TY - JOUR
T1 - Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study
AU - Ronaldson, Kathlyn Joy
AU - Fitzgerald, Paul Bernard
AU - Taylor, Andrew J
AU - Topliss, Duncan J
AU - Wolfe, Rory St John
AU - McNeil, John James
PY - 2012
Y1 - 2012
N2 - 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.
Method: Possible cases of clozapine related myocarditis occurring between June 1993 and November 2009
and a comparative group of controls taking clozapine for at least 45 days without cardiac disease were documented
from the patients medical records.
Results: 105 cases, with time to onset of 10?33 days, and 296 controls were included in the study. In multivariate
analysis, the risk of myocarditis increased by 26 for each additional 250 mg 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 920 mg of clozapine during the first nine days of dose titration, did
not take sodium valproate and were aged less than 40 years; and nine control patients received sodium
valproate and more than 920 mg 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.
AB - 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.
Method: Possible cases of clozapine related myocarditis occurring between June 1993 and November 2009
and a comparative group of controls taking clozapine for at least 45 days without cardiac disease were documented
from the patients medical records.
Results: 105 cases, with time to onset of 10?33 days, and 296 controls were included in the study. In multivariate
analysis, the risk of myocarditis increased by 26 for each additional 250 mg 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 920 mg of clozapine during the first nine days of dose titration, did
not take sodium valproate and were aged less than 40 years; and nine control patients received sodium
valproate and more than 920 mg 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.
UR - http://www.sciencedirect.com/science/article/pii/S0920996412005014
U2 - 10.1016/j.schres.2012.08.018
DO - 10.1016/j.schres.2012.08.018
M3 - Article
SN - 0920-9964
VL - 141
SP - 173
EP - 178
JO - Schizophrenia Research
JF - Schizophrenia Research
IS - 2-3
ER -