Memantine and Donepezil – Unity is Strength

Mechanism of Action

Memantine is a voltage-dependent, moderately-affined non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors. It modulates the effects of pathologically increased tonic levels of glutamate, which can lead to neuronal dysfunction. It is indicated for patients with moderate to severe Alzheimer's disease.

Donepezil is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride has in vitro 1000× higher inhibitory effect on this enzyme than on butyrylcholinesterase, the enzyme mainly found outside the central nervous system. It is indicated for the symptomatic treatment of mild to moderate Alzheimer's disease.

Memantine Therapy in Patients Treated with Donepezil

The aim of a randomized double-blind placebo-controlled clinical trial by authors from Rochester, published in the prestigious journal of the American Medical Association (JAMA), was to compare the efficacy and safety of memantine versus placebo in patients with moderate to severe Alzheimer's dementia who were already on donepezil therapy.

The study involved 404 patients with MMSE (Mini Mental State Exam) scores of 5–14 points. These patients were on stable doses of donepezil. Adding memantine to the combination led to a significant improvement in cognitive functions and daily living activities. Memantine in combination with donepezil was also very well tolerated.

The Effect of Memantine and Donepezil on Behavior

The aim of another study, this time by California authors published in Neurology, was to assess the behavioral effect of memantine in patients with moderate to severe Alzheimer's disease on stable donepezil therapy. In this 25-week double-blind study, patients on donepezil therapy were given either 20 mg of memantine daily or placebo.

To assess the impact of therapy on behavior, the authors used the NPI (Neuropsychiatric Inventory) questionnaire at the start of the study, and at 12 and 24 weeks. This questionnaire evaluates the occurrence, frequency, and severity of hallucinations, delusions, eating disorders, sexual behavior disorders, anxiety, depression, irritability, aggression, sleep disorders, and aberrant motor behaviors. Memantine treatment, compared to placebo, reduced agitation, irritability, and eating disorders.

Conclusion

In addition to cognitive functions, memantine positively influences patient behavior. Adverse side effects are rare. The clinical efficacy of memantine + acetylcholinesterase inhibitor combinations has been demonstrated by multiple clinical studies. This therapeutic approach is widely used; the only disadvantage may be the increased financial costs of treatment.

In conclusion, it is also essential to emphasize the importance of a comprehensive treatment approach to patients with dementia. Reliance should not be placed solely on pharmacological therapy. A combination of biological and psychosocial approaches is necessary. Patients should be guided towards appropriate physical activity and involved in meaningful activities. Cognitive training, such as reading and interpreting texts, word games, and crossword puzzles, is beneficial. Music therapy has also proven effective. The patient's environment should be adjusted to help them orient better.

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Sources:
1. Tariot P. N., Farlow M. R., Grossberg G. T. et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291 (3): 317–324, doi: 10.1001/jama.291.3.317.
2. Cummings J. L., Schneider E., Tariot P. N., Graham S. M.; Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006; 67 (1): 57–63, doi: 10.1212/01.wnl.0000223333.42368.f1.