Chlorpromazine in psychosis (Delay & Deniker)

In the early 1950s, the acute psychiatric wards of European hospitals had limited options beyond physical restraint, barbiturate sedation, and electroconvulsive therapy. Patients in manic or psychotic states were frequently kept under heavy sedation or in isolation, and the sedation itself prevented any assessment of whether the underlying psychosis was improving. The standard drugs blunted behavior broadly without touching hallucinations or delusions. Henri Laborit, a military surgeon at the Val-de-Grace hospital in Paris, found that a new Rhone-Poulenc compound, chlorpromazine, added to his pre-surgical cocktail produced relaxation and emotional detachment without loss of consciousness. In February 1952 his team reported that it calmed anxious patients without oversedation, and he urged psychiatrists to try it.

Paul Charpentier had synthesized chlorpromazine at Rhone-Poulenc on December 11, 1950, while trying to make a stronger version of the antihistamine promethazine. A month after Laborit's report, three Val-de-Grace psychiatrists described calming manic patients with it, given along with an analgesic or barbiturate. At the Sainte-Anne Hospital in Paris, Jean Delay and Pierre Deniker gave chlorpromazine on its own to acutely psychotic patients. Their first case was a 57-year-old laborer whose manic behavior had led him to assault strangers; after three weeks of treatment he had recovered. In May 1952 they reported reductions in agitation, hallucinations, and delusional thinking without the stupor that barbiturates produced.

The distinction mattered clinically. Earlier sedatives suppressed behavior; chlorpromazine appeared to reduce the psychosis itself while leaving the patient awake and able to talk. Delay and Deniker's name for drugs of this kind, neuroleptic, meant "taking hold of the nerves." How chlorpromazine worked was unknown for years: in 1966 Jacques van Rossum proposed that such drugs block dopamine receptors, and studies in the 1970s showed that effective doses tracked blockade of the D2 receptor.

By November 1952 chlorpromazine was available by prescription in France as Largactil. Smith Kline and French bought the American rights and in 1954 received FDA approval to sell it in the United States as Thorazine. The drug's arrival coincided with a period of administrative and political pressure on state psychiatric institutions. The daily census of U.S. state and county mental hospitals averaged about 559,000 in 1955, and by 1975 the number of patients in mental hospitals had fallen to 212,000. New federal benefits, civil rights rulings, weak outpatient services, and chlorpromazine all contributed, in proportions that are still debated.

Chlorpromazine also started the search for its mechanism, which led to the dopamine hypothesis of schizophrenia and to a generation of antipsychotic drug development. Arvid Carlsson, who showed that dopamine is a transmitter in the brain, received the Nobel Prize in Physiology or Medicine in 2000. Oral chlorpromazine is still on the World Health Organization's 2023 list of essential medicines, one of only two first-generation antipsychotics kept there, though second-generation drugs have largely replaced it in high-income settings.