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 2010-2019. 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 (0.5mg) 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.