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Tuesday, 11.05.2021

Ruth Koeppe: Largactil - Six Preliminary Clinical Observations

 

Thomas A. Ban’s comment on John Griffin’s letter to the editor. Chronology of recorded early publications on chlorpromazine*

 

         In his letter to the editor of Dialogue, the Journal of the Ontario Psychiatric Association, published on December 3, 1993, John Griffin , a former Director of the Canadian Mental Health Association, suggested that it was a ”A historical oversight” that Ruth Koeppe’s presentation on chlorpromazine on November 27, 1953,  is not included in the history of the substance. The following is an extract of my Concluding Remarks, presented at a synthesium on “50 Years Chlorpromazine” at the 24th Congress of the Collegium Internationale Neuro-Psychopharmacologicum in 2004 in Paris. Looking at the chain of events in the history of the substance, it shows that Ruth’s presentation took place before any paper on the substance was published outside of France, Austria, Italy  and Switzerland.

 

         The following is an extract of my Concluding Remarks:

 

         Chlorpromazine was synthesized on December 11, 1951, by Paul Charpentier in the laboratories of Rhône-Poulenc, a French pharmaceutical company, and released for clinical investigation in May 1952 as a possible potentiator of general anesthesia (Charpentier, Gailliot, Jacob et al 1952).

         The potential use of CPZ in psychiatry was first recognized by Henri Laborit (1952), a surgeon and physiologist in the French army, in the course of his research with artificial hibernation in the prevention of surgical shock In collaboration with Huguenard and Alluaume he employed the drug as an adjunct to surgical anesthetics (“anesthetic cocktail,” “lytic cocktail”) because of its body temperature lowering effect. He found that CPZ, in the dosage of 50 to 100 mg given intravenously, produced disinterest without loss of consciousness and with only a slight tendency to sleep.  His first paper on CPZ was published in the February 13th issue of La Presse Médicale in 1952 with the title “A new vegetative (autonomic) stabilizer” (Laborit, Huguenard and Alluaume 1952).

         Since cooling with water had been used in France for controlling agitation (Burger 1976), Laborit was able to persuade Hamon, Paraire and Velluz at the neuropsychiatric service of Val de Grâce, the military hospital in Paris, to try CPZ in the treatment of one of their patients (Caldwell 1970). Jacques Lh., a 24-year-old severely agitated psychotic (manic) male, was the first psychiatric patient to receive CPZ; he was administered 50 mg of the drug, intravenously, at 10 AM, on January 19, 1952. The calming effect of CPZ was immediate but since it lasted only a few hours several treatments were required before the patient’s agitation was controlled. Repeated administration of the drug caused venous irritation and perivenous infiltration. Hence, on several occasions barbiturates and electroshock were substituted for CPZ. Nonetheless, after 20 days of treatment, with a total of 855 mg of CPZ, the patient was ready “to resume normal life.” The effects of CPZ on Jacques Lh. were reported on February 22, 1952, by Colonel Paraire, at a meeting of the Société Médico-Psychologique in Paris, and, based on this presentation, the first paper on CPZ in psychiatry was published in the March 1952 issue of the Annales Médico-Psychologiques, the official journal of the Society (Hamon, Paraire and Velluz 1952).        

         Clinical investigations with CPZ at Saint-Anne’s hospital -- at Pierre Deniker’s service in Jean Delay’s department -- in Paris began on March 24, 1952 (Caldwell 1970). Since it was believed that the drug worked by inducing “artificial hibernation,” ice packs were used to enhance “cooling.” It did not take long to recognize that “cooling” did not contribute to the drug’s therapeutic effect (Thuillier 1999). In most patients CPZ alone, in the daily dosage of 75 mg, was sufficient for controlling behavior. Early findings with CPZ at Saint-Anne were presented on May 25, 1952, at the Centennial Meeting of the Société Médico-Psychologique (Delay, Deniker and Harl 1952a). The six publications of Delay and Deniker during the six months that followed (Delay and Deniker 1952a,b,c; Delay, Deniker and Harl 1952a,b; Delay et al 1952), set the stage for the introduction of CPZ in psychiatry (Olie 2004). Other publications in 1952 included a report by Follin (1952), on the successful treatment of an aggressive paranoiac patient with CPZ at Montauban Mental Hospital in France (Caldwell 1970); an article by Rigotti (1952) on 20 psychiatric patients treated with CPZ in Padua, Italy; and a paper by Arnold, Hilt and Solma (1952) on the use of CPZ in psychiatry in Vienna.

         CPZ became available on prescription in France under the proprietary name of Largactil, i.e., large in action, in November 1952 (Caldwell 1970). The proprietary name was chosen to reflect the diversity of pharmacological actions and potential clinical indications of the drug (Burger 1976; Courvoisier, Fournel, Ducrot et al. 1953; Thuillier 2000). Subsequently, within a short period of three years, from 1953 to 1955, CPZ treatment in psychiatry spread around the world. By the end of 1955 there were reports on the effects of CPZ in psychiatric patients from Switzerland (Staehelin and Kielholz 1953; Staehelin 1954), England (Anton-Stephens 1954; Elkes and Elkes 1954), Canada (Lehmann 1954; Lehmann and Hanrahan 1954), Germany (Bente and Itil 1954), Hungary (Kardos and Pertorini 1954), Latin America (Saly y Rosas, Jerí and Sanchez 1954), United States (Winkelman 1954), Australia (Webb 1955) and the USSR (Tarasov 1955). Heinz Lehmann, a German-born Canadian psychiatrist at the Verdun Protestant Hospital in Montreal, was first to suggest that CPZ selectively inhibits affective drive (Lehmann 1954). His paper, co-authored by Hanrahan and published in the Archives of Neurology and Psychiatry (USA), had a major impact on the introduction of CPZ in North America (Lehmann and Hanrahan 1954).   

         The first international colloquium on the therapeutic uses of CPZ in psychiatry was held at Saint-Anne’s Hospital in Paris, on October 1955 (Hollister 1994; Thuillier 1999) with 257 participants from 19 countries (Austria, Belgium, Brazil, Canada, Cuba, France, Germany, Great Britain, Holland, Luxembourg, Peru, Portugal, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States and Venezuela). 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, for bringing the full practical significance of CPZ to the attention of the medical community (Ban 1994).  

 

References:

Anton-Stephens D. Preliminary observations on the psychiatric uses of chlorpromazine (Largactil).  Journal of Mental Science 1954; 100: 543-57.

Arnold OH, Hilt S, Solma W. Über die Anwendung eines vegatativen Hemmungs stoffes in der psychiatrischen Therapie.  Wiener Medizinische Wochenschrift 1952; 102: 965-9.

Ban TA. Nobel Prize and Albert Lasker Award. In: Ban TA, Hippius H, editors. Towards CINP. Brentwood: JM Productions; 1994, pp 8-14.

Bente D, Itil TM. Zur Wirkung des Phenothiazin Körpers Megaphen auf das menschliche Hirnströmbild. Arzneimeittel Forschung,  1954; 4: 418-23.

Burger A. History. In: Usdin E, Forrest IS, editors. Psychotherapeutic Drugs. Part I Principles. New York and Basel: Marcel Dekker; 1957, pp 11-57.

Caldwell AE.  Origins of Psychopharmacology From CPZ to LSD. Springfield: Charles C. Thomas; 1970, pp 23-35.

Charpentier P, Gailliot P, Jacob R, et al.  Recherches sur les diméthylaminopropyl-N phénothiazines substituées. Comptes rendus de l’Académie des sciences  (Paris) 1952; 235: 59-60.

Courvoisier S, Fournel J, Ducrot R, et al. Pharmacodynamiques du chlorhydrate de chloro-3-(diméthylamino-3’-propyl)-10-phénothazine (4560 RP). Étude expérimentale d’un niveau corps utilisé dans l’anesthésie potentialisée et dans l’hibernation artificielle. Archives internationales de pharmacodymnamie et de thérapie,1953; 92: 305-361.

Delay J, Deniker P. Le traitments de psychoses par une méthode neurolytique dérivée de l’hibernothérapie; le 4560 RP utilisée seul en cure prolongée et continue. CR Congr Mé d Alién Neurol (France), 1952a; 50: 497-502.

Delay J, Deniker P. 38 cas de psychoses traitèes par la cure prolongèe et continuè de 4560 RP. CR Congr Méd Alién Neurol (France) 1952b; 50: 503-13.

Delay J, Deniker P. Réactions biologiques observées au cours du traitement par l’chlorhydrate de deméthylaminopropyl-N-chlorophénothiazine. CR Congr Méd Alién Neurol (France), 1952c; 50: 514-8.

Delay J, Deniker P, Harl JM. Utilisation en thérapeutique d’une phénothiazine d’action centrale selective. Annales Médico-psychologiques, 1952a; 110: 112-7.

Delay J, Deniker P, Harl JM. Traitement des ètats d’excitation et d’agitation par une méthode médicamenteuse dérivè de l’hibernothèrapie. Annales Médico-psychologiques, 1952b; 110: 267-73.

Delay J, Deniker P, Harl JM, Grasset A. Traitements d’ètats confusionnels par l’chlorhydrate de diméthylaminopropyl – N – chlorophénothiazine (4560 RP). Annales Médico-psychologiques, 1952; 110: 112-7.

Elkes J, Elkes Ch. Effects of chlorpromazine on the behavior of chronically overactive psychotic patients. British Medical Journal 1954; 2: 560-76.

Follin S. Discussion. Annales Médico-psychologique 1952; 110: 126-7.

Gyermek L. Chlorpromazine: A serotonin antagonist? The Lancet  1955; 2: 724.

Gyermek L, Lázár GT, Csák Zs. The antiserotonin action of chlorpromazine and some other phenothiazine derivatives. Arch Int Pharmacodyn, 1956; 107: 62-74.

Hamon J, Paraire J, Velluz J.  Remarques sur l’action du 4560 RP sur l’agitation maniaque. Annales Médico-psychologiques (Paris). 1952; 110: 331-5.

Hollister LE. 1994. Review of International Colloquium on Chlorpromazine. In: Ban TA, Hippius H, editors. Towards CINP. Brentwood: JM Productions, 1994, pp 18-23.

Kardos G, Pertorini R.  Largactil a psychiátriában. Ideggyogyászati Szemle, 1955; 8: 65-9.

Laborit H, Huguenard P, Alluaume R. Un noveau stabilisateur végétatif (le 4560 RP). La  Presse Médicale, 1952; 60: 206-8.

Lambert P. Chlorpromazine: A true story of the progress affected by this drug. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and the Story of CINP. Budapest: Animula. 1998, pp 237-43.

Lambert P, Perrin J, Revol L, et al. Essai de classification des neuroleptiques d’après leurs activités psycho-pharmacologiques et cliniques. In: Bradley PB, Deniker P, Radouco-Thomas C, ediors. Neuropsychopharmacology. Amsterdam: Elsevier: 1959,  pp 619-24.

Lehmann HE. Selective inhibition of affective drive by pharmacological means. American Journal of Psychiatry, 1954; 110: 856-7.

Lehmann HE, Hanrahan GE. Chlorpromazine, new inhibiting agent for psychomotor exctietemnt and manic states. Archives of Neurology and Psychiatry (Chicago), 1954;   71: 227-37.

Olie JP. The discovery of chlorpromazine: A historical account. The   International Joirnal of Neuropsychopharmacology, 2004;  7 (suppl. 1): 21.

Rigotti S. Del blocco del SN vegetativo all’ibernazione artificiale primi risultati di un nuevo indirizzo di terapia psichiatrica. Rassegna di neurologia vegetative. 1952; 9: 197-210.

Sal y Rosas F, Jerí R, Sanchez J. Chlorpromzine in neuropsychiatry Journal of the American Medical Association 1954;  156: 558.

Staehelin JE. Einige allgemeine Bemerkungen  uber die Largactil-therapie in der psychiatrischen Universitatsklinik Basel. Schweizerische  Archives für  Neurologie und  Psychiatrie, 1954; 288-91.

Staehelin JE, Kielholz P. Largactil, ein neues vegatativen Dämpfungsmittel bei psychischen Störungen. Schweizerische  Medizinische  Wochenschrift, 1953;  83: 581-6.

Tarasov GK. Aminazine, review of the literature on the psychiatric use of a phenothiazine derivative. Zhurnal Nevropatologii i  Psikhiatria Korsakov 1955; 55: 296-310.

Thuillier J.  Ten Years That Changed the Face of Mental Illness London: Martin Dunitz.; 1999; pp 111-23.

Webb RR. Largactil in psychiatry. The Medical Journal of Australia  1955; 1: 759-61.

Winkelman NW. Chlorpromazine in the treatment of neuropsychiatric disorders. Journal of the American Medical Association 1954; , 155: 18-21.

Winter CA, Flataker L. The effect of antihistaminic drugs upon the performance of trained rats. Journal of Pharmacology and  Experimental Therapeutics, 1951; 101: 156-62.

Woolley DW, Shaw E. A biochemical and pharmacological suggestion about certain mental disorders. Proceedings of the  National Academy of Sciences (USA) 1954; 40: 228-31.

 

 

 *This manuscript is based on my concluding remarks presented at the synthesium on 50 Years Chlorpromazine, at the 24th CINP congress, held in Paris in 2004.

 

May 28, 2020