Raising Placebo Efficacy in Antidepressant Trials Across Decades Explained by Small-Study Effects: A Meta-Reanalysis

Abstract

Background: Recent meta-analyses reported placebo response rate in antidepressant trials to be stable since the 1970s. These meta-analyses however were limited in considering only linear time trends, assessed trial-level covariates based on single-model hypothesis testing only, and did not adjust for small-study effects (SSE), a well-known but not yet formally assessed bias in antidepressant trials.

Methods: This secondary meta-analysis extends previous work by modeling nonlinear time trends, assessing the relative importance of trial-level covariates using a multimodel approach, and rigorously adjusting for SSE. Outcomes were placebo efficacy (continuous), based on the Hamilton Depression Scale, and placebo response rate.

Results: Results suggested that any nonlinear time trends in both placebo efficacy (continuous) and response rate were best explained by SSE. Adjusting for SSE revealed a significant gradual increase in placebo efficacy (continuous) from 1979 to 2014. A similar observation was made for placebo response rate, but did not reach significance due higher susceptibility to SSE. By contrast, trial-level covariates alone were found to be insufficient in explaining time trends.

Conclusion: The present findings contribute to the ongoing debate on antidepressant placebo outcomes and highlight the need to adjust for bias introduced by SSE. The results are of clinical relevance because SSE may affect the evaluation of success or failure in antidepressant trials.

Keywords: antidepressants; meta-analysis; placebo; small-study effects; time trend.

Figure 1

Efficacy (continuous). Meta-regression plot illustrating the effect of study year on placebo efficacy (continuous) for the model adjusted for year only and the multimodel average considering both main and interaction effects, before and after accounting for small-study effects (SSE). Values larger on the log-transformed change score scale indicate increase in efficacy (continuous). Circle size is proportional to study size. Circle color is proportional to the power of individual studies (100% high power [white], 100-80% adequate power [light gray], <80% low power [dark gray]). Slopes are illustrated at the means of all covariates.

Figure 2

Response rate. Meta-regression plot illustrating the effect of study year on placebo response rate. Shown are the model adjusted for year only and the multimodel average considering both main and interaction effects, before and after accounting for small-study effects (SSE). Values smaller on the log-transformed proportion scale indicate increase in response rate. Circle size is proportional to study size. Circle color is proportional to the power of individual studies (100% high power [white], 100-80% adequate power [light gray], <80% low power [dark gray]). Slopes are illustrated at the means of all covariates.