Memantine for Alzheimer’s Disease: An Updated Systematic Review and Meta-Analysis
Abstract
Background: The clinical benefit of memantine for Alzheimer’s disease (AD) remains inconclusive.
Objective: This study presents an updated systematic review and meta-analysis of the efficacy and safety of memantine in AD patients.
Methods: Randomized controlled trials examining memantine for AD were included. The primary measures were cognitive function scores, behavioral disturbances scores, and all-cause discontinuation. Effect sizes were calculated using a random-effects model.
Results: Thirty studies (n = 7,567) were identified, evaluating memantine alone versus placebo (N = 11, n = 3,298) and memantine plus cholinesterase inhibitors (M+ChEIs) versus ChEIs alone (N = 17, n = 4,175). Memantine alone significantly improved cognitive function (standardized mean difference, SMD = –0.24) and reduced behavioral disturbances (SMD = –0.16) compared to placebo. In patients with moderate to severe AD, memantine significantly reduced behavioral disturbances without considerable heterogeneity.
Combination therapy (M+ChEIs) produced a greater reduction in behavioral disturbances than ChEIs alone (SMD = –0.20) and showed a trend toward improved cognitive function. In sensitivity analyses restricted to double-blind, placebo-controlled studies, M+ChEIs significantly reduced behavioral disturbances. When only donepezil studies were analyzed, M+ChEIs significantly improved cognitive function. No differences in all-cause discontinuation were observed between treatment groups.
Conclusions: This meta-analysis supports the efficacy and safety of memantine for treating AD, either alone or in combination with ChEIs, especially donepezil.
Keywords: Alzheimer’s disease, behavioral disturbances, cognitive function, memantine, meta-analysis, systematic review
Introduction
Alzheimer’s disease is a major global health concern and a leading cause of dementia. Memantine is one of five approved drugs for AD, indicated for moderate-to-severe stages. It acts as a low-to-moderate affinity, noncompetitive, voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist. By blocking pathologically elevated glutamate activity, it may prevent neuronal dysfunction.
Previous meta-analyses suggested that memantine, especially in combination with ChEIs, may yield benefits, but results were sometimes inconclusive due to small sample sizes and heterogeneity. The increasing number of randomized trials warrants an updated review to provide definitive evidence.
Methods
This systematic review followed PRISMA guidelines and was registered on PROSPERO. Databases including MEDLINE, Cochrane Library, Scopus, and PsycINFO, as well as clinical trial registries, were searched for eligible randomized, placebo- or usual-care-controlled trials of memantine in AD lasting more than two weeks. Studies with over 50% of participants receiving combination therapy were categorized accordingly.
Primary outcomes included cognitive function (measured by MMSE, ADAS-cog, or SIB), behavioral disturbances (Neuropsychiatric Inventory or Behavioral Pathology in Alzheimer’s Disease Rating Scale), and all-cause discontinuation. Secondary outcomes included activities of daily living, global function assessments, staging scales, verbal fluency, and discontinuation due to inefficacy or adverse events.
Two independent reviewers extracted data and assessed methodological quality. Analyses used a random-effects model, and heterogeneity was assessed with the I² statistic. Sensitivity and subgroup analyses were conducted based on study characteristics. Meta-regression explored potential outcome modulators.
Results
From 2,239 search results, 30 studies met the inclusion criteria, encompassing 11 monotherapy trials and 17 combination therapy trials. Seven studies were published in non-English journals.
In monotherapy trials, mean duration was 28.4 weeks, mean patient age was approximately 75 years, and most participants had moderate to severe AD. All were double-blind, placebo-controlled, and typically used memantine 20 mg/day.
In combination therapy trials, mean duration was 29.4 weeks, mean age was 76.5 years, and five studies were open-label. The majority involved donepezil, with others involving galantamine or rivastigmine.
Memantine monotherapy significantly improved cognitive function (SMD = –0.24) and reduced behavioral disturbances (SMD = –0.16) compared with placebo. In moderate-to-severe AD, the reduction in behavioral disturbances was greater (SMD = –0.20) and heterogeneity was lower. Meta-regression indicated that baseline MMSE and proportion of male participants influenced cognitive outcomes, and sample size influenced behavioral disturbance outcomes.
No significant difference was seen for all-cause discontinuation between memantine and placebo. Memantine was associated with a slightly higher incidence of dizziness and somnolence, but lower rates of agitation, hyperkalemia, and psychotic symptoms.
For combination therapy, cognitive improvement showed only a trend (SMD = –0.11), but behavioral disturbances were significantly reduced (SMD = –0.20) versus ChEIs alone. Donepezil-based combination therapy significantly improved cognition (SMD = –0.18) without marked heterogeneity, while combination with galantamine was not beneficial and possibly less effective than galantamine monotherapy.
Combination therapy showed no significant difference in all-cause discontinuation but was linked to more frequent reports of at least one adverse event, somnolence, and weight gain.
Discussion
This comprehensive review supports memantine’s efficacy in improving cognition and behavior in AD, with the largest benefits observed in moderate-to-severe stages and when combined with donepezil. The effects on cognition were modest, consistent with other anti-dementia drugs, highlighting the importance of combination strategies.
Heterogeneity in results was partly explained by disease severity, type of ChEI, and study design quality. The apparent incompatibility with galantamine in one study suggests pharmacological interactions may influence efficacy.
Although adverse effects were relatively minor, clinicians should monitor for dizziness, somnolence, and weight changes. Given the small effect sizes, future research should explore patient subgroups most likely to benefit, optimal timing of intervention, and long-term outcomes.
Conclusions
Memantine is a well-tolerated treatment for AD that can improve cognitive function and reduce behavioral disturbances, especially in moderate-to-severe cases. Combination therapy, particularly with donepezil, may provide added benefits. These findings support memantine as a first-line option for AD, with careful patient monitoring.