ArticleAlzheimer's research & therapy2015
Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis.
Article in Alzheimer's research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
36 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Indirect Comparison of the Efficacy of Zanubrutinib vs Ibrutinib and Acalabrutinib in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-Up.Advances in therapy · 2026Pooled it
- Memantine for dementia.The Cochrane database of systematic reviews · 2019Pooled it
- Memantine ER Maintains Patient Response in Moderate to Severe Alzheimer's Disease: Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors.Alzheimer disease and associated disordersTrial
- Dynamic GCS Trajectories and Mortality Risk in ICU Patients with Stroke: A Multicenter, Age-Stratified Study.Neurocritical care · 2026Article
- Donepezil Research in Cognitive Impairment: A Bibliometric and Scientometric Analysis of Global Trends and Pharmacological Perspectives.Brain and behavior · 2026Article
- A meta-analysis update evaluating the treatment effects of donepezil alone versus donepezil combined with memantine for Alzheimer's disease.IBRO neuroscience reports · 2025Review
- Dynamic associations of cholinesterase inhibitors and memantine with cognitive trajectories in individuals with Alzheimer's or mixed dementia: a real-world analysis using the quality registry SveDem.Alzheimer's research & therapy · 2025Observational
- Differential cognitive enhancer effects of acetylcholinesterase inhibitors and memantine on age-related deficits in vigilance and sustained attention: a preclinical validation study.Behavioral and brain functions : BBF · 2025Article
- Primary Progressive Aphasia Treatment: Current Treatment Options in Neurology Article Topic: Management of Primary Progressive Aphasia.Current treatment options in neurology · 2025Review
- Combined use of Donepezil and Memantine increases the probability of five-year survival of Alzheimer's disease patients.Communications medicine · 2024Article
- Antidementia Medication Use in Nursing Home Residents.Journal of geriatric psychiatry and neurology · 2024Article
- Article
- Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Cell Membrane Biomimetic Nanoparticles with Potential in Treatment of Alzheimer's Disease.Molecules (Basel, Switzerland) · 2023Review
- Current Pharmacotherapy and Multi-Target Approaches for Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer's disease: A randomized, double-blind, phase 2, proof-of-concept study.Alzheimer's & dementia (New York, N. Y.) · 2022Article
- Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice.International journal of molecular sciences · 2021Article
- Diagnosis and Treatment of Alzheimer's Disease:: An Update.Delaware journal of public health · 2021Article
- Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.Journal of internal medicine · 2021Review
- New approaches to symptomatic treatments for Alzheimer's disease.Molecular neurodegeneration · 2021Review
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionTreatment in moderate or severe Alzheimer's disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index.
methodsData were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline ("snapshot analysis"), performed using a mixed-effects model with repeated measures (MMRM).
resultsOver the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: -74.3 versus -28.2, P = 0.003; CIBIC-Plus: -2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: -74.3 versus -7.4, P <0.001; CIBIC-Plus: -2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (-0.9), P = 0.407; versus memantine-only (-12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both.
conclusionsThis large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.
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