Antidepressant initiation and the risk of treatment-emergent mania in children and adolescents with depression

Background: Whether starting antidepressants (ADs) precipitates treatment-emergent mania (TEM) in young people with major depressive disorder (MDD) is still debated. A recent nationwide cohort study found no short-term risk, but its transferability to more diverse settings is unknown. Methods: Using the TriNetX global electronic-health-record network, we emulated a target trial in children and adolescents aged 6–17 years with a first MDD diagnosis (2016–2024). Patients who initiated an AD within 3 months formed the exposed cohort, and those who did not served as controls. After 1:1 propensity-score matching, 105,728 participants (52,864 per group) were followed for 3 months. The primary outcome was a composite of new mania/bipolar diagnosis or lithium initiation. Results: The exposed group had a significantly higher risk of the primary composite outcome compared to the unexposed group (45 vs. 27 events; Hazard ratio = 1.64, 95% confidence interval, 1.01–2.63, p = 0.041). However, it lost statistical significance when disaggregating the composite outcome, in landmark time-split analyses, and when restricting the cohort to patients with a prior history of healthcare encounters. Conclusion: In a large, multinational real-world cohort, AD initiation was associated with a non-robust increase in short-term TEM risk. The observed association appeared susceptible to unmeasured confounding factors. These results underscore the importance of careful assessment and monitoring rather than indiscriminate AD use or avoidance in this population.