Title:Clozapine-induced Myocarditis: Pathophysiologic Mechanisms and Implications
for Therapeutic Approaches
Volume: 16
Author(s): Simon W. Rabkin*Jacky K. K. Tang
Affiliation:
- Division of Cardiology, University of British Columbia, Vancouver, B.C., Canada
Keywords:
Clozapine, myocarditis, apoptosis, oxidative stress, proteomics, mitochondrial malate dehydrogenase, pyruvate kinase.
Abstract: Clozapine, a superior treatment for treatment-resistant schizophrenia can cause potentially
life-threatening myocarditis and dilated cardiomyopathy. While the occurrence of this condition
is well known, its molecular mechanisms are unclear and may be multifactorial. Putative mechanisms
warrant an in-depth review not only from the perspective of toxicity but also for understanding
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 IgEmediated
(type I hypersensitivity) response and perhaps a cytokine release syndrome (ii) catecholaminergic
activation (iii) induction of free radicals and oxidative stress (iv) activation of cardiomyocyte
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 dehydrogenase,
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