title: A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Epidemiology, and Preventive Medicine, Monash University, The Alfred Centre, Melbourne, Victoria, Australia. kathlyn.ronaldson@monash.edu
authors.forename: Kathlyn J
authors.initials: KJ
authors.lastname: Ronaldson
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fitzgerald
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Taylor
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Topliss
authors.forename: John J
authors.initials: JJ
authors.lastname: McNeil
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002097:C-Reactive Protein; D016022:Case-Control Studies; D002985:Clinical Protocols; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods*; D004452:Echocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis*; D014336:Troponin / Q000097:blood
chemical_list: D014150:Antipsychotic Agents; D014336:Troponin; D002097:C-Reactive Protein; D003024:Clozapine