ArticlemedRxiv : the preprint server for health sciences2025
Testing the internal validity of the maintenance/discontinuation study design for antidepressant medications in depression using simulations.
Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
3 authors.
Funding
Abstract
Background: Evidence for longer-term use of antidepressant medications (ADM) in major depressive disorder (MDD) derives from maintenance/discontinuation (M/D) trials showing that approximately 20% of patients who remitted on ADMs relapse by 1 year when treatment is maintained vs. approximately 40% if ADMs are discontinued. This treatment effect is larger than that demonstrated in acute-phase trials and has been criticized as "too good to be true." The enrichment design of M/D trials has been proposed as one explanation for this larger effect size, but it is unclear whether enrichment design alone is a sufficient explanation, raising questions about the internal validity of M/D trials. Objective: To test whether the enrichment design of M/D trials is sufficient to account for the larger-than-expected effect of maintenance treatment. Methods: We simulated M/D trials by applying the study characteristics including the enrichment phase of 9 real M/D trials to depression trajectories derived from the STAR-D pragmatic trial and depression efficacy data derived from acute-phase trial and compared the resulting relapse rates by arm between the simulated data and real data. Results: The simulated ADM average treatment effect increased 1.7-fold after selection on remitters from the enrichment phase from 1.75 Hamilton Depression Rating Scale points in unselected participants to 2.91 HAM-D points in just the participants who pass the enrichment filter from phase 1 to phase 2. Simulated relapse rates and the relative risks between arms had excellent fit on the withheld post-randomization aggregated real trial data. Conclusions: Our simulations indicate that the enrichment design of M/D trials is sufficient to explain their larger effect sizes. These results support the internal validity of M/D studies in characterizing the benefits of ADM maintenance treatment.
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