Reserpine, an Early Psychiatry Drug

   (from 1954)

   Although Ayurvedic practitioners in India had used the roots of the Rauwolfia plant for centuries in the treatment of mental illness, it was only in the early 1950s that the drug became part of the revolution in psychopharmacology then underway. In 1952, three scientists of the Ciba company in Basel—J. M. Müller, E. Schlittler, and H. J. Bein—in an article in Experientia, isolated the alkaloid reserpine as the sedative principle of Rauwolfia serpentina Benth. Clinical use began, as Albert Kurland (1914–), director of research at Spring Grove State Hospital in Catonsville, Maryland, tells the story, on a spring Sunday in May 1953, as Nathan Kline was reading an article in the New York Times about R. A. Hakim, an Indian psychiatrist "of the Western school" at the Hospital for Mental Health of Ahmedabad, who had received a medal for his work on the cure of schizophrenia with a preparation from the Rauwolfia plant. Two U.S. pharmaceutical companies were already making Rauwolfia and its alkaloids available for the treatment of hypertension; from Squibb and Sons, Kline got a preparation of the whole root marketed as Raudixin, and from Ciba he obtained the alkaloid reserpine, which had been marketed under the trade name of Serpasil. Kline and co-workers gave them both to psychotic inpatients at the Rockland State Hospital in Orangeburg, New York. In April 1954, Kline reported in the Annals of the New York Academy of Sciences on the effectiveness of both the extract (reserpine) and the root; this was almost exactly at the time that chlorpromazine was being launched in the United States. In July 1954, Jean Delay and Pierre Deniker gave a similar account of reserpine in the Congrès des aliénistes et neurologues de langue française. These findings were confirmed in 1955, in a randomized controlled trial, as David Lewis Davies (1911–1983) and Michael Shepherd of the Maudsley Hospital established that reserpine had some effectiveness in the treatment of anxious and depressed patients.* This important research, published in 1955 in the Lancet, was widely ignored.

   On August 26, 1955, at the Laboratory of Chemical Pathology of the National Heart Institute, Alfred Pletscher (1917–), who was a guest scientist from Roche in Basel, Parkhurst A. Shore (1924–), and Bernard B. Brodie (1909–1989), the head of the laboratory, announced in Science that administering reserpine to rabbits seemed to drive down the levels of serotonin in the cells of their intestines (the drug caused release of serotonin, in other words).† Because there was already evidence that reserpine affected behavior, the authors speculated that, "some of the central [brain] effects of reserpine are mediated through the release of serotonin. It is conceivable that the beneficial effects of reserpine in mental disturbances result from the liberation of serotonin" (p. 375). This was one of the earliest empirical findings pointing to the psychiatric role of the neurotransmitter serotonin and really represents the birth of biochemical psychiatry (although later psychopharmacologists sought to keep the level of serotonin up rather than to drive it down, or "liberate" it). (See Selective Serotonin Reuptake Inhibitors.)

   Using Brodie’s reserpine model, Swedish pharmacologist Arvid Carlsson (1923–), then at Lund University, and his colleague Bertil Waldeck discovered in 1958 that dopamine ("3-hydroxytryptamine") was a neurotransmitter (see his article in Science, February 28; he actually submitted the article in 1957); in 1959 in Pharmacological Reviews, Carlsson speculated that it might be deficient in Parkinson’s disease. In 1961, reserpine ceased being marketed for psychiatric indications because of side effects. Yet, interest in reserpine as a potentially useful psychiatric drug has continued, and in 1998, in an article entitled "Reserpine exhumed" in the British Journal of Psychiatry, Irish psychiatrist David Healy (1954–) suggested that reserpine should be reexamined for its potential as an antidepressant.