Antidepressant‐Associated Risk of Manic and Mixed Episode Hospitalization in Bipolar I Disorder: A 10‐Year Population‐Based Cohort Study

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.