Oral administration of aripiprazole to <i>Drosophila</i> causes intestinal toxicity

Aripiprazole is a third-generation antipsychotic medication that was introduced to mitigate the poor tolerability of older antipsychotics. In contrast to the older antipsychotic drugs that act as dopamine receptor antagonists in the brain, aripiprazole functions as a partial agonist. Aripiprazole has been identified as an off-target inhibitor of mitochondrial respiratory complex I. We observed that patients prescribed aripiprazole often report gastrointestinal disturbances, but the mechanism underlying these side effects is not clear. We modelled the potential mitochondrial toxicity of aripiprazole in the gastrointestinal system using the fruit fly (Drosophila melanogaster). Aripiprazole consumption impaired Drosophila gut function and faecal output. It also reduced the mitochondrial membrane potential and increased reactive oxygen species (ROS) levels in intestinal cells. ROS activate the c-Jun N-terminal kinase (JNK) pathway, which induces cellular stress and cell death. Aripiprazole increased JNK activation in the intestinal cells of flies, resulting in cell death, which was suppressed by antioxidants. We conclude that aripiprazole activates the JNK pathway of cell death via mitochondrial ROS production. Using antioxidant supplements may help reduce aripiprazole-induced toxicity.