Clozapine associated cardiotoxicity: Issues, challenges and way forward

Abstract

Objective: To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge.

Results: Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Re-challenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5-24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT.

Conclusion: Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.

Keywords: Cardiomypathy; Cardiotoxicity; Clozapine; Myocarditis; Subclinical Cozapine Cardiotoxicity.