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The development of antipsychotic drugs changed the practice of psychiatry. Prior to the introduction of chlorpromazine in 1950, patients with schizophrenia were treated with nonspecific sedatives such as barbiturates and chloral hydrate. Highly 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 psychotic disorders were hospitalized in the United States. The advent of antipsychotics 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 caused significant toxicity following overdose, a common occurrence in patients with mental illness. Moreover, they were also associated with a host of adverse effects, principally 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 of several chemical classes. These drugs exhibited varying potencies and markedly different adverse effect profiles. The novel antipsychotic clozapine was first synthesized in 1959, but it did not enter widespread clinical use until the early 1970s. Clozapine was unusual because it conferred a relatively low risk of EPS, but also because it was often effective in patients who had not responded well to other xenobiotics. Moreover, unlike the other available xenobiotics, it often improved the “negative” symptoms of schizophrenia such as avolition, alogia, and social withdrawal—symptoms that, while 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 1990.9,49 However, the unique therapeutic and pharmacologic properties of clozapine 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 xenobiotics.

Most antipsychotic toxicity occurs by one of two mechanisms. Following overdose, antipsychotic toxicity is dose dependent and reflects an extension of the effects of the drug on neurotransmitter systems and other biologic processes. The features of antipsychotic drug overdose are therefore generally predictable based upon an understanding of the pharmacology of the drug. Unpredictable (idiosyncratic) adverse reactions also occur in the context of routine therapeutic use. These toxicities result from individual susceptibility, are sometimes pharmacogenetic in nature, and are less reliably correlated with the dose. In both types of toxicity, the severity of illness can range from minor to life threatening, depending on a number of other factors, including concomitant drug exposures, comorbidity, and access to medical care.

The true incidence of antipsychotic overdose and adverse reactions is ...

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