DOI: 10.1002/alz.080199 ISSN: 1552-5260

Antidepressant exposure and long‐term dementia risk in a nationwide study on U.S. Veterans with major depressive disorder

Jaime Ramos Cejudo, June Corrigan, Chunlei Zheng, Kaitlin N. Swinnerton, Sean R Jacobson, Jennifer La, Rebecca A Betensky, Ricardo S Osorio, Sharon Madanes, Nunzio Pomara, Dan Iosifescu, Mary T Brophy, Nhan V Do, Nathanael R Fillmore
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Major depressive disorder (MDD) is associated with dementia risk. The use of antidepressants in MDD has been reported to influence long term risk of Alzheimer’s disease and related dementias (ADRD), but studies are conflicting.


We used inverse probability weighted Cox models with time‐varying covariates in a retrospective cohort study among Veterans with MDD within the US Veterans Affairs health‐care system from 1/1/2000 to 6/1/2022. We focused on patients receiving their first diagnosis of MDD at the age of 60 or above. Our outcome was incident ADRD and unrelated death was considered as a competing risk event. Exposed intervals were defined using prescription data. Models were weighted for the inverse probability of falling in each of the treatment arms (exposed or not) at the beginning of each treatment period based on demographic and clinical covariates updated with most recent information (1‐year prior). The cumulative effect of antidepressant exposure (No. days) was also studied.


A total of 24,964 patients with MDD were identified, of which 45% were on antidepressants (Table 1). Median treatment time was 4.10 years [2.56, 6.10]. No relationship was observed between the number of days on antidepressants and the risk of ADRD (Figure 1). No significant associations were seen for the effect of being exposed to antidepressants (any) vs unexposed (HR = 0.94, 95%; CI: 0.81‐1.09) or exposed to each antidepressant drug classes vs unexposed (SSRI HR = 0.93, 95%; CI: 0.79‐1.10; NDRI HR = 0.80, 95%; CI: 0.42‐1.54; SNRI HR = 0.87, 95%; CI: 0.54‐1.41). (Table II). In sensitivity analysis stratified by sex, a reduction in risk due to antidepressant exposure was suggested in female patients, however the number of cases was small (HR = 0.30, 95%; CI: 0.12‐0.81; P = 0.02)).


Our study conducted in a large population and after accounting for confounders shows that antidepressant exposure has no effect on ADRD risk. Our result suggesting an association in female patients should be interpreted with caution due to a small sample size and deserves further attention. Replication of results in an external population with a larger representation of female patients is needed for further validation

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