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

Summary Background Understanding patterns of relapse in patients who respond to antidepressant treatment can inform strategies for prevention of relapse. We aimed to identify distinct trajectories of depression severity, assess whether similar or different trajectory classes exist for patients who continued or discontinued active treatment, and test whether clinical predictors of trajectory class membership exist using pooled data from clinical trials. Methods We analysed individual patient data from four double-blind discontinuation clinical trials of duloxetine or fluoxetine versus placebo in major depression from before 2012 (n=1462). We modelled trajectories of relapse up to 26 weeks during double-blind treatment. Trajectories of depression severity, as measured by the Hamilton Depression Rating Scale score, were identified in the entire sample, and separately in groups in which antidepressants had been continued or discontinued, using growth mixture models. Predictors of trajectory class membership were assessed with weighted logistic regression. 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 significantly lowered the odds of membership in the relapse trajectory (odds ratio 0·47, 95% CI 0·37–0·61), whereas female sex (1·56, 1·23–2·06), shorter length of time with clinical response by 1 week (1·10, 1·06–1·15), and higher Clinical Global Impression score at baseline (1·28, 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% (33% vs 46%). 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 modest protection against relapse. These data highlight the need to incorporate treatment strategies that prevent relapse as part of the treatment of depression. Funding National Institutes of Health, the US Department of Veterans Affairs Alcohol Research Center, and National Center for Post-Traumatic Stress Disorder.