Comparative Mortality Risk of Aripiprazole, Olanzapine, Quetiapine, and Risperidone in Alzheimer's Disease: A Real‑World Retrospective Cohort Study with Treatment Effect Heterogeneity Analysis.

BACKGROUND

Second-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimer's disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited. In this study, we aim to compare all-cause mortality among patients with AD treated with one of the commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning.

METHODS

We conducted a retrospective cohort study using deidentified electronic health records from the Truveta platform. Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using a new-user design. Exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation were used to identify subgroups with heterogeneous treatment effects.

RESULTS

Among 17,004 patients with AD, aripiprazole was associated with significantly lower mortality than olanzapine (adjusted hazard ratio [AHR] 0.667, 95% confidence interval [CI] 0.472-0.941) and quetiapine (AHR 0.677, 95% CI 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (AHR 0.833, 95% CI 0.702-0.990) and risperidone (AHR 0.830, 95% CI 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes mellitus (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (AHR = 0.604 versus the combined group of quetiapine and risperidone, p = 0.002).

CONCLUSIONS

Mortality risks vary substantially across SGAs in patients with AD with single-medication usage. Aripiprazole and quetiapine were associated with lower mortality compared with olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.