It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo-controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.

中文翻译：

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在没有副作用的情况下选择性5-羟色胺再摄取抑制剂的功效：西酞普兰和帕罗西汀在成人抑郁症中的大规模分析。

已经提出，在对照试验中抗抑郁药优于安慰剂仅仅是副作用的结果，该副作用通过使患者意识到他/她没有服用安慰剂而增强了对改善的期望。我们在患者水平的事后分析中探讨了这一假设，包括所有由行业支持，食品和药物管理局注册的西酞普兰或帕罗西汀在成人严重抑郁症中使用安慰剂对照的试验，该试验使用了汉密尔顿抑郁量表（HDRS），其中包括第6周症状评估（n = 15）。初步分析比较了在没有发生早期不良事件的情况下积极治疗的完成者与在安慰剂（有或没有不良事件）方面的完成者在减少HDRS抑郁情绪项方面的比较，发现接受积极治疗的患者的症状减轻更大，西酞普兰的作用大小为0.48，帕罗西汀的作用大小为0.33。在报告早期不良事件的积极治疗的受试者中，其表现也优于接受安慰剂的受试者，不良事件的严重程度无法预测其反应。例如，进行了几项敏感性分析，其中包括（i）使用所有HDRS-17项目总和的变化作为效果参数的分析，（ii）排除所有具有不良事件的受试者（也就是安慰剂组的受试者）和（iii）进行的敏感性分析。以意向治疗人群为基础的那些，均与主要分析一致。发现帕罗西汀和西酞普兰在不产生不良事件以及不良事件的严重程度与反应之间缺乏关联的情况下也明显优于安慰剂，