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Phenibut is a gamma aminobutyric acid derivative with activity at γ-aminobutyric acid (GABA) B , A and β-phenethylamine receptors. It was developed as a drug in the former Soviet Union to overcome anxiety and improve cognitive function in military personnel. In the last decade, it has made inroads into the European and U.S. markets, being marketed for purported nootropic properties. Here, we summarize the current knowledge on phenibut, its toxicology, pharmacology, adverse health effects, and patterns of use. Publications in peer-reviewed journals were searched in PubMed, Web of Science, and Google Scholar databases. Available literature points to adverse side effects associated with intoxication, withdrawal, and addiction to phenibut. Some of these effects can be life-threatening, requiring hospitalization and therapeutic interventions. Supportive efforts are often complicated by a lack of knowledge regarding phenibut's toxicology and pharmacology. Ingestion of phenibut was often associated with concomitant use of other substances of abuse. As control over its online marketing seems unrealistic, current efforts need to be focused on the addition of phenibut to current drug screening tests and the development of generally accepted treatment strategies for phenibut-associated toxicities., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background and Objectives: Antipsychotics and cognitive enhancers are often used to treat psychosis and behavioral disturbances in individuals with dementia; however, these drugs have been linked with various adverse events including both metabolic and cerebro/cardiovascular events. Thus, this study sought to estimate the risk of major adverse cardiovascular/cerebrovascular events (MACCE) across four behavioral and psychological symptoms of dementia (BPSD) treatment models by exploring potential associations between antipsychotics (APs), cognitive-enhancing medications, dosage, and earlier MACCE onset., Methods: Patients were obtained from the Loma Linda University Medical Center database who were age ≥ 50 or older and who were diagnosed with dementia and BPSD symptoms. Treatment group and drug dosing were analyzed using Cox regression analyses to predict time until MACCE onset. Patient age at dementia diagnosis, sex, smoking status, race/ethnicity, and previous MACCE diagnoses were included as covariate variables., Results: The final study population consisted of 1162 individuals. Results indicated a significant effect of medication type on duration until MACCE, (p < 0.001), with the odds of experiencing a MACCE being 96.3% higher for individuals treated with both APs and cognitive enhancers (p < 0.001). There was also a significant effect of AP dosage on duration until MACCE (p < 0.001) and a significant effect of cognitive enhancer dosage on duration until a MACCE, (p < 0.001). The odds of experiencing a MACCE sooner were 238% higher for those on high doses of APs (p < 0.001) and 76% higher for individuals on high doses of cognitive enhancers (p < 0.010)., Conclusion: The use of APs at high doses was associated with the greatest risk of an adverse medical outcome in older adults with dementia with concurrent behavioral symptoms. Use of AP medications in this population should include close monitoring for cardiovascular/cerebrovascular events., (© 2024. The Author(s).)

Background and Objective: Cerebral small vessel disease (CSVD) often coexists with cognitive dysfunction in patients, leading to significant challenges in treatment and management. This study aimed to examine the efficacy of combined application of donepezil and nimodipine on patients with comorbid CSVD and cognitive dysfunction and the effects on patients' albumin and prealbumin levels., Methods: The records of 112 patients with comorbid CSVD and cognitive dysfunction treated at the People's Hospital of Suzhou New District from January 2019 to December 2022 were analysed retrospectively. A total of 50 patients receiving donepezil were allocated to the control group, and 62 patients receiving both nimodipine and donepezil to the study group. Outcomes compared between the two groups included serum homocysteine (Hcy), high sensitivity C-reactive protein (hs-CRP), albumin, and prealbumin before and after therapy, efficacy, and adverse reactions. Additionally, logistic regression was performed to analyze the risk factors impacting patient prognosis., Results: Prior to therapy, the two groups did not differ significantly in Hcy and hs-CRP levels (p > 0.05), whereas after therapy, the levels in both groups dropped significantly (p < 0.01), with more obvious lower levels in the study group (p < 0.05). After treatment, the study group presented significantly higher albumin and prealbumin levels than the control group (p < 0.001). An obvious higher overall response rate was observed in the study group compared to the control group (p = 0.012). No significant inter-group discrepancy was found regarding the total incidence of adverse reactions (p = 0.752). Univariate analysis identified age, course of disease, heart rate (HR), Montreal Cognitive Assessment (MoCA) score, diastolic blood pressure (DBP), systolic blood pressure (SBP), drinking history, as well as medication regimen as risk factors impacting patient prognosis. Multivariate logistic regression analysis identified SBP, DBP, and medication regimen as the independent risk factors., Conclusion: Combined application of donepezil and nimodipine can effectively treat patients with comorbid CSVD and cognitive dysfunction. It can significantly lower the Hcy and hs-CRP levels and improve the nutritional status without increasing the frequency of adverse reactions. In addition, for CSVD patients with cognitive dysfunction, age, course of disease, MoCA score, HR, SBP, DBP, drinking history, and medication regimen are risk factors impacting patient prognosis, while SBP, DBP, and medication regimen are independent risk factors.

Purpose: To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy., Patients and Methods: Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time., Results: Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results., Conclusion: BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

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., (© 2024 The Authors. Psychogeriatrics published by John Wiley & Sons Australia, Ltd on behalf of Japanese Psychogeriatric Society.)

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., (© 2023. The Author(s).)

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., Competing Interests: None

Background: The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ 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.)., (Copyright © 2022 Massachusetts Medical Society.)

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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

'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., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.

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., (© 2022. The Author(s).)

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.

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.

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., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2021 S. Karger AG, Basel.)

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.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

Nootropics are drugs used to either treat or benefit cognition deficits. Among this class, methylphenidate is a popular agent, which acts through indirect dopaminergic and noradrenergic agonism and, therefore, is proposed to enhance performance in catecholamine-dependent cognitive domains such as attention, memory and prefrontal cortex-dependent executive functions. However, investigation into the efficacy of methylphenidate as a cognitive enhancer has yielded variable results across all domains, leading to debate within the scientific community surrounding its off-label use in healthy individuals seeking scholaristic benefit or increased productivity. Through analysis of experimental data and methodological evaluation, it is apparent that there are dose-, task- and domain-dependent considerations surrounding the use of methylphenidate in healthy individuals, whereby tailored dose administration is likely to provide benefit on an individual basis dependent on the domain of cognition in which benefit is required. Additionally, it is apparent that there are subjective effects of methylphenidate, which may increase user productivity irrespective of cognitive benefit. Whilst there is not extensive study in healthy older adults, it is plausible that there are dose-dependent benefits to methylphenidate in older adults in selective cognitive domains that might improve quality of life and reduce fall risk. Methylphenidate appears to produce dose-dependent benefits to individuals with attention-deficit/hyperactivity disorder, but the evidence for benefit in Parkinson's disease and schizophrenia is inconclusive. As with any off-label use of pharmacological agents, and especially regarding drugs with neuromodulatory effects, there are inherent safety concerns; epidemiological and experimental evidence suggests there are sympathomimetic, cardiovascular and addictive considerations, which might further restrict their use within certain demographics.

This article investigated the clinical effects of piracetam with nimodipine in the treatment of vascular dementia (VD) after cerebral infarction. 98 patients with vascular dementia after cerebral infarction were selected and divided into the control group and the study group according to the treatment method. The control group was treated with nimodipine alone. The study group was treated with piracetam on the basis of this observation, and we test the ADL (life ability score), MoCA(montreal cognitive assessment scale), ADAS-Cog(alzheimer's scale-cognition), MMSE(mental status examination) scores and quality of life scores before and after treatment in the two groups. Before treatment, there were no significant differences in ADL, MoCA, and ADAS-Cog scores between the two groups (P>0.05). After treatment, the ADL, MoCA, and ADAS-Cog scores of the study group were superior to the control group. The difference was statistically significant (P<0.05). There was no significant difference in MMSE scores between the two groups before treatment and 1 month after treatment (P>0.05). The MMSE scores of the study group were better than the control group after 3 months of treatment and half a year after treatment. The difference was statistically significant (P <0.05). Before treatment, there was no significant difference in the quality of life scores between the two groups (P>0.05). After treatment, the quality of life scores was significantly higher than the control group, and the difference was statistically significant (P<0.05). For patients with vascular dementia after cerebral infarction, piracetam combined with nimodipine can improve the cognitive function, improve the quality of life, and have a significant clinical effect.

Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABA B receptor and the α 2 -δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5-100 g/day) were much higher than the recommended daily dose (0.25-2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open., Competing Interests: The authors declare no conflict of interest., (Thieme. All rights reserved.)

Background: Stroke is one of the leading causes of long-lasting disability and mortality and its global burden has increased in the past two decades. Several therapies have been proposed for the recovery from, and treatment of, ischemic stroke. One of them is citicoline. This review assessed the benefits and harms of citicoline for treating patients with acute ischemic stroke., Objectives: To assess the clinical benefits and harms of citicoline compared with placebo or any other control for treating people with acute ischemic stroke., Search Methods: We searched in the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS until 29 January 2020. We searched the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. Additionally, we also reviewed reference lists of the retrieved publications and review articles, and searched the websites of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)., Selection Criteria: We included randomized controlled trials (RCTs) in any setting including participants with acute ischemic stroke. Trials were eligible for inclusion if they compared citicoline versus placebo or no intervention., Data Collection and Analysis: We selected RCTs, assessed the risk of bias in seven domains, and extracted data by duplicate. Our primary outcomes of interest were all-cause mortality and the degree of disability or dependence in daily activities at 90 days. We estimated risk ratios (RRs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We conducted our analyses using the fixed-effect and random-effects model meta-analyses. We assessed the overall quality of evidence for six pre-specified outcomes using the GRADE approach., Main Results: We identified 10 RCTs including 4281 participants. In all these trials, citicoline was given either orally, intravenously, or a combination of both compared with placebo or standard care therapy. Citicoline doses ranged between 500 mg and 2000 mg per day. We assessed all the included trials as having high risk of bias. Drug companies sponsored six trials. A pooled analysis of eight trials indicates there may be little or no difference in all-cause mortality comparing citicoline with placebo (17.3% versus 18.5%; RR 0.94, 95% CI 0.83 to 1.07; I² = 0%; low-quality evidence due to risk of bias). Four trials found no difference in the proportion of patients with disability or dependence in daily activities according to the Rankin scale comparing citicoline with placebo (21.72% versus 19.23%; RR 1.11, 95% CI 0.97 to 1.26; I² = 1%; low-quality evidence due to risk of bias). Meta-analysis of three trials indicates there may be little or no difference in serious cardiovascular adverse events comparing citicoline with placebo (8.83% versus 7.77%; RR 1.04, 95% CI 0.84 to 1.29; I² = 0%; low-quality evidence due to risk of bias). Overall, either serious or non-serious adverse events - central nervous system, gastrointestinal, musculoskeletal, etc. - were poorly reported and harms may have been underestimated. Four trials assessing functional recovery with the Barthel Index at a cut-off point of 95 points or more did not find differences comparing citicoline with placebo (32.78% versus 30.70%; RR 1.03, 95% CI 0.94 to 1.13; I² = 24%; low-quality evidence due to risk of bias). There were no differences in neurological function (National Institutes of Health Stroke Scale at a cut-off point of ≤ 1 points) comparing citicoline with placebo according to five trials (24.31% versus 22.44%; RR 1.08, 95% CI 0.96 to 1.21; I² = 27%, low-quality evidence due to risk of bias). A pre-planned Trial Sequential Analysis suggested that no more trials may be needed for the primary outcomes but no trial provided information on quality of life., Authors' Conclusions: This review assessed the clinical benefits and harms of citicoline compared with placebo or any other standard treatment for people with acute ischemic stroke. The findings of the review suggest there may be little to no difference between citicoline and its controls regarding all-cause mortality, disability or dependence in daily activities, severe adverse events, functional recovery and the assessment of the neurological function, based on low-certainty evidence. None of the included trials assessed quality of life and the safety profile of citicoline remains unknown. The available evidence is of low quality due to either limitations in the design or execution of the trials., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Currently there is no effective treatment for vascular dementia (VaD). Pharmacological treatment often lead to severe complications and require drug dosage adjustment. This study investigated the effect of scalp electroacupuncture combined with Memantine in VaD. The safety and antioxidative effect of scalp electroacupuncture were also explored.A retrospective study was conducted and data of inpatients of Linyi Central Hospital with VaD between June 2017 and May 2018 were collected and sorted. The patients were divided into scalp electroacupuncture-medication (A), scalp electroacupuncture (B) and medication (control) (C) groups, in which Memantine was prescribed as medication. Cognitive function, activities of daily living and quality of life assessed by Montreal Cognitive Assessment (MoCA), Barthel index and dementia quality of life questionnaire; the contents of superoxide dismutase, lipid peroxide and nitric oxide in blood samples; and adverse reaction were compared.Data from a total of 150 patients were collected (Group A, n = 55; Group B, n = 50; Group C, n = 45). The post-treatment/follow-up Montreal Cognitive Assessment, Barthel index and dementia quality of life questionnaire scores were significantly improved in all groups compared to pre-treatment (groups A and B, P<.01; group C, P<.05). The improvements were significant for groups A vs C, B vs C (P<0.01, both), and group A vs B (P<.05). The post-treatment/follow-up levels of lipid peroxide and nitric oxide decreased significantly while superoxide dismutase increased significantly in groups A and B compared to pre-treatment (P<.01, both). The differences were significant for groups A vs C, and B vs C (P < .01, both), but not significant between groups A and B (P > .05). There were no significant adverse events occurred during the study and follow-up.In combined treatment, scalp electroacupuncture works in parallel with Memantine and significantly increase the therapeutic effect in VaD with no significant adverse events. Scalp electroacupuncture may have the potential to serve as an option or alternative treatment for VaD. Scalp electroacupuncture may alleviate VaD symptoms through its antioxidative mechanism.

Objectives: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and a well-recognized cause of dementia with ageing. In this review, we have represented the ChE and MAO inhibitory potential of TV 3326 against AD based on current scientific evidence., Key Findings: The aetiology of AD is quite complex and not completely understood. However, it has been observed that AD involves the deposition of abnormal amyloid beta (Aβ), along with hyperphosphorylation of tau, oxidative stress, low acetylcholine (ACh) level and biometal dyshomeostasis. Due to the complex nature of AD aetiology, active research is required in the areas of development of multitarget drugs with 2 or more complementary biological functions, as they might represent significant progress in the AD treatment. Interestingly, it has been found that TV 3326 (i.e. ladostigil) is regarded as a novel therapeutic agent since it has the potential to cause inhibition of monoamine oxidase (MAO) A and B, and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Furthermore, it has the capacity to reverse memory impairments, which further suggests the ability of this drug to elevate cholinergic activity in the brain., Summary: TV 3326 can avert oxidative-nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD., (© 2020 Royal Pharmaceutical Society.)

Aim: Phosphodiesterase 10A (PDE10A) inhibitors not only have antipsychotic-like effects but also cause cognitive enhancement without affecting extrapyramidal side effects in rodents, suggesting that PDE10A may be a novel approach for the treatment of schizophrenia. However, how a combination of PDE10A inhibitor with a currently available antipsychotic drug, risperidone contributes to the effect of each compound in rats remains unclear. The purpose of the present study was to examine the combination effects of MR1916 with a currently available antipsychotic drug, risperidone, in rats., Methods: We examined the combination effects of the PDE10A inhibitor, MR1916 with risperidone on conditioned avoidance response (CAR) to assess antipsychotic-like effects in rats. We also examined them on catalepsy as extrapyramidal side effects and novel object recognition test in cognitive functions in rats., Results: MR1916 (0.025-0.2 mg/kg, p.o.) and risperidone (0.75-6 mg/kg, p.o.) alone attenuated the CAR in a dose-dependent manner. The combination of MR1916 (0.025 mg/kg, p.o.) with risperidone (0.75 mg/kg, p.o.) significantly enhanced the attenuation of CAR without increasing the escape failure response. At the same dosage, the cataleptic effects were not enhanced by combined treatment of MR1916 with risperidone. Furthermore, the enhancement of object recognition memory induced by MR1916 (0.3 mg/kg, p.o.) was not affected by the combination with risperidone (0.75 mg/kg, p.o.)., Conclusion: The combination of MR1916 with risperidone may have additive antipsychotic-like effects without affecting extrapyramidal side effects, and the cognitive-enhancing effect of MR1916 may not be interfered with the addition of risperidone., (© 2020 Mochida Pharmaceutical Co., Ltd. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology.)

This pilot study designed to evaluate the efficacy and safety of MAO-B inhibitor in comparison with Donepezil (DNP) in elderly Chinese patients with Alzheimer disease (AD). In the present clinical trial, Chinese elderly patients aged ≥65 years with a confirmed diagnosis of AD were enrolled. The patients received MAO-B inhibitor (Selegiline 5 mg) or DNP 10 mg daily (reference) for 6 months. The efficacy and safety data were collected from 120 patients (60 patients in each group) every 3 weeks until 6 months. The primary endpoints were to assess the change in cognitive score from baseline in both the treatment group. The result of the present study showed that the patients treated with MAO-B inhibitor and DNP have similar efficacy and safety profile Considering the clinical benefit, mean (SD) improvement in sign and symptoms was numerically greater in DNP-treated patients as compared to MAO-B inhibitor at endpoint visit (SIB: 12.3 (3.7) vs 11.3 (4.2); AD severity: 14.2 (3.5); CIBIS+/CIBIC: 10.2 (2.7) vs 9.4 (3.2); ADCS-ADL: 14.3 (4.2) vs 13.2 (3.4); MMSE: 14.3 (3.7) vs 12.2 (3.2), P>0.05 respectively for each comparison). However, a statistical difference in terms of clinical benefit was similar between both the treatment groups (p>0.05). Overall, both the study drugs were found comparable in relieving the symptoms of AD (severity score after end of treatment: 14.2 vs 13.4 respectively; p >0.05). This indicates that MAO-B inhibitor is a potential target for the treatment of AD in China. The results of the present study may help to design a large clinical trial to evaluate the efficacy and safety of MAO-B inhibitor in comparison with DNP in AD patients.

Objective: The objective of this study was to clarify the types and prevalence of, and the risk factors for, the adverse events that occur in patients receiving anti-dementia drugs., Methods: A questionnaire survey was conducted. The respondents were pharmacists who were dispensing anti-dementia drugs. The pharmacists responded to questions about patients who were receiving anti-dementia drugs delivered to them at home by the pharmacists. The survey questions included questions about whether or not the patients experienced adverse reactions to the drugs, about the patients' background characteristics, about the numbers of drugs the patients were taking when the pharmacists first visited the patients at home, and about the pharmacists' assessments of the appropriateness of the use of the anti-dementia drugs., Results: Data were collected on 3712 patients from 1673 pharmacies in a nationwide survey. Anti-dementia drugs had been prescribed to 863 of these patients; and 801 (92.8%) of these 863 patients were 75 years of age or older, and. confirmed adverse events occurred in 170 (21%) of these 863 patients. The most common adverse event was excitation/anxiety, at 45.1%. A multivariate analysis found that polypharmacy (10 or more types of drugs per day) (P = 0.030), inappropriate use (P = 0.002), and irregular medication use (P = 0.034) were risk factors., Interpretation: In order to avoid adverse events when using anti-dementia drugs, doctors and pharmacists should carefully examine the prescribing of multiple medications, assess the applicability of the use of anti-dementia drugs, and investigate how to best manage patients' drug use., Competing Interests: The authors have declared that no competing interests exist.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that is characterized by tremor, cerebellar ataxia, frequent falls, cognitive decline, and progressive loss of motor function. There are currently no approved treatments for this disorder. The purpose of this study was to determine if citicoline was safe for the treatment of tremor and balance abnormalities and to stabilize cognitive decline in patients with FXTAS. Ten participants with diagnosed FXTAS were administered 1000 mg of citicoline once daily for 12 months. Outcome measures and neurological examination were performed at baseline, 3 months, 6 months, and 12 months. The primary outcome was the FXTAS Rating Scale score. Secondary outcomes included change in a battery of neuropsychological tests, an instrumented Timed up and go test, computerized dynamic posturography, 9-hole pegboard test, and balance confidence and psychiatric symptom questionnaires. Safety was also evaluated. Citicoline treatment resulted in minimal adverse events in all but one subject over the course of the study. There was a significant improvement in the Beck Anxiety Inventory (p = 0.03) and the Stroop Color-Word test (p = 0.03), with all other measures remaining stable over the course of 12 months. This open-label pilot trial of citicoline for individuals with FXTAS showed that it is safe and well tolerated in this population. Registration: This trial was registered at ClinicalTrials.gov. Identifier: NCT0219710., Competing Interests: The authors have declared that no competing interests exist.

Dehydration risk increases with frailty and functional dependency, but a limited number of studies have evaluated this association in hospitalized geriatric patients. This cross-sectional study aimed to assess the prevalence and determinants of dehydration in patients admitted to the geriatric ward. Dehydration was diagnosed when calculated osmolarity was above 295 mMol/L. Logistic regression analyses (direct and stepwise backward) were used to assess determinants of impending dehydration. 358 of 416 hospitalized patients (86.1%) were included: 274 (76.5%) women, and 309 (86.4%) 75+ year-old. Dehydration was diagnosed in 209 (58.4%) cases. Significantly higher odds for impending dehydration were observed only for chronic kidney disease with trends for diabetes and procognitive medication when controlling for several health, biochemical, and nutritional parameters and medications. After adjusting for "dementia" the negative effect of "taking procognitive medications" became a significant one. Chronic kidney disease, diabetes, taking procognitive medications and hypertension were the main variables for the outcome prediction according to the stepwise backward regression analysis. This may indicate an additional benefit of reducing the risk of dehydration when using procognitive drugs in older patients with dementia., Competing Interests: The author declares no conflict of interest.

Background: Efficacy and dose-effect relationship of donepezil for treating patients with Alzheimer's disease (AD) have been proven. However, few studies focused on the safety of donepezil, particularly in Chinese patients., Objective: To assess the safety of donepezil 10 mg/day in Chinese patients with mild-to-moderate AD., Methods: In this single-arm, prospective, multicenter trial, 241 patients with mild to moderate AD who had been treated with donepezil 5 mg/day for at least 4 weeks were enrolled. All patients received donepezil 10 mg/day for 20 weeks. Primary outcome was the incidence of adverse events (AEs). Safety profile was evaluated by physical examinations including vital signs and weight, clinical laboratory tests and electrocardiograms, and also correlation analysis between AEs and APOE genotypes., Results: 241 patients were enrolled. Of which, 38.59% patients experienced at least one AE and 17.43% discontinued due to AEs. Most AEs were mild to moderate, with diarrhea, vomiting, and nausea the most frequently reported. Risk of AEs was significantly increased by concomitant use of drugs for cardiovascular and cerebrovascular diseases. Mean changes in heart rate and corrected QT relative to baseline were -1.08±6.02 beat/min (p = 0.009) and -3.91±18.68 ms (p = 0.0062) at week 4 and -1.48 beat/min±7.18 (p = 0.0028) and -0.66 ms±19.66 (p = 0.6561) at week 20, respectively. There were no significant changes in other vital sign parameters. Patients' MMSE scores improved significantly after treatment (p = 0.0038), especially for non-APOEɛ4 allele carriers and patients ≤75 years., Conclusion: Donepezil 10 mg/day can be tolerated and is effective in Chinese patients with mild-to-moderate AD.

Purpose: There is considerable interest in positive allosteric modulators (PAMs) of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) subtype of ionotropic glutamate receptors as therapeutic agents for a range of cognitive and mood disorders. However, the challenge is to increase AMPA receptor (AMPAR) function sufficient to enhance cognitive function but not to the extent that there are mechanism-related pro-convulsant or convulsant side effects. In this present study, we report the preclinical pharmacology data for MDI-222, an AMPAR PAM which enhances cognition but has a much reduced side-effect (i.e. convulsant) liability relative to other molecules of this mechanism., Methods: The pharmacological effects of MDI-222 were characterised in in vitro and in vivo preclinical electrophysiology, efficacy (cognition), side-effect (pro-convulsant/convulsant), tolerability and toxicity assays., Results: We demonstrate that MDI-222 is an AMPAR PAM, since it enhanced AMPAR function in vitro at human (hGluA1-4) and rat (rGluA2) homomeric receptors, and potentiated hetero-oligomeric AMPARs in rat neurons. MDI-222 enhanced electrically evoked AMPAR-mediated synaptic transmission in the anaesthetised rat at 10 mg/kg (administered intravenously) and did not significantly lower the seizure threshold in the pro-convulsant maximal electroshock threshold test (MEST) at any dose tested up to a maximum of 30 mg/kg (administered by oral gavage (p.o.)). MDI-222 reversed a delay-induced deficit in novel object recognition (NOR) in rats with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) following acute administration, which was reduced to 0.1 mg/kg following sub-chronic administration, and improved passive avoidance performance in scopolamine-impaired rats with a MED of 10 mg/kg p.o. On the other hand, MDI-222 was not pro-convulsant in the MEST, resulting in a therapeutic window between plasma concentrations that enhanced cognitive performance and those associated with mechanism-related side effects of ⩾1000-fold. Unfortunately, despite the excellent preclinical profile of this compound, further development had to be halted due to non-mechanism-related issues., Conclusions: We conclude that MDI-222 is an AMPAR PAM which enhances cognitive performance in rats and has a significantly improved safety profile in preclinical species.

Introduction: Vascular dementia (VaD), a severe neurologic condition related to aging of the cerebrovascular structure, has been treated with herbal medications and products. In this overview of systematic reviews (SRs) on the effects of herbal medications, we aimed to summarize the current clinical evidence on the benefits of herbal drugs and to propose an evidence map outlining their effects on VaD., Methods: SRs assessing their effects on cognitive function or performance and the associated safety, published until December 2018, were located from PubMed, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, China National Knowledge Infrastructure, and Oriental Medicine Advanced Searching Integrated System. A Measurement Tool to Assess systematic Reviews 2 was used to assess their overall confidence. A bubble plot was proposed to present the depth and width of the current status of the evidence supporting the use of individual herbal drugs., Results: Ten SRs (4 on individual herbal medications and 6 on various herbal drugs) were included. The overall evidence on herbal medicines suggests that they are effective in improving cognitive function and performance. Individual herbal medications including FuFangHaiShe, NaoXinTong, YinDanXing- NaoTong, NaoMaiTai, ShenFuTang, and TongXinLuo showed favourable effects when assessed via a minimal mental state examination score but have limited evidence supporting their effectiveness due to the scarcity of randomized controlled trials. Concerning safety, most SRs did not outline the estimated risk ratio of adverse events., Conclusion: Herbal medications might have benefits for VaD patients but they need to be evaluated further., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pharmacological cognitive enhancement (PCE) usually refers to the use of medical substances by healthy individuals to improve mental performance. Given that certain substances have been frequently used for years, the long-term effectiveness and safety are essential to know but particularly difficult and costly to determine. Although PCE is a widespread and frequent phenomenon among university students in other countries, PCE prevalence in Japan has not been elucidated. The present study aimed to investigate the prevalence of and the attitude toward PCE among Japanese undergraduates over 3 years (2017-2019). Almost no student had ever used prescription drugs for cognitive enhancement. When asked, "Would you like to use drugs to enhance your cognitive performance?" 68.6-72.0% of the students answered, "No," 25.4-26.7% answered, "I couldn't say," and 2.5-4.8% answered, "Yes." These answers were associated with sex (2017-2018) and stress sensitivity (2019) but not with drinking, smoking, or stress of academic performance. Half of the students had used energy drinks for neural enhancement prior to an examination, which is similar to Western usage. The users of soft enhancers, such as energy drinks, are more likely to use other drugs. Given that caffeine can be a gateway for cognitive enhancement, future education addressing PCE among students should emphasize the side effects of prescription drugs as well as health risks of caffeine products.

Electroencephalography (EEG) systems and brain-computer interfaces (BCIs) are terms frequently involved in the field of neurological research. Under a technological point of view, BCI is considered to be a significant achievement within the frame of learning disabilities rehabilitation. Nevertheless, the specifications for efficient use for cognitive enhancement and its potential boundaries are under concern. Author's main objective is to discuss BCI concrete components and potential advances as well as depict potential limitations while using technological devices within the frame of the learning procedure. Within this context, requirements, advantages, possible addiction risks, and boundaries regarding the specifications for brain-computer interfaces and technology in order to serve long-term research and developmental learning goals are discussed.

Background: Alzheimer's disease (AD) and vascular dementia (VaD) are major types of dementia, both of which cause heavy economic burdens for families and society. However, no currently available medicines can control dementia progression. Rhizoma coptidis, a Chinese herbal medicine, has been used for >2000 years and is now gaining attention as a potential treatment for AD and VaD., Methods: We reviewed the mechanisms of the active ingredients of Rhizoma coptidis and Rhizoma coptidis-containing Chinese herbal compounds in the treatment of AD and VaD. We focused on studies on ameliorating the risk factors and the pathological changes of these diseases., Results: The Rhizoma coptidis active ingredients include berberine, palmatine, coptisine, epiberberine, jatrorrhizine and protopine. The most widely studied ingredient is berberine, which has extensive therapeutic effects on the risk factors and pathogenesis of dementia. It can control blood glucose and lipid levels, regulate blood pressure, ameliorate atherosclerosis, inhibit cholinesterase activity, Aβ generation, and tau hyperphosphorylation, decrease neuroinflammation and oxidative stress and alleviate cognitive impairment. Other ingredients (such as jatrorrhizine, coptisine, epiberberine and palmatine) also regulate blood lipids and blood pressure; however, there are relatively few studies on them. Rhizoma coptidis-containing Chinese herbal compounds like Huanglian-Jie-Du-Tang, Huanglian Wendan Decoction, Banxia Xiexin Decoction and Huannao Yicong Formula have anti-inflammatory and antioxidant stress activities, regulate insulin signaling, inhibit γ-secretase activity, neuronal apoptosis, tau hyperphosphorylation, and Aβ deposition, and promote neural stem cell differentiation, thereby improving cognitive function., Conclusion: The "One-Molecule, One-Target" paradigm has suffered heavy setbacks, but a "multitarget- directed ligands" strategy may be viable. Rhizoma coptidis active ingredients and Rhizoma coptidiscontaining Chinese herbal compounds have multi-aspect therapeutic effects on AD and VaD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the Alzheimer's disease (AD) brain, accumulation of the amyloid-β (Aβ) peptide starts 15-20 years before clinical symptoms become apparent and is believed to be the initial event of the pathological process. Unfortunately, candidate drugs targeting production, clearance and deposition of Aβ have failed to show clinical benefit in patients with established or prodromal disease, or in cognitively normal subjects with high risk of developing AD. Surprisingly, several potent anti-Aβ drugs accelerated cognitive decline of AD and, in some cases, worsened neuropsychiatric symptoms (NPS) and triggered suicidal ideation. Clarifying the relationships between the AD-related pathology and NPS of AD patients may be useful for elucidating the underlying pathophysiological process. We believe that steady overproduction of Aβ in AD may represent an attempt of the brain to mitigate or repair neuronal damage/insult. Sudden reductions of brain Aβ levels with potent anti-Aβ drugs may worsen cognition and exacerbate NPS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To assess the comparative efficacy and safety of both pharmacological and non-pharmacological therapies for the behavioral and psychological symptoms of dementia, using direct and indirect evidence from randomized data., Method: A systematic review and Bayesian network meta-analysis was conducted on only randomized controlled trials (RCTs) of all the available interventions for BPSD. RCTs were selected from Pubmed, EMBASE, the Cochrane library, and CINAHL. The efficacy outcomes were Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory (CMAI). The outcomes of safety were total adverse events (AEs), diarrhea, dizziness, headache, falls, nausea, vomiting, and cerebrovascular diseases., Result: 146 RCTs comprising 44,873 patients with BPSD were included in this study. On NPI, aripiprazole (MD - 3.65, 95% credible interval (CrI) = - 6.92 to - 0.42), escitalopram (MD - 6.79, 95% CrI - 12.91 to - 0.60), donepezil (MD - 1.45, 95% CrI - 2.70 to - 0.20), galantamine (MD - 1.80, 95% CrI - 3.29 to - 0.32), memantine (MD - 2.14, 95% CrI - 3.46 to - 0.78), and risperidone (MD - 3.20, 95% CrI - 6.08 to - 0.31) were superior to placebo. On CMAI, aripiprazole (MD - 4.00, 95% CrI - 7.39 to - 0.54) and risperidone (MD - 2.58, 95% CrI - 5.20 to - 0.6) showed superiority to placebo. On the risk of total AEs, donepezil (OR 1.27, 95% CrI 1.07-1.50), galantamine (OR 1.91, 95% CrI 1.58-2.36), risperidone (OR 1.47, 95% CrI 1.13-1.97), and rivastigmine (OR 2.02, 95% CrI 1.53-2.70) owned higher risk than placebo., Conclusion: Pharmacological therapies should be the first choice for BPSD. Aripiprazole, haloperidol, quetiapine, and risperidone of antipsychotics showed the significant efficacy, while memantine, galantine, and donepezil may provide the modest effectiveness. The safety of all was thought to be acceptable.

The safety and efficacy of a novel combination treatment of AChE inhibitors and choline supplement was initiated and evaluated in children and adolescents with autism spectrum disorder (ASD). Safety and efficacy were evaluated on 60 children and adolescents with ASD during a 9-month randomized, double-blind, placebo-controlled trial comprising 12 weeks of treatment preceded by baseline evaluation, and followed by 6 months of washout, with subsequent follow-up evaluations. The primary exploratory measure was language, and secondary measures included core autism symptoms, sleep and behavior. Significant improvement was found in receptive language skills 6 months after the end of treatment as compared to placebo. The percentage of gastrointestinal disturbance reported as a side effect during treatment was higher in the treatment group as compared to placebo. The treatment effect was enhanced in the younger subgroup (younger than 10 years), occurred already at the end of the treatment phase, and was sustained at 6 months post treatment. No significant side effects were found in the younger subgroup. In the adolescent subgroup, no significant improvement was found, and irritability was reported statistically more often in the adolescent subgroup as compared to placebo. Combined treatment of donepezil hydrochloride with choline supplement demonstrates a sustainable effect on receptive language skills in children with ASD for 6 months after treatment, with a more significant effect in those under the age of 10 years.

Background: Amnestic mild cognitive impairment (aMCI) is a syndrome characterized by significant forgetfulness that does not meet the criteria of dementia. Individuals with aMCI are at greater risk of progressing to dementia. Current studies suggest that good sleep quality is linked with preserved cognition in the elderly, and sleep complaints are common among the elderly with amnesia. Therefore, improving their sleep may be helpful for maintaining and improving their cognitive capacity. According to the theory of traditional Chinese medicine, Yi-Zhi-An-Shen is an herbal compound which may ameliorate forgetfulness and sleep disorders. As growing evidence indicates that the gut microbiome is associated with major mental symptoms, a hypothesis was proposed that Yi-Zhi-An-Shen granules (YZASG) might work by alternating microbial abundance and diversity. In this study, the investigators intend to assess the efficacy of YZASG on global cognition in the elderly suffering from aMCI and evaluate its safety as well as its potential mechanisms via sleep quality, fecal microbial 16S ribosomal DNA and metagenomics analyses, and serum markers., Methods/design: This study is a randomized, double-blind, placebo-controlled clinical trial. A total of 80 patients (aged 60-85 years) will be recruited and allocated randomly to a treatment group and a placebo group in a 1:1 ratio and will then be administered YZASG or isodose placebo three times a day. The intervention course is 16 weeks, with an 18 months follow-up. The primary outcome is the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Secondary outcome measures are the Mini-Mental State Examination, Montreal Cognitive Assessment, Pittsburgh Sleep Quality Index, serum concentrations of immunological factors and inflammatory cytokines, and fecal microbiota. Fecal microbiota will only be collected at the baseline and endpoint of the intervention., Discussion: The results of this trial will be conducive to assessing the safety and effectiveness on cognition of YZASG in intervening aMCI among the elderly and determining if it takes effect via the improvement of sleep quality, regulation of gut microbiota, and concentration of certain serum markers., Trial Registration: ClinicalTrials.gov, NCT03601000 . Registered on 26 July 2018.

Aim: To evaluate the prevalence of potentially inappropriate prescribing (PIP), as defined by the internationally validated Screening Tool of Older Person's Prescriptions (STOPP) criteria, in 12 months before and after initiation of medicines for dementia., Methods: A retrospective cohort study was carried out involving people with their first claim for dispensing of medicines for dementia (cholinesterase inhibitor or memantine) between 1 January 2015 and 31 December 2015, aged ≥65 years at 1 January 2016 and alive at the end of 2016. The index date was defined as the date of first supply of medicines for dementia. PIP was identified using the Screening Tool of Older Person's Prescriptions criteria, and PIP prevalence was compared in the 12 months pre- and post-index date. The McNemar's test was used to test differences in the prevalence of PIP between the two time periods., Results: The cohort included 1176 patients: 60% were women and the median age was 80 years. The overall PIP prevalence was 85% in the 12 months pre-initiation of medicines for dementia compared with 89% in the 12 months post-initiation (P < 0.0001). The median number of Screening Tool of Older Person's Prescriptions criteria was two (interquartile range 1-4) in the 12 months pre-initiation of medicines for dementia, increasing to three (range 2-4) in the 12 months post-initiation., Conclusions: PIP was common in people dispensed medicines for dementia, with a significant increase in prevalence post-initiation of medicines for dementia compared with pre-initiation. These results highlight the need for targeted interventions to minimize inappropriate use of medicines in people with dementia. Geriatr Gerontol Int 2019; 19: 654-659., (© 2019 Japan Geriatrics Society.)