Donepezil offers benefits in moderate or severe Alzheimer's; adding memantine doesn't

Donepezil offers cognitive and functional benefits in patients with moderate or severe Alzheimer's disease, while adding memantine does not, a study concluded.

Researchers wanted to assess three factors:

• whether donepezil would be associated with better cognition and function at one year compared to not using the drug,
• whether memantine compared with placebo would be associated with better cognition and function, and
• whether combining donepezil and memantine would provide any benefits.

Researchers conducted a multicenter, double-blind, placebo-controlled trial among 295 community-dwelling residents and assessed outcomes for 52 weeks. Patients had moderate or severe Alzheimer's disease, were already taking donepezil and scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE).

Participants were randomly assigned to one of four treatments:

• continuing donepezil and starting placebo,
• stopping donepezil and starting placebo,
• stopping donepezil and starting memantine, or
• continuing donepezil and starting memantine.

Results appeared in the March 8 New England Journal of Medicine.

Patients who continued taking donepezil had higher SMMSE scores (indicating better cognitive function) compared with those who stopped it by an average of 1.9 points (95% CI, 1.3 to 2.5; P<0.001) and lower scores on the Bristol Activities of Daily Living Scale (BADLS) (indicating less functional impairment) by an average of 3 points (95% CI, 1.8 to 4.3; P<0.001).

Patients taking memantine as compared with placebo had higher SMMSE scores by an average of 1.2 points (95% CI, 0.6 to 1.8; P<0.001) and lower BADLS scores by an average of 1.5 points (95% CI, 0.3 to 2.8; P=0.02). Both these values were smaller than the minimum clinically important differences, researchers noted.

There was no significant benefit of adding memantine to donepezil. Scores on the SMMSE were 0.8 point higher with memantine than with placebo (95% CI, −0.1 to 1.6; P=0.07). Scores on the BADLS were 0.5 point lower with memantine than with placebo (95% CI, −2.2 to 1.2; P=0.57).

Donepezil offered larger benefits in patients with moderate disease (SMMSE score, 10 to 13) than in those with severe disease (SMMSE score, 5 to 9). The average difference in scores between the groups assigned to continue donepezil and the groups assigned to discontinue donepezil was 2.6 points (95% CI, 1.5 to 3.7) among patients with moderate disease (P<0.001) and 1.3 points (95% CI, 0.2 to 2.4) among patients with severe disease (P=0.02).

Patients who received memantine instead of placebo had lower Neuropsychiatric Inventory (NPI) scores (indicating fewer behavioral and psychological symptoms) by an average of 4 points (99% CI, 0.6 to 7.4; P=0.002), which did not meet the standard of a clinically important difference. There wasn't a significant difference in scores on the NPI between continuing and stopping donepezil (2.3 points lower with continuation; 95% CI, −1.1 to 5.7; P=0.08). Adding memantine to donepezil resulted in a decrease in the NPI score that was greater by 5.1 points (99% CI, 0.3 to 9.8; P=0.006) than that from placebo.