Risk of suicide attempts and intentional self-harm on alprazolam

Background: From 2000 -2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend. Methods: An exposure -only within -subject time -to -event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2 -years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019. Findings: Alprazolam was associated with over a doubling of risk of suicide attempts (HR =2.21, 95 % CI =2.06,2.38). A duration -response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR =1.05, 95 % CI =1.04,1.07). Parallel analyses with long -acting (diazepam) and short -acting (lorazepam), found similar associations (diazepam HR =2.87, 95 % CI =2.56,3.21; lorazepam HR =1.83, 95 % CI =1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR =1.25, 95 % CI =1.13,1.38), and no increased risk in patients with an attempt history (HR =1.05, 95 % CI =0.70,1.59). Interpretation: This study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide.