A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls

Aust N Z J Psychiatry. 2011 Jun;45(6):458-65. doi: 10.3109/00048674.2011.572852. Epub 2011 Apr 27.


Objective: To develop an evidence-based monitoring protocol for clozapine-induced myocarditis.

Methods: Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients' medical records.

Results: A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10-33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation until features resolve. Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/L. Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%. The sensitivity for asymptomatic disease is unknown.

Conclusion: This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / therapeutic use
  • C-Reactive Protein
  • Case-Control Studies
  • Clinical Protocols
  • Clozapine / adverse effects*
  • Clozapine / therapeutic use
  • Drug Monitoring / methods*
  • Echocardiography
  • Female
  • Humans
  • Male
  • Middle Aged
  • Myocarditis / blood
  • Myocarditis / chemically induced*
  • Myocarditis / diagnosis*
  • Troponin / blood


  • Antipsychotic Agents
  • Troponin
  • C-Reactive Protein
  • Clozapine