A guide to the management of clozapine-related tolerability and safety concerns

Clozapine is a highly effective antipsychotic medication, which provides a range of significant benefits for patients with schizophrenia, and is the standard of care for treatment-resistant schizophrenia as well as for reducing the risk of suicidal behaviors in schizophrenia and schizoaffective disorder. However, clozapine is widely underutilized, largely because prescribing clinicians lack experience in prescribing it and managing its adverse events (AEs). Clozapine is associated with three uncommon but immediately dangerous AEs - agranulocytosis, myocarditis/cardiomyopathy, and seizures - as well as AEs that may become dangerous if neglected, including weight gain, metabolic syndrome and constipation, and others that are annoying or distressing such as sedation, nighttime enuresis and hypersalivation. Because of the risk of agranulocytosis, clozapine formulations are available only through restricted distribution via a patient registry, with mandatory, systematized monitoring for absolute neutrophil count using a specific algorithm. We identified articles on managing clozapine-associated AEs by searching PubMed using appropriate key words and search techniques for each topic. A review of the prevalence and clinical characteristics of clozapine-associated AEs shows that these risks can be managed efficiently and effectively. The absolute risks for both agranulocytosis and myocarditis/cardiomyopathy are low, diminish after the first six months, and are further reduced with appropriate monitoring. Weight gain/metabolic disorders and constipation, which develop more gradually, can be mitigated with regular monitoring and timely interventions. Sedation, hypersalivation, and enuresis are common but manageable with ameliorative measures and/or medications.