Journal Review: Memantine shows benefit for moderate-to-severe AD

New approach warrants further research

Memantine (Namenda) helped lessen the symptoms of patients with moderate-to-severe Alzheimer’s disease (AD) who were already receiving treatment with donepezil (Aricept), according to a study published in the Jan. 21 issue of the Journal of the American Medical Association.

Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. The U.S. Food and Drug Administration approved it October 2003 for the treatment of moderate-to-severe AD. Researchers decided to study it in patients who were already receiving a cholinesterase inhibitor. Forest Laboratories, which markets memantine, provided financial and material support for the research.

About 400 participants with moderate-to-severe AD and Mini-Mental State Examination scores of 5-14 began the randomized, double-blind trial, which was conducted at 37 U.S. sites between June 11, 2001, and June 3, 2002. The participants must have received ongoing cholinesterase inhibitor therapy with donepezil for more than six months before the trial and be at a stable dose (5-10 mg/d) for at least three months.

When the trial began, the participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d) or placebo for 24 weeks. Participants not tolerating the target dose by week 8 were removed from the trial. A total of 322 patients completed the study. Significantly more participants in the memantine group (85% as compared to 75% in the placebo group) completed the study.

The researchers found that measures of cognitive function, activities of daily living, behavior, and clinical global status were significantly improved with memantine compared with placebo. The drug seemed to be well tolerated, too. Significantly more patients in the placebo group discontinued the trial than in the memantine group. In addition, fewer participants in the memantine group discontinued the trial due to adverse events.

The primary adverse effect attributed to memantine use was confusion, which occurred at a median of 32 days. The confusion, however, was usually mild and did not last long. Some participants also complained of headache, but this seldom lasted more than one day. Gastrointestinal adverse effects, such as diarrhea and fecal incontinence, were reported more in the placebo group.

The researchers concluded from their study that memantine "represents a new approach for the treatment of patients with moderate-to-severe AD." However, the researchers say there are limitations to their results. First, the trial did not address different doses or titration rates, the use of other cholinesterase inhibitors besides donepezil, or the impact of beginning memantine therapy before donepezil.

In addition, the trial does not address the long-term effects of memantine and cholinesterase inhibitor treatment. The researchers say that this will be the focus of an open-label extension and other ongoing trials.