Thomas A. Ban

Introduction

Neuropsychopharmacology studies the relationship between neuronal and mental events with the employment of centrally acting drugs. Developments that lead to the birth of neuropsychopharmacology began in the early 1950s with the introduction of therapeutically effective psychotropic drugs. It continued with the identification of monoamine neurotransmitters in the brain, and the construction of the first spectrophotofluorometer, an instrument with a resolution power to detect and measure changes in the concentration of monoamine neurotransmitters (Ban and Ucha Udabe, 2006).

One of the essential prerequisites of successful neuropsychopharmacological research is a continuous exchange of information between basic scientists and clinicians. It was in 1957 that communication between the various disciplines involved in neuropsychopharmacological research began. Three major events heralded the beginning of the psychopharmacological era: (1) the organization of the First International Symposium on Psychotropic Drugs in Milan; (2) the inclusion of a Psychopharmacology Symposium, at a World Psychiatric Association Congress, and (3) the founding of the Collegium Internationale Neuro-Psychopharmacologicum, an international organization that provided a platform for interaction for the disciplines involved in neuropsychopharmacological research (Ban and Ray, 1996).

Lithium

Arguably, developments that lead to the birth of neuropsychopharmacology began in 1949 with the rediscovery of the therapeutic effect of lithium in mania by John Cade, an Australian psychiatrist. The original discovery dates back to 1896 when Carl Georg Lange, a Danish psychiatrist reported on the therapeutic effect of lithium in periodic mood disorders (Ban, 2006 a).

Cade’s rediscovery of lithium was followed by the publication of several papers on the therapeutic and adverse effects of the substance. Trautner and his associates between 1951 and 1956 established the therapeutic window for lithium in the plasma and demonstrated lithium’s effectiveness in maintaining manic patients in remission after successful treatment with electroconvulsive therapy (Gershon and Trautner EM, 1956; Noack and Trautner, 1951; Trautner et al., 1955). And Schou and his associates in 1954, verified lithium’s therapeutic effects in mania. Still, the acceptance of lithium by the psychiatric establishment, and especially the British psychiatric establishment, was slow. It was a series of articles by Mogens Schou in the late 1950s that helped to break the barriers and set the stage for the introduction of lithium in the treatment of manic-depressive illness around the world (Schou, 1957, 1959).

Chlorpromazine

The rediscovery of the therapeutic effect of lithium in mania was followed in 1952 by the discovery of the therapeutic effect of chlorpromazine (CPZ) in psychoses. Developments that lead to the synthesis of CPZ began in the 1930s with the synthesis of the first antihistaminic drugs. CPZ, an antihistaminic phenothiazine, was synthesized on December 11, 1951 by Paul Charpentier, in the laboratories of Rhône-Poulenc, a French pharmaceutical company, and the potential use of CPZ in psychiatry was first recognized by Henri Laborit, a surgeon and physiologist in the French army, in the course of his research with artificial hibernation in the prevention of surgical shock (Caldwell, 1970; Laborit  and Huguenard, 1952).  Clinical investigations with CPZ at Saint-Anne’s hospital in Paris began on March 24, 1952, and the six historical publications of Delay and Deniker during the six months that followed set the stage of the introduction of CPZ in psychiatry (Delay and Deniker, 1952a, b, c; Delay, Deniker and Harl a, b, c).

CPZ became available on prescription in France in November 1952, under the proprietary name of Largactil. Subsequently, within a short period of three years, from 1953 to 1955, CPZ treatment in psychiatry spread around the world. The first international colloquium on the therapeutic uses of CPZ in psychiatry was held at Saint-Anne’s Hospital in Paris, in October 1955.  And two years later, in 1957, the importance of CPZ was recognized by the scientific community with the presentation of the American Public Health Association’s prestigious Albert Lasker Award to the three key players in the clinical development of the drug: Henri Laborit, for using CPZ as a therapeutic agent first and recognizing its potential for psychiatry; Pierre Deniker, for his leading role in introducing CPZ into psychiatry and demonstrating its influence on the clinical course of psychosis; and Heinz Lehmann, a German born Canadian psychiatrist, for bringing the full practical significance of CPZ to the attention of the medical community (Lehmann and Hanrahan, 1954). In the same year, Daniel Bovet, a Swiss born Italian pharmacologist was awarded the Nobel Prize in Medicine for the identification of curare alkaloids and the synthesis of antihistaminic drugs, which, through Feldberg’s recognition of the sedating effect of these compounds, led to the development of chlorpromazine (Ban, 1996).  

Reserpine

In 1952, the same year as the therapeutic effect of chlorpromazine in psychosis was discovered, Muller, Schlittler and Bein in the laboratories of CIBA, one of the major Swiss pharmaceutical companies at the time, isolated reserpine, the substance that accounted for about 50% of the antihypertensive and psychotropic effect of the Rauwolfia serpentina root (Bein, 1970).

Rauwolfia serpentina (snakeroot plant) had been in use for hundreds of years in various preparations by the Ayurwedic practitioners of India.  Yet, it was only in 1949 that Rustom Vakil brought to the attention of Western medicine the potential use of these preparations in hypertension, and mental illness, and it was only in 1953 that R.A. Hakim focused attention on the potential use of Rauwolfia preparations in schizophrenia (Ban, 1996).

Hakim’s paper triggered clinical research in psychiatry with Rauwolfia serpentina first, and reserpine, subsequently. The findings of this research were published in 1954 in four papers written by Delay and his associates, Klin, Noce et al, and Weber (Kurland, 1996). Three years later, in 1957, in recognition of the importance of these compounds in psychiatric therapy, three of the key players in the clinical development of reserpine were honored with the Lasker Award: Rustom Vakil “for producing a document which brought Rauwolfia alkaloids finally and decisively into Western medicine”; Nathan Kline “for his outstanding work since early in 1953 bringing to the attention of American and European psychiatrists the value of Rauwolfia alkaloids and especially of reserpine in the treatment of mental and nervous disorders”; and Robert Noce for recognizing “the potentialities of reserpine not only as a treatment for the mentally ill” but also “in mentally defectives in state schools” (Ban, 1996).

Imipramine

The serendipitous discovery of the therapeutic effect of imipramine in depression was the result of search for a CPZ-like substance for the treatment of schizophrenia by Geigy, at the time a major Swiss pharmaceutical company. The discovery is linked to the name of Roland Kuhn, a Swiss psychiatrist, working at the Cantonal mental hospital of Münsterlingen (Ban, 2006).

The story of imipramine begins in the mid-1950s when Kuhn suggested the testing of G 22,355, the dibenzazepine compound of Geigy that showed the closest structural resemblance to CPZ with the hope that it would have similar effects in schizophrenia. His expectations were not fulfilled. Yet, in January 1956 when he administered the substance to one of his female-patients with severe endogenous depression, he recognized that G 22,355 might have therapeutic effects in depression. Encouraged by his findings Kuhn administered G 22,355 to 2 more female patients with severe endogenous depression. In both patients the drug had favorable effects. Furthermore in all 3 patients discontinuation of treatment resulted in relapse that was reversed by resumption of the medication. Subsequently, Kuhn treated 40 depressed patients with G 22,355 at the clinic, and it was on the basis of his observations of these patients that he concluded that the drug is effective in endogenous depression in which vital disturbance was in the foreground (Kuhn, 1970, 1996).

Kuhn’s first paper on the treatment of depressive states with an iminobenzylderivative, G 22,355 was published in 1957, in the August 31^st issue of the Swiss Medical Journal.  Two days later, on the 2^nd of September, he also presented his findings at the 2^nd World Congress of Psychiatry in Zurich. G 22,355, the first tricyclic antidepressant, was released for clinical use in Switzerland by the end of 1957 with the generic name of imipramine, and the brand name of Tofranil.

Iproniazid

In 1957, the same year that imipramine was released for clinical use in Switzerland, Loomers, Saunders and Kline presented their findings on the therapeutic effect of iproniazid, a monoamine oxidase inhibitor, in depression, at a regional meeting of the American Psychiatric Association in Syracuse, New York (Kline, 1970).

Iproniazid, an isonicotinic acid hydrazide , was synthesized in 1951 by Herbert Fox at Roche laboratories in Nutley, New Jersey (USA) for the chemotherapy of tuberculosis (Fox and Gibas, 1953). In 1952, using iproniazid in tubercular patients, Selikoff, Robitzek and Orenstein noted that the drug produced euphoria and overactive behavior in some patients. In the same year (1952), Zeller and his associates revealed the potent monoamine oxidase inhibiting properties of the drug. It took five years from the time of these early findings before the therapeutic effect of iproniazid were reported in the United States (Ban, 2001).

Early Neuropharmacological Advances

Monoamine oxidase (MAO) is the enzyme responsible for the oxidative deamination of neurotransmitter monoamines, such as serotonin and norepinephrine.  The presence of these substances in the brain was first shown in 1953 and 1954 respectively; and the first spectrophotofluorometer, with a resolution power to measure the concentration of these monoamines and their metabolites in the brain, was constructed in 1955 (Bowman, Caulfield and Udenfriend, 1955; Twarog and Page, 1953; Vogt, 1954).  One year later, in 1956, Pletscher reported a decrease in brain serotonin levels after the administration of the Rauwolfia alkaloid, reserpine, a substance that produced depression in some patients when used in the treatment of hypertension, and an increase in brain serotonin levels after the administration of the monoamine oxidase inhibitor, iproniazid, a substance, as noted above that produced euphoria in some patients when used in the treatment of tuberculosis. Also in the same year (1956), Holzbauer and Vogt published their findings that reserpine depleted not only serotonin but also norepinephrine in the brain; and Brodie, Pletscher and Shore demonstrated that among the available Rauwolfia alkaloids only those with a sedative action cause depletion of 5-HT. Then, in 1957, at the First International Symposium on Psychotropic Drugs, Carlsson and his associates had conclusively demonstrated that reserpine depleted both catecholamines, dopamine and norepinephrine. They had also shown that pretreatment with iproniazid prevented the disappearance of catecholamines after reserpine injection (Pletscher, 2006).

Concluding Remarks

In 1957 Abraham Wikler published his classic text on The Relation of Psychiatry to Pharmacology in which the words “psychiatry” and “pharmacology” were linked for the first time. Wikler raised the possibility that from studying the mode of action of psychotropic drugs with known clinical effects, one might be able to deduce the biochemical basis of mental disorders. In reviewing Wikler’s book, Leo Hollister, one of the pioneering neuropsychopharmacologists, noted that “This bootstrap operation is at the heart of neuropsychopharmacology and has dominated the dialogue between psychiatry and pharmacology since“(Hollister, 1996). 

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June 6, 2013