Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer’s dementia: a pooled area under the curve analysis

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.

Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer’s Disease and Related Dementias and Strategic Implications for Stakeholders

“…Moreover, despite improvements in the quality of care for patients and the identification of several potentially modifiable risk factors [118], the causal mechanisms of ADRD are complex, multifactorial and not fully elucidated, and no disease-modifying intervention is available to delay, halt, or reverse the underlying pathology. Approved symptomatic treatments for AD (i.e., cholinesterase inhibitors and memantine), on average modestly improve or stabilize dementia-related cognitive and behavioral symptoms over short intervals of 6-12 months, and mitigate inevitable clinical decline over the course of several years [119][120][121][122]. Driven by greying populations across the globe, unrelenting growth in the prevalence of ADRD will therefore only magnify the human, societal, and economic burden of the disease-potentially overwhelming increasingly fragile support systems beyond the threshold of sustainability.…”

Effects of neural stem cell transplantation in Alzheimer’s disease models

“…1). This combined therapy appears to be more effective [11]. However, it also carries greater possibility of occurrence of more serious side effects such as seizure, slow heartbeats and severe gastrointestinal problems compared with single drug treatment [12].…”

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

“…The organic phase was evaporated under reduced pressure, and the aqueous phase was 4.1.8. N-(6-Chloro-1,2,3,4-tetrahydroacridin-9-yl)-N'- (9-fluoro-7H-5,6,8,9,10,11hexahydro-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-1, 5- 4.1.9. tert-Butyl (9-fluoro-7H-5,6,8,9,10,11-hexahydro-2-nitro-5,9:7,11dimethanobenzo[9]annulen-7-yl)carbamate (15) To a mixture of amine 14 [59] (496 mg, 1.79 mmol) and 2N NaOH (1.4 mL) in THF 4.1.10. tert-Butyl (2-amino-9-fluoro-7H-5,6,8,9,10,11-hexahydro-5,9:7,11dimethanobenzo[9]annulen-7-yl)carbamate (16) A suspension of the nitro derivative 15 (583 mg, 1.54 mmol) and PtO2 (48 mg, 0.12 mmol) in EtOH (100 mL) was hydrogenated at 1 atm of H2 at room temperature for 4 h. Hz, 1H, 4-H); 13 4.1.11. N-(7-Amino-9-fluoro-7H- 5,6,8,9,10,11-hexahydro-5,9:7,11-…”

“…On the one hand, the combination of the AChE inhibitor donepezil with the glutamate NMDA antagonist memantine has proven to lead to additive or synergistic effects in mouse models and AD patients [15][16][17], and a fixed-dose combination of both drugs (Namzaric®) is now being used as the standard of care to treat dementia associated with moderate to severe stages of the disease [18,19]. On the other hand, AD is one of the therapeutic areas where the development of multitarget drugs has been more intensively pursued in the past decade [20][21][22].…”