Memantine in moderate-to-severe Alzheimer’s disease
Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S and Möbius for the Memantine Study Group;
Commented by , 30 Apr 2003
Aim of the study
Establish the efficacy and safety of memantine, a NMDA receptor antagonist, for the treatment of Alzheimer’s disease (AD) in moderate-to-severe stages.´
Method
Patients with moderate-to-severe AD defined as Mini Mental State Examination (MMSE) scores of 3 to 14 and Global Deterioration Scale (GDS) stage 5 or 6 were randomized to memantine 20mg per day or a placebo during 28 weeks.
The primary efficacy measures were the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev).
The secondary efficacy measures were the Severe Impairment Battery (SIB), the MMSE, the GDS and its companion the Functional Assessment Staging scale (FAST), the Neuropsychiatric Inventory 12 item version (NPI-12), the Resource Utilization in Dementia (RUD).
Safety assessments at specified intervals included neurologic and physical examinations, vital signs, electrocardiography, laboratory tests from blood and urine and recording of adverse events (AE). Treatment differences between baseline and end point were analyzed using Wilcoxon-Mann-Whitney test for independent samples.
Results
252 patients were randomized in 32 U.S. centers; 42 of the 126 assigned to placebo and 29 of the 126 assigned to memantine discontinued their assigned treatment before week 28, mainly because of agitation, which was more common on placebo (overall dropout rate of 28%).
Baseline characteristics were similar between the two groups at baseline, with a mean MMSE of 7.9 for the entire study population. Significant difference for the memantine treated group on last observation carried forward and/or observed cases were found for CIBIC-Plus, ADCS-ADLsev, SIB, FAST, RUD. No significant differences were found for MMSE, GDS or NPI.
On the basis of a predetermined definition of a response in the study protocol, 29% of the patients receiving memantine and 10% of those receiving placebo had a response (P<0.001). No significant AE differences were seen between patients treated with memantine and those on placebo.
Discussion
This study provides evidence that modulation of NMDA receptors and reduction of glutamate-excitotoxicity alleviates symptoms of AD, at the moderate-to-severe stage. Furthermore memantine is very well tolerated.
This novel neurochemical approach is distinct from the cholinomimetic mechanism of currently approved drugs for AD and does not carry dose-limiting gastrointestinal side-effects.
Further analysis is required on the apparent anti-agitation effects of memantine which did not translate into significant changes in total scores for the NPI-12 but may be quite important in the management of patients with AD in these late stages.
Compatibility with cholinesterase inhibitors has been established (Hartmann S, Möbius HJ. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int Clin Psychopharmacol 18, 81-85, 2003) and additive benefit to donepezil has been found in a recently completed randomized study (Farlow MR, Tariot PN, Grossberg GT et al.
Memantine/donepezil dual therapy is superior to placebo/donepezil therapy for treatment of moderate to severe Alzheimer’s disease. Neurology 60 (Suppl 1), A412, 2003). This publication in the New England Journal of Medicine will play a key role in making memantine available to patients with AD in North-America.
It remains to be established if the pattern of efficacy is even better in mild stages of AD as well as in amnestic Mild Cognitive Impairment, considering the potential disease-modifying action of the drug.