Memantine is one of only four commonly prescribed drugs for the treatment of memory loss in Alzheimer’s disease. The FDA approved the drug for moderate to severe AD in 2003, but since then many physicians have taken to prescribing it off-label for people at mild stages of the disease as well. Does memantine (trade name Namenda) help in the earliest stages of dementia? A comprehensive meta-analysis just put paid to that idea. In the April 11 Archives of Neurology online, researchers led by Lon Schneider at the University of Southern California, Los Angeles, and colleagues Rupert McShane at the University of Oxford and Julian Higgins at the Medical Research Council, Cambridge, both in the U.K., report that memantine is no better than placebo for people with mild AD, and only marginally effective in moderate cases.
The study is important for two reasons, Schneider told ARF. It counters prior claims that memantine, a glutamate receptor antagonist, works “across the spectrum of the disease, from mild to severe cases.” And it provides physicians and patients with independent information to make informed decisions. Many people with mild AD are taking the drug; for example, 45 percent of volunteers enrolled in the Alzheimer’s Disease Neuroimaging Initiative and 25 percent of those registered with the National Alzheimer’s Coordinating Center at the National Institutes of Health (Schneider et al., 2011) are on it. Many patients ask for memantine, and physicians can feel compelled to prescribe it. “We are not in the business of crushing hope [by not prescribing it off-label or for patients who ask],” said Schneider, “but this study provides a reality check.”
The drug maker would not provide raw data for the researchers to analyze the effects of memantine on people with mild AD, but Schneider and colleagues were able to use analyses published by the sponsors to tease out the necessary data.
Sponsors in the U.S. (Forest Laboratories, Inc.) and Europe (Merz Pharma) used the same three clinical trials of people with mild to moderate AD (Mini-Mental State Exam scores of 10-23) to argue for an expansion of approval to mild AD. In July 2005, the U.S. Food and Drug Administration rejected that application. In November 2005, the European Medicines Agency offered limited expansion of their approval from “moderately severe to severe,” to “moderate to severe” AD, but also declined approval for mild forms. One meta-analysis by the European sponsor had focused on patients only with moderate to severe AD (MMSE less than 20), which allowed Schneider and colleagues to obtain data on mild AD patients (MMSE 20-23) by subtraction. On analysis, they found no significant difference between the drug and placebo groups on a variety of outcomes, including cognitive, activities of daily living, psychiatric, and global measures. People with moderate AD who took memantine did marginally better on cognitive and global measures.
The study speaks to the thorny issue of healthcare management. Who should decide whether someone gets to take a drug of limited benefit? It may depend on who is paying for it. In the U.K., there was a furor in 2005 when the National Institute for Clinical Excellence (NICE), which sets guidance for the National Health Service, shot down cholinesterase inhibitors for AD because they deemed them of little benefit over the long term. NICE recanted a year later, officially recommending cholinesterase inhibitors for patients with moderate disease. Last October, NICE had another change of heart, extending their recommendation to mild AD as well (see related news from the BBC). NICE does not, however, recommend memantine for mild AD. The U.S. does not have a national healthcare system, though taxpayers subsidize the cost of memantine through Medicare prescription drug coverage. Memantine typically costs $170 a month. Medicare can cover up to 95 percent.—Tom Fagan
- Schneider LS, Insel PS, Weiner MW, . Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol. 2011 Jan;68(1):58-66. PubMed.
- Doody RS, Tariot PN, Pfeiffer E, Olin JT, Graham SM. Meta-analysis of six-month memantine trials in Alzheimer's disease. Alzheimers Dement. 2007 Jan;3(1):7-17. PubMed.
- Winblad B, Jones RW, Wirth Y, Stöffler A, Möbius HJ. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord. 2007;24(1):20-7. Epub 2007 May 10 PubMed.
- Knopman DS. Commentary on "Meta-analysis of six-month memantine trials in Alzheimer's disease." Memantine has negligible benefits in mild to moderate Alzheimer's disease. Alzheimers Dement. 2007 Jan;3(1):21-2. PubMed.
- Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011 Aug;68(8):991-8. PubMed.