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Neuropharmacology Jun 2021Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral... (Review)
Review
Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders.
Topics: Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Galantamine; Humans; Receptors, N-Methyl-D-Aspartate; Rivastigmine
PubMed: 33035532
DOI: 10.1016/j.neuropharm.2020.108352 -
Brain and Behavior Nov 2020Alzheimer's disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and... (Meta-Analysis)
Meta-Analysis
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).
CONCLUSIONS
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.
Topics: Alzheimer Disease; China; Donepezil; Humans; Memantine; Network Meta-Analysis
PubMed: 32914577
DOI: 10.1002/brb3.1831 -
Cognitive and Behavioral Neurology :... Dec 2021Behavioral and psychological symptoms of dementia (BPSD) are common in individuals with Alzheimer disease (AD). Donepezil and memantine are both widely used for the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Behavioral and psychological symptoms of dementia (BPSD) are common in individuals with Alzheimer disease (AD). Donepezil and memantine are both widely used for the treatment of moderate AD.
OBJECTIVE
To evaluate the effects of donepezil and memantine in relieving BPSD in individuals with moderate AD.
METHOD
We conducted a prospective, randomized, 6-month clinical trial involving 85 individuals with moderate AD divided into two groups: group 1 (n = 42) was treated with donepezil; group 2 (n = 43) was treated with memantine. We used the Neuropsychiatric Inventory (NPI) to assess the prevalence and severity of BPSD at baseline and after 6 months of treatment with donepezil or memantine.
RESULTS
The two groups' baseline characteristics, including age, sex, mean length of education, and disease duration, were comparable, as were their baseline Mini-Mental State Examination scores. The NPI Total score improved from baseline to month 6 in both groups (P < 0.0001). Analyses of the NPI subdomains revealed that both donepezil treatment and memantine treatment produced statistically significant improvement in all of the NPI domains except euphoria and apathy, for which no improvement was observed after memantine treatment. Both treatments were well tolerated, with mostly mild and transient adverse effects.
CONCLUSION
Specific drugs for AD, including donepezil and memantine, may be effective in treating BPSD in individuals with moderate AD, with a favorable safety profile.
Topics: Alzheimer Disease; Behavioral Symptoms; Donepezil; Humans; Indans; Memantine; Piperidines; Prospective Studies; Treatment Outcome
PubMed: 34851866
DOI: 10.1097/WNN.0000000000000285 -
Neurology Oct 2023Lecanemab, a novel amyloid-sequestering agent, recently received accelerated Food and Drug Administration approval for the treatment of mild dementia due to Alzheimer...
Lecanemab, a novel amyloid-sequestering agent, recently received accelerated Food and Drug Administration approval for the treatment of mild dementia due to Alzheimer disease (AD) and mild cognitive impairment (MCI). Approval was based on a large phase 3 trial, Clarity, which demonstrated reductions in amyloid plaque burden and cognitive decline with lecanemab. Three major concerns should give us pause before adopting this medication: Its beneficial effects are small, its harms are substantial, and its potential costs are unprecedented. Although lecanemab has a clear and statistically significant effect on cognition, its effect size is small and may not be clinically significant. The magnitude of lecanemab's cognitive effect is smaller than independent estimates of the minimally important clinical difference, implying that the effect may be imperceptible to a majority of patients and caregivers. Lecanemab's cognitive effects were numerically smaller than the effect of cholinesterase inhibitors and may be much smaller. The main argument in lecanemab's favor is that it may lead to greater cognitive benefit over time. Although plausible, there is a lack of evidence to support this conclusion. Lecanemab's harms are substantial. In Clarity, it caused symptomatic brain edema in 11% and symptomatic intracranial bleeding in 0.5% of participants. These estimates likely significantly underestimate these risks in general practice for 3 reasons: (1) Lecanemab likely interacts with other medications that increase bleeding, an effect minimized in Clarity. (2) The Clarity population is much younger than the real-world population with mild AD dementia and MCI (age 71 years vs 85 years) and bleeding risk increases with age. (3) Bleeding rates in trials are typically much lower than in clinical practice. Lecanemab's costs are unprecedented. Its proposed price of $26,500 is based on cost-effectiveness analyses with tenuous assumptions. However, even if cost-effective, it is likely to result in higher expenditures than any other medication. If its entire target population were treated, the aggregate medication expenditures would be $120 billion US dollars per year-more than is currently spent on all medications in Medicare Part D. Before adopting lecanemab, we need to know that lecanemab is not less effective, vastly more harmful, and 100× more costly than donepezil.
Topics: Aged; Humans; Alzheimer Disease; Dementia; Donepezil; Medicare; United States; Antibodies, Monoclonal, Humanized
PubMed: 37479527
DOI: 10.1212/WNL.0000000000207505 -
BMJ Open Apr 2022To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).
DESIGN
Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.
DATA SOURCES
MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.
PARTICIPANTS
80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.
INTERVENTIONS
Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.
DATA EXTRACTION AND SYNTHESIS
We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).
PRIMARY AND SECONDARY OUTCOMES
We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.
RESULTS
Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.
CONCLUSIONS
The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.
PROSPERO REGISTRATION NUMBER
CRD42015023507.
Topics: Adult; Alzheimer Disease; Donepezil; Galantamine; Humans; Memantine; Network Meta-Analysis; Nootropic Agents; Rivastigmine
PubMed: 35473731
DOI: 10.1136/bmjopen-2021-053012 -
Journal of Alzheimer's Disease : JAD 2022Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse.
OBJECTIVE
We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients.
METHODS
We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles.
RESULTS
Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD.
CONCLUSION
Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.
Topics: Activities of Daily Living; Alzheimer Disease; Amino Acids; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Ginkgo biloba; Humans; Nootropic Agents; Patient Safety; Plant Extracts; Rivastigmine
PubMed: 34924395
DOI: 10.3233/JAD-215423 -
The Cochrane Database of Systematic... Feb 2021Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these medications are effective in VCI and whether there are differences between them with regard to efficacy or adverse events.
OBJECTIVES
(1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI. (2) To compare the effects of different cholinesterase inhibitors on cognition and adverse events, using network meta-analysis.
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 19 August 2020.
SELECTION CRITERIA
We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration.
DATA COLLECTION AND ANALYSIS
Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time points using random-effects methods. We also performed a network meta-analysis using Bayesian methods.
MAIN RESULTS
We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg (n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from very low to high level of certainty. For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the effect is unlikely to be clinically important (mean difference (MD) -0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95% confidence interval (CI) -1.44 to -0.40; high-certainty evidence). Donepezil 10 mg (MD -2.21 ADAS-Cog points, 95% CI -3.07 to -1.35; moderate-certainty evidence) and galantamine 16 to 24 mg (MD -2.01 ADAS-Cog point, 95%CI -3.18 to -0.85; moderate-certainty evidence) probably also improve cognition, although the larger effect estimates still may not be clinically important. With low certainty, there may be little to no effect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI -3.04 to 3.10; low-certainty evidence). Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results showed that there was probably little to no difference between donepezil 5 mg and placebo in the number of adverse events (odds ratio (OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The effect of rivastigmine 3 to 12 mg on adverse events was very uncertain (OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence). In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes.
AUTHORS' CONCLUSIONS
We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to 24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain. The data suggest that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.
Topics: Activities of Daily Living; Bias; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Donepezil; Galantamine; Humans; Network Meta-Analysis; Nootropic Agents; Physical Functional Performance; Placebos; Randomized Controlled Trials as Topic; Rivastigmine
PubMed: 33704781
DOI: 10.1002/14651858.CD013306.pub2 -
Neurology Apr 2024The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer... (Comparative Study)
Comparative Study
The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer disease, quickly led to approval by the FDA and widespread acceptance of lecanemab treatment. However, there are a number of matters that deserve further consideration. The success of blinding was not assessed, even as infusion reactions and the cerebral pathology underlying amyloid-related imaging abnormalities could have signaled to many participants that they were on drug, potentially exerting a potent placebo effect. The value of the outcome to participants is not defined in the absolute terms necessary for clinical decision-making, and the difference attributable to lecanemab was between 18% and 46% of estimates of the minimal clinically important difference on the Clinical Dementia Rating Scale Sum of Boxes. The attenuation of change on the Alzheimer's Disease Assessment Scale-Cognitive 14 achieved by lecanemab at 18 months was 50% of that achieved by donepezil at 6 months. Lecanemab treatment imposes a high treatment burden. The fact that the burden commences at the initiation of lecanemab treatment, whereas the benefit accrues years later requires us to take into account value discounting over time, which would significantly reduce the benefit/burden ratio. Finally, treatment with monoclonal antibodies to cerebral amyloid has consistently been associated with progressive cerebral atrophy. At the least, these issues should be raised in treatment discussions with patients. They also suggest a need to very seriously reconsider how we evaluate clinical trial results preparatory to translating them into clinical practice. Some suggestions are provided.
Topics: Humans; Alzheimer Disease; Antibodies, Monoclonal, Humanized; Cognition; Donepezil; Randomized Controlled Trials as Topic
PubMed: 38484213
DOI: 10.1212/WNL.0000000000209320 -
The Senior Care Pharmacist Jul 2023Prevalence of dementia continues to increase with limited pharmacotherapy options available. Acetylcholinesterase inhibitors remain a mainstay of treatment. The US FDA... (Review)
Review
Prevalence of dementia continues to increase with limited pharmacotherapy options available. Acetylcholinesterase inhibitors remain a mainstay of treatment. The US FDA has approved three oral medications within this class- donepezil, galantamine, and rivastigmine. In 2022, the US Food and Drug Administration approved a novel patch formulation for donepezil that could be beneficial for patients with dysphagia as well as potentially decreasing the side effect burden. The purpose of this analysis is to review the efficacy, safety, tolerability, and clinical considerations related to this novel formulation.
Topics: Humans; Acetylcholinesterase; Donepezil; Drug-Related Side Effects and Adverse Reactions; Rivastigmine; United States; United States Food and Drug Administration
PubMed: 37381137
DOI: 10.4140/TCP.n.2023.300