Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil.
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S and Gergel I; Memantine Study Group.;
Commented by , 23 Feb 2004
Aim of the study
To compare the efficacy and safety of memantine vs. placebo in patients with moderate to severe Alzheimer’s disease (AD) already on a stable dose of the acetylcholinesterase inhibitor (AChEI) donepezil.
Method
404 community-living patients from 37 sites in the United States with moderate to severe probable AD defined as MMSE 5 to 14 on donepezil 5 or 10mg QD for at least 6 months were randomized to memantine 10mg BID or to placebo for 24 weeks.
The main outcome measures werechanges from baseline on the Severe Impairment Battery (SIB, possible score range 0-100) and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL; possible score range 0-54).
Secondary outcomes included a Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus; possible score range 1-7), the NeuroPsychiatric Inventory (NPI; possible score range 0-144) and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale).
Results
322 (80%) completed the study, 85.1% in the donepezil with memantine group and 74.6% on the donepezil with placebo group; 198 vs. 197 were included in the primary analysis using a Last Observation Carried Forward approach.
Statistically significant differences were found for all outcomes at 24 weeks:
- SIB change from baseline was 0.9 on memantine and -2.5 on placebo (P <0.001)
- ADCS-ADL change was -2.0 vs. -3.4 (P=0.03), CIBIC-Plus was 4.41 vs. 4.66 (P=0.03)
- NPI total score was -0.1 vs. 3.7 (P=0.002)
- BGP Care Dependency Subscale was 0.8 vs 2.3 (P=0.001)
Treatment discontinuation because of adverse events for memantine vs placebo were 15 (7.4%) vs. 25 (12.4%).
Discussion
This study is important in many respects. It proved the safety and efficacy of combination therapy in AD using medications with different mechanisms of action. It demonstrated the validity of appropriate measurement tools in moderate to severe stages of AD, in particular the value of an ADL scale as a primary outcome, which has been proposed by Canadian and European Regulatory Agencies.
Noteworthy and perhaps not emphasized enough in this very well written article is the large effect size on the NPI total score, indicating a beneficial effect of memantine on behavioral symptoms, a most important feature of later stages of AD.
Secondary analysis of the NPI individual items will help in defining the pattern of improvement of a NMDA receptor antagonist, which may be different from behavioral effects observed with AChEI, in particular donepezil at similar severity stages (1). These studies will greatly influence management guidelines and clinical practice for the moderate to severe stages of AD.
References
1. Gauthier S, Feldman H, Hecker J, Vellas B, Ames D, Subbiah P, Whalen E, Emir B. The Donepezil MSAD Study Investigators Group. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. International Psychogeriatrics, 14, 389-404, 2002