**2.4 Clozapine-induced myocarditis: role of catecholamines in a murine model**

Clozapine, an atypical neuroleptic agent, is very effective in the treatment of resistant schizophrenia. However, cardiotoxicity of clozapine, particularly in young patients, has raised concerns about its its safety and smoking may have a significant effect on serum concentrations of clozapine (Seppala et al., 1999). A particularly high incidence of myocarditis has been reported among patients treated with atypical neuroleptic drugs, including clozapine and risperidone. Clozapine has been shown to markedly increase circulating levels of catecholamines (Coulter et al., 2001; Elman et al., 2002). Increased catecholamines have been postulated to trigger an inflammatory response resulting in myocarditis, dilated cardiomyopathy, and death, although this has not yet been thoroughly studied. Here (Wang et al., 2008), we used the mouse to study whether clozapine administration could caused adverse myocarditis associated with an increase in catecholamines. Male BALB/c mice, age ~6 weeks, were administered 5, 10 or 25 mg/kg clozapine daily for 7 and 14 days; one group was administered 25 mg/kg clozapine plus 2 mg/kg propranolol for 14 days. Saline-treated mice served as controls. Heart sections were stained with hematoxylin and eosin for histopathological examination. Plasma catecholamines were measured with HPLC. Myocardial TNF-α concentrations were determined by ELISA. Histopathologic examination of clozapine-treated mice showed a significant dose-related increase in myocardial inflammation that correlated with plasma catecholamine levels and release of TNF-α. Propranolol significantly attenuated these effects. A hypercatecholaminergic state induced by clozapine could explain the occurrence of myocarditis in some patients. Our data suggest that βadrenergic blocking agents may be effective in reducing the incidence and severity of clozapine-induced myocarditis.
