Our newest research-advisor Prof. Randall J. Bateman, MD.
Memantine, Donepezil, or Combo
Pat & Dennis Bender Early Dementia Diagnosis & Prognosis Fund
J. Dennis Bender
Office, Home & Cell Phone: 859-391-5226
5726 La Jolla Blvd. – Suite 311
La Jolla, CA 92037-7345
&
Office - 100 Riverside Pl. - Suite 303
Covington, KY 41011-5711
We support the development of improved diagnostic methods for the early detection and diagnosis of MCI, Alzheimer’s, vascular and other dementias, their likely prognosis, and best treatment. We focus on the development of Bayesian-based medical-decision-support systems, comparative-effectiveness research, and the better utilization of these for the above. (After incorporating in KY as a 501(c)(3) in 2002, we dissolved that entity for a simplified form of two entirely self-financed, private philanthropies utilizing a Vanguard Charitable Trust for making annual-research-grants for early-dementia-detection and its correct differential-diagnosis and likely-prognosis. They will continue on, after I am gone, either mentally or physically. Prof. Randall Bateman is the first of our fund’s research advisors.
See: https://www.alz.org/alzheimers-dementia/research_progress/earlier-diagnosis )
www.JDBender.com – EMS/eVTOL Experimental Aviation Fund (Vanguard Charitable Trust)
www.JDBender.org – Dementia Diagnosis Fund (Vanguard Charitable Trust)
“Memantine-plus-donepezil showed superior outcomes for cognition, global-assessment, daily-activities, and neuropsychiatric-symptoms, but lower-acceptability than monotherapy and placebo. Combination-therapy may be more cost‐effective, because memantine-slows-the-progression-of-AD.”
I have often written about the usefulness of network-meta‐analyses and similar analytical approaches. Here is a perfect example answering exactly the question I wondered about, given my own situation. Such studies are extremely useful, and I highly recommend paying attention to them, as I certainly am doing in choosing my own treatment regime. These research studies are expensive to execute and require a tremendous amount of largely-thankless work, so at least I am thanking Zhenyu Wang, [Department of Rehabilitation Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160, China.
Email: moc.361@rduynehzgnaw] and all of the others who participated and noting how much we enjoyed are vacation travels in China.
Memantine and donepezil are frequently used in both MCI and dementia treatment, both as monotherapy and in combination. This multiple-treatment-comparison-meta‐analysis assessed the efficacy of these regimens and placebo in the management-of-AD. This is the same combination that I am currently taking, from previously only using low-dose-donepezil. One thing to be careful of is to ignore the timing misinformation on the label. Take it in the morning, not the evening, as usually labeled, unless there are noticeable negative daytime side-effects, in which case switch it to evening dosage. Under US Medicare, these two inexpensive-generic-drugs are essentially no-cost, at least under my own Humana Medicare-Plus plan.
Brain Behav. 2020 Nov; 10(11): e01831. - Published online 2020 Sep 10. doi: 10.1002/brb3.1831 - PMCID: PMC7667299 - PMID: 32914577
Memantine, Donepezil, or Combination-Therapy—What is the Best Therapy for Alzheimer’s-Disease? A Network-Meta‐Analysis
Jiaxun Guo, 1 Zhenyu Wang,
1 Ruishu Liu, 2 Yunxia Huang, 1 Nan Zhang, 1 and Ruihan Zhang 1
Abstract
Introduction Alzheimer’s-disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple-treatment-comparison meta‐analysis assessed the efficacy of these regimens and placebo in the management-of-AD.
Methods We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo‐controlled-trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global-assessment, daily-activities, neuropsychiatric-symptoms, adverse-events, and the acceptability and cost of these treatment regimens.
Results Of 936 records screened, we included 54 trials in this analysis. The combination-therapy was more-effective in improving-cognition (mean-difference (MD)‐5.01, 95%-credible-interval (95% Crl) −10.73 to 0.86 in the Alzheimer’s-Disease Assessment Scale‐Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global-assessment (MD −2.88, 95% Crl −6.04 to 0.40), daily-activities (MD 13.06, 95% Crl −34.04 to 58.92), and neuropsychiatric-symptoms (MD −6.84, 95% Crl −10.62 to –2.82) compared with placebo. Memantine was more-acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22).
Keywords: Acceptability-of-healthcare, Activities-of-daily-living, Alzheimer-disease, Cognitive-function, Cost-effectiveness, Disease-progress
Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple-treatment-comparison-meta‐analysis assessed the efficacy of these regimens and placebo in the management-of-AD.
Introduction With aging-populations worldwide, the prevalence of chronic-diseases, including Alzheimer’s-disease (AD), increases continuously. Alzheimer’s-disease (AD), the most-common cause of dementia (Alzheimer’s Association, 2020), heavily burdening patients, families, and aging societies worldwide. According to the “World Alzheimer Report, 2015: The Global Impact of Dementia (World Alzheimer Report, 2015),” over 35-million people currently live with AD worldwide. Moreover, the number of patients is estimated to rise to 60 million by 2050 (Ansari, Satar, Perveen, & Ashraf, 2017). AD is a chronic degenerative brain disease, but its cause is not entirely clear at this point. Symptoms of AD include memory loss, difficulty in completing familiar tasks, problems in understanding visual images and spatial relationships, and mood and personality changes, among others(Alzheimer’s Association, 2019). Current studies (Albert et al., 2011; Sperling et al., 2011; Tao et al., 2020) show that before patients are diagnosed with AD, they have experienced a long period of preclinical AD, which is considered to be a critical phase for therapeutic interventions. The pathological cascade does not synchronize with the emergence of clinical symptoms of AD. However, some individuals with the pathological cascade process may not progress to AD. Before AD, there is also the stage of mild cognitive impairment (MCI) of variable length and means that patients will live for many years with this disability before death. Furthermore, there is no must of MCI progressing to AD, and it increases the risk for AD.
Thus, it is difficult to diagnose the condition during the preclinical-phase, and many AD-patients get diagnosed only during the time of symptomatic-predementia-phase, which also refer to MCI due to AD. Unfortunately, all of the currently available pharmacologic treatments are easing rather than curing the symptoms. Donepezil, an acetylcholinesterase-inhibitor (AChEI), is supported by sufficient data (Haake, Nguyen, Friedman, Chakkamparambil, & Grossberg, 2020) to prove its effect-of-symptomatic-treatment. Memantine, an N‐methyl‐D‐aspartate-(NMDA)-receptor-antagonist, has also been confirmed to be effective in improving memory, awareness, and daily-activities of AD-patients (Conway, 2020).
The U.S. Food and Drug Administration (FDA) has approved the use of Namzaric (Allergan Inc., Dublin, Ireland), a combination-of-donepezil-and-memantine-as-an-extended-release-preparation for the combination-therapy of patients with moderate‐to‐severe-AD. However, the European Medicines Agency (EMA) declined the approval of Acrescent (Lundbeck Inc., Copenhagen, Denmark), a fixed‐dose combination of memantine-hydrochloride and donepezil-hydrochloride for use in moderate‐to‐severe AD because of a lack of evidence for the effectiveness of the combination-therapy (Calhoun, King, Khoury, & Grossberg, 2018; Withdrawal assessment report, 2012).
Some studies (Ashraf et al., 2019; Marta, Katarzyna, & Jerzy, 2017; Sung, Lin, Liu, Su, & Tsai, 2020; Yoshiyama, Kojima, Ishikawa, & Arai, 2010 found indications of a potential-infectious-agents and chronic-inflammation of AD and consecutively sought to treat AD-patients with antimicrobial-therapy and anti‐inflammatory therapeutics. However, because of the limited range of antiviral-preparations and the immaturity of these theories, this approach is not-widely-used in clinical. Thus, these traditional antidementia-medications are still of great significance in the clinical-setting.
Therefore, we performed a systematic-review and network-meta‐analysis to compare the effect, acceptability, adverse-events, and cost of memantine and donepezil, both given individually and in combination, with the aim to provide a better choice or new approach for the treatment-of-AD-patients. [My interest exactly!]
Outcomes The outcomes of this study included the efficacy, acceptability, and costs-of-therapy. Considering the characteristics of AD, we divided efficacy into 4 aspects: cognition, global-assessment, daily-activities, and neuropsychiatric-symptoms. Outcomes were assessed using Alzheimer's Disease Assessment Scale‐cognition subscale (ADAS‐cog), the Severe Impairment Battery (SIB) for cognition, the change in the clinical global impression (CGI) for the overall-assessment, Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL) and Activities of Daily Living (ADL) for daily-activities, and the Neuropsychiatric Inventory (NPI) for neuropsychiatric-symptoms (Farlow et al., 2013; Panisset, Roudier, Saxton, & Boller, 1994).
Acceptability was measured as treatment discontinuation for any reason cause the dropouts referred to different circumstances such as unsatisfied with treatment, deterioration of patient's condition, or unbearable adverse events.
Costs discussed in the conclusion involved both the direct costs of treatment and caregivers and the indirect costs, such as inability-to-work.
A validated method was used in the assessment-of-trials with a lack-of-information-or-specific-data (Furukawa, Cipriani, Barbui, Brambilla, & Watanabe, 2005; Zhang, Kang, & Chen, 2016).
Data Analysis We conducted a network-meta‐analysis to compare the efficacy as the mean and standard-deviation (SD), assuming that the heterogeneity of each included trial was comparable and ran both a consistency-model and inconsistency-model. By comparing the potential-scale-reduction-factor (PSRF) of two models, and the median (with 95% credible-interval (Crl)) between random-effects standard-deviation and inconsistency standard deviation to test and verify the choice of consistency model.
Secondly, we chose pooled-odds-ratios (ORs) to assess acceptability because of the dichotomy-of-results. The domains were pooled-separately, and different types of data would not be pooled for the lack-of-comparability. The network-meta‐analysis was accomplished through ADDIS-software (ADDIS Software PLC, Addis Ababa, Ethiopia) that was adopted to analyze acceptability.
Finally, we reviewed the observed-adverse-events of included studies and reported costs from one study.
Results The combination-treatment-of-memantine-plus-donepezil, memantine-alone, and donepezil-alone all showed a statistically-significant-difference compared with placebo in both the ADAS‐cog and SIB scales. The ADAS‐cog showed improvement of scores reduced. From the rank-possibility that the combination-therapy was in the forth rank (MD5.01, 95% Crl −0.86 to 10.73), followed by donepezil in the third-rank (MD2.93, 95% Crl −2.86 to 8.58), and memantine was in the second-rank (MD1.33, 95% Crl −4.18 to 6.64) than placebo, as illustrated in Figure 3a.
Global Assessment We used the change-in-the-CGI for the global-assessment-of-AD and reducing-scores presented treatment-effect. Therefore, lower-rank means better-effect. The consistency-model was appropriate for a PSRF of 1, and the median (95% Crl) of the random-effects-SD and inconsistency-model-SD was close to each other. Figure 4 shows that combination-therapy in rank 4 was more-effective than donepezil (rank 3 (MD‐2.51, 95% Crl −6.07 to 1.09)) or memantine (rank 2.
Network-meta‐analysis on Alzheimer's-disease treatment. Assessment of the change in the clinical-global-impression. Don, donepezil; mem, memantine; mem + don, combination of donepezil and memantine; CGI, clinical global impression; MD, standardized-mean-difference; Crl, credible-interval (MD‐2.59, 95% Crl −4.85 to −0.21)) alone, and placebo was in first rank (MD2.88 95% Crl −0.40 to 6.04), worse than combination therapy.
Daily Activities Some trials chose ADCS‐ADL and others ADL to evaluate the effect of treatment on daily-activities in AD. To expand the sample-size, we merged two scales into one. We ran a node-split and found that the p‐values of all comparisons were above 0.05, and indirect-effects were all zero. Therefore, we chose the consistency-model that showed in Figure 5
Network meta‐analysis on Alzheimer's disease treatment. Assessment of Alzheimer's Disease Cooperative Study‐Activities of Daily Living and Activities of Daily Living. Don, donepezil; mem, memantine; mem + don, combination of donepezil and memantine; ADCS‐ADL, Alzheimer's Disease Cooperative Study‐Activities of Daily Living; ADL, Activities of Daily Living; MD, standardized mean difference; Crl, credible interval that combination therapy was more effective in rank 1(MD16.27, 95% Crl −8.06 to 40.52) than donepezil alone (rank 4) and memantine more effective in rank 2(MD3.89, 95% Crl −40.40 to 46.93) than placebo.
Neuropsychiatric Symptoms NPI was accomplished by caregivers that evaluated the neuropsychiatric-symptoms of AD-patients, as well as the difficulties-in-caring-for-patients, reducing-grades indicated improvement of symptoms and fewer-difficulties-in-caring. The NPI accorded with the consistency-model, and the result was exhibited in Figure 6
Network meta‐analysis on Alzheimer's disease treatment. Assessment of Neuropsychiatric Inventory. Don, donepezil; mem, memantine; mem+don, combination of donepezil and memantine; NPI, Neuropsychiatric-Inventory; MD, standardized-mean-difference; Crl, credible-interval
Combination-therapy was in first-rank (MD‐4.16, 95% Crl −8.06 to –0.15) more-effective than memantine alone, memantine was in rank 2 (MD −1.40, 95% Crl −4.86 to–1.96) more-effective than donepezil, and donepezil was in rank 3 (MD −1.28, 95% Crl −4.43 to –2.00) more-effective than placebo in rank 4.
Acceptability The PSRF of the consistency model ranged from 1.01 to 1.03, but all were below 1.05, which was tolerable. The differences between the random-effects-SD and inconsistency model-SD were acceptable, and we adopted the consistency-model. Figure 7
Network meta‐analysis on Alzheimer's disease treatment. Analysis of acceptability. Don, donepezil; mem, memantine; mem + don, combination of donepezil and memantine. MD, standardized mean difference; Crl, credible interval
shows that memantine had higher acceptability (MD 0.93, 95% Crl 0.69 to 1.22) than placebo, while the difference between donepezil and combination-therapy was small (MD 1.07, 95% Crl 0.31 to 3.3). [My situation is going from donepezil to combo-therapy.]
Costs One study (Martin et al., 2017) had performed a cost‐effectiveness-analysis comparing donepezil, memantine, donepezil-plus-memantine, and placebo. Martin et al. compared outcomes and costs of 295 community‐dwelling patients with moderate‐to‐severe AD after 52-weeks and found if one ignored the cost‐effectiveness-model and only focused on the unadjusted-costs (consisting of health and social-care costs), costs were highest in the placebo-group at a total of £7,964-per-person-per-year, followed by memantine-plus-donepezil at £5,892, and donepezil-alone at £5,418. Memantine costs were lowest at £4,864. When taking into account effectiveness, the combination-therapy showed no superiority in cognition, daily-activities, and quality-of-life than memantine or donepezil alone calculated by The National Institute for Health and Care Excellence (NICE) thresholds for Quality‐adjusted-life-years-(QALY)-gains.
3.4. Adverse-Events Adverse-events were similar across the 54 included trials. They manifested as dizziness, agitation, confusional-state, diarrhea, falls, and emotional-problems, among others. No adverse-events were related to death.
4 Discussion This network-meta-analysis of 54 studies, conducted in Asia, North America, and Europe, included patients randomly assigned to donepezil, memantine, donepezil–memantine, and placebo. It considered both English and Chinese publications, which expanded the scope and made the conclusions more reliable than an analysis of English articles only. The combination therapy of donepezil and memantine was most effective in improving cognition, global assessment, activities of daily living, and neuropsychiatric symptoms in AD patients (mostly moderate-to-severe AD), and the acceptability was slightly higher than that of donepezil and lower than that of memantine.
A previous review (Calhoun et al., 2018) found that the combination of donepezil–memantine had benefits in clinical efficacy over donepezil alone, although it was more expensive than monotherapy. Other two reviews (Farrimond, Roberts, & McShane, 2012; Gauthier & Molinuevo, 2013) reviewed the efficacy in cognition, daily activities, global assessment, and burden of care of adding memantine to different AChEIs (donepezil was one of these AChEIs) and drew positive conclusions. A meta-analysis by Chen et al. (Chen et al., 2017) found that memantine combined with donepezil had better effects on cognitive and overall function and behavioral and psychological symptoms than donepezil alone. Our network meta-analysis involved studies until 2020 in both English and Chinese and also took memantine into analysis.
The ADAS-cog and SIB are both used to measure the severity of AD. The ADAS-cog is usually used in mild or moderate and even preclinical AD, whereas the SIB is more frequently used in severe dementia (Kueper, Speechley, & Montero-Odasso, 2018; Qazi et al., 2005). We adopted both the ADAS-cog and SIB scales in this meta-analysis, and the combination therapy of memantine plus donepezil showed excellent results for both scales, indicating its efficacy in mild and severe dementia. Donepezil showed an advantage over memantine in mild-to-moderate AD, whereas memantine was more effective than donepezil in severe AD.
The combination therapy of memantine plus donepezil achieved better outcomes than placebo in the CGI. The CGI scale combines the severity of illness, global improvement, and efficacy index. Here, the combination of memantine plus donepezil demonstrated its overall superiority to the full extent in clinical global impression.
The ADCS-ADL and ADL scales contain eating, going to the toilet, bathing, showering, and other skills of daily living. They reflect not only the quality of life of patients but also the quality of life of their caregivers (if existent). The combination of memantine plus donepezil was the most effective regimen in this regard, too, followed by memantine. Donepezil alone was less effective than placebo.
The NPI is one of the most commonly used scales to assess the neuropsychiatric symptoms of AD and is also associated with the progress of dementia (Cummings et al., 1994; Mallo et al., 2020). Neuropsychiatric symptoms present a particularly heavy burden for both patients themselves and their caregivers (Lyketsos et al., 2011). Therefore, the efficacy of the combination of memantine plus donepezil in this aspect may delay the progression in patients with AD. Previous studies (Dou et al., 2018; Trinh, Hoblyn, Mohanty, & Yaffe, 2003) have concluded on the efficacy of the combination of memantine plus AChEIs in improving neuropsychiatric symptoms, and our network meta-analysis confirmed that memantine plus donepezil is superior to placebo in this regard.
When taking all four AD dimensions investigated in this meta-analysis into account, we conclude on the superiority of the combination therapy of memantine plus donepezil in the treatment of AD over monotherapy with either of the substances.
All four treatment regimens were well tolerated by most patients. Memantine was the best-tolerated medication, followed by placebo and the combination of memantine plus donepezil. Donepezil was the least tolerable. That means, in patients with substantial intolerance to the combination of memantine plus donepezil, a change to memantine is a better choice than donepezil.
One study concluded (Knapp et al., 2017) that there is no more cost-effective treatment than donepezil. We argue that when taking the effectiveness and the slowing of the clinical progression of AD in patients into account (Wilkinson & Andersen., 2007; Wilkinson, Wirth, & Goebel., 2014), the combination therapy is more cost-effective, even when the costs are slightly higher than those of donepezil alone. Another study (Cappel, Herrmann, Cornish, & Lanctôt, 2010) also found a more positive effect on the cost-effectiveness of the combination therapy than of donepezil alone.
This network meta-analysis has some limitations. The quality of some of the included trials was not high, which may have influenced the entire network meta-analysis. More high-quality studies are needed to analyze the optimal therapy of AD in the future. Secondly, this study only searched published trials but not the Cochrane Central Register of Controlled Trials or some other databases for the registration of clinical trials, which might result in a publication bias of the meta-analysis and have overestimated the study outcomes. Furthermore, this study applied ranking for the outcomes, which has a substantial degree of imprecision for most interventions that have a large width of 95% Crls (Trinquart, Attiche, Bafeta, Porcher, & Ravaud, 2016). Finally, we only reviewed the cost-effectiveness of therapeutic regimens in this meta-analysis, but future studies should take the slowing of clinical progression into account.
5 Conclusion Our study found that the combination of memantine plus donepezil had superior effects on cognitive and neuropsychiatric symptoms, the global assessment, and daily activities, but was less acceptable to patients compared to either memantine alone or placebo. While memantine was most acceptable, the choice of medication should depend on the individual situations of patients. The extent of damage in the four different domains of AD will lead to different treatment decisions. Furthermore, considering the natural course of AD, memantine plus donepezil may be more cost-effective than donepezil because memantine may slow the progression of AD.
Acknowledgments The study was supported by funds from the National Natural Science Foundation of China (NSFC No. 81674066). The study was supported by funds from the Natural Science Foundation of Chongqin (No. cstc2017jcyjAX0397).
Conflict of Interests The authors declare that there have no conflicts of interest.
Authors' Contributions JG designed the study, extracted the data with NZ, did meta-analysis and network meta-analysis with RZ, and wrote and approved the manuscript. ZW designed the study, revised, and approved the manuscript with RL. YH discussed the validity of the trials and revised the manuscript.
[Keywords and compound-keywords (tags) are highlighted-and-hyphenated in italic-and-bold; place-names, organizations and titles are in bold; media-names put in italic. Instead of underlining, I’ve been experimenting with hyphenating entire phrases – long-tail-keywords. This odd style was being tried to enhance generative-AI processing and ease-of-spotting items-of-interest in my specific website-achieved documents. Now experimenting with generative-AI to eliminate this time-consuming distraction.]
{Memantine, Donepezil, or Combo}
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