Meta-analysis of trials comparing antidepressants with active placebos

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Abstract
Background: Unblinding effects may-introduce bias into clinical trials. The use of active placebos to mimic side-effects of medication may therefore produce more rigorous evidence on the efficacy of antidepressants.Method: Trials comparing antidepressants with active placebos were located. A standard measure of effect was calculated for each trial and weighted pooled estimates obtained. Heterogeneity was examined and sensitivity analyses performed. A subgroup analysis of in-patient and out-patient trials was conducted.Results: Only two of the nine studies examined produced effect sizes which showed a consistent significant difference in favour of the active drug. Combining all studies produced pooled effect size estimates of between 0.41 (0.27–0.56) and 0.46 (0.31–0.60) with high heterogeneity due to one strongly positive trial. Sensitivity analyses excluding this and one other trial reduced the pooled effect to between 0.21 (0.03–0.38) and 0.27 (0.10–0.45).Conclusions: Meta-analysis is very sensitive to decisions about exclusions. Previous general meta-analyses have found combined effect sizes in the range 0.4–0.8. The more conservative estimates produced here suggest that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos.