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Memantine for Behavior Problems in Alzheimer Disease
Adding memantine to donepezil improves certain behavioral problems, though the reason remains unclear.
As patients with Alzheimer disease (AD) become increasingly impaired, treating their behavioral problems, such as agitation, becomes paramount. To examine the behavioral effects of memantine, Cummings and colleagues reassessed previously reported neuropsychiatric data from a randomized trial comparing memantine with placebo in 404 patients with moderate-to-severe AD (Journal Watch Neurology May 7 2004). All participants were already taking donepezil.
Compared with the placebo group, the memantine group’s mean total score on the neuropsychiatric inventory at 24-week follow-up clearly improved, by about 4 points (a 25% difference). Three of the 12 neuropsychiatric subscales (agitation/aggression, irritability/lability, and appetite/eating change) showed an overall statistical difference between the groups. Among patients without symptoms at baseline, significantly more in the memantine than in the placebo group remained asymptomatic on three subscales: agitation/aggression, irritability/lability, and nighttime behavior. The authors conclude that, in patients with moderate-to-severe AD who are already taking donepezil, memantine reduces behavioral disturbances.
Comment: The analysis of subscales in the present, hypothesis-generating study was intentionally not corrected for multiple comparisons. If it were, several of the findings would no longer reach statistical significance.
The authors speculate that memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, improves frontal lobe function because it may block excitotoxicity associated with chronic low-level glutamate stimulation. Glutamate stimulation has been associated with tau hyperphosphorylation and neurofibrillary tangles, and neurofibrillary tangles have been linked to frontal lobe dysfunction and agitation. This interesting hypothesis does not explain the fact that patients’ behavioral symptoms actually improved with memantine — an unexpected finding if the medication is solely neuroprotective. A more likely explanation for the behavioral benefit is memantine’s dopaminergic activity. Memantine is a derivative of amantadine — a drug used to treat Parkinson disease (PD). Memantine stimulates dopamine receptors (Neurosci Lett 2003; 343:205), increases dopaminergic function in animals (Eur J Pharmacol 1994; 262:21), and improves function in patients with PD (Clin Neuropharmacol 1999; 22:273). Thus, memantine might improve behavior in patients with AD by augmenting dopamine activity.
Cholinesterase inhibitors alone reduce the emergence of behavior problems and ameliorate agitation and other negative behaviors related to AD (Neurology 2004; 63:214 and Am J Psychiatry 2004; 161:532). Adding memantine to cholinesterase inhibitors alleviates agitation even further — all good news for clinicians treating patients with moderate-to-severe AD and behavior problems, especially agitation. Cholinesterase inhibitors, followed by memantine (if not already initiated), should be started before other treatments for behavioral problems in patients with moderate-to-severe AD.
— Andrew E. Budson, MD
Dr. Budson is Associate Neurologist, Division of Cognitive and Behavioral Neurology, Department of Neurology, Brigham and Women's Hospital; and Lecturer in Neurology, Harvard Medical School. He receives honoraria for lectures from the following companies: Pfizer, Eisai, Johnson & Johnson, and Forest Laboratories.
Published in Journal Watch Neurology November 21, 2006
Citation(s):
Cummings JL et al. for the Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006 Jul 11; 67:57-63.
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