Key Laboratory of Multiple Organ Damages of Major Psychoses (MODMP Lab), Tianjin Fourth Center Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Central Hospital Affiliated to Tianjin Medical University, Tianjin, 300140, China.
The First Affiliated Hospital/Zhengzhou University, Biological Psychiatry International Joint Laboratory of Henan/Zhengzhou University, Henan Psychiatric Transformation Research Key Laboratory/Zhengzhou University, Zhengzhou, 450052, China.
Transl Psychiatry. 2022 Jan 10;12(1):13. doi: 10.1038/s41398-021-01778-w.
Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.
抗精神病药物治疗已被广泛推荐为治疗急性精神分裂症和其他精神障碍的精神病症状的标准治疗方法。然而，人们越来越关注抗精神病药引起的副作用，包括体重增加、代谢综合征（MetS）和锥体外系运动障碍，这不仅降低了患者的依从性，而且还容易导致糖尿病和心血管疾病。迄今为止，大多数关于抗精神病药引起代谢副作用机制的研究和综述都集中在中枢神经系统对食欲和食物摄入的调节上。然而，抗精神病药物引起的葡萄糖和脂质代谢紊乱以及肝脂肪变性可能先于体重增加和 MetS。最近的研究表明，机制/哺乳动物雷帕霉素靶蛋白（mTOR）通路在抗精神病药引起的肝葡萄糖和脂质代谢紊乱的病理生理学中发挥着关键的调节作用。此外，抗精神病药物促进纹状体 mTOR 通路的激活，导致锥体外系运动副作用。尽管最近的发现提高了对 mTOR 通路在抗精神病药引起的副作用中的作用的理解，但很少有关于这一新兴主题的综述。在这篇综述中，我们通过关注肝和纹状体 mTOR 通路在代谢和锥体外系副作用发病机制中的作用，综合了关键发现。我们进一步讨论了用 mTOR 特异性抑制剂使过度的 mTOR 通路激活正常化的潜在治疗益处。对发病机制的更深入了解可能会为使用 mTOR 的药理学或遗传学抑制剂来预防和管理抗精神病药引起的副作用提供未来的干预策略。
