The Great Donepezil/Memantine Debate

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Alvin B. Lin, MD, FAAFP

Associate Professor of Family and Community Medicine, University of Nevada School of Medicine

Adjunct Professor of Family Medicine and Geriatrics, Touro University Nevada College of Medicine

Advisory Medical Director, Infinity Hospice Care

Medical Director, Lions HealthFirst Foundation

Dr. Lin maintains a small private practice in Las Vegas, NV. The posts represent the views of Dr. Lin, and in no way are to be construed as representative of the above listed organizations. Dr. Lin blogs about current medical literature and news at


Donepezil has been around for a while. It wasn't the first acetylcholinesterase inhibitor (rather the second), but it's the one by which all others are judged, since it's a simple once daily medication without any hepatoxicity. In fact, it's been for such a long time that a generic version is now available. In essence, it's the go-to drug for which most family physicians will reach when they diagnose someone with Alzheimer's disease (AD), as it's indicated for mild, moderate, severe stages.

Memantine is the first and thus far only N-Methyl-D-aspartate (NMDA) receptor antagonist on the market. It's indicated for moderate to severe stages of AD, although I recall back in the day that there was some push to use it off-label in the earliest, mild stage rather than to wait for disease progression. If you'll remember back almost a year ago, a meta-analysis of three studies demonstrated no benefit to use of memantine in mild stage AD.

But the debate rages on. Do these drugs really make a difference? Not just numerically on some paper test, but clinically speaking. To answer this question, the authors published in yesterday’s New England Journal of Medicine a randomized, double-blind, placebo-controlled trial for which they found 295 community-dwelling patients average age of 77 years old, with moderate to severe AD who had taken donepezil for at least 3 months. The participants were randomized to one of four groups: (1) continue donepezil; (2) discontinue donepezil; (3) switch from donepezil to memantine; or (4) add memantine to donepezil, and then followed for 52 weeks.

Using standard cognitive function scores as well as functional measurements, specifically activities of daily living (ADLs), continuation of donepezil demonstrated statistically significant higher cognitive function compared to discontinuation. However, use of memantine in isolation did not lead to any difference in cognitive function compared to use of donepezil in isolation, although memantine in isolation was better than placebo. Furthermore, the combination of donepezil and memantine did not lead to any improvement over use of donepezil alone. Which then raises the question, why use memantine? But if you're tempted to discontinue donepezil, think twice and don't, at least not without substituting memantine.