Clozapine may be associated with potentially fatal myocarditis and cardiomyopathy, according to Dr Jens Kilian (department of cardiology, Royal Prince Alfred hospital, Camperdown, Australia) and colleagues.
The researchers found a "high incidence of fatal and non-fatal myocarditis in the first month of treatment of about one in 500 young adult patients with schizophrenia treated with clozapine". However, they comment that clozapine is well tolerated by, and beneficial for, most patients who take it for schizophrenia.
Two cases of sudden cardiac death and myocarditis following initiation of clozapine therapy at the Royal Prince Alfred hospital prompted the researchers to investigate a link to clozapine therapy. Cases of myocarditis and cardiomyopathy were identified from reports to the Australian adverse drug reaction committee. Of 8,000 patients who started treatment with clozapine between January, 1993, and March, 1999, 23 cases associated with clozapine treatment were identified (mean age 36), of which six patients died. There were 15 cases of myocarditis (five deaths) and eight of cardiomyopathy. All cases of myocarditis occurred within three weeks of starting clozapine therapy. Clozapine doses ranged from 100mg to 725mg daily.
The mechanism of cardiac complications is uncertain, the researchers say. It could be related to an allergic reaction (either IgE-mediated hypersensitivity or, less likely, a type 3 serum sickness reaction) or it could be due to a direct toxic effect on the heart.
The authors comment that because reporting of adverse drug reactions is voluntary, the results may underestimate the true incidence of complications and they call for further studies (Lancet 1999;354:1841).