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Review
. 2025 May 29:19:72-82.
doi: 10.1016/j.ibneur.2025.05.016. eCollection 2025 Dec.

A meta-analysis update evaluating the treatment effects of donepezil alone versus donepezil combined with memantine for Alzheimer's disease

Sajjad Hajihosseini  1 , Seyed Amirali Zakavi  2 , Zahra Farrokhi  3 , Mahnaz Amanzadeh  4 , Parham Panahi  5 , Mina Mahram  6 , Nima Eftekhari  7 , Masoud Noroozi  8 , Mohammad Javad Ebrahimi  9 , Alaleh Alizadeh  10 , Pegah Refahi  11 , Melika Arab Bafrani  12 , Maral Moafi  9 , Niloofar Deravi  13
Affiliations
Review

A meta-analysis update evaluating the treatment effects of donepezil alone versus donepezil combined with memantine for Alzheimer's disease

Sajjad Hajihosseini et al. IBRO Neurosci Rep. .

Abstract

Background: Alzheimer's disease (AD) remains a significant global health problem, with ongoing debates about the most effective treatment approach. While donepezil monotherapy has been traditionally used, recent interest has focused on combining it with memantine. This updated meta-analysis aimed to compare the efficacy of donepezil monotherapy versus its combination with memantine for treating AD.

Method: A literature search was conducted in the PubMed, Scopus, and Google Scholar databases up to February 14, 2024. Randomized controlled trials (RCTs) comparing donepezil monotherapy with donepezil combined with memantine in AD patients were included. The quality of each selected study was assessed using the Joanna Briggs Institute (JBI) risk-of-bias tool. Data on cognitive function, measured using the Mini-Mental State Examination (MMSE) and the Severe Impairment Battery (SIB), were extracted and analyzed using a random-effects model.

Results: A total of four RCTs, including 1930 patients, met the inclusion criteria. Analysis using a forest plot revealed no significant difference in MMSE scores between monotherapy and combination therapy (OR = 0.54, 95 % CI: 0.06-4.60, p > 0.05). However, SIB scores showed a significant improvement with combination therapy (OR = 7.00, 95 % CI: 1.13-43.24, p < 0.05). Both analyses exhibited high heterogeneity (I² = 72 % for MMSE; I² = 89 % for SIB). The funnel plots suggested minor publication bias for the MMSE outcomes, but some asymmetry was observed in the results for SIB.

Conclusion: This meta-analysis suggests that combination therapy with donepezil and memantine significantly benefits patients with severe cognitive impairment, as assessed by the SIB, compared to donepezil monotherapy. However, no significant advantage was observed in MMSE scores. The high heterogeneity among studies highlights the need for cautious interpretation and calls for larger, well-designed randomized controlled trials to further elucidate the comparative efficacy of these two therapeutic approaches in Alzheimer's disease.

Keywords: Alzheimer’s disease (AD); Combination therapy; Donepezil monotherapy; Memantine; Mini-Mental State Examination (MMSE); Severe Impairment Battery (SIB).

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Conflict of interest statement

The authors have no conflicts of interest to declare regarding the study described in this article and preparation of the article.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram.
Fig. 2
Fig. 2
Forest plots of the included studies. (A): Forest plot for Mini-Mental State Examination (MMSE) scores and (B): Forest plot for Severe Impairment Battery (SIB) scores. Abbreviation: CI, confidence interval.
Fig. 3
Fig. 3
Sensitivity analyses of the included studies. (A): Sensitivity analyses for Mini-Mental State Examination (MMSE) scores and (B): Sensitivity analyses for Severe Impairment Battery (SIB) scores. Abbreviation: OR, odds ratio; CI, confidence interval.
Fig. 4
Fig. 4
Funnel plots of the included studies. (A): Funnel plot for Mini-Mental State Examination (MMSE) scores and (B): Funnel plot for Severe Impairment Battery (SIB) scores. Abbreviation: SE, standard error; OR, odds ratio.
See this image and copyright information in PMC

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