Myocarditis clozapine

Power B, Williams H, Shymko G. The difficulties of diagnosing clozapine myocarditis daitmed if you do, daitmed if you don t. Australas... 

Myocarditis Analyses of postmarketing safety databases suggest clozapine is associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. In patients in whom myocarditis is suspected, discontinue clozapine treatment promptly. 

Myocarditis - Postmarketing clozapine surveillance data from 4 countries revealed cases of myocarditis, some fatal. 

Cardiovascular effects. Hypotension and tachycardia occur in most patients taking clozapine. Cases of potentially fatal myocarditis and dilated cardiomyopathy have been reported in association with clozapine (Kilian et al. 1999). Myocarditis typically occurred within 3 weeks of starting clozapine, but cardiomyopathy may not be apparent for several years. Although rare, treatment-emergent myocarditis and cardiomyopathy occur at a reportedly higher incidence with clozapine than with other antipsychotics (Coulter et al. 2001). The mechanism by which clozapine may cause myocarditis has not been established, but some authors have speculated that clozapine may cause an immunoglobuhn E (IgE)-mediated type 1 hypersensitivity reaction (Kihan et al. 1999) or a hypereosinophilic syndrome (Hagg et al. 2001). 

Hagg S, Spigset O, Bate A, et al Myocarditis related to clozapine treatment. 

The relation between neuroleptic drug therapy and myocarditis and cardiomyopathy has been examined using the international database on adverse drug reactions run by the World Health Organization (152). Myocarditis and cardiomyopathy were reported rarely as suspected adverse drug reactions, and accounted for under 0.1% (n = 2121) of almost 2.5 million reports. The association of clozapine with those adverse reactions was statistically significant (231 reports out of 24 730), as was the association with other antipsychotics (89 of 60 775). 

In a review of articles on adverse cardiac effects associated with clozapine, the estimated risk of potentially fatal myocarditis or cardiomyopathy was 0.01-0.19% the authors suggested that this low risk of serious adverse cardiac events should be outweighed by a reduction in suicide risk in most patients (41). 

A thorough study of the risk of myocarditis or cardiomyopathy in Australia detected 23 cases (mean age 36 years 20 men) out of 8000 patients treated with clozapine from January 1993 to March 1999 (absolute risk 0.29% relative risk about 1000-2000) (27). All the accumulated... 

The manufacturers analysed 125 reports of myocarditis with clozapine and found 35 cases with fatal outcomes... 

Clozapine rechallenge after myocarditis has been described (44). 

In this case a consultant cardiologist diagnosed myocarditis secondary to clozapine, as no other confounding comorbidity was identified. However, the negative rechallenge suggests either that the clozapine was not responsible or that there was tolerance to the effect. 

Killian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999 354(9193) 1841-5. 

Reid P, McArthur M, Pridmore S. Clozapine rechallenge after myocarditis. Aust NZ J Psychiatry 2001 35(2) 249. 

Possible association between myocarditis and cardiomyopathy and clozapine use, even in physically healthy individuals... 

Advisory Committee (ADRAC) there were 15 cases of myocarditis (five fatal) and 8 of cardiomyopathy (one fatal) associated with clozapine. All cases of myocarditis occurred within 3 weeks of starting clozapine. Cardiomyopathy was diagnosed up to 36 months after clozapine had been started. There were no confounding factors to account for cardiac illness. Necropsy results showed mainly eosinophilic infiltrates with myocytolysis, consistent with an acute drug reaction. 

The manufacturers analysed 125 reports of myocarditis with clozapine and found 35 cases with fatal outcomes (31). A total of 53% occurred in the first month of therapy, and a small number (4.8%) occurred more than 2 years after the start of treatment. In this series, 70% of the patients were men. 

The authors of a report of three cases of myocarditis associated with clozapine claimed that, while the gold standard for the diagnosis of myocarditis is perceived to be by myocardial biopsy, cardiovascular magnetic resonance has also proved... 

In one case clozapine was successfully restarted after suspected myocarditis [75" ]. 

Ronaldson KJ, Taylor AJ, Fitzgerald PB, Topliss DJ, Elsik M, McNeil JJ. Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. J Clin Psychiatry 2010 71 976-81. 

Rosenfeld AJ, Gibbs T, Ivie R, Clarke L, Merrill DB. Successful clozapine retrial after suspected myocarditis. Am J Psychiatry 2010 167 350-1. 

Reviews A review of 16 studies evaluated the incidence of four clozapine-related side effects [98 ]. The incidence of agranulocytosis was between 3.8% and 8.0% (mortality rate was 0.1-0.3%) and case fatality rate was 2.2-. 2%. The incidence of diabetic ketoacidosis was 1.2-3.1% and case fatalify rafe was 20-31%. The incidence of gastrointestitml hypomotility was 4-8% and case fatality rate was 15-27.5%. The incidence of myocarditis was 0.07-0.6% (overall) and 7-34% (Australia). 

A review of the literature on clozapine and therapeutic drug monitoring (11 reviews, 24 studies, 35 case reports) found evidence indicating a dose-relafed (500-600mg per day) increased risk of seizures [99 ]. There were limited data suggestive of a relationship between plasma levels, dose, and side effects such as seizures, myocarditis and agranulocytosis. 

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