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Cardiac Effects of Antipsychotics: Focus on Clozapine-Induced Myocarditis and Cardiomyopathy Scott R. Beach, M.D. Attending Psychiatrist, Massachusetts General Hospital Assistant Professor of Psychiatry, Harvard Medical School

Anticholinergic effects Predispose to metabolic syndrome Quetiapine Clozapine Olanzapine Risperidone Quetiapine Olanzapine Clozapine Alpha-1 blockade Anticholinergic effects Predispose to metabolic syndrome Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Cardiac Effects of Clozapine Tachycardia (10%) Orthostatic hypotension Hypertension EKG abnormalities (<1%) Myocarditis Cardiomyopathy Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Clozapine-Induced Myocarditis Rate: 0.1% to 3% Clozapine-Induced Myocarditis IgE-mediated hypersensitivity Most occur in the first 2 to 3 months Occur in healthy young patients Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Clozapine-Induced Myocarditis Symptoms Tachycardia Shortness of breath Fever Flu-like symptoms Nausea Dizziness Chest discomfort (some cases) Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Cardiac Effects of Clozapine Up to 30% No association with: Dose Rate of increase Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Treatment of Clozapine-Induced Myocarditis Stop clozapine Supportive care Rechallenge with caution Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Diagnostic Considerations with Clozapine-Induced Myocarditis Onset of symptoms: within 45 days of starting clozapine An absence of other causes or a cardiac history New signs of cardiac dysfunction Tachycardia Peripheral edema Ronaldson, K. J., Taylor, A. J., Fitzgerald, P. B., Topliss, D. J., Elsik, M., & McNeil, J. J. (2010). Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. Journal of Clinical Psychiatry, 71(8), 976.

Diagnostic Criteria for Clozapine-Induced Myocarditis At least 1: 1. Peripheral eosinophilia 2. Elevated troponin or CK-MB 3. EKG changes (ST-segment depression or T-wave inversion) 4. Radiographic evidence of pulmonary congestion or heart failure 5. Echocardiographic evidence of ventricular dysfunction Ronaldson, K. J., Taylor, A. J., Fitzgerald, P. B., Topliss, D. J., Elsik, M., & McNeil, J. J. (2010). Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. Journal of Clinical Psychiatry, 71(8), 976.

Additional Criteria for Clozapine-Induced Myocarditis MRI evidence of myocarditis Definitive histological findings from cardiac tissue biopsy Ronaldson, K. J., Taylor, A. J., Fitzgerald, P. B., Topliss, D. J., Elsik, M., & McNeil, J. J. (2010). Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. Journal of Clinical Psychiatry, 71(8), 976.

Clinical Monitoring for Clozapine-Induced Myocarditis Routine vital signs Weekly for the first month CRP ESR Weekly for the first month Troponin CK-MB Baseline EKG With clinical concern Repeat EKG CBC with differential Neutrophil count Weekly Eosinophil count Freudenreich, O. (2015). Clozapine‐induced myocarditis: prescribe safely but do prescribe. Acta Psychiatrica Scandinavica, 132(4), 240-241.

Cardiology consult should precede an echocardiogram. No evidence for baseline or follow-up echocardiogram routinely indicated. Cardiology consult should precede an echocardiogram. Freudenreich, O. (2015). Clozapine‐induced myocarditis: prescribe safely but do prescribe. Acta Psychiatrica Scandinavica, 132(4), 240-241.

Incidence of Clozapine-Induced Cardiomyopathy 1 in 2000 (possibly higher) Most cases are diagnosed in the first 6 to 9 months. Latency up to 6 years Most patients do not have a pre-existing cardiac history. Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Clinical Symptoms of Clozapine-Induced Cardiomyopathy Dyspnea Tachycardia Palpitations Chest pain Fatigue Asymptomatic Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Diagnosis of Clozapine-Induced Cardiomyopathy Echocardiographic evidence of reduced left ventricular ejection fraction: < 50% BNP elevated Mortality rate: 12.5% and 25% Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Treatment of Clozapine-Induced Cardiomyopathy Rechallenge not recommended Stop clozapine Supportive care Will improve cardiac functioning in patients whose EF > 25% Curto, M., Girardi, N., Lionetto, L., Ciavarella, G. M., Ferracuti, S., & Baldessarini, R. J. (2016). Systematic review of clozapine cardiotoxicity. Current psychiatry reports, 18(7), 68.

Key Points Clozapine is commonly associated with tachycardia and orthostatic hypotension. Clozapine-induced myocarditis tends to happen early in the course of treatment. Clozapine-induced cardiomyopathy tends to occur in the first year and can be challenging to detect due to many asymptomatic cases.

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