Evaluation of a Second-line Treatment in Female Adolescents With SSRI-nonresponsive Major Depression: A Real-world Data Analysis on Bupropion Versus Duloxetine

Objective: A significant number of individuals with major depressive disorder (MDD) do not respond adequately to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Approximately 30% of patients fall into this category and often require a switch to a second-line antidepressant. These patients frequently experience more severe and persistent symptoms, along with an elevated risk of suicide. Switching to an alternative monotherapy such as duloxetine or bupropion is a common strategy in cases with inadequate response to SSRIs. Bupropion, in use for over 2 decades, works by inhibiting the reuptake of dopamine and norepinephrine and is sometimes used alongside SSRIs. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has demonstrated strong efficacy, safety, and tolerability in the treatment of MDD. However, antidepressants can occasionally increase suicidal thoughts or behaviors, particularly among adolescents. Therefore, the goal of this study was to compare not only the therapeutic outcomes of duloxetine and bupropion, but also the rates of any suicide attempts in female adolescents while taking these medications. Methods: This retrospective study analyzed medical records of 990 female adolescents diagnosed with MDD who were treated with either duloxetine (120 mg/d; n=464) or bupropion (300 mg/d; n=526). Patients were selected according to strict inclusion and exclusion criteria and followed for up to 24 weeks. Clinical data were extracted from charts at time points corresponding approximately to weeks 4, 8, 12, 16, 20, and 24. Depression severity and treatment outcomes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Goal Attainment Scaling for Depression (GAS-D). The sensitivity of MADRS to symptom changes was also evaluated. Suicide attempts were identified using ICD-9 codes (E950 to E959), clinical notes, and related medication history involving SSRIs and serotonin-norepinephrine reuptake inhibitors. Results: The findings from the study revealed that bupropion led to a greater reduction in depressive symptoms compared with duloxetine. In addition, the incidence of suicide attempts was higher in the duloxetine group than in the bupropion group. Originality: This study is distinct in its focus on female adolescents with MDD, applying a triple-blind design and utilizing both standardized (MADRS) and personalized (GAS-D) outcome measures. By including an analysis of suicide attempt rates, it offers important clinical insights into the comparative effectiveness and safety of bupropion and duloxetine in a particularly vulnerable population.