A history of antipsychotic drug development

The history of antipsychotic drug development has had a long and torturous course, often based on chance findings that bear little relationship to the intellectual background driving observations. In 1891, Paul Ehrlich observed the antimalarial effects of methylene blue, a phenothiazine derivative. Later, the phenothiazines were developed for their antihistaminergic properties. In 1951, Laborit and Huguenard administered the aliphatic phenothiazine, chlorpromazine, to patients for its potential anesthetic effects during surgery. Shortly thereafter, Hamon et al. and Delay et al. extended the use of this treatment in psychiatric patients and serendipitously uncovered its antipsychotic activity. Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States and about 40 throughout the world. Thereafter, there was a hiatus in the development of antipsychotics until the introduction of clozapine treatment in the United States in 1990 opened the era of "atypical" antipsychotic drugs, which show a reduced potential to induce extrapyramidal symptoms (EPS), an increased efficacy for the negative symptoms of schizophrenia, no elevation of prolactin after chronic use (except risperidone), and, at least for clozapine, effectiveness in some patients previously regarded as treatment-refractory. This review describes the available atypical antipsychotic drugs and their characteristics, and concludes by highlighting those in the pharmaceutical "pipeline."