Placebo Response and Its Predictors in Attention Deficit Hyperactivity Disorder: A Meta-Analysis and Comparison of Meta-Regression and MetaForest

Abstract

High placebo response in 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. A systematic review with meta-analysis (SRMA) of RPCCTs 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. Ninety-four studies including 6,614 patients randomized to placebo were analysed. 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 R 2 = 0.0012 and RMSE = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response amongst ADHD patients increased by 63% between 2001 and 2020 and was larger in the US than in other regions of the world. 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 two decades and is grater in the US than the rest of the world.