title: Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases.
abstract: BACKGROUND
  Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality.
  
  
  METHODS
  Cases of myocarditis were documented from the patient's medical records and fatal cases also from autopsy reports.
  
  
  RESULTS
  The fatal cases of myocarditis occurred 1996-2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p < 0.006), after exclusion of one outlier. Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004).
  
  
  CONCLUSIONS
  Routine monitoring for myocarditis for the first 4 weeks of clozapine, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities occurring from early-onset myocarditis. Investigation by cardiac imaging will give a measure of severity and need for intervention. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness.
authors.affiliation: Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004, 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; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects*; D015992:Body Mass Index; D057791:Cardiac Imaging Techniques; D003024:Clozapine / Q000009:adverse effects*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis / Q000139:chemically induced* / Q000175:diagnosis* / Q000401:mortality; D012189:Retrospective Studies; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine