Lilly USA, LLC, Indianapolis, IN 46285, USA.
J Clin Psychiatry. 2012 Jun;73(6):878-85. doi: 10.4088/JCP.10m06744. Epub 2012 Mar 6.
To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination.
A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS).
Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments.
Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2.
Parent study registered at ClinicalTrials.gov identifier: NCT00035321.
确定候选基因中的单核苷酸多态性（SNP）是否与奥氮平-氟西汀联合治疗的反应相关。
对奥氮平-氟西汀联合、氟西汀和奥氮平治疗主要抑郁症（DSM-IV 标准）患者的临床试验（日期：2002 年 4 月至 2005 年 7 月）中预先选择的 SNP 进行了事后分析，这些患者对前期抗抑郁治疗无反应且对研究期间的氟西汀治疗无反应。患者接受氟西汀开放标签治疗 8 周（第 2 周，25mg/d；第 6 周，50mg/d），在结束时，无反应者（汉密尔顿抑郁量表 17 项评分下降<25%）被随机分配接受奥氮平-氟西汀联合（6/50-18/50mg/d，n=71）、氟西汀（50mg/d，n=78）或奥氮平（6-18mg/d，n=56）的双盲单药治疗 8 周。在 P<.05 时评估统计学意义。研究内治疗的主要疗效指标是蒙哥马利-阿斯伯格抑郁评定量表（MADRS）的改善。
rs36024 是去甲肾上腺素转运蛋白（SLC6A2）的内含子 SNP，以及黑素皮质素 3 受体（MC3R）中的 3 个 SNP 和色氨酸羟化酶 2（TPH2）中的 2 个 SNP，与奥氮平-氟西汀联合治疗的 MADRS 定义的反应相关（调整后的 Li-Nyholt P<.05）。除了 TPH2 中的 1 个 SNP 外，鉴定的 SNP 与继续氟西汀或奥氮平治疗的反应均无显著相关性。
我们的发现进一步支持了奥氮平和氟西汀对前额叶皮质去甲肾上腺素和多巴胺水平的协同作用可能是奥氮平-氟西汀联合治疗难治性抑郁症疗效的潜在机制的假设，如果得到复制，可能为预测奥氮平-氟西汀联合治疗与继续氟西汀的反应提供依据，依据是 SLC6A2 中的变体。
母研究在 ClinicalTrials.gov 标识符：NCT00035321 注册。
