SSRI versus SNRI Initiation and Incident Bipolar Disorder in Tertiary Psychiatric Care: An Active-Comparator Cohort Study from the United Arab Emirates

Abstract Background: Whether antidepressant class influences the risk of subsequent bipolar disorder diagnosis remains clinically relevant, though direct active-comparator studies are scarce. We compared incident bipolar disorder risk between selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) initiators using tiered outcome definitions. Methods: We conducted a retrospective cohort study from 2018 to 2025 using a 90-day landmark design at a tertiary psychiatric hospital in the United Arab Emirates. Adults aged 18–60 years initiating SSRIs or SNRIs for depressive disorders were followed for incident bipolar disorder. The primary outcome was anchored bipolar disorder, defined as two or more diagnoses at least 30 days apart plus initiation of a mood stabiliser. Secondary outcomes included confirmed bipolar disorder (two or more diagnoses) and any bipolar diagnosis. Cox proportional hazards models adjusted for age, sex, schizophrenia spectrum disorder, substance use disorder, and prior psychotropic use. Exploratory analyses examined individual antidepressants. Results: Among 1,095 antidepressant initiators (818 SSRI; 277 SNRI), 72 (6.6%) developed anchored bipolar disorder over 1,610.6 person-years. SNRI versus SSRI initiation was not associated with increased risk of anchored bipolar disorder (adjusted hazard ratio [aHR] 1.07, 95% CI 0.63–1.84, p = 0.80). Findings were consistent across secondary outcomes (confirmed: aHR 1.24, 95% CI 0.96–1.60; any diagnosis: aHR 1.12, 95% CI 0.92–1.37) and drug-level comparisons, including venlafaxine versus pooled SSRIs (aHR 1.27, 95% CI 0.62–2.60). Event rates varied seven-fold by outcome stringency (6.6% to 46.3%). Conclusions: Antidepressant class was not associated with incident bipolar disorder using stringent outcome definitions. The marked variation in event rates across outcome tiers suggests that high conversion rates reported in prior literature may partly reflect diagnostic revision rather than pharmacological effects.