How Does Memantine Currently Stand in Alzheimer's Disease and Other Dementias

Memantine is used in the treatment of moderate to severe Alzheimer's disease, and often in case of mild forms as off-label use. According to published studies so far, does this drug have the desired effect? Do its benefits outweigh the risks? Does it also have significance in patients already taking cholinesterase inhibitors?

Mechanism of Action

Memantine is a voltage-dependent, non-competitive NMDA (N-methyl-D-aspartate) receptor antagonist with moderate affinity. It modulates the effects of pathologically elevated tonic levels of glutamate, which can lead to neuron dysfunction. Generally, it is very well tolerated. Rare adverse effects may include headaches, dizziness, excessive excitement or sedation, and hallucinations.

Analyzed Studies

The meta-analysis included double-blind, randomized, placebo-controlled studies listed in the ALOIS registry (Cochrane Dementia and Cognitive Improvement Group's register of trials) up to March 25, 2018, where patients took 20 mg memantine/day or 28 mg extended-release memantine/day. The studies had to last at least 6-7 months, and researchers separately examined mild, moderate, and severe forms of Alzheimer's dementia.

Results

Efficacy

For moderate to severe Alzheimer's disease, 14 studies with a total of 3700 patients demonstrated a significant positive effect of memantine on cognitive functions, activities of daily living, mood, and behavior compared to placebo. The risk of discontinuing treatment in patients receiving memantine was identical to that in patients on placebo. Combined treatment with memantine and cholinesterase inhibitors did not show a greater effect compared to memantine alone.

For 600 patients (4 studies) with mild Alzheimer's disease (Mini Mental State Exam – MMSE score 20–23), no effect of memantine was demonstrated compared to placebo.

A total of 2 studies involving approximately 750 participants examined the effect of memantine on mild and moderate vascular dementia. Their analysis suggests a possible effect of memantine, particularly concerning cognitive functions, mood, and behavior. Regarding other neurodegenerative diseases (Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, AIDS-related dementia), an effect of memantine was also suggested – though not conclusively proven.

Safety Profile

Compared to placebo, memantine has a 1.6× higher likelihood of causing dizziness and a 1.3× higher likelihood of causing headaches. However, the frequency of falls is comparable between memantine and placebo cases.

Conclusion

The recent meta-analysis confirmed that patients with moderate to severe Alzheimer's disease showed significant improvements in tests assessing cognitive functions, overall performance, psychological symptoms, and behavioral disorders after receiving memantine compared to the placebo group. Current knowledge thus affirms the role of memantine in the treatment of this disease.

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Source: McShane R., Westby M. J., Roberts E. et al. Memantine for dementia. Cochrane Database Syst Rev 2019 Mar 20; 3 (3): CD003154, doi: 10.1002/14651858.CD003154.pub6.