Clozapine (sold as Clozaril, Leponex, Fazaclo; Gen-Clozapine in Canada) was the first of the atypical antipsychotics to be developed. It was approved by the United States Food and Drug Administration (FDA) in 1989 and is the only FDA-approved medication indicated for treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour in patients with schizophrenia.

Clozapine has been shown to be superior in efficacy in treating schizophrenia. Were it not for its side effects it would be first line treatment; however the rare but potentially lethal side effects of agranulocytosis and myocarditis relegate it to third-line use. Furthermore it may rarely lower seizure threshold, cause hepatic dysfunction, weight gain and be associated with type II diabetes. More common side effects are predominantly anticholinergic in nature, with dry mouth, sedation and constipation. It is also a strong antagonist at different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors.

Safer use of clozapine requires weekly blood monitoring for around five months followed by four weekly testing thereafter. Echocardiograms are recommended every 6 months to exclude cardiac damage.