Evidence for Memantine Efficacy in Mild Alzheimer's Lacking

Megan Brooks

April 14, 2011

April 14, 2011 — Despite its frequent off-label use, there is very little evidence that memantine is effective in mild Alzheimer's disease (AD) and there is only "meager" evidence for its efficacy in moderate AD, according to a report published online April 11 in Archives of Neurology.

Memantine is currently approved in the United States and Europe for moderate to severe AD but not for mild AD.

However, "a lot of physicians, and neurologists in particular, are using memantine in mild AD and MCI [mild cognitive impairment]," first study author Lon S. Schneider, MD, MS, of the University of Southern California Keck School of Medicine in Los Angeles, noted in an interview with Medscape Medical News.

"There's nothing wrong with off-label use, we do it all the time in the best interest of our patients, but here there seems to be an absence of data," he said.

Where's the Evidence?

To judge the evidence for efficacy in mild AD and moderate AD, Dr. Schneider's team systematically searched manufacturer-sponsored meta-analyses, registries, presentations, and publications for randomized, placebo-controlled, parallel-group clinical trials of memantine in patients with mild to moderate AD.

They identified 3 trials that included 431 patients with mild AD (Mini-Mental State Examination [MMSE] score of 20-23) and 697 patients with moderate AD (MMSE score of 10-19). Using several different scales, the researchers assessed cognition, global change, functional activities, and behavior.

According to Dr. Schneider and colleagues, "There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined."

Table 1. Outcomes of the Subsets of Patients With Mild Alzheimer's Disease From 3 Trials

Outcome Mean Difference (95% CI)
ADAS-cog −0.17 (−1.60 to 1.26)
CIBIC-plus −0.09 (−0.30 to 0.12)
ADCS-ADL scale 0.62 (−1.46 to 2.71)
NPI 0.09 (−2.11 to 2.29)

ADAS-cog = AD Assessment Scale–cognitive subscale; ADCS-ADL scale = AD Cooperative Study–activities of daily living; CI = confidence interval; CIBIC-plus = Clinician's Interview-Based Impression of Change plus caregiver's input; NPI = Neuropsychiatry Inventory

Among patients with moderate AD, there were small differences on the AD Assessment Scale–cognitive subscale (ADAS-cog) and the Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC-plus) but not on the AD Cooperative Study–activities of daily living (ADCS-ADL) scale or the Neuropsychiatry Inventory (NPI).

Table 2. Outcomes for the Subsets of Patients With Moderate Alzheimer's Disease From 3 Trials

Outcome Mean Difference (95% CI)
ADAS-cog −1.33 (−2.28 to −0.38)
CIBIC-plus −0.16 (−0.32 to −0.00)
ADCS-ADL scale −0.57 (−1.75 to 0.60)
NPI 0.25 (−1.48 to 1.99)

ADAS-cog = AD Assessment Scale–cognitive subscale; ADCS-ADL scale = AD Cooperative Study–activities of daily living; CI = confidence interval; CIBIC-plus = Clinician's Interview-Based Impression of Change plus caregiver's input; NPI = Neuropsychiatry Inventory

"There was no evidence for heterogeneity or inconsistency for any of the outcomes in either the mild AD or moderate AD groups," the study authors note.

An Ongoing Dilemma

Despite the lack of evidence of efficacy in mild AD, currently in the United States, nearly half of the patients with mild AD and a substantial proportion of patients with MCI are receiving memantine, the investigators note in their report.

With memantine, Dr. Schneider said, "it's always been a bit of a conundrum. You have a drug that is approved for moderate to severe AD; so it doesn't appear to be effective, in its label, until a patient becomes moderate. So what do you do with the patient that has mild AD, is on a cholinesterase inhibitor, and they ask what else can be done? It's up to physicians to judge the evidence and decide.

"Clearly, studies to determine the effects of memantine in mild AD or even mild cognitive impairment would seem to me to be important," Dr. Schneider told Medscape Medical News.

However, because the drug will soon go off patent, "there is very little incentive for the company to do these studies," he noted.

The study was supported in part by the California Alzheimer Disease Center program and the University of Southern California Alzheimer research Center. Dr. Schneider reports being an editor on the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees systematic reviews of drugs for cognitive impairment and dementia. He and his coauthors have various relationships with various pharmaceutical companies. A complete list can be found with the original article.

Arch Neurol. Published online April 11, 2011.

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