Comparative effectiveness of antidepressant augmentation regimens in children and adolescents with major depressive disorder
AI Summary
Active-comparator new-user cohort of 4,089 children and adolescents (ages 8 to 18) with MDD who augmented SSRI with AAP or bupropion, 2010–2022.
AAP augmentation associated with higher risk versus bupropion for composite outcome (HR 1.69, 95% CI 1.43–1.99) and individual outcomes.
AAPs did not reduce hospitalisation or suicide-related outcomes compared with bupropion; findings robust in sensitivity analyses; further research required.
J Affect Disord. 2026 Jun 7:122057. doi: 10.1016/j.jad.2026.122057. Online ahead of print.
ABSTRACT
BACKGROUND: Limited evidence guides augmentation strategies after selective serotonin reuptake inhibitor (SSRI) in pediatric major depressive disorder (MDD).
METHODS: We conducted an active-comparator new-user cohort study to evaluate depression-related outcomes among children and adolescents with MDD receiving SSRI augmentation. Using a 25% random sample of the US IQVIA PharMetrics® Plus Closed Health Plan claims from January 2010 to October 2022, we identified individuals aged 8 to 18 with MDD who initiated an atypical antipsychotic (AAP) or bupropion following ≥4 weeks of SSRI and ≥ 7 days of concomitant use with the SSRI. The primary outcome was time to a composite of depression-related hospitalization, emergency department (ED) visit, or a suicide-related outcome. Secondary analyses evaluated each event separately. Propensity scores with inverse-probability-of-treatment-weighting adjusted for baseline covariates, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Sensitivity analyses were conducted to assess the robustness of our findings.
RESULTS: The cohort included 4089 individuals (mean age 15.6 years [SD 2.1]; 65.1% female). Compared with bupropion, AAP augmentation was associated with a higher risk of the composite outcome (HR = 1.69; 95% CI:1.43-1.99), hospitalization (HR = 1.86; 95% CI: 1.52-2.26), ED visits (HR = 1.50; 95% CI: 1.15-2.90), and suicide-related outcomes (HR = 1.88; 95% CI: 1.07-3.33). Sensitivity analyses were consistent with primary findings.
CONCLUSIONS: Augmentation strategies for children and adolescents prescribed an AAP do not reduce the risk of hospitalization or suicide-related outcomes relative to bupropion. Further research is needed to guide evidence-based augmentation strategies.
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