Emulating a Target Trial of Dynamic Treatment Strategies for Major Depressive Disorder Using Data From the STAR∗D Randomized Trial

Abstract

Background: Clinical guidelines recommend adding a second drug for patients with major depressive disorder who have a partial response and switching antidepressants for those who show no response or intolerance. This guidelines-based strategy was compared with other strategies for the management of unresponsive depression.

Methods: A total of 1436 individuals experiencing treatment failure with citalopram and still requiring antidepressant therapy were identified in the STAR∗D (Sequenced Treatment Alternatives to Relieve Depression) trial. A (hypothetical) target trial was then designed and emulated. The following strategies for decision making were compared: sequential monotherapy, sequential dual non-selective serotonin reuptake inhibitor therapy (SD), and a guidelines-based strategy. The primary outcome was symptomatic remission defined as a Hamilton Depression Rating Scale score ≤7 or 2 consecutive scores ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated. Secondary outcomes were serious events (hospitalizations, suicide, and mortality). Inverse probability weighting was used to control for possible confounding.

Results: A total of 971 patients were eligible for our emulation. Patients initiating SD had the lowest levels of depression at baseline. The estimated 9-month probability of remission was 43.5% for the sequential monotherapy group, 47.6% for the SD group, and 53.2% for the guidelines-based strategy group. Compared with the sequential monotherapy group, the difference in 9-month probability of remission was -4.2% (95% CI, -15.6 to 4.6) for the SD group and -9.7% (-19.3 to 1.9) for the guidelines-based strategy group. The 9-month relative risks of remission were 1.09 (0.90 to 1.38) and 1.22 (0.96 to 1.46), respectively. Results were consistent across sensitivity analyses. The 9-month relative risks of serious events were 0.77 (0.38 to 1.40) and 0.62 (0.33 to 1.00), respectively.

Conclusions: Using the guidelines-based strategy was associated with an increased probability of remission and a lower risk of serious adverse events. The potential implications are substantial given the large number of patients experiencing treatment failure to antidepressants.

Keywords: Antidepressant-resistant depression; Antidepressants; Epidemiology; Major depressive disorder; Methodology.