Myocarditis in patients on long-term antipsychotics -mechanism, management and recent updates

Abstract

Objective: Clozapine is the first atypical antipsychotic drug and was frequently cited as the most effective antipsychotic for treatment-resistant schizophrenia, but it is associated with a concert of significant cardiotoxic side effects. Clozapine-induced Myocarditis (CIM) is diagnosed based on the combination of clinical symptoms, laboratory investigations, radiological findings, and sometimes biopsy. The literature on CIM management and clinical consensus on the best course of action is mixed.

Methodology: An all-language literature search on Medline, Cochrane, Embase, and Google Scholar until April 2022. The following search strings and Medical Subject Heading (MeSH) terms were used: "CIM," "clozapine," "cardiotoxicity," and "myocarditis." We explored the literature on CIM for its pathophysiology, diagnosis, monitoring, and management.

Results: The clinical features of CIM may be highly variable, ranging from asymptomatic disease to fulminant heart failure, and cessation of medication was the mainstay treatment of CIM, followed by supportive therapy. Other antipsychotics have also been linked with cardiotoxic side effects.

Conclusion: Despite being the most effective antipsychotic, clozapine is associated with a cardiotoxic side effect. Current literature suggests that these antipsychotic-related cardiotoxic events impact the treatment selection for schizophrenia and other psychotic disorders, and they must be kept in mind while designing new treatment protocols in the future.

Keywords: Antipsychotic agents; Cardiotoxic agents; Clozapine; Myocarditis.

Fig. 1

Clozapine-induced cardiotoxicity is caused by several different mechanisms, including (i) Immunomodulation and proinflammatory mechanisms, possibly including both a) an IgE-mediated (type I hypersensitivity) reaction and b) cytokine release syndrome; (ii) Catecholaminergic activation; (iii) Free radical-induced oxidative stress; (iv) Stimulation of cardiomyocyte apoptotic pathways, ischemia by the decrease in coronary blood flow caused by shifts in endothelial nitric oxide production and vasoconstriction by norepinephrine and other substances released by cardiac mast cells; (v) Effects like impaired enzymes in cellular metabolism including pyruvate kinase, mitochondrial malate dehydrogenase, and proteins such as α-enolase, and triosephosphate isomerase, may explain the clozapine-induced decrease in myocardial energy generation for viable cells and contractile function.