Maciukiewicz M, Marshe V S, Tiwari A K, Fonseka T M, Freeman N, Kennedy J L, Rotzinger S, Foster J A, Kennedy S H, Müller D J
Pharmacogenetic Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Pharmacogenomics J. 2018 May 22;18(3):406-412. doi: 10.1038/tpj.2017.29. Epub 2017 Jul 11.
We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18-75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery-Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (β=0.69, P=1.25 × 10) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; β=-0.46, P=1.55 × 10), NCAM1 (rs2303377; β=0.45, P=1.76 × 10) and MLL5 (rs117986340; β=0.91, P=3.04 × 10). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.
我们采用全基因组方法，对使用抗抑郁药度洛西汀或安慰剂治疗的抑郁症患者中与治疗反应相关的变异体进行了研究。我们的样本（N = 391）包括年龄在18 - 75岁之间、被诊断为重度抑郁症且接受度洛西汀或安慰剂治疗长达8周的个体。我们对治疗反应进行了全基因组关联分析，治疗反应通过蒙哥马利 - 阿斯伯格抑郁评定量表评分相对于基线的百分比变化来衡量，同时还对五个时间点进行了混合模型分析。在接受安慰剂治疗的子样本（N = 205）中，我们在STAC1上游观察到与rs76767803存在全基因组关联（β = 0.69，P = 1.25 × 10）。使用混合模型分析，STAC1 rs76767803也与反应相关（χ = 3.95；P = 0.001）。在接受度洛西汀治疗的子样本（N = 186）中，我们观察到与ZNF385D（rs4261893；β = -0.46，P = 1.55 × 10）、NCAM1（rs2303377；β = 0.45，P = 1.76 × 10）和MLL5（rs117986340；β = 0.91，P = 3.04 × 10）存在提示性关联。我们的研究结果表明，STAC1上游的一个变异体与安慰剂反应相关，这可能对治疗优化、临床试验设计和药物开发具有重要意义。
