamine hypothesis before and thereafter,” in Reflections in Twentieth-Century Psychopharmacology volume 4 in The History of Psychopharmacology and the CINP (Ban, Healy and Shorter 2004; Schildkraut 2004). The information in Schildkraut’s autobiography is covered also, in part, in David Healy’s interview of Schildkraut, published in Volume 5, “Neuropsychopharmacology,” in “An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews (Ban 2011; Gershon 2011).




Axelrod J, Whitby LB, Hertting G. Effect of psychotropic drugs on the uptake of 3H norepinephrine by tissues. Science 1961; 133: 383-4.


Ban TA. Depression and the Tricyclic Antidepressants. Montreal: Ronalds Federated; 1974.


Ban TA. Psychopharmacology of Depression. New York: Karger; 1981.

Ban TA. Preface. In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume Five (Gershon S, editor. Neuropsychopharmacology). Budapest: Animula; 2011, pp. 9-29.


Ban TA, Healy D, Shorter E, editors. Reflections in Twentieth-Century Psychopharmacology, The History of Psychopharmacology and the CINP, Volume 4. Budapest: Animula; 2004, 254-61.


Ban TA, Lehmann HE. Clinical trial with desmethylimipramine (G35020), an antidepressive compound. Canadian Medical Association Journal 1962; 86: 1030.


Brodie BB, Dick P, Kielholz P, Pöldinger W, Theobald W. Preliminary pharmacological and clinical results with desmethylimipramine (DMI) G 35020, a metabolite of Tofranil. Psychopharmacologia 1961; 19: 46-74.


Costa E, Garattini S, Valzelli L. Interaction between reserpine, chlorpromazine and imipramine. Experientia 1960; 15: 461-3.


Davies DI, Shepherd M. Reserpine in the treatment of anxious and depressed patients. Lancet 1955; 2: 117-21. 


Domenjoz R, Theobald W. Zur Pharmacolgie des Tofranil. Arch Int Pharmacodyn 1959; 120: 450-89.


Elmadjian F, Hope JM, Lawson ET. Excretion of epinephrine and norepinephrine in various emotional states. J Clin Endocr 1957 17: 608-20.


Gershon S, editor. Neuropsychopharmacology. In: Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume Five). Brentwood: American College of Neuropsychopharmacology; 2011.


Kline NS, Simpson G, Brodie BB. The clinical application of desmethylimipamine. Anew type of antidepressant. International Journal of Neuropsychopharmacology 1962; 1: 55-60.


Mann AM. Clinical trial with desmethylimipramine (G35020), a new antidepressive compound. Can Med Assoc J 1962; 86: 1830-1


Muller JC, Pryor WW, Gibbons JE, Orgain ES. Depression and anxiety occurring during reserpine therapy. JAMA 1955; 159: 836-9.


Oltman JE, Freedman S. Preliminary investigation of desmethylimipramine (G 35020). Am J Psychiatry 1962; 119: 370-1.


Schanberg SM, Schildkraut JJ, Breese DR, Kopin IJ. Metabolism of normetanephrine (3H) in rat brain: identification of conjugated 3-methoxy-4-hydroxy-phenyl glycol as the major metabolite. Biochem Pharmacol 1968; 17: 247-54.


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

Schildkraut JJ. The catecholamine hypothesis: Before and thereafter. In: Ban TA, Healy D, Shorter E, editors. Reflections on Twentieth-Century Psychopharmacology. Budapest: Animula; 2004. p. 254 -61.


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, LaBrie 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.

Selbach H. Über die vegetative Dynamik in der psychiatrischen Phramkotherapie. Dutch med J 1961; 12: 511-7. 

Selbach H. Über die vegetative Dynamik in der psychiatrischen Phramkotherapie. Med exp 1962; 7 (supplement); 133 – 65.

Sigg EG. Pharmacological studies with Tofranil. Canad Psychiat Assoc J 1959; 4: 75-83.


Ström-Olsen R, Weil-Malherbe H. Humoral changes in manic-depressive psychosis with particular reference to excretion of catecholamines in urine.  J Ment Sci 1958; 101: 696-706.


Sulser F. The 1960s. My early years with tricyclics. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1998. p. 81-3.

Sulser F, Bickel MH, Brodie BB. The action of desmethylimipramine in counteracting sedation and cholinergic effects of reserpine-like drugs. Journal of Pharmacol and Experimental Ther 1964; 144: 321-30.


Sulser F, Watts F. On the antireserpine action of imipramine (Tofranil). In: Tonini G, editor. Techniques for the Study of Psychotropic Drugs. Modena: Societa Tipographica Modenese; 1960. 


World Health Organization. Research in Psychopharmacology. Technical Report Series No.371. Geneva: WHO; 1967.



April 19, 2018