Memantine, Acetylcholinesterase Inhibitors, and Their Combination in the Treatment of Alzheimer's Disease − Findings from Meta-Analyses

Alzheimer's Disease and Its Treatment

The therapy of Alzheimer's disease (AD) remains quite challenging. According to recent studies, the preclinical phase of AD is considered critical for initiating therapeutic intervention; however, diagnosing the disease during this phase is very difficult. Furthermore, all available pharmacotherapy options mainly alleviate symptoms rather than fully suppress them.

In the treatment of AD, the acetylcholinesterase inhibitor (AChEI) donepezil, an effective drug in symptomatic treatment, and the N-methyl-D-aspartate receptor (NMDA) antagonist memantine, which improves memory, awareness, and daily activities of patients, are often used. Both drugs are used in monotherapy or in combination. 

Comparison with Placebo

A 2020 network meta-analysis focused on comparing monotherapy and combination treatment of donepezil and memantine versus placebo in patients with AD. The analysis included 54 clinical studies. The key findings were as follows:

• Combination therapy is more effective than placebo in improving cognition on the Alzheimer's Disease Assessment Scale − Cognitive Subscale, with a mean difference (MD) of −5.01 (95% credibility interval [CrI] −10.73 to 0.86), and in the Severe Impairment Battery test, where the MD was 9.61 (95% CrI 2.29–16.97).
• Combination therapy was also more effective than placebo in improving overall condition according to the Clinical Global Impression (CGI) scale, with an MD of −2.88 (95% CrI −6.04 to 0.40), daily activities according to the Activities of Daily Living (ADL) questionnaire and the Alzheimer's Disease Cooperative Study − Activities of Daily Living (ADCS‐ADL) scale, with an MD of 13.06 (95% CrI −34.04 to 58.92), and neuropsychiatric symptoms according to the Neuropsychiatric Inventory (NPI) questionnaire, with an MD of −6.84 (95% CrI −10.62 to −2.82). In all assessed areas, combination therapy was also superior to monotherapy.
• Regarding acceptability, combination therapy showed a higher probability of treatment discontinuation compared to memantine and placebo; monotherapy with memantine was best tolerated by patients.

Combined Therapy or Monotherapy?

Another source is a meta-analysis of randomized controlled trials comparing the efficacy and safety of combination therapy with AChEI and memantine versus monotherapy with individual drugs in patients with moderate to severe AD. Data from 2604 patients from 9 randomized controlled trials were included in the analysis: 

• In short-term follow-up (6 months), combination therapy had a significantly greater effect on cognition compared to monotherapy with AChEI, with a standardized mean difference (SMD) of 0.20 (95% confidence interval [CI] 0.05–0.35; low quality of evidence [QoE]), and also showed a better clinical global impression (CGI: SMD −0.15; 95% CI −0.28 to −0.01; moderate QoE). However, a significant benefit in daily activities (SMD 0.09; 95% CI −0.01 to 0.18; moderate QoE) or behavioral and psychological symptoms of dementia (MD −3.07; 95% CI −6.53 to 0.38; low QoE) was not confirmed.
• No significant difference was observed in the occurrence of adverse events.
• There is insufficient data from long-term follow-up (> 9 months).

Conclusion and Discussion

The first meta-analysis showed that combination therapy with memantine and donepezil demonstrated better outcomes in cognition, overall condition, daily activities, and neuropsychiatric symptoms compared to monotherapy and placebo, but had lower acceptability. According to the second meta-analysis, combination therapy is significantly more effective than monotherapy in improving cognition and overall condition, but the real significance of these results is uncertain because the overall quality of evidence was low. Further randomized controlled trials with long-term follow-up focusing on functional outcomes or delaying placement of patients in care facilities are needed to validate the benefits of combination therapy in the treatment of AD.

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Sources:
1. Guo J., Wang Z., Liu R. et al. Memantine, donepezil, or combination therapy − what is the best therapy for Alzheimer's disease? A network meta-analysis. Brain Behav 2020; 10 (11): e01831, doi: 10.1002/brb3.1831.
2. Glinz D., Gloy V. L., Monsch A. U. et al. Acetylcholinesterase inhibitors combined with memantine for moderate to severe Alzheimer's disease: a meta-analysis. Swiss Med Wkly 2019; 149: w20093, doi: 10.4414/smw.2019.20093.