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Most antipsychotics produce toxicity by one of two mechanisms—dose related and idiosyncratic. Overdose, whether intentional or unintentional, causes dose-related toxicity, which reflects an extension of the pharmacologic effects of the drug on neurotransmitter systems and other biologic processes. Such features of antipsychotic overdose are therefore generally predictable. Idiosyncratic adverse reactions may also occur in the context of routine therapeutic use resulting from individual susceptibility, which usually is pharmacogenetic in nature and only partially correlated with dose. In both instances, the severity of illness may range from minor to life threatening, depending on a number of other factors, including concomitant drug exposures, comorbidity, and access to medical care.

Before the introduction of chlorpromazine in 1950, patients with schizophrenia were treated with nonspecific sedatives such as barbiturates. Highly agitated patients were housed in large mental institutions and often placed in physical restraints. By 1955, approximately 500,000 patients with psychotic disorders were hospitalized in the United States. The advent of antipsychotics in the 1950s revolutionized care. Originally termed major tranquilizers and subsequently neuroleptics, these drugs dramatically reduced the hallucinations, delusions, and paranoia, which are "positive" symptoms that characterize schizophrenia.

Shortly after their introduction, however, it became apparent that the xenobiotics had potential danger in an overdose and were also associated with serious adverse effects, principally involving the endocrine and nervous systems, even when properly prescribed. Neurological sequelae included the extrapyramidal syndromes (EPS), a constellation of disorders that were relatively common, sometimes irreversible, and occasionally life threatening.

The search for antipsychotics led to the development of new types of xenobiotics from several different chemical classes characterized by varying potencies and markedly different adverse effect profiles. One novel antipsychotic, clozapine, was first synthesized in 1959 but did not enter widespread clinical use until the early 1970s. Clozapine was unique in that it was not only relatively free of EPS, but it was also an extremely effective antipsychotic even in patients who had not responded well to other drugs. Moreover, unlike other antipsychotics available at the time, it often improved the "negative" symptoms of schizophrenia, such as avolition, alogia, and social withdrawal, symptoms that are not as readily apparent as the positive symptoms but that also cause significant disability. Reports of agranulocytosis, sometimes fatal, led to the withdrawal of clozapine from the market in 1974, although it was reintroduced in 1990.9 The unique therapeutic and pharmacologic properties of clozapine make it an atypical antipsychotic, the forerunner and prototype of more than a dozen compounds that have collectively become the most widely used antipsychotics over the past decade.

Unfortunately, the true incidence of antipsychotic drug reactions is not known with certainty with some patients not seeking medical attention, and others may be misdiagnosed. Even among those who seek medical attention and are correctly diagnosed, notification of poison centers or other adverse event reporting systems is discretionary and incomplete (see Chaps. 135 and 139). With these limitations in mind, a ...

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