Mode of action

Ebixa (memantine) has a unique mode of action and is the only approved N-methyl-D-aspartate (NMDA) receptor antagonist, indicated for the treatment of moderate to severe Alzheimer’s disease (ref. 1).

There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at
NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia (ref. 2).  In Alzheimer’s disease, the NMDA receptors are pathologically activated by excessively high synaptic levels of glutamate – resulting in neuronal cell death and impaired cognitive function. Ebixa restores the physiological glutamatergic signalling by blocking the pathological activation of NMDA receptors while preserving the physiological activation required for learning and memory formation (ref. 1).

It is perhaps not surprising that patients treated with the combination of Ebixa and an AChEI perform better those treated with AChEI monotherapy (ref. 3).  Not surprising in the sense that targeting two pathways, both the glutamatergic and the cholinergic, is naturally expected to be more effective that targeting only one pathway.  Intriguingly, however, instead of a simple additive effect, there is pre-clinical support indicating that Ebixa and donepezil have a synergistic effect (ref 4). 

Combination therapy may potentiate the individual symptomatic improvements owing to memantine and AChEI alone (ref. 5).

References:

1. Parsons CG et al. Neuropharmacology 2007;53(6):699-723

2. Ebixa SmPC

3. Tariot PN et al. JAMA 2004;291:317-324

4. Gauthier S European Journal of Neurology 17(Suppl.3):351–625

5. Atri A et al. Alzheimer Dis Assoc Disord 2008;22:209-221