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The N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, might be useful for patients with moderate-to-severe Alzheimer disease (AD), according to David Geldmacher, MD, Director of the Memory Disorders Program and Associate Professor of Neurology at the University of Virginia Health System in Charlottesville.

“It appears that adding memantine to donepezil somehow ‘refacilitates’ or ‘reactivates’ the action of the cholinesterase inhibitor,” Dr. Geldmacher said. He was commenting on a paper published in the Journal of the American Medical Association in January, reporting the results of combining memantine with donepezil (JAMA 2004;291(3):317–324).

Lead investigator on the study, Pierre Tariot, MD, who is Professor of Psychiatry, Neurology, and Medicine at the University of Rochester Medical Center, said that the combination improved behavioral, functional, and global measures without compromising tolerability.

Memantine maintained cognitive function as measured by the Mini-Mental Status Examination, while patients in the donepezil plus placebo group experienced a decline. The difference between groups was significant. Measures of activities of daily living and clinical global status improved significantly in memantine patients.

“Of particular note was the improvement in behavior in the memantine group,” Dr. Tariot said. “Fewer behavioral symptoms, such as agitation, were seen and no new behavioral symptoms were reported.”

Asked to comment on possible reasons for the improvement seen with combination therapy, Dr. Tariot pointed to the differing mechanisms of action of the two drugs. Donepezil and memantine affect different neurotransmitter systems and may confer independent clinical benefits, he said. Memantine, an NMDA receptor antagonist targets natural neurotransmitters – that is, excitatory amino acids such as glutamate; while donepezil is a selective inhibitor of acetylcholinesterase.

“However,” he added, “given, the complex interconnection of different neurotransmitter systems, a synergistic mechanism is also possible.”


Dr. Geldmacher leans towards the synergistic theory. He bases his opinion on the findings of two other studies performed in patients with moderate-to-severe AD – donepezil was used in one study and memantine in the other. Patients in both studies were treatment naïve.

“In a trial where donepezil was used as a single agent, patients on the whole remained stable and in some cases improved compared to their baseline scores,” Dr. Geldmacher said (Neurology 2001;57:489–495). “On the other hand, in the memantine monotherapy trial patients taking the active drug did better than those on placebo, however, they still declined” (N Engl J Med 2003;348:1333–1341).

Prescribing memantine for a patient who has been taking a cholinesterase inhibitor for a while may give the patient an opportunity to restabilize and continue to benefit from both therapies, he said.

When asked if they would recommend adding memantine to a cholinesterase inhibitor routinely in patients with moderate-to-severe AD, both Dr. Tariot and Dr. Geldmacher pointed out that a combination regimen is not currently approved by the FDA.


“I can't comment on the cost-effectiveness of such a regimen, but cost aside, this study provides evidence suggesting that combining an NMDA receptor antagonist with a cholinesterase inhibitor may offer patients better quality of life and an opportunity to maintain autonomy for longer periods,” Dr. Tariot said.

Dr. Geldmacher agreed, noting that he has not seen any pharmacoeconomic data. He commented that he has been using the combination of memantine and a cholinesterase inhibitor in what he described as “desperate” patients and, in the short-term, he has seen some stabilization and improvement.

Dr. Tariot added that the combination was better tolerated than donepezil alone. There were more withdrawals due to side effects in the donepezil plus placebo group than in the combination group.

“Interestingly, fewer patients taking donepezil plus memantine experienced diarrhea and fecal incontinence, well-known effects of cholinesterase inhibitors, than those taking donepezil alone,” Dr. Tariot said. “One of the side effects of memantine is low-grade constipation so perhaps some interaction contributed to the lower incidence of diarrhea.”


Dr. Pierre Tariot: “Of particular note was the improvement in behavior in the memantine group. Fewer behavioral symptoms, such as agitation, were seen and no new behavioral symptoms were reported.”

The long-term effects of combining memantine and donepezil are being investigated in an open-label extension of the current study, Dr. Tariot noted.

“There are still a number of questions to be answered, including whether or not added benefits would be seen if an NMDA receptor antagonist such as memantine were started before a cholinesterase inhibitor and whether agents such as memantine are effective in mild to moderate AD,” he said.

The study was sponsored by Forest Laboratories.


✓ Dr. Pierre Tariot, of the University of Rochester Medical Center, reported in a study that the combination of memantine and donepezil improved behavioral, functional, and global measures in moderate-to-severe Alzheimer disease without compromising tolerability.


• Tariot PN, Farlow MR, Grossberg GT, Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291(3):317–324.
    • Winblad B, Engedal K, Soininen H, A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489–495.
      • Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333–1341.