端粒-线粒体轴在未服药双相障碍患者中的研究

Bipolar Disorder (BD) is a major psychiatric condition affecting 1-8% of the population. Patients can experience severe episodes of mania and life-threatening depression. About half of the patients become psychotic and the suicide rate is up to 15%. BD is a genetically and mechanistically heterogeneous disorder with few biomarkers available in diagnosis and prediction of medication response. Recently, accumulating evidence have suggested accelerated cellular aging may be involved in the pathophysiology of BD. Telomere-mitochondrial axis, as the key mechanism in regulating cellular aging and apoptosis, has become a hot target in the study of BD. However, clinical studies have shown inconsistent results in the association of telomere length, mitochondria copy number and activity with BD. Drug effect may be an important factor that masks the true relationship between telomere-mitochondrial axis and BD. In this research proposal, by recruiting drug-free BD patients and using systematic brain imaging techniques, we 1) investigate the baseline association of telomere-mitochondrial axis and BD in a case-control study design; 2) investigate the short-term and long-term treatment effect on telomere-mitochondrial axis in BD; 3) investigate the underlying genetic, epigenetic and brain-related neurological mechanisms that contribute to the dysfunctional telomere-mitochondrial axis in BD. We expect to establish the association of “peripheral telomeric and mitochondrial biomarkers-central nervous system endophenotype-BD symptoms”. This study will provide novel mechanisms in the pathophysiology of BD and establish potential biomarkers for early diagnosis, and provide predictive information for treatment response. The findings will tremendously improve our knowledge in designing personalized medical plan for psychiatric patients.

双相障碍（Bipolar Disorder, BD）是常见的重性精神疾病，发病机制未明，早期诊断和治疗难度大，严重影响患者预后。以往研究提示，细胞的加速衰老在BD的发生发展过程中发挥重要作用。作为调节细胞衰老与凋亡的关键机制，端粒-线粒体轴功能异常是否与BD的发生发展密切相关，尚不清楚。本研究首先通过病例对照设计，关注未服药BD患者端粒-线粒体轴的功能改变，分析可能的遗传及表观遗传学机制，并进一步探索端粒-线粒体轴功能异常在BD发生发展中的脑影像学机制。随后，通过前瞻性队列研究，确定药物对BD患者端粒-线粒体轴以及脑结构与功能的影响，建立疗效预测模型。本研究旨在揭示“端粒-线粒体轴外周标记物—中枢神经系统内表型—BD症状”的关联，为明确BD发展与转归的病理生理机制提供新证据；筛选辅助BD诊断的客观生物标记物，并建立药物疗效预测模型，服务于个体化诊疗方案的制定，具有重要的科研价值及临床意义。

相障碍（Bipolar Disorder, BD）是常见的重性精神疾病，致死致残率高，疾病负担重。但目前BD的病因及病理生理机制并不明确，缺少有效的生物学标记物，因此早期诊断无法实现，治疗难度大，预后差，疾病负担重。探索与BD鉴别诊断及治疗反应性有关的生物标记物，具有重要的临床意义。以往研究提示，细胞的加速衰老参与了BD的病理生理过程。近年来，端粒-线粒体轴作为调节细胞衰老与凋亡的关键机制，开始引起研究者重视，但临床研究较少且结果异质。本研究按照研究计划初步建立了双相障碍（Bipolar disorder, BD）患者随访队列，纳入首发BD患者及入院前两周内未服用抗精神病治疗药物的BD患者，研究发现，在双相I型患者中线粒体DNA拷贝数随着用药时间减少，并且与用药剂量以及既往用药时长有关，端粒长度与线粒体DNA拷贝数的变化趋势存在显著正相关，双相II型患者中无显著性改变，并且上述现象只发生在未服用锂盐的患者中。在原有研究计划基础上，利用荟萃分析探索了与抗抑郁药物治疗反应性有关的外周血细胞因子，并在BD人群中进行检测，发现细胞因子可作为预测药物治疗反应性的潜在标记物，并且不同精神疾病对应不同类型的细胞因子。此外，发现环境因素对于精神科急救事件及自杀行为的发生具有影响，提示环境中的急性应激可触发精神疾病发病和复发，应同时考虑基因与环境因素对精神疾病进程和预后的影响。