We may think of clozapine as a drug of the ‘90s, but Sandoz began research on the drug in the early ‘60s, and the first paper appeared in 1966, the Medical Journal of Vienna. A group of German psychiatrists presented positive findings from a multicenter trial of clozapine at about the same time, and the drug was introduced in Europe in 1972, the delay apparently because people were skeptical about an antipsychotic without extrapyramidal side effects. It seems that concerns about hypotension and seizures kept the drug from being introduced in North America at that time. In September 1975, The Lancet published a report from Finland of 18 cases of agranulocytosis, eight of them fatal, which ultimately led to the drug’s being taken off the market. It was reintroduced in Europe in the late ‘80s, and by 1990 it was available in the U.S., with mandatory blood tests to monitor for agranulocytosis. The term "atypical" was initially used to connote clozapine’s lack of extrapyramidal effects, but when receptor studies were introduced, it was soon shown that clozapine has an affinity for different receptor subtypes than the "typical" antipsychotics. This soon led to the "rational" drug design that has given us a smorgasbord of atypical (or second-generation, or new-generation) antipsychotics, each targeting a somewhat different set of receptors.

Source: Can J Psychiatry 1997; 42:152-162