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The development of antipsychotic drugs dramatically altered the practice of psychiatry and eventually, medical care in general. Before the introduction of chlorpromazine in 1950, patients with schizophrenia were treated with nonspecific sedatives such as barbiturates or chloral hydrate. Agitated patients were housed in large “mental institutions” and often placed in physical restraints, and thousands underwent surgical disruption of the connections between the frontal cortices and other areas of the brain (leucotomy). By 1955, approximately 500,000 patients with mental health disorders were institutionalized in the United States. The advent of antipsychotic drugs in the 1950s revolutionized the care of these patients. These drugs, originally termed major tranquilizers and subsequently neuroleptics, dramatically reduced the characteristic hallucinations, delusions, thought disorders and paranoia—the “positive” symptoms of schizophrenia.

Shortly after the introduction of these drugs, it became apparent that they were capable of causing significant toxicity after overdose, a common occurrence in patients with mental illness. Moreover, they were also associated with a host of adverse effects during routine therapeutic use, particularly involving the endocrine and nervous systems. The latter includes the extrapyramidal syndromes (EPS), a constellation of disorders that are relatively common, sometimes irreversible, and occasionally life threatening.

The search for new drugs led to the development of multiple antipsychotics in several distinct chemical classes. These drugs exhibited varying potencies and markedly different adverse effect profiles. The novel antipsychotic clozapine was first synthesized in 1959 but did not enter widespread clinical use until the early 1970s. Clozapine was unusual because it conferred a relatively low risk of EPS and was often effective in patients who had not responded well to other antipsychotics. Moreover, unlike other antipsychotic drugs available at the time, it often improved the “negative” symptoms of schizophrenia, such as avolition, alogia, and social withdrawal, symptoms that, although often less outwardly apparent than the positive symptoms, result in significant disability. Reports of life-threatening agranulocytosis led to the withdrawal of clozapine from the market in 1974, although it was reintroduced in 1990 with stringent monitoring requirements.8,56 However, clozapine’s unique therapeutic and pharmacologic properties led to its characterization as an atypical antipsychotic, the forerunner and prototype of many other second-generation antipsychotics that have now largely supplanted the earlier drugs in clinical practice.

Most antipsychotic toxicity occurs through one of two mechanisms. After overdose, antipsychotic toxicity is dose dependent and reflects an extension of the drug’s effects on neurotransmitter systems and other biologic processes. The features of antipsychotic overdose are therefore generally predictable based on an understanding of the drug’s pharmacology. Unpredictable (idiosyncratic) adverse effects also occur in the context of therapeutic use. These toxicities result from individual susceptibility, which may in part have a genetic basis, and are less reliably correlated with the antipsychotic dose. In both types of toxicity, the severity of illness ranges from minor to life threatening, depending on variety of other factors, including concomitant drug exposures, comorbidity, and ...

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