Memantine with Donepezil Superior to Single Treatment in Moderate to Severe Alzheimer's Disease

Findings from a study on the efficacy of memantine only, donepezil only, or memantine and donepezil together for moderate to severe Alzheimer’s disease were presented during a poster session at the 2013 Annual Meeting of the American Neurological Association in New Orleans, LA. The study’s lead author is Stephen Graham, PhD, Senior Director at Forest Research Institute.

The US Food and Drug Administration has approved two drugs for the treatment of moderate-to-severe Alzheimer’s disease (AD). The cholinesterase inhibitor donepezil is currently approved for AD in all severity levels, and it is often the first medication such patients receive. Memantine is an uncompetitive antagonist of N-methyl-D-aspartate receptors. It is approved for moderate to severe AD, and it can be prescribed alone or in combination with a cholinesterase inhibitor.

Several clinical trials and longitudinal studies have shown significant benefits from treatment with a cholinesterase inhibitor plus memantine, but a small randomized trial produced conflicting results. Thus, the authors of this current study pooled all available data from four large randomized trials to compare the efficacy of patients treated with memantine only, donepezil only, placebo only, or memantine with donepezil. The researchers did not analyze the effects of treatment with cholinesterase inhibitors other than donepezil.

To evaluate efficacy of the drugs, the four studies used the Severe Impairment Battery Test (SIB), the Alzheimer’s Disease Cooperative Study— Activities of Daily Living Scale (ADCS-ADL), the Neuropsychiatric Inventory (NPI), and the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus).

The four studies in this analysis were all 6-month, randomized, multicenter, parallel-group, double-blind, placebo-controlled studies of patients with moderate to severe AD. In their final analysis, the researchers adjusted for baseline characteristics such as age, sex, race, weight, and Mini-mental state examination score.

Graham and colleagues found that patients given memantine and donepezil significantly outperformed the other three groups in cognition (based on the SIB scores). Both single therapies also significantly outperformed the placebo group. The donepezil-only group also did significantly better than the memantine-only group.

In terms of function (as measured by the ADCS-ADL), the memantine and donepezil group also outperformed the other three groups. Both monotherapies significantly outperformed the placebo, but there was no significant difference between the two monotherapies.

The NPI showed significantly improved behavioral outcomes in the combined therapy group compared to the other three groups. On this measure, the other three groups did not significantly differ.

Global Clinical Status as measured by the CIBIC-Plus also showed significant improvements in the combined therapies group compared to the other three groups. Both monotherapy groups outperformed the placebo, though they did not significantly differ from each other.

Memantine combined with donepezil showed superiority along all four clinical measures. The study authors advise appropriately powered, long-term prospective studies to evaluate the value of add-on therapy in Alzheimer’s disease. Currently the FDA has approved donepezil as a stand-alone or dual therapy treatment; memantine is currently only approved for use as a monotherapy drug.

Forest Laboratories, Inc. sponsored the study.