Donepezil and Memantine for moderate-to-severe Alzheimer's Disease

Robert Howard, Rupert McShane, James Lindesay, Craig Ritchie, Ashley Baldwin, Robert Barber, Alistair Burns, Tom Dening, David Findlay, Clive Holmes, Alan Hughes, Robin Jacoby, Rob Jones, Roy Jones, Ian McKeith, Ajay Macharouthu, John O'Brien, Peter Passmore, Bart Sheehan, Edmund JuszczakCornelius Katona, Robert Hills, Martin Knapp, Clive Ballard, Richard Brown, Sube Banerjee, Caroline Onions, Mary Griffin, Jessica Adams, Richard Gray, Tony Johnson, Peter Bentham, Patrick Phillips

    Research output: Contribution to journalArticlepeer-review

    473 Citations (Scopus)


    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.)

    Original languageEnglish
    Pages (from-to)893-903
    Number of pages11
    JournalNew England Journal of Medicine
    Issue number10
    Publication statusPublished - 2012


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