Trajectories of relapse in randomized placebo-controlled trials of treatment discontinuation in major depressive disorder: an individual patient level data meta-analysis

BACKGROUND: Understanding patterns of relapse in antidepressant treatment responders can inform strategies for preventing relapse. METHODS: We re-analyzed individual-patient data from four double-blind discontinuation clinical trials of duloxetine or fluoxetine vs. placebo in major depression (N=1462). Trajectories of depression severity (Hamilton Depression Rating Scale scores) were identified in the entire sample, and separately in arms where antidepressant had been continued or discontinued. Predictors of trajectory membership were assessed. FINDINGS: We identified similar “relapse” trajectories and two trajectories of stable depression scores in the normal range on active medication and on placebo. Active treatment (OR=0.47, 95% CI: (0.37, 0.61)) significantly lowered the odds of membership in the “relapse” trajectory whereas female sex (OR=1.56, 95% CI: (1.23, 2.06)), shorter length of time with clinical response (OR=1.10, 95% CI: (1.06, 1.15)) and higher Clinical Global Impressions score at baseline (OR=1.28, 95% CI: (1.01, 1.62)) increased the odds. Overall, the protective effect of antidepressant medication relative to placebo on the risk of being classified as a relapser was about 13% (46% vs. 33%). INTERPRETATION: The existence of similar relapse trajectories on active medication and on placebo suggests that there is no specific relapse signature associated with antidepressant discontinuation. Furthermore, continued treatment offers only a modest protection against relapse. These data highlight the need for incorporating treatment strategies that prevent relapse as part of the treatment of depression.