Chlorpromazine and the Phenothiazine Antipsychotics

   (from 1952).

   Prehistory: In 1883, August Bernthsen (1855–1931), a postdoctoral student in chemistry at Heidelberg, synthesized a hydrocarbon molecule with two benzol rings connected to each other by a sulfur and a nitrogen atom. Writing in the Reports of the German Chemical Society (Berichte der Deutschen Chemischen Gesellschaft), Bernthsen called it "thiodiphenylamine" and later scholars rebaptized it as "phenothiazine." Only in 1934 was this base developed as an insecticide.

   Then in 1944, a research group headed by Paul Charpentier at the Rhône-Poulenc research labs in Vitry-sur-Seine, searching for new antihelminthics, hit on the idea of hooking an amino group to a hydrocarbon chain that they dangled from the base of the phenothiazine. The following year, in 1945, others at Rhône-Poulenc started screening Charpentier’s compounds as possible antihistamines, and out of this backand-forth came a drug called promethazine (RP 3277), which had as a side effect pronounced sleepiness. This led the researchers to think the drug might have central (brain) effects—and indeed it did: an antihistamine with strong sedative qualities, it is still widely available for sale today as Phenergan.

   In the late 1940s, a French naval surgeon named Henri Laborit (1914–1995) obtained some promethazine and used it in a "lytic cocktail" with other drugs to slow down the autonomic nervous system and reduce shock in surgery. Stimulated by these successes, Charpentier synthesized still more compounds from the phenothiazine nucleus and in December of 1950 sent one, RP 4560, to Simone Courvoisier for pharmacological testing; it was a compound that he had developed not as an antihistamine but with high hopes for central effect.

   RP 4560 was chlorpromazine, the single most important drug in the history of psychiatry: As it was launched for trials in 1952 (upon the recommendation of Laborit), first at the Val-de-Grâce military hospital, then by Jean Delay and Pierre Deniker at Ste.-Anne mental hospital, it tamed the symptoms of psychosis without unduly sedating the patients. In 1953, in an article in Presse médicale that was widely ignored outside of France because it had no statistics, Jean Sigwald (born 1903, lic. med. qualified 1932) and Daniel Bouttier (lic. 1948) at the Brousse Psychiatric Hospital reported "chloropromazine" [sic] effective in a wide variety of outpatient conditions. They emphasized especially its antidepressant qualities.

   No one connected with this story ever won a Nobel Prize. Yet in 1957, Deniker and Laborit received Lasker Awards (along with Heinz Lehmann) for their part in this story. They had touched off a pharmacological revolution, demonstrating that a major psychiatric illness could be improved, not with psychotherapy but with chemotherapy, and that the seat of such illnesses must therefore be in the brain rather than in the mind.

   Outside of France, chlorpromazine was tested first in Switzerland. In 1953, John Eugen Staehelin (1891–1969), director of the Basel university psychiatric clinic, and Paul Kielholz (1916–1990), then an assistant psychiatrist (later Staehelin’s successor), reported in the Swiss Medical Weekly (Schweizer Medizinische Wochenschrift) on the usefulness of the drug in "psychic disturbances" where the "vegetative tone" was down, and in those where a "reduction" of the patient’s emotional drives was desirable, in order to make him or her more accessible to psychotherapy. Despite the opaque language, however, it is clear they were administering it to patients with major psychiatric illnesses.

   Rhône-Poulenc took out a U.S. patent in 1953, selling the license for the drug to Smith Kline & French Laboratories in Philadelphia. Trials by Heinz Lehmann in Canada and by Willis H. Bower (1916–2000) at McLean Hospital, the latter trial published in 1954 in the New England Journal of Medicine, proved especially influential. Smith Kline marketed the drug in 1954 as Thorazine; Rhône-Poulenc brought it out elsewhere as Largactil. Interestingly, in the early days chlorpromazine was tried for indications going far beyond psychosis: it was marketed for pain, high-grade anxiety, nausea, hyperactivity in children, and menopausal distress, among many other conditions (and it does have a pharmacological effect in pain and nausea, at least). Only later, in the Drug Efficacy Study Implementation (DESI) of the U.S. Food and Drug Administration during the years between 1968 and 1972 were the indications for chlorpromazine limited essentially to psychosis.

   Because of the great commercial success of chlorpromazine, other phenothiazines followed in short order. None was ever therapeutically superior to chlorpromazine— the gold standard in antipsychotic therapy—yet had differing side-effect profiles. In order of year of U.S. patent, the main phenothiazine antipsychotics were as follows:

   ♦ 1956: perphenazine (Schering launched as Trilafon in 1957).

   ♦ 1957: prochlorperazine (Smith Kline & French launched as Compazine in 1956 [sic]); this ceased relatively soon to be used as a psychiatric drug and was indicated instead for gastrointestinal upset.

   ♦ 1958: thioridazine (Sandoz launched as Mellaril in 1959).

   ♦ 1959: trifluoperazine (first described 1957; Smith Kline & French launched as Stelazine in 1958).

   ♦ 1960: fluphenazine (White Laboratories launched as Permitil in 1959; Squibb launched as Prolixin in 1960).

   A page was turned in the history of antipsychotic therapy in 1967 when E. R. Squibb & Sons brought out Prolixin Enanthate, a twice-a-month injectable form of fluphenazine. This was the first of the so-called "depot" antipsychotics, long-acting injectable doses that made possible the community treatment of schizophrenic patients, who no longer had to take medications daily in a supervised setting. In 1973, Squibb launched Prolixin Decanoate, an injectable form administered once every 3 weeks.

   The early days of phenothiazine therapy were marked by the administration of very high doses. It was not unheard of in the United States for patients on chlorpromazine to receive up to 3000 mg a day, at a time when 150 mg per day was considered in Europe to be a healthy dose. The big decline in dosages began with the publication of the book The Action of Neuroleptic Drugs (1965) by Hans-Joachim Haase (1922–), professor of psychiatry in Düsseldorf, and by Paul Janssen (1926–2003), director of research of a pharmaceutical company in Beerse, Belgium, named after his family. The authors built upon a discovery that Haase had made in 1955 about the shrinking size of handwriting under neuroleptic treatment: In 1965, they said that when the patient’s handwriting starts to get smaller, the therapeutic dose ("neuroleptic threshold") has been reached: it became clear that the threshold was reached at much smaller doses.

   Another body blow to large doses came in 1991 as Stephen R. Marder (1945–) and associates at the West Los Angeles Veterans Administration Medical Center emphasized in Schizophrenia Research that in order to limit the symptoms of extrapyramidal syndromes (EPS) such as tardive dyskinesia (TD), "the lowest effective dose" should not be exceeded. Then in 1994, Paula Bollini (otherwise at the International Organization for Migration in Geneva) and co-workers at the Technology Assessment Group of the Harvard School of Public Health, in a "meta-analysis" (pooling of data) of 22 published trials that appeared in Psychological Medicine, offered a definitive demonstration of the harmfulness of high doses: at doses above 375 mg-equivalents of chlorpromazine, patients stopped getting better, but the rate of side effects increased signifi-cantly.

   Leo Hollister (1920–2000), a veteran U.S. psychopharmacologist, said that in his lifetime he had been present at three medical miracles: one was penicillin and he had witnessed the spectacle of patients with bacterial endocarditis, "an otherwise fatal illness," saved with the drug; the second was seeing patients wheelchair-bound with rheumatoid arthritis get up and walk around the ward after treatment with corticosteroids; the third was chlorpromazine (Healy, Psychopharmacologists, II, p. 235).