系统评价与Meta分析：选择性5-羟色胺再摄取抑制剂在重度抑郁症中的剂量-反应关系
Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.
作者信息
Jakubovski Ewgeni, Varigonda Anjali L, Freemantle Nicholas, Taylor Matthew J, Bloch Michael H
机构信息
From the Yale Child Study Center, New Haven, Conn.; the University of Vermont College of Medicine, Burlington, Vt.; Child Study Center and Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Primary Care and Population Health, University College London; and the Department of Psychosis Studies, King's College London.
出版信息
Am J Psychiatry. 2016 Feb 1;173(2):174-83. doi: 10.1176/appi.ajp.2015.15030331. Epub 2015 Nov 10.
OBJECTIVE
Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.
METHOD
The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.
RESULTS
Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54).
CONCLUSIONS
Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.
目的
既往研究表明，在治疗剂量范围内，重度抑郁症患者对选择性5-羟色胺再摄取抑制剂（SSRI）的治疗反应呈平缓曲线。本研究旨在阐明重度抑郁症患者剂量与治疗反应之间的关系。
方法
作者检索了PubMed上关于SSRI治疗成人重度抑郁症疗效的随机安慰剂对照试验。试验还需评估多个时间点的抑郁严重程度改善情况。收集了关于治疗反应以及全因停药和副作用相关停药的其他数据。所有药物剂量均换算为丙咪嗪等效剂量。采用混合回归模型分析纵向数据。使用Meta回归和按预定义的SSRI剂量类别进行分层亚组分析进行终点和耐受性分析，以评估SSRI剂量对重度抑郁症患者使用SSRI的疗效和耐受性的影响。
结果
纳入了40项研究共10039名参与者。纵向建模（剂量×时间交互作用=0.0007，95%可信区间=0.0001-0.0013）和终点分析（Meta回归：β=0.00053，95%可信区间=0.00018-0.00088，z=2.98）显示，SSRI剂量与疗效之间存在虽小但具有统计学意义的正相关。较高剂量的SSRI与因副作用导致停药的可能性增加（Meta回归：β=0.00207，95%可信区间=0.00071-0.00342，z=2.98）以及全因停药的可能性降低（Meta回归：β=-0.00093，95%可信区间=-0.00165至-0.00021，z=-2.54）相关。
结论
较高剂量的SSRI在重度抑郁症中似乎略更有效，但这种益处似乎在约250mg丙咪嗪等效剂量（50mg氟西汀）时趋于平稳。较高剂量SSRI带来的益处略有增加在一定程度上被高剂量时耐受性降低所抵消。
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