Clozapine

Clozapine, antipsychotic drug primarily used in the treatment of severe schizophrenia, especially in instances when other treatments fail to improve symptoms. Clozapine is also particularly useful for reducing the risk of suicide in individuals with schizophrenia or schizoaffective disorder who have made repeated suicide attempts. It may also be used to treat certain other psychotic conditions, such as psychosis arising in Parkinson disease.

Classification and mechanism of action

Clozapine is considered a second-generation atypical antipsychotic drug. Unlike older first-generation “typical” antipsychotics that solely block dopamine receptors, clozapine blocks serotonin receptors while weakly inhibiting dopamine receptors. Clozapine is further described as atypical because of its comparatively low risk of extrapyramidal side effects (movement disorders associated with antipsychotic drugs); for instance, it rarely causes muscle rigidity, muscle tremors, or repetitive involuntary movements. In addition, first-generation antipsychotics tend to increase blood levels of the hormone prolactin, leading to issues with bone, reproductive, and sexual health—a side effect resulting directly from their inhibition of dopamine receptors. Clozapine, by comparison, because it binds only loosely to these receptors, has minimal impact on blood prolactin levels.

Even with weak inhibition of dopamine receptors, clozapine effectively calms so-called positive symptoms of schizophrenia, such as hallucinations and delusions, which occur when dopamine is overactive in certain parts of the brain. Negative symptoms, including apathy and reduced emotional expression, are associated with altered activity of serotonin. Clozapine strongly blocks serotonin receptors, thereby helping alleviate these symptoms. Clozapine also has complex interactions with other neurotransmitter pathways, including those involving acetylcholine, histamine, and norepinephrine, which contribute to its pharmacological and toxicity profile.

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Discovery and development

Clozapine was named in 1959 by researchers at the Swiss pharmaceutical company Wander AG, where it had been initially synthesized the previous year and assigned the identifier HF-1854. It was one in a series of compounds under investigation for development as tricyclic antidepressants. In 1961, however, studies in animals revealed that clozapine acts primarily as a sedative and exerts its effects without inducing muscle rigidity, as previous antipsychotics had. These observations shifted clozapine’s course of development from that of an antidepressant medication to investigation of its potential use as an antipsychotic drug.

Clozapine, however, failed in its first clinical trials, carried out in 1962, partly because the doses were too low and supplies of the drug were limited. Subsequent trials in the late 1960s and ’70s eventually proved its effectiveness, and the drug ultimately was recognized for exerting strong antipsychotic effects with virtually no adverse impacts on motor function. By 1971 it was being prescribed in Europe, where it rapidly gained traction in the treatment of schizophrenia. With more widespread use, however, a rare, life-threatening side effect known as agranulocytosis (a severe reduction in white blood cells) emerged, prompting clozapine’s withdrawal from the market. Nonetheless, because of its unique effectiveness in patients who do not respond to other medications, clozapine was approved by the U.S. Food and Drug Administration (FDA) in 1989 and made available worldwide in the early 1990s. Its return to the market was initially accompanied by strict requirements for blood monitoring to ensure patient safety. Over time these requirements loosened, and in 2025 the FDA ended mandatory blood testing in conjunction with clozapine use.

Side effects

Clozapine’s most notable adverse effect is agranulocytosis, in which an extreme reduction of white blood cells, particularly neutrophils, undermines the body’s ability to defend against infection. However, the drug also carries other risks, among them excessive salivation, gastrointestinal disorders, metabolic abnormalities, myocarditis (inflammation of heart muscle tissue), and seizures. Thus, the use of clozapine is associated with close medical monitoring for some patients, in the form of blood tests to measure the absolute neutrophil count.