Peng Aineng, Chai Jianbo, Wu Haiyuan, Bai Bing, Yang Huihui, He Weizhi, Zhao Yonghou
Heilongjiang University of Chinese Medicine, Harbin, 150040, People's Republic of China.
Heilongjiang Mental Hospital, Harbin, 150036, People's Republic of China.
Neuropsychiatr Dis Treat. 2024 Mar 20;20:607-620. doi: 10.2147/NDT.S455279. eCollection 2024.
Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.
精神分裂症是一种病理机制复杂且受多个基因影响的疾病。其发病机制的研究主要基于多巴胺假说，以及其他一些假说，如5-羟色胺假说、谷氨酸假说、免疫炎症假说、基因表达异常假说和神经发育异常假说。第一代抗精神病药物是基于多巴胺能受体拮抗作用研发的，它通过阻断大脑中的多巴胺D2受体来发挥抗精神病作用。第二代抗精神病药物通过对5-羟色胺和多巴胺受体的双重阻断起作用。从第三代抗精神病药物开始，抗精神病药物治疗精神分裂症的靶点扩展到D2受体阻断之外，开始探索D2受体部分激动作用以及D3、5-HT1A、5-HT7和mGlu2/3受体等新靶点的抗精神病作用。第二代和第三代抗精神病药物相对于第一代抗精神病药物的主要优势在于副作用减少和阴性症状改善，尽管第三代抗精神病药物不直接阻断D2受体，但多巴胺递质系统的调节仍是其抗精神病过程的重要组成部分。根据最近的研究，包括5-羟色胺、谷氨酸、γ-氨基丁酸、乙酰胆碱受体和去甲肾上腺素在内的几种受体在精神分裂症的发病过程中发挥作用。因此，开发新型抗精神病药物的重点已转向对这些受体的激动或抑制。具体而言，NMDARs激动剂、GABA受体激动剂、mGlu受体调节剂、胆碱能受体调节剂、5-HT2C受体激动剂和α-2受体调节剂的开发已成为主要方向。动物实验已证实这些药物具有抗精神病作用，但其药代动力学和临床适用性仍需进一步探索。抗精神病药物除多巴胺D2受体之外的替代靶点研究，拓展了精神分裂症的潜在治疗选择，为应对难治性精神分裂症的挑战提供了重要途径。本文旨在全面概述精神分裂症治疗靶点和药物的研究，为该领域的治疗和进一步研究提供有价值的见解。
