Schneider et al. present a reanalysis of three studies of memantine in mild to moderate Alzheimer’s disease (AD) in which they were able to isolate the data for the mild subjects. They find no benefits for memantine in milder AD dementia patients. Schneider and I had drawn the same conclusion from the industry-sponsored meta-analysis of the same studies published in 2007 (Knopman, 2007; Schneider, 2007).

What is particularly disturbing to me is another finding of detective Schneider: that a large fraction of patients with mild AD in the research projects of the Alzheimer’s Disease Neuroimaging Initiative or the Alzheimer’s Disease Centers’ programs are prescribed memantine. The widespread use of memantine in mild AD and even in people with mild cognitive impairment (MCI) points out how desperate patients, families, and treating physicians are to employ a medication for these disorders, even when the data show the drug has no benefits. As Schneider et al. illustrate in their timeline,...  Read more

Schneider et al. present a reanalysis of three studies of memantine in mild to moderate Alzheimer’s disease (AD) in which they were able to isolate the data for the mild subjects. They find no benefits for memantine in milder AD dementia patients. Schneider and I had drawn the same conclusion from the industry-sponsored meta-analysis of the same studies published in 2007 (Knopman, 2007; Schneider, 2007).

What is particularly disturbing to me is another finding of detective Schneider: that a large fraction of patients with mild AD in the research projects of the Alzheimer’s Disease Neuroimaging Initiative or the Alzheimer’s Disease Centers’ programs are prescribed memantine. The widespread use of memantine in mild AD and even in people with mild cognitive impairment (MCI) points out how desperate patients, families, and treating physicians are to employ a medication for these disorders, even when the data show the drug has no benefits. As Schneider et al. illustrate in their timeline, there were long gaps between the completion of the mild to moderate AD trials with memantine and their eventual publication. And, the reports of the memantine trials, for whatever reason, were published in journals that are far out of the mainstream, including one to which my institution didn’t even subscribe. Physicians bear responsibility for ignoring the lack of demonstrated efficacy of memantine in mild AD dementia patients.

I am acutely aware of the frustration of families, patients, and physicians when it comes to therapy for mild AD dementia. I have to face patients and families with dementia or MCI and tell them how bleak the therapeutic landscape is. But why waste resources and expose patients to unnecessary medications? Physicians interested in the best care of AD patients should speak out against the against the wasteful use of memantine in mild AD dementia, and I applaud Schneider et al. for calling attention to this embarrassment.

View all comments by David Knopman

Memantine has been approved by the U.S. Food and Drug Administration as a safe and effective treatment for moderate to severe Alzheimer’s disease based upon evidence from randomized, double-blind, placebo-controlled trials (1,2). The recent meta-analysis (3) by Schneider et al. is an attempt to use post hoc subpopulations from previous clinical trials to examine the potential benefits and risks of memantine in patients with mild AD. In a previously published meta-analysis (4), we demonstrated that memantine was associated with significant cognitive and global benefits compared to placebo in patients with mild to severe Alzheimer’s disease. This meta-analysis included six randomized, placebo-controlled trials of memantine: three in mild to moderate patients and three in moderate to severe patients. The moderate ranges of the two groups obviously overlapped, although each study recruited patients independently. It is worth noting that the mild to moderate trials analyzed in our previous meta-analysis are the same ones that were re-analyzed by Schneider et al. In our analysis of the...  Read more

Memantine has been approved by the U.S. Food and Drug Administration as a safe and effective treatment for moderate to severe Alzheimer’s disease based upon evidence from randomized, double-blind, placebo-controlled trials (1,2). The recent meta-analysis (3) by Schneider et al. is an attempt to use post hoc subpopulations from previous clinical trials to examine the potential benefits and risks of memantine in patients with mild AD. In a previously published meta-analysis (4), we demonstrated that memantine was associated with significant cognitive and global benefits compared to placebo in patients with mild to severe Alzheimer’s disease. This meta-analysis included six randomized, placebo-controlled trials of memantine: three in mild to moderate patients and three in moderate to severe patients. The moderate ranges of the two groups obviously overlapped, although each study recruited patients independently. It is worth noting that the mild to moderate trials analyzed in our previous meta-analysis are the same ones that were re-analyzed by Schneider et al. In our analysis of the mild to moderate studies, patients treated with memantine outperformed those given placebo on tests of both cognitive and global function. Furthermore, these effects were homogeneous, or consistent across the individual included studies, which heightened our confidence in these findings. Because no memantine trials recruited and randomized only mild AD patients, we did not investigate this subgroup alone.

Schneider et al. defined mild AD patients as those with MMSE scores ranging from 20 to 23; in comparison, moderate AD patients had MMSE scores from 10 to 19. Clearly, the range of MMSE scores in the mild AD sample was quite limited; this restriction of MMSE range probably resulted in a subsequent restriction of the range on other cognitive (e.g., ADAS-cog) and functional measures, thereby reducing the researchers’ ability to detect differences between changes over time in the drug and placebo groups. There was also a relatively small number of patients in the mild AD category; for example, on the ADAS-cog measure, across the three studies, the average number of patients per treatment group per study was 71; in the moderate category, the average number of patients per treatment group per study was 114. It is likely that the meta-analysis of the mild AD subgroup was relatively underpowered to detect differences between memantine and placebo on the selected outcome measures.

The meta-analysis by Schneider et al. also combined two trials of memantine versus placebo monotherapy with one trial of background cholinesterase inhibitors (ChEIs) plus memantine versus placebo. Including these two different types of trials in the single category of “memantine treatments” ignores the potential interaction between memantine and cholinesterase inhibitors (5), as well as the possible benefits of cholinesterase inhibitors alone. Equating the comparison of memantine to placebo with that of memantine plus ChEI to placebo plus ChEI assumes that the effects of these two classes of drugs are simply additive and ignores any potential interaction between them. The meta-analysis by Schneider et al. did not examine this issue.

In conclusion, the recent meta-analysis, while interesting and well executed, leaves open the question of whether or not memantine, either as a monotherapy or combined with cholinesterase inhibitors, is beneficial to patients with mild Alzheimer’s disease. These criticisms of the current meta-analysis should not be interpreted as advocacy for the off-label use of memantine in patients with mild AD. Indeed, our standard practice is not to prescribe memantine to mild patients, but rather to do so only when they show rapid progression on a cholinesterase inhibitor alone, or a decline to the moderate stage of disease. We agree with the authors that studies specifically designed to look at the efficacy of memantine in a range of mild AD patients are necessary in order to fully answer this question. Our response is motivated by the unsupported use of this recently published meta-analysis by some in the lay press to suggest that memantine is ineffective and should not be used by any patients with AD. Clearly, the authors of the current meta-analysis were not questioning either the wisdom of the FDA or their decision to approve memantine as a treatment for patients with moderate to severe Alzheimer’s disease.

References:
1. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003; 348:1333-41. Abstract

2. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291: 317-24. Abstract

3. Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. Published online April 11, 2011. doi:10.1001/archneurol.2011.70. Abstract

4. Doody RS, Tariot PN, Pfeiffer E, Olin J, Graham SM. Meta-analysis of six-month memantine trials in Alzheimer’s disease. Alzheimers Dement. 2007;3(1):7-17. Abstract

5. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2008; 22(3):209-221. Abstract

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