抗精神病药物影响首发精神分裂症患者脑结构和功能连接及其与肠道菌群的相关研究

The available documents and preliminary study of the research group have shown that the therapeutic mechanism of antispychotics on schizophrenia was probably closely related to the change of brain structural and functional connectivity caused by the antispychotics. And intestine microbiotas may play a role in the therapeutic process with the help of “gut-brain” axis. But the detailed mechanism of how intestine microbiotas affect drug efficiency and brain image remains unkown. Therefore, we hypothesise that: antipsychotics act on the classic neurotransmitter receptors, and then influence the neural signal transmission and synaptic plasticity so as to change the abnormal brain structural and functional connectivity of the schizophrenics. The above process may be adjusted by intestine microbiotas. We are going to perform brain scan and analysis, and 16s rDNA detection and analysis of intestine microbes on 60 patients with first-onset drug-naive schizophrenia and 60 healthy people with roughly the same age and gender. We attempted to analyze and discover the differences between schizophrenics and those correspondent heathy people and the differences between schizophrenics before treatment and after treatment, in terms of such variables as psychiatric symptoms, cognitive function, brain structural and functional connectivity, and the diversity and bacteria abundance of the intestine microbiotas, and then try to establish the interrelation among those variables. We would explore the detailed pharmacological mechanism of antipsychotics in relieving the disease. The prospective research findings will provide us with clues to the precise treatment of schizophrenia.

既往文献及课题组前期研究提示，抗精神病药治疗精神分裂症的疗效机制可能与其改变患者脑结构和功能连接密切相关，而肠道菌群借助“肠-脑”轴在治疗过程中发挥重要作用；但肠道菌群调节药物疗效及脑影像学的详细机制有待阐明。本项目的科学假说：抗精神病药通过作用于经典神经递质受体，影响神经信号传导和神经突触可塑性，改变精神分裂症患者异常脑结构和功能连接，缓解精神症状；此过程可能受到肠道菌群的调节作用。本项目拟对60例首次发病、未用药的精神分裂症患者（治疗前及利培酮治疗12周后）和60名匹配的正常对照者，进行脑影像学扫描和肠道菌群16s rDNA检测与分析，分析患者与对照之间、患者治疗前与治疗后在临床症状群、认知功能、脑结构和功能连接、肠道菌群种属与丰度的差异，建立上述多个变量之间的彼此关联；探索抗精神病药物改善精神症状的具体药理机制及分裂症本身的病理机制。预期结果有望为精神分裂症的精准治疗提供线索。

精神分裂症是一种常见的、重性、高致残性精神疾病，由于病因未明，目前主要采用抗精神病药物治疗，但药物并非对所有的患者都有效，且长期用药也可能存在副作用。因此，了解抗精神病药物的作用机制，对于发展更好的治疗方式以及了解精神分裂症本身的病理机制都有重要的意义。本研究分析了首发未服药精神分裂症患者治疗前、治疗12周的大脑结构和功能差异及与临床资料的关系，发现抗精神病药可能通过改变精神分裂症患者异常的脑区功能活性，如左侧中央沟盖、左侧顶上回等区域，缓解了精神症状，支持这些脑区的异常与精神分裂症的疾病状态和疾病易感性有关。进一步分析了首发未服药精神分裂症患者在治疗前、治疗6周和对照者的微生物组、血清代谢组学变化，发现一些微生物菌群菌株，如普氏菌属_9和拟杆菌属，可以作为精神分裂症患者的生物标志物或富集特征。一些重要的代谢物，如L-蛋氨酸、L-脯氨酸、高香草酸、N-乙酰5-羟色胺和维生素B6等代谢异常与微生物群的改变有显著的相关性。研究显示了精神分裂症患者涉及的异常脑功能紊乱区域及抗精神病药物作用的可能脑区靶点。也表明了肠道菌群、血清代谢产物在抗精神病药物机制中的作用及对精神分裂症发生发展的影响。结果有望为精神分裂症的精准诊治提供线索。