Memantine for Advanced Alzheimer’s Disease
Abstract & Commentary
Source: Reisberg B, et al. Memantine for advanced Alzheimer’s disease. N Engl J Med. 2003;348:1333-1341.
Currently, there are no medications specifically approved in the United States for treatment of the advanced stages of Alzheimer’s disease (AD). Results of the first US large-scale, prospective, double-blind study of memantine in the treatment of moderate-to-severe AD indicate that memantine-treated advanced AD patients fare better than those who received placebo, with no significant treatment-related side effects.
Memantine is an inhibitor of the postsynaptic N-methyl-D-aspartate (NMDA) receptor, which modulates calcium transport into neurons. Overstimulation of NMDA receptors by the excitatory neurotransmitter glutamate may cause excitotoxic damage to neurons and has been implicated in the pathogenesis of various degenerative disorders, including AD. Memantine reportedly limits glutamate-mediated excitotoxic damage, while permitting lower levels of NMDA activity that facilitate memory processes. These effects provided a biological rationale for the study of memantine as a potential treatment for AD.
The 32-center US trial enrolled 252 AD patients with a mean age of 76 years in a 28-week study comparing 10 mg b.i.d. of memantine to placebo. Primary outcome measures included a clinician/caregiver estimate of global response (CIBIC-plus) and an assessment of capacity to carry out daily activities (ADCS-ADL). Several secondary measures of cognitive function and behavior were examined using test instruments appropriate to the advanced stages of AD. Safety, as well as efficacy of treatment, was examined.
Of the 252 patients enrolled, 181 (72%) completed the trial, with fewer dropouts occurring from the memantine group (29) than among the controls (42). The most robust primary treatment response was seen on the measure of daily function (ADCS-ADL), which showed significantly better outcome in the memantine-treated patients than controls. A trend toward better outcome (P = .06) on the global outcome measure (CIBIC-plus) was seen in an intend-to-treat type analysis, which reached significance (P = .03) when the analysis was restricted to those who actually completed the study. Among the secondary outcome measures, the cognitive assessment instrument (SIB) and a measure of the stage of disease (FAST) showed a significant benefits in association with memantine treatment. Other measures, such as the Minimental State Exam, Global Deterioration Scale and the Neuropsychiatric Inventory were not significantly different between memantine and placebo groups.
As in other studies carried out in the elderly AD population, a majority of patients (85%) had 1 or more adverse events during the study. However, there were no significant differences in the frequencies of adverse events in the memantine group (106) vs placebo (109). Likewise, there were no serious adverse events related to memantine treatment.
Memantine is not a new treatment for AD. It has been approved in Germany for treatment of dementia for more than a decade and throughout the European Union since May 2002. It is marketed in Germany under the trade name "Axura" and throughout the rest of Europe as "Ebixa." In Germany, where experience with memantine is the most extensive, this agent is used to treat all stages of AD, as well as a variety of other forms of dementia.
The value of using a medication that brings about only a mild symptomatic improvement to treat advanced stages of AD is controversial. A handful of studies have suggested that patients with moderate-to-severe AD (and their caregivers) may benefit from treatment with cholinesterase inhibitors. It is more difficult to establish efficacy in advanced AD than milder stages because more severely affected patients often perform at the floor of the measures traditionally used for AD pharmacological studies, such as the ADAS-cog. The memantine trial used measures such as the SIB that are normed for severely impaired patients, to some extent circumventing this difficulty. The 0.3 point difference on the CIBIC-plus observed between memantine and placebo approached statistical significance but may not be clinically significant. Improvements on the Severe Impairment Battery and the ADCS-ADL functional scale are numerically more impressive and suggest that memantine may provide meaningful benefits in the treatment of advanced AD.
In the United States, the mainstay of treatment for AD are the acetylcholinesterase inhibitors (AchEIs). Since memantine acts via a completely different mechanism than AChEIs, combined use of memantine and cholinesterase inhibitors is under study. Preliminary results of a study recently presented at the 2003 American Academy of Neurology meeting (Farlow, et al. 48.003) suggested good safety and added efficacy when memantine is used in combination with the cholinesterase inhibitor donepezil.
Memantine is now under consideration by the FDA for approval in the United States as a monotherapy for AD. Since there are no approved therapies for advanced AD in the United States, memantine could gain a strong foothold in the AD pharmaceutical market if it receives the FDA’s nod for this indication. It seems likely based on the European experience that use in mild-to-moderate AD, as well as in combination with cholinesterase inhibitors, would quickly follow. With its relatively benign side effect profile and long-standing track record of successful use in Germany, this agent has excellent potential for approval as the next treatment for AD in North America. — Norman R. Relkin
Dr. Relkin is Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital-Cornell Campus