Major Depressive Disorder (MDD) is the leading cause of disability worldwide. Genetic factors influence the effect of its main treatment option, antidepressant drugs (ATD). The GRIK4 rs1954787(T>C) genetic polymorphism was associated with response following 1–3 months of ATD treatment in some studies, but not others. We aimed to analyze its association with clinical outcomes in a cohort of 6-month ATD-treated patients and meta-analysis. Clinical data were obtained at baseline and after 1 (M1), 3 (M3), and 6 (M6) months of ATD treatment in 390 patients of the METADAP cohort. Mixed-effects models were used to assess the association of the GRIK4 rs1954787 polymorphism with the Hamilton Depression Rating Scale (HDRS) score and response and remission rates across time. Meta-analyses of ATD treatment response were performed with previously meta-analyzed data and METADAP. Compared to C allele carriers at M3 (n = 200), TT homozygotes at M3 (n = 66) had higher HDRS scores (coef = 3.37, 95% CI [1.30–5.54], P_adj = 0.0046) and lower remission rates (OR = 0.36, 95% CI [0.16–0.76], P_adj = 0.029). At M6, greater differences between TT homozygotes (n = 53) and C allele carriers (n = 152) were observed for HDRS scores (coef = 4.68, 95% CI [2.17–7.18], P_adj = 0.00091) and remission rates (OR = 0.26, 95% CI [0.12–0.54], P_adj = 0.0016). Meta-analyses of response were significant when comparing C vs T alleles (OR = 1.31, 95% CI [1.06–1.62], P = 0.014) and CC vs TT genotypes (OR = 1.63, 95% CI [1.10–2.38], P = 0.019). Altogether, our results support an association of the GRIK4 rs1954787(T>C) polymorphism with clinical improvement following ATD treatment. This association should be further assessed in other longitudinal studies. Its position within the glutamatergic system may help in understanding the mechanism of ATD action.

重度抑郁症 （MDD） 是全球残疾的主要原因。遗传因素会影响其主要治疗选择抗抑郁药 （ATD） 的效果。在一些研究中，GRIK4 rs1954787（T>C） 基因多态性与 ATD 治疗 1-3 个月后的反应相关，但在其他研究中则不相关。我们旨在分析其与 6 个月 ATD 治疗患者队列和荟萃分析临床结果的关联。在 METADAP 队列的 390 例患者基线和 ATD 治疗 1 （M1） 、 3 （M3） 和 6 （M6） 个月后获得临床数据。混合效应模型用于评估 GRIK4 rs1954787 多态性与汉密尔顿抑郁量表 （HDRS） 评分以及随时间变化的反应和缓解率的相关性。使用先前的 meta 分析数据和 METADAP 对 ATD 治疗反应进行 meta 分析。与M3 （n = 200）的C等位基因携带者相比，M3 （n = 66）的TT纯合子具有更高的HDRS评分（coef = 3.37， 95% CI [1.30–5.54]，_{P adj} = 0.0046）和较低的缓解率（OR = 0.36， 95% CI [0.16–0.76]，P_adj = 0.029）。在M6时，观察到TT纯合子（n=53）和C等位基因携带者（n=152）之间的HDRS评分（coef=4.68,95% CI [2.17–7.18]，P_调整=0.00091）和缓解率（OR=0.26,95% CI [0.12–0.54]，P_调整率=0.0016）之间的差异更大。在比较C与T等位基因（OR=1.31,95%CI [1.06–1.62]，P=0.014）和CC与TT基因型（OR=1.63,95%CI [1.10–2.38]，P=0.019）时，反应的Meta分析具有显著意义。 总而言之，我们的结果支持 GRIK4 rs1954787（T>C） 多态性与 ATD 治疗后临床改善的关联。这种关联应在其他纵向研究中进一步评估。它在谷氨酸能系统中的位置可能有助于理解 ATD 作用的机制。