Stein Murray B, Keshaviah Aparna, Haddad Stephen A, Van Ameringen Michael, Simon Naomi M, Pollack Mark H, Smoller Jordan W
Department of Psychiatry and Family and Preventive Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Neuropsychopharmacology. 2014 May;39(6):1340-6. doi: 10.1038/npp.2013.301. Epub 2013 Oct 24.
Only a minority of patients with social anxiety disorder (SAD) has a robust therapeutic response to evidence-based serotonin reuptake inhibitor (SSRI) treatment. To help improve the personalized medicine approach to psychiatric care, we evaluated several candidate genetic predictors of SSRI response in SAD. At the start of a randomized controlled trial (NCT00282828), 346 patients with SAD at three sites received protocol-driven, open-label treatment with sertraline, up to 200. mg/d over 10 weeks. Efficacy was determined using a continuous measure of outcome (Liebowitz Social Anxiety Scale (LSAS)) and dichotomous indicators of response (LSAS ≤ 50) and remission (LSAS ≤ 30). Predictors of efficacy were examined in multivariate regression models that included eight polymorphic variants in four candidate genes (four in RGS2, two in HTR2A, one in SLC6A2, and one in SLC6A4). Adjusting for genetic ancestral cluster and non-genetic predictors of response, all four single-nucleotide polymorphisms (SNPs) in RGS2 predicted change in LSAS over time, at study-wise significance (p=0.00833), with the minor allele associated with less improvement over time. After adjusting for genetic ancestral cluster and non-genetic predictors of remission, two of the four RGS2 SNPs predicted likelihood of remission at or just below study-wise significance (p=0.025): rs4606 (AOR=0.49 (95% CI=0.27-0.90), p=0.022) and rs1819741 (AOR=0.50 (95% CI=0.28-0.92), p=0.027). Variation in RGS2, a gene previously shown to be associated with social anxiety phenotypes and serotonergic neurotransmission, may be a biomarker of the likelihood of substantially benefiting from sertraline among patients with SAD.
只有少数社交焦虑障碍（SAD）患者对循证性5-羟色胺再摄取抑制剂（SSRI）治疗有强烈的治疗反应。为了帮助改进精神科护理的个性化医疗方法，我们评估了SAD中SSRI反应的几个候选基因预测指标。在一项随机对照试验（NCT00282828）开始时，三个地点的346名SAD患者接受了方案驱动的舍曲林开放标签治疗，剂量高达200mg/d，持续10周。使用连续的结局指标（利博维茨社交焦虑量表（LSAS））以及反应（LSAS≤50）和缓解（LSAS≤30）的二分指标来确定疗效。在多变量回归模型中检查疗效的预测指标，该模型包括四个候选基因中的八个多态性变体（RGS2中有四个，HTR2A中有两个，SLC6A2中有一个，SLC6A4中有一个）。在调整了遗传祖先聚类和反应的非遗传预测指标后，RGS2中的所有四个单核苷酸多态性（SNP）均预测了随时间推移LSAS的变化，具有研究水平的显著性（p = 0.00833），次要等位基因与随时间改善较少相关。在调整了遗传祖先聚类和缓解的非遗传预测指标后，四个RGS2 SNP中的两个预测了缓解的可能性，略低于研究水平的显著性（p = 0.025）：rs4606（比值比=0.49（95%置信区间=0.27 - 0.90），p = 0.022）和rs1819741（比值比=0.50（95%置信区间=0.28 - 0.92），p = 0.027）。RGS2基因的变异先前已显示与社交焦虑表型和5-羟色胺能神经传递相关，它可能是SAD患者从舍曲林中大幅获益可能性的生物标志物。
