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Donepezil and memantine for moderate-to-severe Alzheimer’s disease


Howard, Robert, McShane, Rupert, Lindesay, James, Ritchie, Craig, Baldwin, Ashley, Barber, Robert, Burns, Alistair, Dening, Tom, Findlay, David, Holmes, Clive, Hughes, Alan, Jacoby, Robin, Jones, Rob, 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, Onions, Caroline, Griffin, Mary, Adams, Jessica, Gray, Richard, Johnson, Tony, Bentham, Peter, Phillips, Patrick


The New England Journal Of Medicine, Volume: 366, No.: 10, Pages.: 893-903

Year of Publication



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.).;

Bibtex Citation

@article{Howard_2012, doi = {10.1056/nejmoa1106668}, url = {}, year = 2012, month = {mar}, publisher = {New England Journal of Medicine ({NEJM}/{MMS})}, volume = {366}, number = {10}, pages = {893--903}, author = {Robert Howard and Rupert McShane and James Lindesay and Craig Ritchie and Ashley Baldwin and Robert Barber and Alistair Burns and Tom Dening and David Findlay and Clive Holmes and Alan Hughes and Robin Jacoby and Rob Jones and Roy Jones and Ian McKeith and Ajay Macharouthu and John O{textquotesingle}Brien and Peter Passmore and Bart Sheehan and Edmund Juszczak and Cornelius Katona and Robert Hills and Martin Knapp and Clive Ballard and Richard Brown and Sube Banerjee and Caroline Onions and Mary Griffin and Jessica Adams and Richard Gray and Tony Johnson and Peter Bentham and Patrick Phillips}, title = {Donepezil and Memantine for Moderate-to-Severe Alzheimer{textquotesingle}s Disease}, journal = {New England Journal of Medicine} }


adverse effects, aged, aged, 80 and over, alzheimer disease, antagonists inhibitors, cholinesterase inhibitors, donepezil, double-blind method, drug synergism, drug therapy, drug therapy combination, excitatory amino acid antagonists, female, humans, indans, male, memantine, patient dropouts, piperidines, psychological tests, therapeutic use, treatment outcome

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Randomised Controlled Trial

Type of Outcomes

ADLs/IADLs, Cognition



Type of Interventions

Pharmaceutical Interventions

Pharmaceutical Interventions

Anti-Alzheimer medications, e.g.: donezepil, galantamine, rivastigmine, memantime