Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease

Am J Psychiatry. 2003 Nov;160(11):2003-11. doi: 10.1176/appi.ajp.160.11.2003.


Objective: The authors examined the effect of the acetylcholinesterase inhibitor donepezil on magnetic resonance markers of neurodegeneration in Alzheimer's disease.

Method: In this randomized, double-blind, placebo-controlled pilot study, 67 patients with mild to moderate Alzheimer's disease received 24 weeks of treatment with donepezil (5 mg/day for the first 28 days and 10 mg/day thereafter) or placebo. Patients were reevaluated at 6-week intervals to measure change from baseline in several outcome measures, including right, left, and total hippocampal volumes, measured with magnetic resonance imaging; brain concentrations of N-acetylaspartate, measured with proton magnetic resonance spectroscopy; and cognition, assessed with the Alzheimer's Disease Assessment Scale cognitive subscale.

Results: At some interim assessments, mean normalized measures of N-acetylaspartate concentration tended to be higher in the donepezil-treated patients than in the patients who received placebo, but these differences were not significant at endpoint. At endpoint, the donepezil-treated patients had significantly smaller mean decreases in total and right hippocampal volumes and a smaller, nearly significant mean decrease in left hippocampal volume, compared with the placebo-treated patients. Mean Alzheimer's Disease Assessment Scale cognitive subscale scores were improved after treatment with donepezil, relative to placebo, at weeks 6, 12, 18, and 24.

Conclusions: These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / psychology
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / analysis
  • Biomarkers / analysis*
  • Brain Chemistry / drug effects
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use*
  • Donepezil
  • Double-Blind Method
  • Female
  • Hippocampus / anatomy & histology
  • Hippocampus / drug effects*
  • Humans
  • Indans / pharmacology
  • Indans / therapeutic use*
  • Inositol / analysis
  • Magnetic Resonance Spectroscopy
  • Male
  • Neurons / chemistry
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Placebos
  • Psychiatric Status Rating Scales
  • Severity of Illness Index
  • Treatment Outcome


  • Biomarkers
  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Placebos
  • Aspartic Acid
  • Inositol
  • Donepezil
  • N-acetylaspartate