Background Summarizing evidence from clinical trials of patients with schizophrenia with predominant or prominent negative symptoms (NS), a prior meta-analysis reported a large placebo effect in negative symptoms (Cohen’s d = 2.909). Assuming that such an effect was clinically not plausible, we performed a critical re-assessment and an update of the previous results with newly available data from add-on and monotherapy studies. Study Design Random-effect meta/regression analysis of trials that focused on predominant or prominent NS; and adopted a double-blind, randomized, placebo-controlled design. The final pooled meta-analytic database, based on the available add-on and monotherapy studies combined, included 24 publications containing data on a total of 25 studies (21 add-on, 4 monotherapy). Study Results The pooled overall estimate for the placebo effect from the primary analysis for all included studies had a medium effect size, with a Cohen’s d value of 0.6444 (SE = 0.091). The estimates were similar in the add-on and monotherapy studies. Meta-regression indicated that the high placebo response was significantly associated with clinical trial characteristics, including the high ratio of patients assigned to active vs. placebo treatment and short trial duration. Conclusions These results represent a major downward correction for a current effect size estimate of the placebo response in the negative symptoms of schizophrenia. Our findings also pinpoint certain clinical trial characteristics, which may serve as important predictors of the placebo response. The knowledge of these factors can have important implications for drug development and trial design for new drugs for negative symptoms of schizophrenia.

中文翻译：

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精神分裂症阴性症状试验中的安慰剂反应：对证据的批判性重新评估

背景 总结来自具有显着或显着阴性症状 (NS) 的精神分裂症患者的临床试验证据，先前的荟萃分析报告了阴性症状的大安慰剂效应 (Cohen's d = 2.909)。假设这种效果在临床上不合理，我们进行了严格的重新评估，并使用来自附加和单一疗法研究的新数据更新了之前的结果。研究设计 侧重于主要或显着 NS 的试验的随机效应元/回归分析；并采用了双盲、随机、安慰剂对照设计。最终汇总的荟萃分析数据库基于可用的附加疗法和单一疗法研究的组合，包括 24 篇出版物，其中包含总共 25 项研究（21 项附加疗法，4 项单一疗法）的数据。研究结果 所有纳入研究的主要分析对安慰剂效应的综合总体估计具有中等效应量，Cohen's d 值为 0.6444 (SE = 0.091)。附加疗法和单一疗法研究的估计值相似。Meta 回归表明，高安慰剂反应与临床试验特征显着相关，包括分配到活性治疗与安慰剂治疗的患者比例高和试验持续时间短。结论 这些结果代表了对精神分裂症阴性症状中安慰剂反应的当前效应量估计值的重大向下修正。我们的研究结果还指出了某些临床试验特征，这些特征可以作为安慰剂反应的重要预测指标。