Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects. Pig brain-isolated mitochondria were used to evaluate antidepressant-induced changes in the activity of electron transport chain (ETC) complexes, monoamine oxidase (MAO), mitochondrial respiratory rate, and ATP. Bupropion, escitalopram, fluvoxamine, sertraline, paroxetine, and trazodone were tested. All tested antidepressants showed significant inhibition of complex I and IV activities at high concentrations (50 and 100 µmol/L); complex II + III activity was reduced by all antidepressants except bupropion. Complex I-linked respiration was reduced by escitalopram >> trazodone >> sertraline. Complex II-linked respiration was reduced only by bupropion. Significant positive correlations were confirmed between complex I-linked respiration and the activities of individual ETC complexes. MAO activity was inhibited by all tested antidepressants, with SSRIs causing a greater effect than trazodone and bupropion. The results indicate a probable association between the adverse effects of high doses of antidepressants and drug-induced changes in the activity of ETC complexes and the respiratory rate of mitochondria. In contrast, MAO inhibition could be linked to the antidepressant, procognitive, and neuroprotective effects of the tested antidepressants.

• Keywords
• ATP, antidepressants, mitochondrial respiration, monoamine oxidase, oxidative phosphorylation, reactive oxygen species,
• Publication type
• Journal Article MeSH

The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 µM brexpiprazole and lurasidone and at 100 µM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.

• Keywords
• ATP, Dopamine system stabilizers, Mitochondrial respiration, Monoamine oxidase, Oxidative phosphorylation, Reactive oxygen species,
• MeSH
• Adenosine Triphosphate biosynthesis   MeSH
• Antipsychotic Agents classification   pharmacology   MeSH
• Quinolones pharmacology   MeSH
• Electron Transport Chain Complex Proteins drug effects   MeSH
• Energy Metabolism drug effects   MeSH
• Monoamine Oxidase Inhibitors pharmacology   MeSH
• Loxapine pharmacology   MeSH
• Lurasidone Hydrochloride pharmacology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Hydrogen Peroxide metabolism   MeSH
• Piperazines pharmacology   MeSH
• Swine MeSH
• Reactive Oxygen Species metabolism   MeSH
• Receptors, Neurotransmitter drug effects   MeSH
• Oxygen Consumption drug effects   MeSH
• Thiophenes pharmacology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Antipsychotic Agents MeSH
• brexpiprazole MeSH Browser
• cariprazine MeSH Browser
• Quinolones MeSH
• Electron Transport Chain Complex Proteins MeSH
• Monoamine Oxidase Inhibitors MeSH
• Loxapine MeSH
• Lurasidone Hydrochloride MeSH
• Hydrogen Peroxide MeSH
• Piperazines MeSH
• Reactive Oxygen Species MeSH
• Receptors, Neurotransmitter MeSH
• Thiophenes MeSH