Association of atypical antipsychotic use with mortality risk in patients with behavioural and psychological symptoms of dementia

Atypical antipsychotics (AAPs) are widely used to treat behavioral and psychological symptoms of dementia (BPSD). The mortality risk posed by AAP treatment remains unclear. This global, population-based, retrospective cohort study compared all-cause mortality risk between patients with dementia prescribed AAPs and those prescribed nonpharmacological interventions instead of AAPs. Propensity score matching was performed to optimize comparability. Participants were enrolled between 2015 and 2024 by using the Global Collaborative Network of the TriNetX platform. The primary outcome was the rate of all-cause mortality from initial AAP use until death or June 30, 2025, using the Intent-to-Treat principle to define exposure status and Kaplan–Meier analyses. 72 805 patients with dementia prescribed AAPs were included in an AAP group, and 3645 patients treated with concomitant nonpharmacological interventions instead of AAPs were included in a control group. After propensity score matching, AAP use was associated with a 59.0% increased risk of all-cause mortality compared with nonpharmacological interventions (HR = 1.590, 95% CI 1.422–1.777). Regarding the risk of specific AAPs, all-cause mortality HRs, in descending order, were as follows: 1.926 (95% CI 1.728–2.147) for risperidone, 1.787 (95% CI 1.598–2.000) for olanzapine, 1.520 (95% CI 1.363–1.694) for quetiapine, 1.230 (95% CI 1.067–1.418) for aripiprazole, and 1.157 (95% CI 0.705–1.900) for brexpiprazole. This study showed that AAP use is associated with a significantly increased risk of mortality in patients with dementia. These findings highlight the importance of cautious AAP use for BPSD and suggest that brexpiprazole has a more favorable safety profile.