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Pharmacotherapy for moderate-to-severe Alzheimer disease (AD) often starts with an acetylcholinesterase inhibitor and subsequently adds or substitutes memantine, the N-methyl-d-aspartate–receptor antagonist. Little controlled evidence exists on the effects of continuing, stopping, or switching medications. This double-blind, placebo-controlled study (planned sample size of 430 patients) enrolled 295 community-dwelling patients with moderate-to-severe AD (Mini-Mental State Examination [MMSE] scores, 5–13) who were already receiving donepezil 10 mg for at least 6 weeks. Donepezil was continued or discontinued (discontinuers received placebo) and augmented with memantine or placebo. Authors established “clinically relevant” changes at 52 weeks on the MMSE (change, 1.4 points) and the Bristol Activities of Daily Living Scale.
Although cognitive and functional status declined in all patients, deterioration differed among groups. Donepezil continuers had better cognitive function (MMSE change, 1.9 points) and less functional impairment than donepezil discontinuers; these changes equaled 32% and 23%, respectively, of the deterioration in double-placebo recipients. Donepezil had a greater effect in moderate than in severe AD. Memantine recipients had better cognition and function than placebo recipients, but these differences were not clinically meaningful. Combining medications did not improve the benefit from donepezil.
Howard R et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012 Mar 8; 366:893.
Schneider LS. Discontinuing donepezil or starting memantine for Alzheimer's disease. N Engl J Med 2012 Mar 8; 366:957.
Comment
The clinical question is whether slower deterioration in Alzheimer disease translates into a prolonged improved quality of life. These data suggest that the answer is yes for continuing donepezil for patients with moderate-to-severe AD. Combination therapy, frequently implemented in the U.S., showed no benefit. Memantine had a statistically, but not clinically, significant effect.
Other notable points: A larger study sample might have yielded additional differences. The findings may not pertain to patients with mild AD. Whether findings generalize to other acetylcholinesterase inhibitors is unclear. Memantine alone remains effective in persons who cannot take acetylcholinesterase inhibitors. Also, in an earlier study (JAMA 2004; 291:317), adjunctive memantine showed positive effects, which conflicts with the current results.