Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA

Abstract

Background: Relapse prevention trials build the scientific foundation for recommendation of antidepressant continuation and maintenance therapy. However, the validity of the evidence is disputed and may be biased due to withdrawal confounding. Methods: We analysed survival curves from all antidepressant relapse prevention trials submitted to the United States (US) Food and Drug Administration (FDA) between 1987 and 2012 for 13 approved drugs. The main outcome was the percent of the drug effect (placebo-antidepressant difference in relapse events) at any week of the maintenance phase in relation to the total drug effect at the endpoint of the randomised maintenance phase. Results: Altogether, 14 studies with a mean observation period of 38.9 weeks (Kaplan–Meier estimators) were analysed. At week 3, a mean of 20.6% [95% confidence interval (CI) = 10.9–30.3%] of the total drug effect was achieved. At weeks 6 and 12, the corresponding figures were 50.3% (37.3–63.3%) and 69.0% (55.1–82.8%). No further antidepressant–placebo separation was observed as of week 24 [101.0% of total drug effect (94.6–107.3%)]. This means that censoring relapse events that occurred in the first 3, 6, 12 and 24 weeks would reduce the total drug effect at study endpoint by 20.6%, 50.3%, 69.0% and 101.0%, respectively. Assuming antidepressants had a constant prophylactic effect over 38.9 weeks, we further showed that, around week 6, the antidepressant–placebo separation was about three times larger than expected. Conclusion: The placebo–antidepressant separation was disproportionally large between weeks 3 and 6 of the randomised maintenance phase. The benefits of continuing antidepressants relative to abrupt/rapid discontinuation declined sharply after week 6. This indicates an excess of relapse events in the placebo arms during the early maintenance phase that may be due to withdrawal reactions caused by abrupt/rapid discontinuation of active treatment. If these early relapse events are due to a direct pharmacological effect, then antidepressants’ true prophylactic long-term effects are substantially overestimated.