Variation in Catechol-O-Methyltransferase Is Associated with Duloxetine Response in a Clinical Trial for Major Depressive Disorder
Variation in Catechol-O-Methyltransferase Is Associated with Duloxetine Response in a Clinical Trial for Major Depressive Disorder
复制标题
DOI：
10.1016/j.biopsych.2008.10.002
复制
发表时间：
2009-05-01
影响因子：
10.6
通讯作者：
Houston, John P.
中科院分区：
文献类型：
--
作者：
Perlis, Roy H.;Fijal, Bonnie;Houston, John P.
背景资料：本研究的目的是评估与度洛西汀治疗重度抑郁症（MDD）相关的抗抑郁作用机制的基因变异：我们在一项随机、双盲的MDD患者研究中，评估了250例度洛西汀治疗的白人患者在6周内的反应。单核苷酸多态性（SNPs）基因分型的基础上选择的证据参与抗抑郁药的作用机制的19个候选基因。主要分析检查基线至终点的17项汉密尔顿抑郁评定量表（HAMD 17）总分的降低，使用基于集合的检验每个基因的相关性。随访分析检查了任何显著基因内的单个SNP与HAMD 17和30项抑郁症状临床医师评分量表（IDS-C-30）降低的相关性。结果：多重比较校正后，只有COMT与HAMD 17的变化相关（实验范围p = 0.018）。检测到rs 165599的峰值关联（p = .006），其占HAMD 17变化的方差的约3%和IDS-C-30变化的方差的>4%（p = .001）。对于GG、GA和AA基因型患者，rs 165599基因型的HAMD 17评分的最小二乘均数变化（SE）分别为-10.8（1.2）、-8.7（.6）和-6.5（.7）。5-羟色胺2A受体（HTR 2A）的SNPs先前与西酞普兰反应，包括rs7997012，没有显着的证据与度洛西汀反应的关联被identified.Conclusions：单核苷酸多态性在COMT与度洛西汀治疗的MDD患者的症状变化。如果重复，COMT基因型效应的大小具有临床相关性。
Background: The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD).Methods: We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30).Results: After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experimentwide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was -10.8 (1.2), -8.7 (.6), and -6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified.Conclusions: Single nucleotide polymorphisms in COMT were associated with symptom change in duloxetine-treated patients with MDD. If replicated, the magnitude of the COMT genotype effect is of clinical relevance.