Differential Risks of Dementia, Depression, and Injury Among Common α-Blockers, with Tamsulosin as the Reference Drug: A Real-World Cohort Study in Men with Lower Urinary Tract Symptoms

<b>Background/Objectives:</b> Although α-blockers are commonly used to treat lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH), their differential neuropsychiatric safety profiles remain underexplored. Some studies have suggested an increased risk of cognitive decline, mood disorders, and falls, but the results remain inconclusive. <b>Methods:</b> We conducted a large retrospective cohort study using the TriNetX global network, identifying over 264,000 men treated with a single α-blocker between 2005 and 2023. Patients were grouped by α-blocker type-tamsulosin, doxazosin, terazosin, alfuzosin, silodosin, or prazosin-and matched 1:1 using propensity scores to adjust for demographic, clinical, and psychosocial variables. The primary outcomes were new-onset dementia, depression, and unintentional injuries, assessed at 1-, 3-, and 10-year intervals. The median follow-up duration was approximately 5.5 years, ranging from 1824 to 2200 days across cohorts, indicating balanced observation periods among the six α-blocker groups. <b>Results:</b> Among the included patients, tamsulosin (<i>n</i> = 213,690) and prazosin (n = 1184) were associated with significantly higher risks of neurodegenerative, psychiatric, and injury-related outcomes. Alfuzosin (n = 10,138) exhibited the most favorable safety profile across all endpoints. The findings remained robust in sensitivity analyses, excluding patients with prior malignancy or other α-blocker exposure. <b>Conclusions:</b> Substantial differences in long-term neuropsychiatric safety exist among α-blockers. Given its favorable profile, alfuzosin may be the preferred agent in patients at elevated risk of cognitive or psychiatric disorders. These findings highlight the need for individualized α-blocker selection and long-term pharmacovigilance in BPH management.