Acute Exposure to Clozapine and Sodium Valproate Impairs Oxidative Phosphorylation in Human Cardiac Mitochondria

Abstract

The only antipsychotic that is approved and recommended for the treatment of otherwise treatment-resistant schizophrenia is clozapine (CLZ). Unfortunately, CLZ can cause serious cardiotoxicities such as myocarditis and cardiomyopathy. The co-administration of sodium valproate (VPA) during initiation is a well-established risk factor for the development of CLZ-induced myocarditis. However, the mechanisms behind these cardiac adverse effects and the role of VPA co-administration are not understood. Preliminary evidence for the development of cardiac mitochondrial dysfunction has previously been reported in both rodent models and immortalised cell lines. This investigation aimed to determine the functional effects of CLZ and VPA on human cardiac mitochondria to improve the current understanding of how cardiotoxicity develops. Small samples of human atrial tissue from consenting patients undergoing a coronary artery bypass grafting procedure were freshly collected and utilised to investigate the acute effects of each drug on mitochondrial O2 consumption using high-resolution respirometry. Both drugs significantly decreased mitochondrial O2 consumption by a magnitude of 32 % following CLZ exposure, 25 % following VPA exposure, and 25 % following combined CLZ+VPA exposure during complex I- and II-linked oxidative phosphorylation. These results demonstrate acute bioenergetic dysfunction with exposure to both drugs, alone and in combination. We propose that cardiac mitochondria become a key focus in future research seeking to improve the risk-predictive, diagnostic, and treatment guidelines surrounding CLZ-induced cardiotoxicity.