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
Starting Up (Volume One): 3. Drugs
(Bulletin 35)

            It was against the background presented in Bulletin 34 that within a period of five years five effective pharmacological treatments appeared on the psychiatric scene.

The first,chlorpromazine(CPZ), was synthesized on December 11, 1950, in the Laboratories of Rhône-Poulenc, a French pharmaceutical company, in a program that aimed to develop drugs for use in general anesthesia (Caldwell 1970).Its potential use in psychiatry was recognized by Laborit in the course of using artificial hibernation for the prevention of surgical shock; its therapeutic effect in psychoses and especially in schizophrenia was demonstrated in a series of clinical studies by Delay and Denikerat Ste. Anne’s Hospital in Paris. Chlorpromazine was released for clinical use in France in November 1952 (Ban 2007; Delay and Deniker 1952 a,b,c; Delay, Deniker and Harl 1952 a,b; Delay, Deniker, Harl and Grasset1952; Laborit, Huguenard and Alluaume 1952).

The second, reserpine, was isolated from the Rauwolfia root in 1952 by Műller, Schlittler and Bein in the laboratories of CIBA, a Swiss pharmaceutical company(Műller, Schlittler, Bein 1952). The substance was responsible for about 50% of the antihypertensive and tranquilizing action of the snakeroot plant (Rauwolfia serpentina) that had been in use for hundreds of years in various preparations by Ayurvedic practitioners in India (Bein 1970).In 1954, Delay et al., Kline, and Noce, William and Rapoportindependently demonstrated the therapeutic effect of the substance in schizophrenia (Delay et al. 1954; Kline 1954; Noce, Williams and Rapaport 1954). In the same year, Steck reported on the similarities in therapeutic and adverse effects of reserpine and CPZ (Steck1954). Yet another line of research indicated that reserpine may induce depression and deplete monoamines (serotonin and norepinephrine) in the brain.

The third, meprobamate (2-methyl-2-n-propyl-prapanediol), was synthesized in 1950 by Ludwig at Wallace Laboratories in New Jersey (U.S.) in order to prolong the duration of mephenesin’s “tranquilizing and muscle relaxant” action. Mephenesin had been discovered during the mid-1940s in the laboratories of British Drug Houses in London by Frank Bergerwhile trying to develop non-toxic antibacterial agents that would inhibit the growth of Gram-negative micro-organisms that caused enzymatic destruction of penicillin (Berger 1970; 1998). In 1956 Lowell Selling reported on the therapeutic effect of meprobamate in anxiety and tension states; a few months later the substance was introduced for clinical use in the United States (Burger 1976).

The fourth, imipramine, a dibenzazepine, was selected from the chemical library of Geigy, a Swiss pharmaceutical company, by psychiatrist Roland Kuhn. Because of its structural similarity to CPZ he hoped that it would have similar therapeutic effects in schizophrenia (Kuhn 1996).His expectations were not fulfilled, but he found the drug effective in endogenous depression in which “vital disturbance” was in the background. Kuhn presented and published his findings in 1957 (Kuhn 1957).

The fifth, iproniazid, was synthesized in 1951 by Herbert Fox at Roche Laboratories in Nutley, New Jersey, for the chemotherapy of tuberculosis (Fox and Gibbs 1952). The following year, Zeller et al. at Northwestern University in Chicago, demonstrated the monoamine oxidase inhibiting properties of the substance (Zeller et al.   1952). In 1952 there were also reports that iproniazid induced euphoria and overactive behavior in some tubercular patients (Flaherty1952; Selikoff, Robitzek and Orenstein 1952). In 1956 Alfred Pletscher, working as a visiting scientist in Bernard Brodie’s laboratory at the (U.S.) National Heart Institute – on leave from his position as research director of Roche – showed that iproniazid increased brain serotonin levels and attenuated reserpine-induced depletion of serotonin (Besendorf and Pletscher 1956; Pletscher 1956).Finally, in 1957 Crane, and Loomer, Saunders and Kline independently published their findings on the “psychic energizing”/“antidepressant” effect of the drug (Crane 1957; Loomer, Saunders and Kline 1957). Iproniazid was the first psychotropic drug introduced with a proposed rational for its possible mode of action.

It was the therapeutic and commercial success in the mid-1950s of chlorpromazine for the treatment of schizophrenia that generated interest within the pharmaceutical industry in developing drugs for other psychiatric conditions (Ban 2007).

By 1957 the pharmaceutical industry, recognizing the potential market for psychopharmaceuticals, was moving ahead industriously synthesizing and developing new drugs for psychiatric disorders. Pharmacology was ready to meet the challenge of identifying new drugs that might have similar clinical effects to the ones already in use by adopting a behavioral methodology for the detection of the mode of action of psychotropic drugs. The onus was on psychiatry to provide the necessary feedback by identifying the populations affected by the new drugs. Yet, mainstream psychiatry was split into a small group that flatly rejected the new drugs as chemical strait-jackets that interfered with psychotherapy and a large group that accepted the new drugs as more effective treatments than any other pharmacological treatment in the past but attributed their effectiveness to facilitation of the natural healing process. In the case of CPZ, for example, the idea was that the drug freed the psyche from the disruptive interference of excessive affect without grossly interfering with cognitive processes, allowing the “patient’s psyche to reorganize” itself (Lehmann 1993). Nevertheless, by the end of the 1950s there were several effective drugs in clinical use for the treatment of psychosis, depression and anxiety; with the help of the pharmaceutical industry, pharmacotherapy with psychotropic drugs had become an accepted treatment modality and psychopharmacology had become part of the teaching curriculum at medical schools (Ban and Ucha Udabe 2006).

References:

Ban TA. Fifty years chlorpromazine. A historical perspective. Neuropsychiat Dis Treat 2007; 3: 483–8.

Ban TA, Ucha Udabe R. The neurotransmitter era in neuropsychopharmacology. In: Ban TA, Ucha Udabe R. editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2006. p. 265–74.

Bein H. Biological research in the pharmaceutical industry with reserpine. In: Ayd FJ Jr, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia: Lippincott; 1970. p. 142–54.

Berger FM. Anxiety and the discovery of the tranquilizers. In: Ayd FJ Jr, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia: Lippincott; 1970. p. 115–29.

Berger FM. As I remember. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and the Story of CINP. Budapest: Animula; 1998. p. 59–62.

Besendorf H, Pletscher A. BeeinflussungzentralerWirkungen von Reserpin und 5-hydroxytryptamin durchIsonicotinic–säuerhydrazine. HelvPhysiol Acta 1956; 14: 383–90.

Burger A. History. In: Usdin E, Forrest IS,editors. Psychotherapeutic Drugs. Part IPrinciples.New York: Marcel Dekker; 1976. p. 11–57.

Caldwell AE. Origins of Psychopharmacology. From CPZ to LSD.Springfield: Charles C. Thomas; 1970. p. 23–35.

Crane GE. Iproniazid (Marsilid) phosphate a therapeutic agent for mental disorders. Psychiatr Res Reports 1957; 8: 142-54.

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September 13, 2018