Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

[Recognan (citicoline) efficacy and safety in cognitive impairment correction of various nosological forms]. / Effektivnost' i bezopasnost' Rekognana (tsitikolin) pri korrektsii kognitivnykh narushenii razlichnoi etiologii.

Insufficiency of a choline derivative (acetylcholine) can lead to the development of cognitive impairment (CI). One of the most well-known and well-studied medical drugs (MD) containing choline and having neuroprotective properties is citicoline (Recognan). A number of studies have demonstrated the effectiveness of Recognan in relation to mild CI, chronic cerebrovascular diseases (CVD), acute vascular disorders (including post-traumatic genesis). Recognan improves memory and other cognitive functions in healthy young people against the background of asthenia due to stress or increased cognitive and emotional stress or infection, and also has a preventive effect on fading cognitive functions in the process of age-related changes. The duration of neuroprotection can reach 6 months or more - up to 12 months, depending on the patient's condition. Therapy regimens include two-stage Recognan prescribing: with CVD intramuscularly (i/m) at 1000 mg /d for 30 days, in the acute period of ischemic stroke, i/m or intravenously (i/v) at 1000 mg every 12 hours from the first day after diagnosis, 3-5 days after the start of therapy, with preservation functions of swallowing, it is possible to switch to per oral (p/o) drug administration.

Citicoline on the Barthel Index: Severe and moderate brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is a paramount factor in mortality and morbidity. The clinical trials conducted to investigate the efficacy of neuroprotective agents, such as citicoline, as a therapeutic alternative for TBI have presented divergent findings. Therefore, this study aimed to evaluate and compare citicoline's effect on the Barthel Index in patients with severe and moderate brain injury. MATERIALS AND METHODS: The study is a randomized clinical trial. Patients in the case group (35 patients) were treated with citicoline and the control group (34 patients) received a placebo. Data were analyzed using SPSS 16 software. RESULTS: The results showed that changes in the Glasgow Coma Scale, changes in quadriceps muscle force score, Barthel Index score changes, achieving the status without intubation, and spontaneous breathing in patients treated with citicoline were not a statistically significant difference in the two groups (P > 0.05). CONCLUSION: Findings revealed that citicoline did not impact the recovery process of severe and moderate TBI patients.

Therapeutic dilemmas: cognitive enhancers and risk of falling in older adults-a clinical review.

PURPOSE: Cognitive enhancers are the primary pharmacological therapy prescribed to those with dementia, comprising of memantine and the acetylcholinesterase inhibitors (AChEIs). The long-term cognitive and behavioural benefits of these medications, as well as their potential contribution to falls is currently debated, with recent Delphi studies being unable to reach consensus on whether these medications should be deprescribed. In this narrative clinical review, as part of a series on deprescribing in people at risk of falls, we explore the potential falls-related side effects experienced in people taking cognitive enhancers, alongside situations where deprescribing may be appropriate. METHODS: We undertook a literature search of PubMed and Google Scholar, using terms capturing falls and cognitive enhancers, as well as consulting the British National Formulary and published Summary of Medicinal Product Characteristics. These searches informed the subsequent clinical review. RESULTS: Cognitive enhancers should be subject to regular review, including confirmation of appropriate treatment indication, and occurrence of side effects in the context of falls. AChEIs, in particular, are associated with a broad range of side effects that can contribute to increased falls risk. These include bradycardia, syncope and neuromuscular effects. Where these have been identified, deprescribing should be considered, as well as alternative treatment options. Deprescribing studies have shown mixed results, likely due to considerable methodological heterogeneity. Several suggested guidelines exist to aid deprescribing decisions, many of which are highlighted in this review. CONCLUSIONS: The use of cognitive enhancers should be regularly reviewed and decisions to deprescribe made on a case-by-case basis, considering both the risks and benefits of stopping these medications.

Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

[Pharmacological Cognitive Enhancement: Current Situation and Perspectives].

Pharmacological cognitive enhancement (PCE) refers to the use of biochemical enhancers for achieving improved mental performance in healthy individuals. One particular use of PCE prevalence is the misuse of these enhancers among university students for academic performance enhancement. The prevalence rates demonstrate the use of a broad spectrum of substances for PCE that can be classified as OTC, prescription, and illegal drugs. Given that certain substances have been widely used for years, their long-term effectiveness and side effects in the healthy population are essential to know. The question of safety and efficacy or benefit versus risk is not only of individual and societal interest but also bears implications for regulatory and policy decision-making. As far as safety is concerned, there is a particular problem with healthy children, whose brains are still in development. Soft enhancers, such as energy drinks, might be commonly used worldwide. Performance pressure, stress, and psychiatric disorders may be associated with PCE use and need to be considered when planning anti-PCE-themed educational activities. In an increasingly complex information society, demands for cognitive functioning are growing; however, it is doubtful whether we should welcome the use of PCEs for the support of work productivity or the improvement of our life quality. Societal discussions on PCE might give an opportunity to consider a meaningful life in all aspects.

Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals.

'Smart drugs' (also known as 'nootropics' and 'cognitive enhancers' [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a 'pharmaceutical cognitive doping behaviour'. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.

Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network 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.

Potential risk groups and psychological, psychosocial, and health behavioral predictors of pharmacological neuroenhancement among university students in Germany.

Aiming to develop and implement intervention strategies targeting pharmacological neuroenhancement (PN) among university students more specifically, we (1) assessed the prevalence of PN among German university students, (2) identified potential sociodemographic and study-related risk groups, and (3) investigated sociodemographic, psychological, study-related psychosocial, general psychosocial and health behavior related factors predicting the 12-month prevalence of PN. Therefore, a cross-sectional online survey was administered to students of the University of Mainz, Germany. A binary logistic regression with stepwise inclusion of the five variable groups was performed to predict PN. A total number of 4351 students out of 31,213 registered students (13.9%) participated in the survey, of which N = 3984 answered the question concerning PN. Of these, 10.4% had used one substance for PN at least once in the past 12 months. The regression analysis revealed 13 variables that were significantly related to the 12-month prevalence of PN. Specifically, the group of health behavior related variables showed the strongest relationship with PN. Therefore, an approach to the prevention of PN should be multifactorial so that it addresses social conditions, as well as education on substance use and healthy behaviors in terms of non-pharmacological strategies as alternatives of PN.

Compared of efficacy and safety of high-dose donepezil vs standard-dose donepezil among elderly patients with Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Donepezil is a first-line drug for the treatment of Alzheimer's disease (AD). However, there are no meta-analyses on efficacy and safety of high-dose versus standard-dose donepezil in the treatment of moderate-to-severe AD. RESEARCH DESIGN AND METHODS: We searched for randomized controlled trials (RCTs) from 1993 to May 2021 PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases. The outcomes of the meta-analysis included cognitive function, global assessment, and the incidence of adverse events and serious adverse events. RESULTS: Five RCTs (2974 people) were included in this meta-analysis. The improvement of cognitive function was significant among the patients with the treatment of high-dose donepezil [SMD = 0.12, 95% CI: 0.03 ~ 0.22; p = 0.01]. Between the two groups, there was no significant difference in global assessment. Compared with standard-dose donepezil, there was no difference in the incidence of adverse events when high-dose donepezil was used. However, it was found that high-dose donepezil administration increased the risk of heart problems through subgroup analysis of the two serious adverse events. CONCLUSION: High-dose donepezil is more effective than standard-dose donepezil in improving cognitive function of the elderly with moderate-to-severe AD. However, more attention should be paid to patients with heart problems when high-dose donepezil was used.

The Safety and Efficacy of Botanicals with Nootropic Effects.

Recent estimates for the global brain health supplement category, i.e. nootropic market size, will grow to nearly $5.8 billion by 2023. Overall, nearly one-quarter (23%) of adults currently take a supplement to maintain or improve brain health or delay and reverse dementia. Not surprisingly, the use of such supplements increases with age - more than one-third of the oldest generation (ages 74 and older) takes a supplement for brain health. This widespread use is being driven by a strong desire both in the younger and older generations to enhance cognitive performance and achieve healthy aging. The most prevalent botanicals currently dominating the nootropic marketplace include Gingko biloba, American ginseng, and Bacopa monnieri. However, other botanicals that affect stress, focus, attention, and sleep have also been procured by dietary supplement companies developing products for improving both, short and long-term brain health. This review focuses on efficacy data for neuroactive botanicals targeted at improving cognitive function, stress reduction, memory, mood, attention, concentration, focus, and alertness, including Bacopa monnieri, Ginkgo biloba, Holy basil, American ginseng, Gotu kola, Lemon balm, Common and Spanish sages and spearmint. Botanicals are discussed in terms of available clinical efficacy data and current safety profiles. Data gaps are highlighted for both efficacy and safety to bring attention to unmet needs and future research.

Efficacy and Safety of Divaza for the Correction of Oxidative Disturbances in Patients with Cerebral Atherosclerosis: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to determine if Divaza, a drug with nootropic and antioxidant effects, was safe and effective for the correction of oxidative disturbances and to stabilize cognitive impairment in patients with cerebral atherosclerosis. STUDY DESIGN: The study design consisted of a 12-week multicenter, randomized, double-blind, placebo-controlled, prospective trial in parallel groups. SETTING: The setting in which the study was conducted comprised 10 clinical centers across the Russian Federation. INTERVENTIONS: Patients were randomized into 2 groups and instructed to take either 2 tablets of the study drug or a placebo 3 times per day in conjunction with basic therapy. OUTCOMES: The primary outcome was a change in the average endogenous antioxidant potential after the completion of the study. The blood indicators of the oxidative stress (OS) were analyzed at the baseline and then after 12 weeks of therapy using iron-induced chemiluminescence analysis. The Montreal cognitive assessment test was used as a secondary outcome measure to evaluate cognitive impairment at the end of the study. RESULTS: 124 outpatients with a mean age of 60.7 ± 7.6 years were enrolled and randomly assigned to receive Divaza (n = 65) or a placebo (n = 59). An improvement of cognitive function was observed in all patients of the Divaza group at the end of the treatment; this was significantly better than the placebo group (100 [100] vs. 89.5 [89.1]%, respectively, p = 0.0272 [p = 0.0128]). The administration of Divaza restored the activity of the endogenous antioxidant system. The change in the average level of lipoprotein resistance to oxidation after 12 weeks of therapy, compared to the baseline, was significantly higher in the Divaza group (14.8 ± 14.7 [14.8 ± 14.7] seconds latent period vs. 6.4 ± 16.9 [6.9 ± 16.7] seconds in the placebo group (p = 0.007 [p = 0.0107]). CONCLUSIONS: Divaza is a safe and effective therapeutic option for attenuating OS and recovery of cognitive impairment in patients with cerebral atherosclerosis.

Safety and Tolerability of GRF6019 Infusions in Severe Alzheimer's Disease: A Phase II Double-Blind Placebo-Controlled Trial.

BACKGROUND: The plasma fraction GRF6019 shows multiple benefits on brain aging in mice, including enhanced cognition, neurogenesis, and synaptic density, as well as reduced neuroinflammation. OBJECTIVE: To evaluate the safety, tolerability, and preliminary efficacy of GRF6019 in patients with severe Alzheimer's disease (AD). METHODS: A phase II, double-blind, placebo-controlled study in patients with severe AD (Mini-Mental State Examination score 0-10). Patients were randomized 2 : 1 to GRF6019 (N = 18) or placebo (N = 8) and received daily 250 mL intravenous infusions over 5 days. The primary endpoints were the rates of adverse events (AEs) and the tolerability of GRF6019 as assessed by the number of patients completing the study. Change from baseline in cognitive and functional assessments was also evaluated. RESULTS: All patients completed 100%of study visits and infusions. The rate of AEs was similar in the GRF6019 (8/18 patients [44.4%]) and placebo (3/8 patients [37.5%]) groups, and there were no deaths or serious AEs. The most common AEs considered related to treatment were mild, transient changes in blood pressure in the GRF6019 group (hypotension: 2 patients [11.1%]; hypertension: 1 patient [5.6%]); there were no related AEs in the placebo group. The trial was not powered to detect statistically significant differences between treatment groups. At the end of the study, patients in both treatment groups remained stable or improved on all cognitive and functional endpoints. CONCLUSION: GRF6019 demonstrated excellent safety, feasibility, and tolerability. Future trials designed to characterize the potential functional benefits of GRF6019 and related plasma fractions in severe AD are warranted.

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network 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.

Bradycardia Due to Donepezil in Adults: Systematic Analysis of FDA Adverse Event Reporting System.

BACKGROUND: Bradycardia is a physiological condition characterized by a decrease in heart rate and is a side effect of many drug classes. Bradycardia has been reported as an adverse event for patients receiving donepezil for Alzheimer's disease (AD) treatment. OBJECTIVE: The purpose of the paper is to systematically investigate the association between the occurrence of bradycardia in adults and the usage of donepezil using clinical data derived from the FDA Adverse Event Reporting System (FAERS) database. METHODS: The risk of bradycardia in patients who only took donepezil was compared with those of patients who only took over-the-counter medications, multiple arrhythmia drugs, or other medications for AD treatment. In addition, this study sought to determine if this heightened bradycardia risk was influenced by sex, age, and dosage. RESULTS: The results indicated that there was a significant greater likelihood of reporting bradycardia in patients administered donepezil than most of the drugs investigated. There was no significant association between age or the dosage of donepezil and the likelihood of reporting bradycardia. However, males were found to be more likely than females to report bradycardia as an adverse event. Tumor necrosis factor inhibition and the stimulation of endothelial nitric oxide synthase were proposed to be the primary mechanism of actions which confer elevated bradycardia risk when using donepezil. CONCLUSION: These findings identified strong association between the usage of donepezil and bradycardia in adults as well as provided insight into the underlying molecular mechanisms that induce bradycardia by donepezil.

Understanding the relationship between safety beliefs and knowledge for cognitive enhancers in UK university students.

BACKGROUND: Cognitive enhancers (CE) are prescription drugs taken, either without a prescription or at a dose exceeding that which is prescribed, to improve cognitive functions such as concentration, vigilance or memory. Previous research suggests that users believe the drugs to be safer than non-users and that they have sufficient knowledge to judge safety. However, to date no research has compared the information sources used and safety knowledge of users and non-users. OBJECTIVES: This study compared users and non-users of CE in terms of i) their sources of knowledge about the safety of CE and ii) the accuracy of their knowledge of possible adverse effects of a typical cognitive enhancer (modafinil); and iii) how the accuracy of knowledge relates to their safety beliefs. METHODS: Students (N = 148) from King's College London (UK) completed an anonymous online survey assessing safety beliefs, sources of knowledge and knowledge of the safety of modafinil; and indicated whether they used CE, and, if so, which drug(s). RESULTS: The belief that the drugs are safe was greater in users than non-users. However, both groups used comparable information sources and have similar, relatively poor drug safety knowledge. Furthermore, despite users more strongly believing in the safety of CE there was no relationship between their beliefs and knowledge, in contrast to non-users who did show correlations between beliefs and knowledge. CONCLUSION: These data suggest that the differences in safety beliefs about CE between users and non-users do not stem from use of different information sources or more accurate safety knowledge.

Long term use of donepezil and QTc prolongation.

BACKGROUND: The neurocognitive benefits of donepezil are well recognised, but the potential side effects on cardiac conduction remain unclear. OBJECTIVE: To investigate whether long-term donepezil therapy is associated with electrocardiographic (ECG) changes and in particular to assess its effects on the QT interval. METHODS: We conducted a single centre retrospective analysis of patients admitted to our trust on donepezil therapy over a 12-month period. An admission resting 12-lead ECG was obtained and compared to their ECG prior to commencement of donepezil therapy to assess for any significant difference in ECG parameters. RESULTS: We identified 59 patients suitable for analysis. PR (177.0 ± 29.0 ms vs. 186.1 ± 34.2 ms, p = 0.04), QRS (101.7 ± 20.3 ms vs. 104.7 ± 22.3 ms, p = 0.04) and QT (393.3 ± 35.6 ms vs. 411.9 ± 44.6 ms, p = 0.002) interval prolongation were all associated with donepezil use. The increase in QT intervals remained significant on correction for heart rate; resulting in 8 (13.6%) patients developing high arrhythmogenic risk based on assessment using QT nomogram plots. Concomitant use of tricyclic antidepressants was associated with significant QT prolongation (QTcB: r pb = 0.344, p = 0.008, QTcFred: r pb = 0.382, p = 0.003, QTcFram: r pb = 0.379, p = 0.003, QTcH: r pb = 0.352, p = 0.006), while the use of rate-limiting calcium channel blockers was associated with significant PR prolongation (r pb = 0.314, p = 0.030), and beta-blockers with a reduction in heart rate (r pb = 0.256, p = 0.050). CONCLUSION: Our results clearly demonstrate that long-term use of donepezil is associated with prolongation of the QT interval. We suggest ECG evaluation should take place before and after donepezil initiation, and clinicians should be even more vigilant in those prescribed tricyclic antidepressants.