Introduction: Selective serotonin reuptake inhibitors (SSRIs) are first-line, evidence-based treatment for adolescent major depressive disorder (MDD). In randomized controlled trials, over 40% of adolescents have a suboptimal response to SSRIs. In clinical practice, this leads to discontinuation, switching to another antidepressant, or augmentation with another psychotropic medication. Real-world evidence of subsequent antidepressant treatment strategies is limited.

Objectives: This research aimed to estimate the proportion of adolescents who experience an antidepressant regimen change following an initial SSRI monotherapy, assess adherence trajectories following a switch or augmentation, and evaluate the outcomes of antidepressant augmentation with an atypical antipsychotic versus bupropion.

Methods: Two population-based cohorts were identified from 2010 through 2022 using the IQVIA PharMetrics® Plus for Academics. The first cohort was adolescents with MDD who initiated an SSRI, continued treatment for at least eight weeks and did not have a regimen change in the first 12 weeks of treatment. The second cohort was children and adolescents with MDD who augmented their SSRI with an atypical antipsychotic or bupropion. A time-to-event analysis evaluated the first regimen change in the 14 weeks following the initial 12 weeks. Among adolescents who switched or augmented their antidepressants, adherence was measured over six months using bi-weekly measures of the proportion of days covered. Group-based trajectory models identified adherence trajectory subgroups. The comparative outcome of antidepressant augmentation with an atypical antipsychotic versus bupropion was a composite measure of hospitalization, emergency department visits, or suicide. Hazard ratios were estimated using Cox proportional hazards models with propensity score weighting to adjust for baseline measured covariates.

Results: Among 15,678 adolescents, 38.8% discontinued, 6.0% switched to another antidepressant, and 2.9% augmented their SSRI. Of adolescents who switched or augmented the initial SSRI (n=1,402), 48.3% and 24.3%, respectively, adhered to the regimen. Children and adolescents with an atypical antipsychotic augmentation had a significantly higher risk of the composite outcome compared to those with bupropion augmentation.

Conclusion: The majority of adolescents who initiate SSRI monotherapy discontinue, switch, or augment their initial regimen. Over half who switched or augmented their antidepressant did not adhere to the treatment. Bupropion augmentation had better outcomes than atypical antipsychotic augmentation.