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Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease.

ABSTRACT: To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer's disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale-cognitive Subscale (ADAS-cog), AD Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+) were used as valid endpoints. Of the 36 trials included, meta-analyses of these placebo-control trials showed that there were significant differences between the donepezil, rivastigmine and placebo groups using ADAS-cog, ADCS-ADL, and CIBIC+. Meta-analyses of these placebo-controlled trials showed that there were significant differences between the galantamine and placebo groups using ADAS-cog, ADCS-ADL, NPI, and CIBIC+. These observations suggest that memantine is beneficial for stabilizing or slowing the decline in ADAS-cog and ADCS-ADL19 changes in AD patients. However, there was no significant effect according to the ADCS-ADL23, NPI, and CIBIC+ tests, which indicated that memantine treatment has no significant effect on these cognitive aspects of AD patients. Different effects of donepezil, rivastigmine, galantamine, or memantine on AD were found in this study. According to the results, we conclude that galantamine is effective in treating all aspects of AD and is the first choice for the treatment of AD. However, due to limited data, we should consider additional data to obtain more stable results.

SUBMITTER: Li DD

PROVIDER: S-EPMC6529534 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease.

Li Dan-Dan DD Zhang Ya-Hong YH Zhang Wei W Zhao Pu P

Frontiers in neuroscience 20190515

To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer's disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale ...[more]

PMID: 31156366

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Project description:BackgroundThe donepezil-memantine combination is a US Food and Drug Administration (FDA)-approved medication to treat Alzheimer's disease (AD). Galantamine is superior to donepezil because it is a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7nAChR). Although galantamine and memantine are both FDA approved for the treatment of AD, the combination is still underutilized in clinical practice.AimThe objective of this review was to critically examine the mechanisms by which the galantamine-memantine combination may be superior to the donepezil-memantine combination in AD by targeting the cholinergic-nicotinic and glutamatergic systems concurrently.MethodPubMed and Google Scholar were searched using the keywords Alzheimer's disease, cholinergic, glutamatergic, α7nAChR, N-methyl-D-aspartate (NMDA) receptors, donepezil, galantamine, memantine, clinical trials, and biomarkers.ResultsAD is associated with several biomarkers such as kynurenine pathway (KP) metabolites, mismatch negativity (MMN), brain-derived neurotrophic factor (BDNF), and oxidative stress. In several preclinical studies, cognitive impairments significantly improved with the galantamine-memantine combination compared to either medication alone. Synergistic benefits were also seen with the combination. In a randomized controlled trial (RCT) in prodrome AD, cognition significantly improved with the galantamine-memantine combination compared to galantamine alone; cognition declined after galantamine was discontinued. However, in an RCT in AD, cognition did not significantly improve with the galantamine-memantine combination compared to galantamine alone. In a retrospective study in AD, the galantamine-memantine combination significantly improved cognition compared to the donepezil-memantine combination. Galantamine and memantine via the α7nACh and NMDA receptors can counteract the effects of kynurenic acid and enhance MMN and BDNF.ConclusionFuture studies with the galantamine-memantine combination with KP metabolites, MMN, and BDNF as biomarkers are warranted. Positive RCTs in AD may lead to FDA approval of the combination, resulting in greater utilization in clinical practice. In the meantime, clinicians may continue to use the galantamine-memantine combination to treat patients with AD.

Project description:BACKGROUND:Agitation in Alzheimer's disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD. METHODS AND FINDINGS:We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p?=?0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p?=?0.012) and 12 (-9.6; -15.0 to -4.3 p?=?0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD. CONCLUSIONS:Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms. TRIAL REGISTRATION:ClinicalTrials.gov NCT00371059. TRIAL REGISTRATION:International Standard Randomised Controlled Trial 24953404.

Dataset Information

Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease.

Publications

Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease.

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