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Memantine: A New Approach to Treatment of Moderate to Severe Alzheimer Disease

Memantine may be effective for certain people with AD, but better treatments are still needed.

The FDA recently approved memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, for treatment of symptoms of moderate to severe Alzheimer disease (AD). One of the pivotal studies was this double-blind, placebo-controlled, randomized, manufacturer-sponsored trial of memantine in 404 community-dwelling patients with a diagnosis of probable AD; these patients had received stable doses of donepezil for an average of more than 2.5 years.

The memantine group performed significantly better than the placebo group on all three outcome measures: the Severe Impairment Battery, a cognitive dysfunction test; the ADCS-ADL inventory of activities of daily living, developed to assess patients with relatively severe dementia; and the CIBIC-Plus, a measure of clinicians' impressions of change based on interviews with both patient and caregiver. The results were due largely to continuing deterioration of the placebo-treated patients. The effect sizes were relatively small, however -- a problem that continues to vex the Alzheimer field. Moreover, the study was not designed to demonstrate more than a symptomatic benefit. Adverse events differed minimally between the two groups: Confusion and headache occurred more often in the memantine group, whereas diarrhea and fecal incontinence were more common with placebo.

Comment: The role of memantine in clinical practice will be established as clinicians gain more experience with use of the drug. We must avoid creating the expectation that the effects of currently available drugs are large. Additional studies of the drug's effects in mild to moderate AD and on behavioral symptoms are to be reported. However, we must intensify our efforts to develop approaches that have a more profound, positive impact on patient and caregiver quality of life. Any memantine-related constipation in this study may actually have balanced out the tendency toward donepezil-related diarrhea. Even though the drug has been used in Germany for 20 years, physicians must be vigilant about reporting newly emerging side effects in practice, especially those involving confusion.

— Peter J. Whitehouse, MD, PhD

Dr. Whitehouse is Director, Integrative Studies, University Memory and Aging Center, Case Western Reserve University, Cleveland.

Published in Journal Watch Neurology May 7, 2004

Citation(s):

Tariot PN et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA 2004 Jan 21; 291:317-24.

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