Donepezil and memantine for moderate-to-severe Alzheimer's disease.


This multicenter, double-blind, placebo-controlled study found that for patients with moderate to severe Alzheimer’s disease, continuing donepezil treatment was associated with significant cognitive and functional benefits, compared with placebo. Adding memantine had no significant benefit to donepezil alone. Previous studies had evaluated cholinesterase inhibitors in treating mild-to-moderate Alzheimer’s disease.


  • N=295 community residents meeting criteria for probable or possible moderate or severe Alzheimer’s disease, and who had been taking donepezil for at least 3 months, and who had a score of 5-13 on the Standardized Mini-Mental State Examination (SMMSE) (maximum score of 30, with higher indicating better cognitive function). Participants had to have at least daily contact with a caregiver and their clinician had to be considering a change in drug therapy.
  • Average participant age = 77.1 (SD=8.4), 65% female.
  • Participants were randomized to one of four treatments, switching from all taking just donepezil, to all taking two pills:
    • Donepezil + placebo memantine (n=73)
    • Placebo donepezil + placebo memantine (n=73)
    • Placebo donepezil + memantine (n=76)
    • Donepezil + memantine (n=73)
  • A randomization minimization procedure was employed to minimize imbalance of variables among study legs.
  • Setting: 15 centers, 2008-2010.
  • Primary outcomes: Scores on SMMSE and the Bristol Activities of Daily Living Scale (BADLS). The authors considered the minimum clinically important difference to be 1.4 points on SMMSE and 3.5 points on BADLS.
  • Outcomes assessed at 52 weeks.


  • For participants taking donepezil, compared with placebo, SMMSE scores were higher by an average of 1.9 points (95% CI, 1.3-2.5, P<0.001), and BADLS scores were lower by an average of 3.0 (1.8-4.3, P<0.001). These indicate better cognitive function and less functional impairment for the donepezil group.
  • For participants taking memantine, compared with placebo, SMMSE scores were higher by 1.2 points (0.6-1.8, P<0.001), and BADLS scores were lower by an average of 1.5 points (0.3-2.8, P<0.02). These improvements are both below what the authors considered to be the minimum clinically important difference.
  • The benefit of adding memantine to donepezil was not significant: 0.8 points higher on SMMSE (95% CI, -0.1-1.6, P=0.07), and 0.5 points lower on BADLS (95% CI, -2.2 to 1.2, P=0.57).
  • While donepezil was associated with higher SMMSE scores at 52 weeks when compared with placebo, this was small compared with the total decline in cognitive function seen in all participants over the 52 weeks study: a decrease of 5.8 SMMSE points. Thus, the benefit of donepezil over placebo was equivalent to approximately one third of the total deterioration in SMMSE score.


Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366(10):893-903. doi:10.1056/NEJMoa1106668.

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