Sunday, 12.07.2020

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

Towards Neuropsychopharmacology in 1957
Bulletin 30

 

 

Preamble

 

Towards Neuropsychopharmacology in 1957 is based on an essay presented with the title The Birth of Neuropsychopharmacologyon INHN website in Textbook on June 6, 2013.

 

 

Towards Neuropsychopharmacology in 1957

 

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. They 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 drug-induced changes in the concentration of monoamine neurotransmitters in the brain(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 in that year: (1) the organization of the First International Symposium on Psychotropic Drugs in Milan (Italy); (2) the inclusion of a Psychopharmacology Symposium at the 2ndWorld Psychiatric Association  (WPA)Congress in Zurich (Switzerland);and (3) the founding of the Collegium Internationale Neuro-Psychopharmacologicum, an international organization  to provide a platform for interaction for the disciplines involved in neuropsychopharmacological researchduring the WPA Congress (Ban and Ray 1996)

 

Lithium

            In the title of his text on the story of lithium in psychiatry Johan Schioldann suggests that “modern psychopharmacologywas born”  in 1949 with the rediscovery of the therapeutic effects of lithium in affective disorder (mania) by John Cade, an Australian psychiatrist(Schioldann 2009). The original discovery dates back to late 19th century when Carl Lange, a Danish psychiatrist reported on the therapeutic effect of lithium in periodic depression (Ban 2006; Cade 1949; Schioldann 2009).

            In 1951, two years after Cade’s report, Noah and Trautner established the therapeutic window for lithium in the plasma; in 1954, Schou, Juel-Nielsen, Stromgren and Voldby verified lithium’s therapeutic effects in mania; in 1956 Gershon and Trautner demonstrated lithium’s effectiveness in maintaining manic patients in remission after successful treatment with ECT; and in 1957, Schou,with an article on “The Biology and Pharmacology of the Lithium Ion” published in Pharmacological Reviews,set the stage for the introduction lithium in the treatment of manic-depressive illness around the world in the years that followed.

 

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 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; 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 for the prevention of surgical shock. Clinical investigations with CPZ at Saint-Anne’s hospital in Paris began on March 24, 1952. The six historical publications of Delay and Deniker during the six months that followed set the stage for the introduction of CPZ in psychiatry (Caldwell 1970).

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.  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. 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 serpentine 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 first with Rauwolfia serpentine and,subsequently, reserpine. The findings of this research were published in 1954 in four historical papers written by (1) Kline, (2) Delay and his associates, (3) Weber, and (4) Noce et al. (Kurland1996). 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 the 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 therapeutic effects. His expectations were not fulfilled. But in January 1956 when he administered the substance to one of his femalepatients with severe endogenous depression, he recognized that G 22,355 might have antidepressant effects. Encouraged by these findings Kuhn administered G 22,355 to two more female patients with severe endogenous depression. In both patients the drug had favorable effects. Furthermore, in all three patients discontinuation of treatment resulted in relapse that was reversed by resumption of the medication. Subsequently, Kuhn treated 40 more depressed patients with G 22,355 at the clinic. 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 is in the foreground (Kuhn 1996).

Kuhn’s first paper on the treatment of depressive states with an iminobenzylderivative G 22,355 was published in 1957 in the August 31st issue of the Swiss Medical Journal. Two days later, on the 2nd of September, he also presented his findings at the 2nd 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 (Ban 2006).

           

Iproniazid

 

            In 1957, the same year that imipramine was released for clinical use in Switzerland, two independent groups of investigators, Loomers, Saunders and Kline, and Crane, 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, 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 antidepressant effects of iproniazid were recognized and reported in the United States (Ban2006).

 

Neuropsychopharmacology

 

            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 drug-induced changes in the concentration of these monoamines and their metabolites in the brain, was constructed in 1955.Within a year, in collaboration with Shore and Brodie, Pletscher reported a dose-dependent 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, in collaboration with Besendorf,  a moderate increase in brain serotonin  levels after the administration of the monoamine oxidase inhibitor, iproniazid, a substance that produced euphoria in some patients when used in the treatment of tuberculosis (Besendorf and Pletscher 1956; Pletscher,Shore and Brodie 1955, 1956).  Also, in the same year(1956) Holzboer 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 with his associates conclusively demonstrated that reserpine depleted both catecholamines, dopamine and norepinephrine. He also showed that pretreatment with iproniazid prevented the disappearance of catecholamines after reserpine injection (Pletscher 2006).

 

Concluding remarks

 

In 1957 Abraham Wikler published his classic text,“The Relation of Psychiatry to Pharmacology,” in which the words “psychiatry” and “pharmacology” were linked for the first time. In the same text,he 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 leading neuropsychopharmacologists at the time, noted that: “This bootstrap operation is at the heart of neuropsychopharmacology and has dominated the dialogue between psychiatry and pharmacology since” (Hollister 1996).

 

References:

 

Ban, T.A. , 1996. Nobel Prize and Albert Lasker Award. In: Ban, T.A., Ray, O.S. (eds.) A History of the CINP. Nashville, J.M. Productions, pp. 265-271.

 

Ban TA. 2001. Pharmacotherapy of depression - a historical analysis. Journal of Neuronal Transmission 108, 707-716.

 

Ban TA. The role of serendipity in drug discovery. Dialogues in Clinical Neuroscience 2006; 8: 335-44.

 

Ban TA, Ray OS, eds. A History of the CINP. Nashville: JM Productions; 1996.

 

Ban TA, Ucha Udabe R.  The Neurotransmitter Era in Neuropsychopharmacology. In Ban TA. Ucha Udabe R, eds. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2005, pp. 265-74.

 

Bein H. Biological research in the pharmaceutical industry with reserpine. In Ayd, FJ, Blackwell B, eds. Discoveries in Biological Psychiatry. Philadelphia/Toronto: JB Lippincott: 1970, pp. 142-154.

 

Besendorf H, Pletscher A. Beeinflussung zentraler wirkungen von Reserpin und 5-Hydroxytrytamin durch Isonikotinsauerehydrazide. Helv Physiolog Acta 1956; 14: 383-90.

 

Cade JFJ. Lithium salts in the treatment of psychotic disorders. Med J Austr 1949; 2: 349-52. 

 

Caldwell AE. Origins of Psychopharmacology from CPZ to LSD. Springfield; Charles C. Thomas: 1970.

 

Carlsson A, Rosengren E, Bertler A, Nilsson J. Effectofreserpine on the metabolismof catecholamines. In Garattini S, Ghetti V, eds. Psychotropic Drugs. Amsterdam: Elsevier; 1956, pp.363 -72. 

 

Fox HH, Gibas JT. Synthetic tuberculostats. VII. Monoalkyl derivatives  of isonicotinyl hydrazine. J org Chem 1953;  18: 994 -1002. 

 

Gershon S, Trautner EM. The treatment of shock dependence by pharmacological agents. Med J Aust 1956; 43: 783-7.  

 

Hollister LE. Review of Wikler’s The Relation of Psychiatry to Pharmacology. In Ban TA, Ray OS, eds. A History of the CINP. Nashville: J.M. Productions; 1996, pp. 339-43

 

Kline NS. Monoamine Oxidase Inhibitors: An unfinished picaresque Tale. In  Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia/Toronto, J.B. Lippincott; 1970, pp. 194-294.

 

Kuhn R. Ueber die Behandlung depressiver Zustande mit einem iminobenzylderivat (G22, 355). Schweiz Med Wochenschr 1957; 87: 1135 - 40.  

 

Kuhn R. The discovery of the tricyclic antidepressants and the history of their use in theearly years. In Ban TA, Ray OS, editors. A History of the CINP. Nashville: JM Productions; 1996, pp. 425- 35.

 

Kurland A. Reserpine. In Ban TA, Ray OS, editors. A History of the CINP. Nashville: J.M. Productions; 1996, pp. 405-9.

 

Noack CH, Trautner EM. The lithium treatment of maniacal psychosis.  Med J Austr 1951; 2: 219 - 22.

 

Pletscher A. The dawn of the neurotransmitter era in neuropsychopharmacology. In Ban, TA, Ucha Udabe R. eds. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2006, pp. 29-37.

 

Pletscher A, ShorePA, Brodie BB. Serotonin release as possible mechanism of reserpine action, Science 1955; 122: 374-75.

 

Pletscher A, Shore PA, Brodie BB. Serotonin as a modulator of reserpine action in brain, J. Pharmacol. Exper Ther 1956; 116. 84-9.

 

Schioldann J. History of the Introduction of Lithium into Medicine and Psychiatry:  Birth of Modern Psychopharmacology 1949 Adelaide: Academic Press: 2009.

 

Schou M. Biology and pharmacology of the lithium ion. Pharmacol Rev 1957; 9: 17-58.

 

Schou M, Juel-Nielsen N, Stromgren E, Voldby H. The treatment of manic psychoses by the administration of lithium salts. JNeurol Neurosurg Psychiat 1954; 17: 250-60.

 

Selikoff IJ, Robitzek EH, Orenstein GG. Treatment of pulmonary tuberculosis  with hydrazine derivatives of isonicotinic acid. JAMA 1952; 150: 973-980

 

Wikler A. The Relation of Psychiatry to Pharmacology. Baltimore: American Society of Pharmacology and Experimental Therapeutics and the Williams and Wilkins Company; 1957.

 

Zeller EA, Barsky J, Fouts JR, Kirschheimer WF, Van Orden LS. Influence of isonicotinic acid hydrazide (INH) and isonicotinyl-2-isopropyl hydrazide (IIH) on bacterial and mammalian  enzymes. Experientia 1952; 8: 349-350.

 

August 9, 2018