Does differential drop-out explain the influence of study design on antidepressant response? A meta-analysis

Response to antidepressants is higher in active comparator relative to placebo-controlled clinical trials. Increased patient expectancy in comparator trials has been hypothesized to explain this finding, but previous analyses have not accounted for the increased drop-out observed in placebo-controlled trials.

A systematic literature review was conducted to identify published antidepressant clinical trials reporting data on intent-to-treat (ITT) as well as completer patient populations. The influence of participant drop-out on observed antidepressant response was investigated by comparing the ITT and completer data sets in separate multilevel meta-analyses of antidepressant response in placebo-controlled and comparator trials.

18 placebo-controlled and 18 active comparator studies were available for analysis. Using the intent-to-treat data, the odds of responding to medication in comparator trials were 1.9 times the odds in placebo-controlled trials (95% CI=1.3-2.7, p=0.001). The same pattern was obtained among study completers, in whom the odds of responding to antidepressant medication were 1.9 times higher in comparator as opposed to placebo-controlled study designs (95% CI=1.2-3.0, p=0.009).

Publication bias, the use of trial-level summary data, and unreported clinical or demographic differences between the ITT and completer patient populations may have influenced the study results.

Increased drop-out in placebo-controlled vs. active comparator studies of antidepressant medications does not appear to explain the difference in response rates between these study types. Rather, increased patient expectancy resulting from the certainty of receiving active medication in comparator trials may lead to improved response rates.