THE IMPACT OF ESKETAMINE ON ALZHEIMER’S DISEASE IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT AND MAJOR DEPRESSIVE DISORDER: A TARGET TRIAL EMULATION
Author(s)
Eszter Garami, MPharm, Jeff Jianfei Guo, BPharm, PhD, Xiaomo (Shawn) Xiong, MS, PhD;
James L Winkle College of Pharmacy, University of Cincinnati, Division of Pharmacy Practice and Administrative Sciences, Cincinnati, OH, USA
James L Winkle College of Pharmacy, University of Cincinnati, Division of Pharmacy Practice and Administrative Sciences, Cincinnati, OH, USA
OBJECTIVES: Patients with mild cognitive impairment (MCI) and major depressive disorder (MDD) have elevated risk of Alzheimer’s disease (AD), yet evidence on whether antidepressant treatment strategies influence progression is limited. Esketamine, a recently approved N-methyl-D-aspartate (NMDA) receptor antagonist, has been hypothesized to be neuroprotective. This study evaluated the association between esketamine and AD risk among these patients.
METHODS: A retrospective cohort study using TriNetX database (2019-2025) was conducted to emulate a target trial among patients with MCI and MDD. The index date was defined as the first MCI diagnosis, and esketamine exposure was defined as initiation on or after index. Patients receiving oral antidepressants with or without esketamine were compared, with AD as the primary outcome. Baseline characteristics, including demographics, comorbidities, and concomitant medications, were identified within one year before index. All study variables were identified using standardized ICD, NDC, and RxNorm codes. Propensity score matching was used to balance baseline characteristics. Kaplan-Meier curves estimated time to AD or censoring, and Cox proportional hazards regression controlled residual confounding.
RESULTS: After matching, the cohort included 1,299 patients (433 with esketamine and 866 without esketamine). During follow-up, AD occurred in 83 patients, including 11 (2.54%) in the esketamine group and 72 (8.31%) among the unexposed. KM analysis demonstrated a significantly lower cumulative AD incidence with esketamine (p<0.001). In the Cox model, esketamine was associated with a significantly lower risk of progression to AD (hazard ratio [HR]: 0.16, 95% CI: 0.06-0.46, p<0.001). In addition, serotonin-norepinephrine reuptake inhibitor use was associated with increased AD risk (HR: 3.21, 95% CI: 1.09-9.44, p=0.034), whereas other antidepressants were not significantly associated.
CONCLUSIONS: In this target trial emulation, esketamine exposure after MCI was associated with statistically significant lower risk of progression to AD. This finding suggests a potential neuroprotective role and clinical relevance in treatment selection, warranting further prospective studies.
METHODS: A retrospective cohort study using TriNetX database (2019-2025) was conducted to emulate a target trial among patients with MCI and MDD. The index date was defined as the first MCI diagnosis, and esketamine exposure was defined as initiation on or after index. Patients receiving oral antidepressants with or without esketamine were compared, with AD as the primary outcome. Baseline characteristics, including demographics, comorbidities, and concomitant medications, were identified within one year before index. All study variables were identified using standardized ICD, NDC, and RxNorm codes. Propensity score matching was used to balance baseline characteristics. Kaplan-Meier curves estimated time to AD or censoring, and Cox proportional hazards regression controlled residual confounding.
RESULTS: After matching, the cohort included 1,299 patients (433 with esketamine and 866 without esketamine). During follow-up, AD occurred in 83 patients, including 11 (2.54%) in the esketamine group and 72 (8.31%) among the unexposed. KM analysis demonstrated a significantly lower cumulative AD incidence with esketamine (p<0.001). In the Cox model, esketamine was associated with a significantly lower risk of progression to AD (hazard ratio [HR]: 0.16, 95% CI: 0.06-0.46, p<0.001). In addition, serotonin-norepinephrine reuptake inhibitor use was associated with increased AD risk (HR: 3.21, 95% CI: 1.09-9.44, p=0.034), whereas other antidepressants were not significantly associated.
CONCLUSIONS: In this target trial emulation, esketamine exposure after MCI was associated with statistically significant lower risk of progression to AD. This finding suggests a potential neuroprotective role and clinical relevance in treatment selection, warranting further prospective studies.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
PT34
Topic
Real World Data & Information Systems
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, SDC: Neurological Disorders