抑郁症患者抗抑郁药物治疗期间脑网络动态变化及其与基因多态性和疗效的关系

抑郁症患者抗抑郁药物治疗疗效个体差异大，机制不明。药物调控脑网络的个体差异及基因多态性均可部分解释抗抑郁药的疗效差异，但不清楚抗抑郁药引起的脑网络动态变化模式及基因、脑网络和疗效的复杂关系。基于项目组前期研究，本项目提出采用影像遗传学研究方法，以未服药抑郁症患者为研究对象，以特异性作用于5-HT的抗抑郁药艾司西酞普兰为工具药开展多时点纵向研究，探索艾司西酞普兰急性期疗效差异的生物学基础。由于既往研究忽略了治疗过程中脑网络的动态变化，本项目将首先通过多个时间点观察急性期治疗期间的脑网络变化，确定药物对脑网络的动态影响及脑网络动态变化与疗效之间的关系；其次，研究5-HT通路关键基因和药物代谢和转运的关键基因在解释疗效差异和脑网络动态变化个体差异中的作用，建立基因-脑-疗效的复杂关系。预期将获得抗抑郁药疗效个体差异机制的新发现，为发现疗效预测的早期生物标记、实现个体化治疗提供理论基础。

Despite dramatic inter-individual differences in clinical efficacy of antidepressants have been observed in patients with major depressive disorder (MDD), the mechanisms underlying the inter-individual variance are not fully understood. The brain networks modulated by antidepressants and genetic polymorphisms can partially explain the inter-individual differences in clinical efficacy of antidepressants in previous studies. However, it is still unknown how brain networks dynamically change during treatment and how the dynamic changes of brain networks link with genetic polymorphisms and the clinical efficacy of antidepressants. Based on our findings in the pilot studies, the current project adopts a longitudinal design, where data is collected during the period of antidepressant treatment with multiple time points among unmedicated MDD patients. The project uses escitalopram as the only antidepressant drug, which is highly potent and selective serotonin reuptake inhibitor. And the project uses imaging genetics methodology to explore the biological bases of inter-individual differences in clinical efficacy of escitalopram during the acute phrase of treatment in MDD patients. This project will make the following contributions. First, as previous studies omitted the dynamic changes in brain networks during treatment, the project firstly investigate the effects of escitalopram on dynamic changes in brain networks by collecting MRI images in multiple time points during acute phrase of escitalopram treatment and determine the relationship between clinical efficiency and dynamic changes in brain networks. Second, this project will investigate the influence of both genetic polymorphisms in 5-HT pathway genes and in genes in charge of escitalopram metabolism and transport on clinical efficiency and dynamic changes in brain networks, and finally build the complex relationship between genes, brain and clinical efficiency in MDD patients. The findings of this project will advance our knowledge about the biological mechanisms of inter-individual differences in the clinical efficacy of antidepressant. This project will thus provide theoretical guidance for identifying biomarkers for efficacy and prognosis evaluation as well as realizing personalized-medicine approaches in MDD.