Clozapine-induced Myocarditis: Pathophysiologic Mechanisms and Implications for Therapeutic Approaches

Abstract

Abstract: Clozapine, a superior treatment for treatment-resistant schizophrenia can cause poten-tially life-threatening myocarditis and dilated cardiomyopathy. While the occurrence of this condi-tion is well known, its molecular mechanisms are unclear and may be multifactorial. Putative mech-anisms warrant an in-depth review not only from the perspective of toxicity but also for understand-ing the molecular mechanisms of the adverse cardiac effects of clozapine and the development of novel therapeutic approaches. Clozapine-induced cardiac toxicity encompasses a diverse set of pathways, including (i) immune modulation and proinflammatory processes encompassing an IgE-mediated (type I hypersensitivity) response and perhaps a cytokine release syndrome (ii) catechol-aminergic activation (iii) induction of free radicals and oxidative stress (iv) activation of cardiomy-ocyte cell death pathways, including apoptosis, ischemia through impairment in coronary blood flow via changes in endothelial production of NO and vasoconstriction induced by norepinephrine as well as other factors released from cardiac mast cells. (v) In addition, an extensive examination of the effects of clozapine on non-cardiac cellular proteins demonstrates that clozapine can impair enzymes involved in cellular metabolism, such as pyruvate kinase, mitochondrial malate dehydro-genase, and other proteins, including α-enolase, triosephosphate isomerase and cofilin, which might explain clozapine-induced reductions in myocardial energy generation for cell viability as well as contractile function. Pharmacologic antagonism of these cellular protein effects may lead to the development of strategies to antagonize the cardiac damage induced by clozapine