Background High placebo response in attention deficit hyperactivity disorder (ADHD) can reduce medication–placebo differences, jeopardizing the development of new medicines. This research aims to (1) determine placebo response in ADHD, (2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and (3) determine the covariates associated with placebo response. Methods A systematic review with meta-analysis of randomized, placebo-controlled clinical trial investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design–, intervention–, and patient–related covariates in predicting placebo response was studied by means of meta-regression and MetaForest. Results Ninety-four studies including 6614 patients randomized to placebo were analyzed. Overall, placebo response was −8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R2 = 0.0012 and root mean squared error = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response among ADHD patients increased by 63% between 2001 and 2020 and was larger in the United States than in other regions of the world. Conclusions Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last 2 decades and is greater in the United States than the rest of the world.

中文翻译：

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注意缺陷多动障碍中的安慰剂反应及其预测因子：Meta 回归和 MetaForest 的 Meta 分析和比较

背景注意力缺陷多动障碍 (ADHD) 的高安慰剂反应可以减少药物-安慰剂的差异，从而危及新药的开发。本研究旨在 (1) 确定 ADHD 中的安慰剂反应，(2) 比较元回归和 MetaForest 在预测安慰剂反应方面的准确性，以及 (3) 确定与安慰剂反应相关的协变量。方法 对研究 ADHD 药物干预的随机、安慰剂对照临床试验进行系统评价和荟萃分析。安慰剂反应被定义为根据 18 项、临床医生评定、基于 DSM 的评定量表评估的 ADHD 症状严重程度相对于基线的变化。研究设计的效果——、干预——、通过元回归和 MetaForest 研究了预测安慰剂反应的患者相关协变量。结果 分析了 94 项研究，包括随机分配至安慰剂的 6614 名患者。总体而言，安慰剂反应为 -8.9 分，表示 ADHD 症状的严重程度降低了 23.1%。元回归的交叉验证准确度指标为 R2 = 0.0012，元回归的均方根误差 = 3.3219，MetaForest 为 0.0382 和 3.2599。ADHD 患者的安慰剂反应在 2001 年至 2020 年期间增加了 63%，并且在美国比世界其他地区更大。结论 在 ADHD 患者中发现了强烈的安慰剂反应。元回归和 MetaForest 在预测安慰剂反应方面表现不佳。