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Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial

Contact Information


Lon S Schneider



Background: Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? Methods: 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. Findings: Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5-1.2; p<0.0001) and functionality 1.0 BADLS points better (0.5-1.6; p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0.4) or progression of disability (58% vs 59% at 3 years; p=0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72-1.30; p=0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74-1.24; p=0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. Interpretation: Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.


Courtney, C., Farrell, D., Gray, R., Hills, R., Lynch, L., Sellwood, E., Edwards, S., Hardyman, W., Raftery, J., Crome, P., Lendon, C., Shaw, H., Bentham, P., & AD2000 Collaborative Group (2004). Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet (London, England), 363(9427), 2105–2115.





Conent Area

C Courtney

EWB-Related Construct

(2) Life Satisfaction
(3) Positive Affect
(4) quality of life

Study Design

Species or Study Population

(5) RCT

Sex (%Female)


Age (Mean, SD)

Donepezil: 76, 7.3
Placebo: 75, 6.5

Younger Controls?


Longitudinal Data?


Sample Size



Long-term donepezil treatment

Ethnicity (%white)

not stated (UK)

Inclusion Criteria

To simplify trial procedures, and to ensure an appropriately heterogeneous, clinically representative group of patients, eligibility for AD2000 was based on uncertainty.12 Patients referred to memory clinics were potentially eligible for AD2000 if they were thought by the treating doctor—on the basis of routine examination using a glossary and diagnostic checklist—to have a DSM IV diagnosis of dementia of Alzheimer type,20 with or without a coexisting diagnosis of vascular dementia. Also, patients were required to have a regular carer, to be living in the community, and not to already be taking a cholinesterase inhibitor nor have a contraindication against donepezil. Clinicians were referred to the product datasheet for potential contraindications.

Exclusion Criteria

not stated

EWB Measures

General health questionnaire

Non-EWB Behavioral

Mini mental state examination (MMSE)
Bristol activities of daily living scale (BADLS)
Neuropsychiatric inventory
Cognitive section of the Alzheimer's disease assessment scale

Physiological Measures


Brain IMaging Modality

Brain IMaging Paradigm


Brain Region/Circuit


Biological Measures


Other Neural Measures

Data Availability?


Data Avalability Details


Diagnostic Measures

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