The issue of unblinded outcome-assessors and patients has repeatedly been stressed as a flaw in allegedly double-blind antidepressant trials. Unblinding bias can for example result from a drug‘s marked side effects. If such unblinding bias is present for a given drug, then it might be expected that the placebos of that drug are rated significantly less effective than that of other antidepressants. To test this hypothesis, the present exploratory analysis conducted a Bayesian network meta-analysis (NMA) comparing the efficacy of 19 different placebos in placebo-controlled trials provided in the dataset by Cipriani et al. (Lancet 2018; 391: 1357–66). Primary outcome was efficacy (continuous) estimated on the standardized mean difference (SMD) scale and defined as the pre-post change on the Hamilton Depression scale (HAMD-17), on which information was available in N = 258 trials. Comparative placebo ranking suggested mirtazapine-placebo (SMD -2.0 [− 5.0–1.0 95% CrI]) to be the most, and amitriptyline- (SMD 1.2 [− 1.6–3.9 95% CrI]) and trazodone- (SMD 2.1 [− 0.9–5.2 95% CrI]) placebos to be the least effective placebos. Other placebos suggested to be more effective than amitriptyline- and trazodone-placebos (based on 95% CrIs excluding zero) were citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, and venlafaxine placebos. These NMA results were corroborated by the observation that the relative efficacy between drug and placebo was considerably larger for amitriptyline and trazodone than for instance mirtazapine, duloxetine, and venlafaxine, supported by a small and insignificant correlation between drug-efficacy and placebo-efficacy (r = − 0.202, p = 0.408). The present exploratory NMA indicates that distinguishable side effects of older drugs may unblind outcome-assessors thus resulting in overestimation of the average drug-placebo difference and underrating bias in placebo-arms, particularly for the older antidepressant drugs amitriptyline and trazodone. If confirmed in prospective studies, these findings suggest that efficacy rankings for antidepressants are susceptible to bias and should be considered unreliable or misleading. The analysis is limited by the focus on the single-comparison placebos (76%, i.e., placebos assessed in two-arm trials), since double-comparison placebos (25%, i.e., placebos assessed in three-arm trials) are hard to interpret and therefore not included in the present interpretation. Another limitation is the problem of multiplicity, which was only approximately accounted for in the Bayesian NMA by modelling treatment effects as exchangeable.

中文翻译：

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安慰剂在重度抑郁症短期抗抑郁试验中的疗效比较：安慰剂对照试验的二次荟萃分析。


在所谓的双盲抗抑郁药试验中，非盲结果评估者和患者的问题一再被强调为缺陷。例如，揭盲偏倚可能是由药物的明显副作用引起的。如果某种药物存在这种揭盲偏倚，那么可以预期该药物的安慰剂的疗效明显低于其他抗抑郁药。为了检验这一假设，本探索性分析进行了贝叶斯网络荟萃分析 (NMA)，比较了 Cipriani 等人提供的数据集中的安慰剂对照试验中 19 种不同安慰剂的功效。 （《柳叶刀》2018 年；391：1357-66）。主要结局是根据标准化均差 (SMD) 量表估计的疗效（连续），并定义为汉密尔顿抑郁量表 (HAMD-17) 的前后变化，该信息可在 N = 258 项试验中获得。比较安慰剂排名表明，米氮平-安慰剂 (SMD -2.0 [− 5.0–1.0 95% CrI]) 最多，阿米替林- (SMD 1.2 [− 1.6–3.9 95% CrI]) 和曲唑酮- (SMD 2.1 [− 0.9–5.2 95% CrI]) 安慰剂是效果最差的安慰剂。其他比阿米替林和曲唑酮安慰剂（基于 95% CrIs，不包括零）更有效的安慰剂有西酞普兰、去甲文拉法辛、度洛西汀、艾司西酞普兰、氟西汀、舍曲林和文拉法辛安慰剂。这些 NMA 结果得到了以下观察结果的证实：阿米替林和曲唑酮的药物和安慰剂之间的相对功效比米氮平、度洛西汀和文拉法辛等药物要大得多，这得到了药物功效和安慰剂功效之间较小且不显着的相关性的支持（r = − 0.202，p = 0.408）。 目前的探索性 NMA 表明，较旧药物的可区分副作用可能会使结果评估者不盲，从而导致高估药物与安慰剂的平均差异，并低估安慰剂组的偏差，特别是对于较旧的抗抑郁药物阿米替林和曲唑酮。如果在前瞻性研究中得到证实，这些发现表明抗抑郁药的疗效排名容易出现偏差，应被视为不可靠或具有误导性。该分析受到对单一比较安慰剂（76%，即在两臂试验中评估的安慰剂）的关注的限制，因为双重比较安慰剂（25%，即在三臂试验中评估的安慰剂）很难解释，因此不包括在本解释中。另一个限制是多重性问题，贝叶斯 NMA 中仅通过将治疗效果建模为可交换来大致解释这一问题。