Clozapine-Induced Cardiotoxicity: A Critical Review of Pathophysiological Mechanisms, Historical Hypotheses, and Current Insights

Purpose of Review Clozapine is an atypical antipsychotic, used as a last-line therapy for patients with treatment-resistant schizophrenia. Despite being an effective medication, its clinical use is limited due to the substantial risk of adverse effects, including cardiotoxicities such as myocarditis and cardiomyopathy. These life-threatening toxicities are either acute in nature (myocarditis) or develop due to chronic, subclinical inflammation and tissue damage (cardiomyopathy). It is likely that the two are related and arise from similar mechanisms that drive cardiac damage and inflammatory cascades. Critical analysis of the historical hypothesis that clozapine cardiotoxicity is an idiosyncratic IgE-mediated (allergic) hypersensitivity reaction suggests that this mechanism is unlikely, although it currently remains an idiosyncratic adverse drug reaction, with involvement of either innate or cell-mediated immune responses. Instead, the identification of clinically observed risk factors, alongside ever-developing in vitro and in vivo assessment of clozapine-associated reactivity and cellular damage, has led to the development of several plausible mechanisms behind the development of clozapine cardiotoxicity. Recent Findings This review compares the contributions of hyper-catecholamines, altered clozapine metabolism, mitochondrial damage, reactive oxygen species, perturbation of endogenous anti-inflammatory processes and receptor-mediated cell death to develop a modern understanding of the melange of processes that are likely to be implicated in cardiotoxicity. It is likely that these tissue-damaging processes are exacerbated by rapid dose titration and concomitant sodium valproate administration. Summary Although no single initiating or effector mechanism has been confirmed for clozapine cardiotoxicity, the available evidence supports an integrated model in which direct cellular injury, altered metabolism, inflammatory amplification and immune cell responses may contribute to the observed damage. Clinical and experimental information should be considered holistically in future research that aims to improve the safe and effective use of clozapine.