The Role of Sodium Valproate in Clozapine-Associated Cardiotoxicities: The Importance of Cellular and Systemic Energetics

Abstract The antipsychotic drug clozapine is associated with one of the broadest spectra of cardiac adverse effects. Many of these are of unknown aetiology, hindering clinicians’ ability to prevent, diagnose, and treat them. Risk factors for clozapine-associated cardiotoxicities include concomitant valproic acid therapy and comorbidities associated with the dysregulation of systemic metabolism, such as obesity and diabetes. Therefore, this review aims to summarise existing evidence for the adverse effects of these drugs on cellular and systemic energetics. Both drugs are strongly associated with mitochondrial dysfunction and oxidative stress, but in different tissues. Clozapine may be bioactivated within cardiomyocytes and their mitochondria, producing reactive species that damage these organelles, thus impairing oxidative phosphorylation. Valproate may have similar effects in hepatocytes but doesn’t appear to be bioactivated in all cell types, though it reportedly has modest inhibitory effects on fatty acid oxidation. Both drugs affect substrate supply, altering serum lipid, carbohydrate, and ketone levels. In concert, these medications are likely to impair cardiac metabolic flexibility and energetics. Considering the absolute dependence of cardiomyocyte function on continuous energy supply, the dysregulation of cardiomyocyte energetics is likely to have a significant role in the development of clozapine-associated cardiotoxicities. However, limited investigation has been made of the effects of these drugs in cardiomyocytes specifically. Rectifying this could inform improved prevention, detection, and management of cardiotoxicities to facilitate the development of clinical strategies to enable the safer use of these medicines. Graphical Abstract Overview of the potential effects of clozapine and valproic acid on cardiomyocyte energetics. Highlighted regions are those where clozapine (orange) or valproic acid (purple) have been shown to have some effect, with colour-coded arrows to indicate the direction of the effect. Partially shaded regions indicate those areas where contradictory effects have been reported in different experimental models. Key enzymes, indicated in brackets, include glutamine synthetase (GS), glutamate synthase (GLS), glutamate dehydrogenase (GDH), glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and fatty acyl-CoA synthetase (FACS).