Clinical Question: Is memantine a safe and effective drug in the treatment of moderate to severe Alzheimer's disease?

Setting: Outpatient (any)

Study Design: Randomized controlled trial (double-blinded)

Synopsis: Overstimulation of the N-methyl-D-aspartate receptor by glutamate occurs in patients with Alzheimer's disease, and meman-tine is a new class of drug that inhibits this receptor. Patients who met standard criteria for Alzheimer's disease and were moderately to severely impaired were randomized (allocation concealed) to oral memantine in a dosage of 20 mg per day or placebo. The average age of participants was 76 years, 67 percent were women, and the mean Mini-Mental State Examination score was 7.9 out of a possible 30.

The 126 patients in each group were followed for 28 weeks, and various validated functional and cognitive scales were measured at baseline and at the end of the study. Patients who withdrew completed the scales at that time, with the results carried forward. Only patients with at least one follow-up measurement were included in the analysis. Sensitivity analyses assumed that patients who were lost to follow-up did the same as patients receiving placebo, or that they had no change from baseline. The investigators also should have done an analysis assuming that patients who dropped out did worse than average, but this was not done. It is somewhat reassuring that more patients in the placebo group than in the treatment group dropped out (42 versus 29).

Investigators used the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) scale, a 7-point scale in which 1 = markedly improved and 7 = markedly worse. At the end of the study, the score was a mean 0.3 points lower in the treatment group, which represents a 5-percent improvement in this scale. The Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory assesses functional capacity on a 54-point scale and was the other primary outcome. Patients in the memantine group had 2.1 points less deterioration during the study period, roughly a 4-percent improvement. Investigators also found a 45.8-hour decrease in the time that caregivers had to spend with patients receiving memantine each month. This may be a clinically important benefit and may make the drug more cost effective. In addition, memantine was generally well tolerated among study participants.

Bottom Line: Memantine, like many other drugs, produces a small improvement in symptoms and function that, although statistically significant, is probably not clinically significant. The reduction in caregiver time is intriguing, though, and the drug is well tolerated. (Level of Evidence: 1b-)