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.

在猪脑线粒体中体外研究了新型抗精神病药（brexpiprazole、cariprazine、loxapine 和 lurasidone）对线粒体作用的鉴定和量化。对线粒体代谢、电子传递链 (ETC) 复合物、柠檬酸合酶 (CS)、苹果酸脱氢酶 (MDH)、单胺氧化酶 (MAO)、线粒体呼吸以及总 ATP 和活性氧 (ROS) 产生的选定参数进行了评估和关联与可能的药物不良反应。所有测试的抗精神病药均降低了 ETC 活性（复合物 IV 除外，其在加入 brexpiprazole 和洛沙平后活性增加）。复合 I 和复合 II 相关呼吸均呈剂量依赖性抑制，复合 I 相关呼吸与复合 I 活动（正相关）和复杂 IV 活动（负相关）之间存在显着相关性。所有药物在较高浓度下均显着降低线粒体 ATP 的产生。10 µM brexpiprazole 和 lurasidone 以及 100 µM cariprazine 和 loxapine 的过氧化氢产量显着增加。所有抗精神病药都作为 MAO-A 的部分抑制剂，brexpiprazole 和洛沙平部分抑制 MAO-B。根据我们的结果，新型抗精神病药可能缺乏氧解偶联特性。新型抗精神病药的线粒体效应可能导致其不良反应，主要与 ATP 产生减少和 ROS 产生增加有关，而 MAO-A 抑制可能有助于其抗抑郁作用，brexpiprazole 和洛沙平诱导的 MAO-B 抑制可能促进神经可塑性和神经保护。药物诱导的线粒体功能障碍的评估对于开发新药以及了解药物不良或副作用的分子机制非常重要。