If such unblinding occurs, does it meaningfully affect trial results? A meta-analysis of antidepressant trials using active placebos, such as those with antihistaminergic or anticholinergic effects, suggested smaller effect sizes than those observed in the presumably less blinded trials with inert placebo (
+6). Estimating the potential impact in published studies is difficult, but certain findings when results are stratified by potentially unblinding adverse effects raise concern. In a trial of quetiapine in bipolar depression (
+7), for example, when investigators examined only the groups reporting sedation, mean change in the Montgomery-Åsberg Depression Rating Scale total score at week 8 was —18.8 in the quetiapine groups (N=195) and —18.9 in the placebo group (N=24). Conversely, when the subset of participants
without sedation were examined, the mean change in the Montgomery-Åsberg Depression Rating Scale total score was —19.3 and —11.7 in the quetiapine and placebo groups, respectively. While only a small subset of patients were in the placebo/sedation arm, the disparity in placebo response might suggest that clinical raters were attempting to "guess" at treatment assignment.