Antipsychotic Initiation Among Older Dementia Patients Using Cholinesterase Inhibitors: A National Retrospective Cohort Study

Drugs Aging. 2021 Jun;38(6):493-502. doi: 10.1007/s40266-021-00851-9. Epub 2021 Mar 25.


Background: Evidence regarding the initiation of antipsychotic medications across individual cholinesterase inhibitors (ChEIs) to manage the behavioral symptoms of dementia is lacking.

Objectives: This study compared the risk of initiation of antipsychotic medications among older adults with dementia treated with the ChEIs donepezil, rivastigmine, or galantamine.

Methods: This retrospective cohort study used multiyear (2013-2015) Medicare claims data involving Parts A, B, and D. The study sample included community-dwelling older adults (aged ≥ 65 years) with a diagnosis of dementia. The study identified new users of ChEIs and followed them for up to 180 days for antipsychotic initiation. The ChEIs included donepezil, rivastigmine, and galantamine, whereas antipsychotics included typical and atypical agents. Donepezil was used as the reference category as it is the most commonly used ChEI and only acts on acetylcholinesterase, whereas both rivastigmine and galantamine have dual mechanisms of action. Multivariable Cox proportional hazards regression compared the risk of and time to antipsychotic initiation among the three ChEIs, adjusting for other risk factors.

Results: The study cohort consisted of 178,441 older adults with dementia who were new users of ChEIs. A total of 23,433 (15.14%) donepezil users, 4114 (19.04%) rivastigmine users, and 324 (15.77%) galantamine users initiated antipsychotics. The mean time to antipsychotic initiation among patients who received antipsychotics was 109.29 ± 69.72 days for donepezil users, 96.70 ± 71.60 days for rivastigmine users, and 104.15 ± 72.53 days for galantamine users. The Cox regression analysis showed that rivastigmine (adjusted hazard ratio [aHR] = 1.27; 95% confidence interval [CI], 1.20-1.34) was significantly associated with antipsychotic initiation compared with donepezil, whereas no significant difference was observed between galantamine and donepezil (aHR = 0.98; 95% CI, 0.81-1.20).

Conclusion: The study found a 27% increased risk of antipsychotic initiation among users of rivastigmine compared with donepezil users. There was no difference between galantamine and donepezil for antipsychotic initiation. Although the limitations of the study should be considered, the results suggest that donepezil or galantamine may be more appropriate treatments for older patients with dementia, to minimize antipsychotic use.

MeSH terms

  • Acetylcholinesterase / therapeutic use
  • Aged
  • Alzheimer Disease* / drug therapy
  • Antipsychotic Agents* / adverse effects
  • Cholinesterase Inhibitors / adverse effects
  • Cohort Studies
  • Humans
  • Indans / therapeutic use
  • Medicare
  • Phenylcarbamates / therapeutic use
  • Piperidines / adverse effects
  • Retrospective Studies
  • United States


  • Antipsychotic Agents
  • Cholinesterase Inhibitors
  • Indans
  • Phenylcarbamates
  • Piperidines
  • Acetylcholinesterase