This determination of the mitochondrial effect of pharmacologically different antidepressants (agomelatine, ketamine and vortioxetine) was evaluated and quantified in vitro in pig brain-isolated mitochondria. We measured the activity of mitochondrial complexes, citrate synthase, malate dehydrogenase and monoamine oxidase, and the mitochondrial respiratory rate. Total hydrogen peroxide production and ATP production were assayed. The most potent inhibitor of all mitochondrial complexes and complex I-linked respiration was vortioxetine. Agomelatine and ketamine inhibited only complex IV activity. None of the drugs affected complex II-linked respiration, citrate synthase or malate dehydrogenase activity. Hydrogen peroxide production was mildly increased by agomelatine, which might contribute to increased oxidative damage and adverse effects at high drug concentrations. Vortioxetine significantly reduced hydrogen peroxide concentrations, which might suggest antioxidant mechanism activation. All tested antidepressants were partial MAO-A inhibitors, which might contribute to their antidepressant effect. We observed vortioxetine-induced MAO-B inhibition, which might be linked to decreased hydrogen peroxide formation and contribute to its procognitive and neuroprotective effects. Mitochondrial dysfunction could be linked to the adverse effects of vortioxetine, as vortioxetine is the most potent inhibitor of mitochondrial complexes and complex I-linked respiration. Clarifying the molecular interaction between drugs and mitochondria is important to fully understand their mechanism of action and the connection between their mechanisms and their therapeutic and/or adverse effects.

Department of Psychiatry 1st Faculty of Medicine Charles University and General University Hospital Prague Ke Karlovu 11 120 00 Prague Czech Republic

Institute of Pharmacology 1st Faculty of Medicine Charles University and General University Hospital Prague Albertov 4 128 00 Prague Czech Republic

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