Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study

J Am Geriatr Soc. 2018 Oct;66(10):1948-1955. doi: 10.1111/jgs.15508. Epub 2018 Sep 17.


Objectives: To determine whether antidepressant use is associated with dementia risk.

Design: Prospective cohort study.

Setting: Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system.

Participants: Community-dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059).

Measurements: Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10-year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models.

Results: During a mean follow-up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0-90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18-2.42; 91-365 TSDDs: HR=1.40, 95% CI=0.88-2.23; 366-1095 TSDDs: HR=2.13, 95% CI=1.32-3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82-2.46).

Conclusion: Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations.

Keywords: antidepressants; dementia; depression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antidepressive Agents / adverse effects*
  • Cholinergic Antagonists / adverse effects*
  • Dementia / chemically induced*
  • Dementia / epidemiology
  • Depression / drug therapy*
  • Female
  • Humans
  • Independent Living
  • Male
  • Paroxetine / adverse effects
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Factors
  • Serotonin Uptake Inhibitors / adverse effects*
  • Time Factors
  • Washington / epidemiology


  • Antidepressive Agents
  • Cholinergic Antagonists
  • Serotonin Uptake Inhibitors
  • Paroxetine