title: Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003.
abstract: BACKGROUND
  Clozapine is an antipsychotic medication associated with a lower suicide rate compared with other antipsychotic agents. Clozapine is used specifically in patients for whom previous therapy was inadequate or not tolerated, and is the only antipsychotic agent associated with the development of myocarditis.
  
  
  OBJECTIVE
  To retrospectively review all adverse drug reaction reports voluntarily submitted to the Australian Adverse Drug Reactions Unit mentioning suspected myocarditis in clozapine-treated patients.
  
  
  METHODS
  We accessed all electronic database entries and case reports citing suspected myocarditis associated with clozapine therapy from January 1993 through to December 2003, inclusive.
  
  
  RESULTS
  116 case reports of suspected myocarditis amongst clozapine-treated patients were identified during the specified time frame (incidence between 0.7% and 1.2% of treated patients). Median patient age for these cases was 30 years (SD 11.1 years) compared with 37 years from the Clopine registry. The condition developed within a median 16 days (mean 19.8 days; SD 17.3 days) of commencing clozapine for the bulk of patients developing myocarditis within 6 months (n=93, 80.2%). For all cases with known treatment commencement and cessation dates (n=106), the condition developed within a median 17 days (mean 171.7 days, SD 530.9 days). Over nine-tenths of cases were prescribed clozapine within the dose range of 100 mg/day to 450 mg/day. Sixty patients (51.8%) recovered from their episode when reported or during follow-up reports, whereas 17 patients (14.7%) had not yet recovered: 27 patients (23.3%) had unknown outcome when reported and the remaining 12 patients (10.3%) died.
  
  
  CONCLUSIONS
  Clozapine is uncommonly but importantly related to myocarditis, often fatal or near fatal and sometimes in relatively young patients with early onset after treatment initiation. The most striking feature about this condition is the wide diversity of nonspecific symptoms that occur in afflicted patients. Additional pharmacovigilance, improved reporting systems and further investigation of mechanisms of drug-induced myocarditis and related cardiovascular conditions (such as heart failure) are clearly warranted. A case-control study would be suitable for investigation of baseline predictors.
authors.affiliation: Department of Epidemiology & Preventive Medicine, Faculty of Medicine, Nursing & Health Sciences, Monash University, Alfred Hospital, Melbourne, Victoria, Australia. Steven.Haas@med.monash.edu.au
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Haas
authors.forename: Richard
authors.initials: R
authors.lastname: Hill
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Danny
authors.initials: D
authors.lastname: Liew
authors.forename: Andrew
authors.initials: A
authors.lastname: Tonkin
authors.forename: Lisa
authors.initials: L
authors.lastname: Demos
authors.forename: Karen
authors.initials: K
authors.lastname: Stephan
authors.forename: John
authors.initials: J
authors.lastname: McNeil
mesh_terms: D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001315:Australia; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis / Q000139:chemically induced* / Q000175:diagnosis / Q000401:mortality
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine