Clinical Question: Is the combination of memantine and donepezil effective in the treatment of Alzheimer’s disease?

Setting: Outpatient (specialty)

Study Design: Randomized controlled trial (double-blinded)

Synopsis: Memantine is an aspartate-receptor antagonist that has demonstrated some effectiveness as monotherapy in the treatment of Alzheimer’s disease. To evaluate the efficacy and safety of memantine combined with donepezil, a cholinesterase inhibitor, the authors identified 404 patients with moderate to severe Alzheimer’s disease and Mini-Mental State Examination scores of 5 to 14. Eligible patients were 50 years or older and had been receiving stable dosages of donepezil for at least three months.

Participants were randomized in a double-blind fashion (concealed allocation assignment) to receive memantine (starting dosage of 5 mg per day, increased to 20 mg per day) or placebo for 24 weeks. Therapeutic effectiveness was measured using the Severe Impairment Battery to evaluate cognition and an Alzheimer Disease Cooperative Study—Activities of Daily Living (ADCS-ADL) inventory. The authors do not specify whether outcomes were assessed by persons blinded to treatment group assignment. Follow-up information was available for 98 percent of the patients.

Using intention-to-treat analysis, changes on the Severe Impairment Battery statistically favored memantine over placebo (+0.9 versus-2.5, respectively; possible score range = zero to 100, with higher scores implying better cognition; P < .001). Likewise, the ADCS-ADL inventory found a statistically significant benefit of memantine over placebo (-2.0 versus-3.4, respectively; possible score range = zero to 54, with high scores implying improved ADLs; P = .03). A bevy of other secondary measures also showed a statistically significant benefit of memantine treatment. Dropouts because of adverse events were more common among patients in the placebo group (12.4 percent versus 7.4 percent in the treatment group).

Bottom Line: The combination of memantine and donepezil appears to be more beneficial in the treatment of Alzheimer’s disease than donepezil alone. Although the benefits are statistically significant when compared with placebo, it is difficult to assess the true clinical benefit of these minimal changes using various evaluation scoring tools. Evidence from trials evaluating more significant patient-oriented outcomes, such as delayed nursing home placement, is necessary before recommending widespread use of this treatment protocol. (Other patient-oriented evidence) (Level of Evidence: 1b–)