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.

• Klíčová slova
• ATP, Dopamine system stabilizers, Mitochondrial respiration, Monoamine oxidase, Oxidative phosphorylation, Reactive oxygen species,
• MeSH
• adenosintrifosfát biosyntéza   MeSH
• antipsychotika klasifikace   farmakologie   MeSH
• chinolony farmakologie   MeSH
• elektronový transportní řetězec účinky léků   MeSH
• energetický metabolismus účinky léků   MeSH
• inhibitory MAO farmakologie   MeSH
• loxapin farmakologie   MeSH
• lurasidon hydrochlorid farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• peroxid vodíku metabolismus   MeSH
• piperaziny farmakologie   MeSH
• prasata MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• receptory neurotransmiterů účinky léků   MeSH
• spotřeba kyslíku účinky léků   MeSH
• thiofeny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosintrifosfát MeSH
• antipsychotika MeSH
• brexpiprazole MeSH Prohlížeč
• cariprazine MeSH Prohlížeč
• chinolony MeSH
• elektronový transportní řetězec MeSH
• inhibitory MAO MeSH
• loxapin MeSH
• lurasidon hydrochlorid MeSH
• peroxid vodíku MeSH
• piperaziny MeSH
• reaktivní formy kyslíku MeSH
• receptory neurotransmiterů MeSH
• thiofeny MeSH

The evaluation of drug-induced mitochondrial impairment may be important in drug development as well as in the comprehension of molecular mechanisms of the therapeutic and adverse effects of drugs. The primary aim of this study was to investigate the effects of four drugs for treatment of depression (bupropion, fluoxetine, amitriptyline, and imipramine) and five drugs for bipolar disorder treatment (lithium, valproate, valpromide, lamotrigine, and carbamazepine) on cell energy metabolism. The in vitro effects of the selected psychopharmaca were measured in isolated pig brain mitochondria; the activities of citrate synthase (CS) and electron transport chain (ETC) complexes (I, II + III, and IV) and mitochondrial respiration rates linked to complex I and complex II were measured. Complex I was significantly inhibited by lithium, carbamazepine, fluoxetine, amitriptyline, and imipramine. The activity of complex IV was decreased after exposure to carbamazepine. The activities of complex II + III and CS were not affected by any tested drug. Complex I-linked respiration was significantly inhibited by bupropion, fluoxetine, amitriptyline, imipramine, valpromide, carbamazepine, and lamotrigine. Significant inhibition of complex II-linked respiration was observed after mitochondria were exposed to amitriptyline, fluoxetine, and carbamazepine. Our outcomes confirm the need to investigate the effects of drugs on both the total respiration rate and the activities of individual enzymes of the ETC to reveal the risk of adverse effects as well as to understand the molecular mechanisms leading to drug-induced changes in the respiratory rate. Our approach can be further replicated to study the mechanisms of action of newly developed drugs.

• Klíčová slova
• Antidepressant, Citrate synthase, Electron transport chain complexes, Mitochondrial respiration, Mood-stabilizing drugs,
• MeSH
• antidepresiva toxicita   MeSH
• antimanika toxicita   MeSH
• buněčné dýchání účinky léků   MeSH
• elektronový transportní řetězec metabolismus   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mozek účinky léků   metabolismus   MeSH
• oxidativní fosforylace účinky léků   MeSH
• subcelulární frakce MeSH
• Sus scrofa MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidepresiva MeSH
• antimanika MeSH
• elektronový transportní řetězec MeSH

BACKGROUND: Mitochondrial dysfunctions are implicated in the pathophysiology of mood disorders. We measured and examined the following selected mitochondrial parameters: citrate synthase (CS) activity, electron transport system (ETS) complex (complexes I, II, and IV) activities, and mitochondrial respiration in blood platelets. PATIENTS AND METHODS: The analyses were performed for 24 patients suffering from a depressive episode of bipolar affective disorder (BD), compared to 68 patients with MDD and 104 healthy controls. BD and unipolar depression were clinically evaluated using well-established diagnostic scales and questionnaires. RESULTS: The CS, complex II, and complex IV activities were decreased in the depressive episode of BD patients; complex I and complex I/CS ratio were significantly increased compared to healthy controls. We observed significantly decreased complex II and CS activities in patients suffering from MDD compared to controls. Decreased respiration after complex I inhibition and increased residual respiration were found in depressive BD patients compared to controls. Physiological respiration and capacity of the ETS were decreased, and respiration after complex I inhibition was increased in MDD patients, compared to controls. Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. CONCLUSION: We can conclude that complex I and its abnormal activity contribute to the defects in cellular energy metabolism during a depressive episode of BD. The observed parameters could be used in a panel of biomarkers that could selectively distinguish BD depression from MDD and can be easily examined from blood elements.

• Klíčová slova
• affective disorder, biomarker, mitochondrial enzyme, oxidative phosphorylation, platelet,
• Publikační typ
• časopisecké články MeSH