Adolescent major depressive disorder (MDD) is a widespread mental health condition for which treatment outcomes remain suboptimal. For adolescents, it remains unclear whether fluoxetine monotherapy or fluoxetine combined with cognitive-behavioral therapy (CBT) is more effective as an initial treatment. Additionally, no research has compared augmentation versus switching strategies after initial fluoxetine failure. We conducted a multistep, multicenter, pragmatical clinical trial with a partially randomized design. In step 1, patients had the opportunity to choose treatment with fluoxetine monotherapy or combined fluoxetine and CBT treatment. In step 2, nonresponders were randomized to switch to sertraline, vortioxetine, or duloxetine, or to augment fluoxetine with aripiprazole, olanzapine, or lithium. The primary outcome was the response rate. Secondary outcomes included changes in depression, anxiety, global severity, sleep quality, and quality of life scores. Safety was assessed through mania, suicidality, and adverse events. No significant differences were observed between treatment strategies in terms of primary outcomes or adverse events. In exploratory analysis, olanzapine augmentation showed greater improvement in sleep quality compared to duloxetine switching, and similar result were found in post hoc comparisons. Aripiprazole augmentation aenhanced life of quality compared to duloxetine switching. Limitations include a small sample size and lack of control and blinding. In this study, fluoxetine combined with CBT showed no significant advantage over fluoxetine monotherapy. All strategies in step 2 were feasible and acceptable. Our findings supported the feasibility of th sequential treatment pathway for adolescent MDD and provided insights for future adequately powered trials. • This is the first sequential pragmatic clinical for adolescent major depressive disorder. • In Step 1, fluoxetine combined with CBT did not show a statistically significant advantage over fluoxetine monotherapy. • In Step 2, no significant differences were observed between the intervention strategies. • Augmentation therapy led to greater improvements in sleep quality compared to switching therapy.
He et al. (Sun,) studied this question.