Certainty of genuine treatment increases drug responses among intellectually disabled patients

Abstract

Objective: To determine the placebo component of treatment responses in patients with intellectual disability (ID).

Methods: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered.

Results: Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was g = 0.602 (p = 0.001). The effect of trial type was statistically significant (p = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID.

Conclusions: Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component.

Figure 1. Flow chart for the open-label drug trials included in the meta-analysis

Figure 2. Forest plot of treatment responses in open-label intellectual disability (ID) drug trials

A significant improvement from pre to post treatment was seen across all studies (p < 0.001). If studies included more than one outcome measure they were combined into one value. A random-effects model was used to calculate significance.

Figure 3. Drug response from pre to post treatment in drug-matched open-label and placebo-controlled trials

There was a significant difference between study effect sizes between drug-matched open-label (k = 12), placebo-controlled drug (k = 12), and placebo-controlled placebo (k = 12) treatment groups. The overall effect was assessed using a univariate analysis of variance and Sidak correction for multiple comparisons was applied to the pairwise comparisons. *Significant at p < 0.01; **significant at p < 0.05.