Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial
Abstract
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.
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Donepezil showed no benefit for clinically significant agitation over 12 weeks in a large RCT, or for overall change in neuropsychiatric inventory scores in a longer term trial with up to four years' follow-up.
“In addition, donepezil showed no benefit for clinically significant agitation over 12 weeks in a large RCT,147 or for overall change in neuropsychiatric inventory scores in a longer term trial with up to four years’ follow-up.98”
From Assessment and management of behavioral and psychological symptoms of dementia (2015) · cites this paper as [98]
Patients taken off, or those inconsistently taking, anti-AD medications progress more rapidly than those who continue treatments, particularly cholinesterase inhibitors.
“Patients taken off, or those inconsistently taking, anti-AD medications progress more rapidly than those who continue treatments, particularly ChEIs.”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [68]
Discontinuation of cholinesterase inhibitor treatment is, on aggregate, harmful.
“Discontinuation of ChEI treatment is, on aggregate, harmful.”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [68]
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- Authors
- AD Collaborative Group
- Affiliations
- University of Birmingham (GB)
- Corresponding author
- AD Collaborative Group
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 363
- Issue
- 9427
- Pages
- 2105-2115
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W180469417
- Cited by
- 892
- References
- 37
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 13 · 2023: 14 · 2022: 19 · 2021: 33 · 2020: 30 · 2019: 26 · 2018: 27 · 2017: 21 · 2016: 18 · 2015: 35 · 2014: 37 · 2013: 32 · 2012: 29
- FWCI
- 70.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- National Institute on Aging (U19AG010483)
- Cilag
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- donepezil, Alzheimer's disease, cholinesterase inhibitors, institutionalization, disability progression, activities of daily living, cognitive function, behavioural and psychological symptoms, caregiver well-being, cost-effectiveness, dose comparison, community-dwelling patients, long-term treatment outcomes, Mini-Mental State Examination
- MeSH terms
- Donepezil, Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Cholinesterase Inhibitors, Cognition, Cost-Benefit Analysis, Double-Blind Method, Female, United Kingdom, Health Resources, Humans, Indans, Institutionalization, Male, Middle Aged, Piperidines, Treatment Outcome, Health Care Costs, Disease Progression
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