A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors
A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors
复制标题
DOI：
10.1038/tp.2016.104
复制
发表时间：
2016-06-07
影响因子：
6.8
通讯作者：
Eriksson, E.
中科院分区：
文献类型：
--
作者：
Hieronymus, F.;Nilsson, S.;Eriksson, E.
选择性血清素再摄取抑制剂（SSRI）的抗抑郁作用可能存在的剂量依赖性仍然存在争议。我们相信我们已经进行了第一次全面的患者级大型分析来探索这个问题，其中一个动机是解决以前的荟萃分析中纳入低剂量组可能导致低估这些药物疗效的可能性。所有公司赞助的、急性期的、安慰剂对照的、固定剂量的试验均使用汉密尔顿抑郁量表 (HDRS) 进行，旨在评估西酞普兰、帕罗西汀或舍曲林对成人重度抑郁症的疗效（11 项试验，n = 2859 名患者）。单项抑郁情绪已被证明是比所有 HDRS 项目的总分更敏感的检测抗抑郁信号的指标，被指定为主要效应参数。低于或处于通常推荐剂量范围下限的剂量（西酞普兰：10-20 mg，帕罗西汀：10 mg；舍曲林：50 mg）优于安慰剂，但不如较高剂量，因此证实了现有的剂量依赖性。相反，在高于这些的剂量中，没有迹象表明存在剂量反应关系。排除次优剂量后的效应大小 (ES) 比通常归因于 SSRI 抗抑郁作用的效应大小 (0.5) 更可观。总之，低剂量的效果不如高剂量的观察结果挑战了经常被引用的观点，即 SSRI 的作用不是剂量依赖性的，因此不是由特定的药理学抗抑郁作用引起的。此外，我们建议，在之前的荟萃分析中纳入次优剂量导致了对这些药物疗效的低估。
The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n = 2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10-20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose-response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs.