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2. 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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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),

13. 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),

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. Next Presentation Cardiac Effects of Antipsychotics: QTc Prolongation