Antipsychotic polypharmacy (APP) is common in the treatment of schizophrenia spectrum disorders. The literature indicates that APP is related to patient, illness, and treatment variables that are proxy measures for greater illness acuity, severity, complexity, and chronicity. The largely unknown relative risks and benefits of APP need to be weighed against the known risks and benefits of clozapine for treatment-resistant patients. To inform evidence-based clinical practice, controlled, high-quality antipsychotic combination and discontinuation trials are necessary to determine the effectiveness, safety, and role of APP in the management of severely ill patients with insufficient response to antipsychotic monotherapy.
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