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Monday, 18.11.2019

Alex Last: BBC Witness History

The First Antipsychotic Drug*

An interview of Thomas Ban

 

AL: When did you become a doctor working on mental illness?

TB: I graduated from medical school (Semmelweis University), in 1954, in Budapest, Hungary, and started my medical career as an assistant physician at the National Institute of Nervous and Mental Diseases of Hungary in Budapest on the 1st of July the same year. I qualified as a psychiatrist in 1960 with a Diploma in Psychiatry, received with distinction from McGill University, in Montreal, Quebec, Canada, in 1960.

 

AL: How were schizophrenic patients treated before chlorpromazine?

TB: After the introduction of physical therapies in the late 1930s patients with schizophrenia were treated with Insulin Coma and/or Electroconvulsive Therapy. Morphine with scopolamine or apomorphine with hyoscine was used to control acute excitement and agitation; paraldehyde, potassium bromide and barbiturates were employed for daytime sedation; and chloral hydrate for nighttime for inducing sleep.

 

AL: When did you first see/hear about CPZ?

TB: Soon after I started to work in the Institute, I heard about passingly that a new drug was introduced in France developed by Rhone-Poulenc, a French drug company, that might be effective in the treatment of psychotic patients.

 

AL:  What did colleagues say about it?

TB: They were skeptical.  

 

AL: When did you first see the effects on patients?

TB: Early, probably January, in 1955.

                                                                                                  

AL: What effect did it have one the patients you treated?

TB: The first patient I treated with chlorpromazine was a man in his mid-50s with a diagnosis of involutional psychosis. He was frightened, agitated, depressed and paranoid. Parenterally administered chlorpromazine promptly controlled the intensity of his symptoms. Another patient of mine, a “speech inactive” catatonic who did not utter a word for at least a year, started to talk and a third, a negativistic catatonic, who resisted any attempt to be moved or even to be fed, became fully cooperative after a short course of treatment.    

 

AL: What was your reaction?

TB: I thought that a new perspective was opened in psychiatry for treating patients and not just controlling their behavior.

 

AL: Must have been excited?

TB: After treating and recording the effects of chlorpromazine in a dozen of our patients I recognized the need for developing an education for our nursing staff to be able to meet the new needs for attending patients. I also recognized the need for rendering the rapidly emerging new information relevant to treatment of psychiatric patients from all around the world readily accessible to our colleagues. I shared my views with Gyorgy (George) Sandor, my service chief and we succeeded in launching two “periodicals,” one for the medical and the other for the nursing staff of the Institute.

 

AL: How does it work? Why does it work?

TB: In 1964 Arvid Carlsson, a Swedish pharmacologist who was to receive the Nobel Prize, postulated that the therapeutic effect of chlorpromazine is related to a blockade of dopamine receptors in the brain. Dopamine is one of the molecules involved in the propagation of impulses in the central nervous system.  Eleven years later, in 1975, two independent teams of investigator, one lead by Philpp Seeman, a Canadian professor of pharmacology, and the other by Sol Snyder, an American professor of pharmacology, demonstrated that chlorpromazine blocks dopamine receptors.

 

AL: How was it discovered?

TB: In the late 1940s Henri Laborit, a surgeon in the French Navy, at the Bizerte Naval Hospital in Sidi-Abdallah, Tunisia, found that promethazine, one of the antihistaminic phenothiazines synthesized in the early 1940s, eminently suited for the prevention of surgical shock. He also noted that the substance produced “euphoric quietude” with a “state of indifference” and when given prior to surgery patients remained “calm, somewhat somnolent, and relaxed.” In 1950 Laborit moved from Bizerte to Paris and asked Dr. Beal from the administration of Rhône-Poulenc for a somewhat similar phenothiazine to promethazine that could hopefully attenuate patients' anxiety while potentiating anesthesia. In 1951 he received a supply of CPZ for his clinical investigations. In February 1952 Laborit, together with Huguenard and Alluaume, reported that in doses of 50 to 100 mg intravenously, CPZ does not cause loss of consciousness or any change in the patient’s mentation, but produces a tendency to sleep and disinterest in the surroundings. In the same report Laborit recognized the potential use of CPZ in psychiatry. The first use of CPZ in a psychiatric patient was reported by Hamon, Paraire, and Velluz, at Val de Grace, the military hospital in Paris, in March 1952, about a month after the report of Laborit. Before the end of the year there were several other reports, including the six papers by Delay and Deniker from the Saint Anne Hospital in Paris that set the stage for CPZ’s development in psychiatry.

AL: What impact has it had? Fair to compare it to the impact of penicillin.

TB: It had a major impact, but its impact is not comparable to penicillin’s. Penicillin is a causal treatment. It kills the bacteria that causes the disease. Treatment with chlorpromazine is palliative treatment that controls symptoms and optimally keeps patients in remission.

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AL: How was it… What the introduction of CPZ do?  

TB: It decreased the need for using physical restraint. It also decreased the schizophrenic population hospitalized for more than one year but less than five years in psychiatric hospitals. As years passed, it shifted the arena of psychiatric care from hospitals to the community. 

 

AL: What about its effect on admissions? Reduction in admissions?

TB: To the contrary. In an analysis of population changes in New York State Mental Hospitals it was shown that simultaneously with the fall of resident population there was an approximately 50% increase in readmissions during the 1955 to 1960 period.

 

AL: So, it was not a cure. Could not help everyone. Did not stop people being readmitted. But it did help to create a new field: psychopharmacology?

TB: The term “psychopharmacology” was introduced by David Macht, an American pharmacologist, in 1920 for describing the effects of drugs used to control fever on neuromuscular coordination tests.  The scope of the term was gradually extended to include all experimental investigations on the psychometric and psychic effects of drugs. By the end of the 1950s with the introduction of the first set of psychotropic drugs and several similar drugs to chlorpromazine, it included research focused on the detection and demonstration of their therapeutic effects.

 

AL: ….new variants of CPZ were created…

TB: …but none of them were shown to be more effective than CPZ

 

AL: People hoped it would lead to a new world of being able to identify and treat specific mental illnesses…

TB: …but this didn't happen.

 

AL: General problem is how to evaluate effectiveness…difficult to say which drug works best for a particular patient.

TB: It required the development of a methodology that would resolve this pharmacological heterogeneity, but instead a methodology was developed for the demonstration of therapeutic efficacy in pharmacologically heterogenous populations.

 

AL: Are we too dependent on drugs now?

TB: This is a matter of opinion, but without resolving the pharmacological heterogeneity within the diagnostic populations we are prescribing psychotropic drugs indiscriminately.

 

*You can access and listen to Alex Last’s podcast version at:  https://www.bbc.co.uk/programmes/p004t1hd/episodes/downloads  and the radio version at https://www.bbc.co.uk/programmes/w3csyx1z

 

November 14, 2019