ABSTRACT Introduction Antidepressant (AD) use in bipolar I disorder (BD‐I) remains controversial due to concerns about inducing manic/mixed episodes. We examined hospitalization risk following AD initiation in BD‐I patients. Methods Using electronic health records from Catalonia (2010–2019), we conducted a retrospective cohort study of 7946 BD‐I patients. We performed 1:1 propensity score matching based on age, sex, comorbidity count, and baseline mood stabilizer and antipsychotic use, yielding 3973 AD users matched to 3973 controls (mean age 50.9 years, 47.3% female) with 12‐month follow‐up. AD users were categorized by treatment strategy: AD monotherapy, AD plus antipsychotic (AD + AP), AD plus mood stabilizer (AD + MS), and AD plus both (AD + MS + AP). We estimated hospitalization risk using Cox proportional hazards models adjusted for clinical and demographic factors. Results During follow‐up, 6.3% of patients experienced manic/mixed episode hospitalization. Overall, AD use was associated with increased risk (HR = 1.27, p = 0.008), with AD monotherapy showing highest risk (HR = 1.51, p < 0.001). Notably, AD + MS combinations showed no significant risk increase. All AD strategies were associated with substantially higher risk for mixed episodes compared to pure mania. Age significantly modified risk, with patients 18–35 years showing greatest vulnerability to AD monotherapy (HR = 2.36, p < 0.001). Conclusion In BD‐I, AD use increases manic/mixed episode hospitalization risk by approximately 30%, with differential effects across treatment strategies and patient subgroups. Combining ADs with mood stabilizers appears to mitigate this risk, while mixed episodes and younger age represent particularly high‐risk scenarios. These findings support guideline recommendations against AD monotherapy while suggesting opportunities for personalized treatment approaches in BD‐I.
Hidalgo‐Mazzei et al. (Mon,) studied this question.