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Neurosyphilis, Malaria, and the Discovery of Antipsychotic Agents

Four of the most disabling human diseases are syphilis, malaria, schizophrenia, and manic-depressive illness. The history of the development of treatments for these seemingly unrelated disorders intersects at several points. Treatment of tertiary cerebral syphilis (general paresis) by inducing fever with malaria led to a Nobel Prize. Although attempts to synthesize quinine, a plant product effective against malaria, failed, these efforts encouraged industrial organic chemists to synthesize many useful substances, including dyes, antibiotics, and antihistamines. The aniline-derived dye methylene blue was a member of a new class of polycyclic chemicals, the phenothiazines. Efforts to modify phenothiazines to find an antimalarial agent also failed but led to novel antiemetic-sedative antihistamines,including promethazine, promazine, and eventually chlorpromazine—the first effective treatment for schizophrenia and mania. Chlorpromazine has antipsychotic and antimanic properties, and it revolutionized the therapeutics of psychotic illnesses. (HARV REV PSYCHIATRY 2008;16:299–307.)