Co-administration of simvastatin mitigates clozapine-induced lifespan extension and mitochondrial functional recovery in Drosophila melanogaster.

Abstract

Antipsychotics and statins can be co-prescribed to combat the increased risk of high blood cholesterol with antipsychotic use. However, statins have been shown to interfere with mitochondrial functioning through reduced coenzyme Q expression, and second-generation antipsychotic, clozapine, has also demonstrated induced mitochondrial respiratory deficits in cell models. Despite this convergence, the combined effect of statins and antipsychotics on mitochondrial function, and mechanisms of overall health, remain poorly understood. Here we exploited the cholesterol auxotrophy of Drosophila melanogaster to investigate the effects of clozapine, simvastatin and their combination on lifespan and mitochondrial bioenergetics independently of cholesterol biosynthesis. Clozapine alone significantly extended median survival, an effect attenuated by simvastatin co-treatment. High resolution respirometry showed signs of clozapine-induced mitochondrial differences diminished with age, but this adaptation was also attenuated by simvastatin co-treatment. Using a spin probe (TEMPOL) with nitrogen-vacancy diamond quantum sensing, we directly measured free radical production and found that clozapine and simvastatin significantly increased free radical generation relative to the untreated control in early life stages. We also observed preliminary evidence of sex-specific differences in treatment response. Together, these findings suggest that clozapine induces an age-related mitochondrial adaptive response that is associated with extended lifespan and mitigated by simvastatin treatment.