School of Biological Sciences & Medical Engineering, Southeast University, Nanjing, China; Child Development and Learning Science, Key Laboratory of Ministry of Education, Nanjing, China.
Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China.
J Affect Disord. 2021 Mar 15;283:130-138. doi: 10.1016/j.jad.2021.01.047. Epub 2021 Jan 27.
Serotonin 2A receptors (HTR2A) play a crucial role in the therapeutic response to antidepressant. The activity of serotonergic system could modulate the connectivity of the default mode network (DMN) in human brain. Our research investigated the influence of the single nucleotide polymorphism (SNP) of HTR2A on the early treatment response of antidepressant and their relation to dynamic changes of DMN for the first time.
A total of 134 major depressive disorder patients and 95 healthy controls from two independent datasets were enrolled. All subjects have genotyped candidate HTR2A polymorphisms, dynamic brain parameters flexibility and integration were calculated according to the resting-state functional magnetic resonance imaging (rs-fMRI) at baseline. Patients received selective serotonin reuptake inhibitors (SSRIs) treatment with conventional dose in the next two weeks.
We found the correlation of the risk-associated variant belonged to HTR2A polymorphism rs3803189 with the achievements of antidepressant early response, and also with the stronger dynamic changes of DMN. Further mediation analysis indicated that the bond between rs3803189 and antidepressant early response was mediated by the integration between the right angular gyrus (AG.R) and the subcortical network (SCN), which were validated over both the main and replication datasets.
Except the AG.R-SCN circuit, other factors which influence the relationship between rs3803189 and antidepressant therapy deserve to be explored further. Besides, heterogeneity of samples limited the power of the current result.
Our findings provided a potential biomarker for individual treatment sensitivity and produced positive effects on revealing the complicated gene-brain-disorder relationship.
5-羟色胺 2A 受体（HTR2A）在抗抑郁治疗反应中起着至关重要的作用。血清素能系统的活性可以调节人类大脑默认模式网络（DMN）的连通性。我们的研究首次调查了 HTR2A 的单核苷酸多态性（SNP）对抗抑郁药早期治疗反应的影响及其与 DMN 动态变化的关系。
共有来自两个独立数据集的 134 名重度抑郁症患者和 95 名健康对照者入组。所有受试者均进行了候选 HTR2A 多态性的基因分型，根据基线静息态功能磁共振成像（rs-fMRI）计算动态脑参数的灵活性和整合性。患者在接下来的两周内接受常规剂量的选择性 5-羟色胺再摄取抑制剂（SSRIs）治疗。
我们发现，HTR2A 多态性 rs3803189 与抗抑郁药早期反应的相关性，以及与 DMN 动态变化的相关性，都与风险相关的变异有关。进一步的中介分析表明，rs3803189 与抗抑郁药早期反应之间的联系是由右侧角回（AG.R）与皮质下网络（SCN）之间的整合介导的，这在主数据集和复制数据集上都得到了验证。
除了 AG.R-SCN 回路外，其他影响 rs3803189 与抗抑郁治疗关系的因素值得进一步探讨。此外，样本的异质性限制了当前结果的效力。
我们的研究结果为个体治疗敏感性提供了一个潜在的生物标志物，并对揭示复杂的基因-脑-疾病关系产生了积极的影响。
