MTHFR基因多态性及DNA甲基化在SSRI耐药的抑郁症中的作用

抑郁症目前仍以药物治疗为主，约三分之一的抑郁症患者对抗抑郁药反应不佳，其耐药机制并不清楚。已知添加5-甲基四氢叶酸（5-MTHF）可明显改善SSRI耐药的抑郁症患者的临床症状，提示SSRI耐药与叶酸代谢异常有关。亚甲基四氢叶酸还原酶（MTHFR）是叶酸代谢中的一个重要酶，参与5-MTHF的生成及DNA甲基化。MTHFR的多态性可改变MTHFR的酶活性并直接影响5-MTHF的形成。而MTHFR基因多态性是否与抗抑郁药疗效有关尚无直接证据。本课题首先在SSRI治疗有效和耐药的两组抑郁症人群中调查MTHFR基因多态性分布，基于MTHFR基因型探索全基因组和候选基因甲基化的改变与SSRI耐药的关系，最后对携带MTHFR风险等位基因的SSRI耐药患者给予5-MTHF治疗，结合疗效评估，验证DNA甲基化异常参与了SSRI耐药的产生。本课题有助于寻找SSRI耐药的新机制，为精准个体化治疗提供依据。

Major depressive disorder is still treated mainly by medicines now. About one-third of patients do not respond to antidepressants and the mechanism of treatment resistance is not clear. There is evidence that 5-methyltetrahydrofolate (5-MTHF) as an adjunctive therapy for SSRI-resistant depression can improve response rate and clinical efficacy, suggesting that the abnormal metabolism of folate may be related to SSRI resistance. Methylenetetrahydrofolate reductase (MTHFR) that is encoded by MTHFR is an important enzyme involved in the metabolism of folate cycle and is related to DNA synthesis and methylation. 5-MTHF is the product of folate catalyzed by MTHFR, and it is also the most active folate. Studies have found that the MTHFR polymorphism directly affects the formation of 5-MTHF. However, there is no direct evidence whether MTHFR gene polymorphism is related to the antidepressant response. This research will first investigate the distribution of MTHFR gene polymorphism in two groups of patients，those who are responsive to SSRI and those who are resistant to SSRI, and further explore the relationship between DNA methylation and SSRI-resistant depression according to genotypes of MTHFR polymorphic loci. Finally, SSRI-resistant patients with MTHFR mutations will receive treatment of 5-MTHF, combined with the evaluation of clinical efficacy and symptom, to prove that abnormal DNA methylation is involved in the SSRI- resistant depression. This study contributes to find the SSRI-resistant mechanism of MTHFR-related depression patients and provides a basis for precise and individualized treatment for patients with major depressive disorder.