Department of Psychiatry, Huai'an No. 3 People's Hospital, Huai'an, Jiangsu Province, China.
Int Clin Psychopharmacol. 2013 Sep;28(5):245-54. doi: 10.1097/YIC.0b013e328362c89f.
Signal transduction has been reported to be involved in antidepressant treatment outcomes; however, its mechanisms remain unclear. The aims of this study were to explore the associations between antidepressant remission and single nucleotide polymorphisms (SNPs), haplotypes, and gene-gene interactions in the Ras-Raf-MAPK intracellular signaling pathway. A total of 302 inpatients with major depressive disorder (DSM-IV Axis I) were assessed using the 17-item Hamilton Depression Rating Scale before and after 8 weeks of antidepressant treatment to determine the remission rate in the samples. Twenty-four SNPs at five kinase genes (Ras-Raf-MEK-ERK-RSK), which are a part of the Ras-Raf-MAPK signaling pathway, were identified to investigate a genetic association with antidepressant drug outcome. Correlations between 24 SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway and antidepressant drug outcome were not found. The percentage of the CCAGA haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed was markedly lower in the remitter group when compared with the nonremitter group in female depressed patients (P=0.04), whereas the proportion of AAAGGG haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed in the remitter group was significantly greater than that in the nonremitter group in male patients (P=0.02). In addition, MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras-Raf-MAPK signaling pathway showed a gene-gene interaction that affected antidepressant drug outcome in female depressed patients (P=0.041). Although this study did not find that SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway are important markers for antidepressant outcome, certain haplotypes that SNPs at the RSK(2/3/4)-RSKL(1/2) gene constructed may be important markers for antidepressant drug efficacy. We observed a gene-gene interaction in this signaling pathway that influenced antidepressant efficacy in female depressed patients. Therefore, it is likely that in female depressed patients, different haplotypes and gene-gene interaction in the Ras-Raf-MAPK signaling pathway are involved in mediating the pharmacological action of an antidepressant, and eventually influence antidepressant efficacy.
信号转导被报道与抗抑郁治疗结果有关；然而，其机制仍不清楚。本研究的目的是探讨 Ras-Raf-MAPK 细胞内信号通路中抗抑郁药缓解与单核苷酸多态性（SNP）、单倍型和基因-基因相互作用之间的关系。采用汉密尔顿抑郁量表（Hamilton Depression Rating Scale，HAMD）对 302 名符合 DSM-IV 轴 I 标准的重性抑郁障碍（major depressive disorder，MDD）住院患者进行评估，在抗抑郁治疗 8 周后评估样本的缓解率。选择 Ras-Raf-MEK-ERK-RSK 激酶基因中的 24 个 SNP 作为 Ras-Raf-MAPK 信号通路的一部分，研究其与抗抑郁药疗效的遗传相关性。未发现 Ras-Raf-MAPK 信号通路中 5 个激酶基因（Ras-Raf-MEK-ERK-RSK）中的 24 个 SNP 与抗抑郁药物疗效相关。在女性抑郁患者中，与非缓解组相比，RSK(2/3/4)-RSKL(1/2)基因座 SNP 构建的 CCAGA 单体型在缓解组中的比例明显较低（P=0.04），而在男性患者中，RSK(2/3/4)-RSKL(1/2)基因座 SNP 构建的 AAAGGG 单体型在缓解组中的比例明显高于非缓解组（P=0.02）。此外，Ras-Raf-MAPK 信号通路中的 MEK1(rs28730804)和 RSK3(rs2229712)表现出基因-基因相互作用，影响女性抑郁患者的抗抑郁药物疗效（P=0.041）。虽然本研究未发现 Ras-Raf-MAPK 信号通路中 5 个激酶基因的 SNP 是抗抑郁疗效的重要标志物，但 RSK(2/3/4)-RSKL(1/2)基因座 SNP 构建的某些单体型可能是抗抑郁药物疗效的重要标志物。我们观察到该信号通路中的基因-基因相互作用影响了女性抑郁患者的抗抑郁疗效。因此，在女性抑郁患者中，Ras-Raf-MAPK 信号通路中的不同单体型和基因-基因相互作用可能参与调节抗抑郁药物的药理作用，并最终影响抗抑郁疗效。
