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

Abstract

Background 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. Methods 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. Results 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. 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 two decades and is grater in the US than the rest of the world.

Nocebo Response in Attention Deficit Hyperactivity Disorder: Meta-Analysis and Meta-Regression of 105 Randomized Clinical Trials

“…In more recent studies, the growing confidence in pharmacological treatment benefit-risks over time could reduce harm assumptions, thereby diminishing nocebo response. This result complements those that showed an increase of placebo response over time in ADHD (Castells, Saez et al, 2021; Khan, Fahl Mar, & Brown, 2017), schizophrenia (Chen et al, 2010; Kemp et al, 2010), and bipolar mania (Sysko & Walsh, 2007; Yildiz et al, 2011). Nevertheless, it must be stressed that this association was not statistically significant in the main analysis ( p =.050).…”

“…To express its considerations, this instrument describes the risk of bias of each entry using tags of “low”—all domains have “low risk”—, “high”—at least one domain was “high risk”—or “unclear” risk. Minerva Database has demonstrated its utility in previous studies (Castells, Baykova et al, 2020; Castells, Ramon et al, 2020; Castells, Saez et al, 2021).…”

Predictors of placebo response in three large clinical trials of the V1a receptor antagonist balovaptan in autism spectrum disorder

“…Though the presence of psychiatric comorbidity could simply be an indicator of higher overall impairment, it is notable that placebo response has been observed in both depression and ADHD randomized controlled trials. Importantly, depression is an episodic disorder more prone to spontaneous remissions [ 39 , 40 ]. Depression and ADHD symptoms may also contribute to impairment in adaptive function, and improvements in these co-occurring conditions would be expected to manifest as better Vineland-II 2DC performance.…”

APPRAISE-RS: Automated, updated, participatory, and personalized treatment recommender systems based on GRADE methodology

“…At the time of the simulation study, the Minerva database had stored data from 348 RCTs (from 1987 to 2021) that include administrative information, study methods, patient characteristics, study results, and risk of bias. The usefulness of the Minerva database has been shown in previous studies [42] .…”