Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized
Pierre N Tariot1, Martin R Farlow, George T Grossberg
1Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, NY 14620, USA. pierre_tariot@urmc.rochester.edu
Context:
Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed.
Objective:
To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil.
Design, Setting, And Participants:
A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial.
Interventions:
Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks.
Main Outcome Measures:
Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale).
Results:
The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively.
Conclusions:
In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.
Insights
Memantine improved cognition and daily living activities in moderate to severe Alzheimer disease (AD) patients already on donepezil. This Alzheimer disease treatment was well-tolerated, showing better outcomes than placebo.
Area of Science:
- Neuroscience
- Pharmacology
- Geriatrics
Background:
- Memantine is an N-methyl-D-aspartate receptor antagonist.
- Previous trials confirmed memantine's efficacy in monotherapy for moderate to severe Alzheimer disease (AD).
- No prior trials assessed memantine in combination with cholinesterase inhibitors.
Purpose of the Study:
- To evaluate the efficacy and safety of memantine compared to placebo.
- To assess memantine's effectiveness in patients with moderate to severe AD already on stable donepezil treatment.
Main Methods:
- A 24-week, randomized, double-blind, placebo-controlled trial involving 404 patients with moderate to severe AD.
- Patients had Mini-Mental State Examination scores between 5 and 14 and were on stable donepezil doses.
- Primary outcomes included changes in Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living (ADCS-ADL19) scores.
Main Results:
- Memantine showed significant improvements over placebo in SIB scores (P<.001) and ADCS-ADL19 scores (P=.03).
- Global outcome measures (CIBIC-Plus) also favored memantine (P=.03).
- Fewer patients discontinued memantine due to adverse events (7.4%) compared to placebo (12.4%).
Conclusions:
- Memantine combination therapy significantly improved cognitive function, daily living activities, and global outcomes in AD patients on donepezil.
- Memantine was well-tolerated in this patient population.
- These findings support memantine as a valuable treatment option for moderate to severe Alzheimer disease.
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