Testing the internal validity of the maintenance/discontinuation study design for antidepressant medications in...

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.

To test whether the enrichment design of M/D trials is sufficient to account for the larger-than-expected effect of maintenance treatment.

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.

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.

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.