title: Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study.
abstract: BACKGROUND
  Despite the implementation of cardiac monitoring guidelines, clozapine-induced myocarditis continues to cause deaths in Australia, and the risk is a barrier to prescription of this effective drug for the treatment of schizophrenia. This study was designed to identify clinical and phenotypic risk factors for clozapine-induced myocarditis.
  
  
  METHODS
  Possible cases of clozapine related myocarditis occurring between June 1993 and November 2009 and a comparative group of controls taking clozapine for at least 45days without cardiac disease were documented from the patients' medical records.
  
  
  RESULTS
  105 cases, with time to onset of 10-33days, and 296 controls were included in the study. In multivariate analysis, the risk of myocarditis increased by 26% for each additional 250mg of clozapine administered in the first nine days of clozapine titration (odds ratio 1.26; 95% confidence interval 1.02-1.55; p=0.03) and concomitant sodium valproate more than doubled the risk (2.59; 1.51-4.42; 0.001). Further, each successive decade in age was associated with a 31% increase in risk (1.31; 1.07-1.60; 0.009). Nevertheless, 33 cases received less than 920mg of clozapine during the first nine days of dose titration, did not take sodium valproate and were aged less than 40years; and nine control patients received sodium valproate and more than 920mg of clozapine in the first nine days without developing myocarditis.
  
  
  CONCLUSIONS
  Clozapine should be initiated by slow dose titration and sodium valproate is best avoided, if clinically feasible, during this period. All patients commencing clozapine should be monitored for myocarditis up to Day 28.
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: Rory
authors.initials: R
authors.lastname: Wolfe
authors.forename: John J
authors.initials: JJ
authors.lastname: McNeil
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D015992:Body Mass Index; D016022:Case-Control Studies; D003024:Clozapine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis / Q000139:chemically induced*; D012189:Retrospective Studies; D012559:Schizophrenia / Q000188:drug therapy; D013997:Time Factors; D014635:Valproic Acid / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014150:Antipsychotic Agents; D014635:Valproic Acid; D003024:Clozapine