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Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease
Open accessAbstract
BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).
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“In moderate and severe AD, short-term efficacy of memantine monotherapy compared with placebo is reported in several RCTs of 12 to 50 weeks duration and supported by meta-analyses.”
From The Alzheimer’s Disease Clinical Spectrum (2019) · cites this paper as [71]
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Metadata
- Authors
- Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., Burns, A., Dening, T., Findlay, D., Holmes, C., Hughes, A., Jacoby, R., Jones, R., Jones, R., McKeith, I., Macharouthu, A., O'Brien, J., Passmore, P., Sheehan, B., Juszczak, E., Katona, C., Hills, R., Knapp, M., Ballard, C., Brown, R., Banerjee, S., Onions, C., Griffin, M., Adams, J., Gray, R., Johnson, T., Bentham, P., & Phillips, P.
- Affiliations
- King's College London (GB)
- Churchill Hospital (GB)
- University of Leicester (GB)
- Whiston Hospital (GB)
- Newcastle University (GB)
- University of Manchester (GB)
- Fulbourn Hospital (GB)
- University of Oxford (GB)
- Inverclyde Royal Hospital (GB)
- Crichton Royal Hospital (GB)
- Queen's University Belfast (GB)
- University of Warwick (GB)
- University College London (GB)
- University of Wales (GB)
- Avon and Wiltshire Mental Health Partnership NHS Trust (GB)
- University of Cambridge (GB)
- Queen Elizabeth Hospital Birmingham (GB)
- ORCID
- Howard, Robert
- McShane, Rupert
- Ritchie, Craig
- Baldwin, Ashley
- Barber, Robert
- Burns, Alistair
- Dening, Tom
- Findlay, David
- Holmes, Clive
- Jones, Roy
- McKeith, Ian
- Macharouthu, Ajay
- O'Brien, John
- Passmore, Peter
- Sheehan, Bart
- Juszczak, Edmund
- Katona, Cornelius
- Hills, Robert
- Knapp, Martin
- Ballard, Clive
- Brown, Richard
- Banerjee, Sube
- Gray, Richard
- Johnson, Tony
- Bentham, Peter
- Phillips, Patrick
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-03-08
- Volume
- 366
- Issue
- 10
- Pages
- 893-903
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2151585937
- Cited by
- 782
- References
- 31
- Citations by year
- 2026: 43 · 2025: 49 · 2024: 44 · 2023: 58 · 2022: 51 · 2021: 48 · 2020: 45 · 2019: 58 · 2018: 47 · 2017: 55 · 2016: 54 · 2015: 54 · 2014: 59 · 2013: 74 · 2012: 40
- FWCI
- 52.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- Leicester Research Archive (University of Leicester) (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Figshare (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Alzheimer's Society
- King's College London
- Medical Research Council
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, donepezil, memantine, cholinesterase inhibitors, NMDA receptor antagonists, combination therapy, cognitive function, activities of daily living, functional disability, treatment continuation, community-dwelling patients, minimal clinically important difference, treatment discontinuation
- MeSH terms
- Donepezil, Aged, Aged, 80 and over, Alzheimer Disease, Cholinesterase Inhibitors, Double-Blind Method, Drug Synergism, Drug Therapy, Combination, Female, Humans, Indans, Male, Memantine, Patient Dropouts, Piperidines, Psychological Tests, Receptors, N-Methyl-D-Aspartate, Treatment Outcome, Excitatory Amino Acid Antagonists, Kaplan-Meier Estimate
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