Comparative study of choline alfoscerate as a combination therapy with donepezil: A mixed double-blind randomized controlled and open-label observation trial.

BACKGROUND: Choline alfoscerate (alpha-glycerylphosphorylcholine) is a phospholipid that includes choline, which increases the release of acetylcholine. The ASCOMALVA trial, a combination of donepezil and choline alfoscerate, slowed cognitive decline in Alzheimer disease. This study aims to replicate the effect by combining donepezil with other nootropics currently used in South Korea. METHODS: The 119 patients with cognitive decline who were eligible to use donepezil, with an mini-mental state examination (MMSE) score of 26 or less, were assigned to: donepezil alone (DO); donepezil and choline alfoscerate (DN); donepezil and acetyl-l-carnitine (DA); or donepezil and ginkgo biloba extract (DG). Cognitive evaluations such as MMSE, clinical dementia rating, Alzheimer disease assessment scale-cognitive subscale (ADAS-Cog), and Alzheimer disease assessment scale-noncognitive subscale were performed at the 12th and 24th weeks from the baseline time point. RESULTS: At the 12th week, the MMSE score increased 3.52% in the DN group, whereas it increased by 1.36% in the DO group. In the DA + DG group, it decreased by 2.17%. At the 24th week, the MMSE score showed an increase of 1.07% in the DO group and 1.61% in the DN group, but decreased by 5.71% in the DA + DG group. ADAS-Cog decreased by 0.9% in the DO group, while it improved by 13.9% in the DN group at the 12th week. At the 24th week, ADAS-Cog showed improvement in the DN group by 18.5%, whereas it improved by 9.4% in the DO group. Alzheimer disease assessment scale-noncognitive subscale also revealed better performance in the DN group than in the DO group at the 12th and 24th weeks. CONCLUSION: Choline alfoscerate exhibits additional cognitive improvement in both cognitive and noncognitive domains, supporting the findings of the ASCOMALVA trial.

Preparation and evaluation of injectable microsphere formulation for longer sustained release of donepezil.

In this study, donepezil-loaded PLGA and PLA microspheres (Dp-PLGA-M/Dp-PLA-M) and Dp-PLA-M wrapped in a polyethylene glycol-b-polycaprolactone (PC) hydrogel (Dp-PLA-M/PC) were prepared to reduce the dosing frequency of injections to treat Alzheimer's disease patients. Dp-PLGA-M and Dp-PLA-M with a uniform particle size distribution were repeatably fabricated in nearly quantitative yield and with high encapsulated Dp yields using an ultrasonic atomizer. The injectability and in vitro and in vivo Dp release, biodegradation, and inflammatory response elicited by the Dp-PLGA-M, Dp-PLA-M, and Dp-PLA-M/PC formulations were then compared. All injectable formulations showed good injectability with ease of injection, even flow, and no clogging using a syringe needle under 21-G. The injections required a force of <1 N. According to the biodegradation rate of micro-CT, GPC and NMR analyses, the biodegradation of Dp-PLA-M was slower than that of Dp-PLGA-M, and the biodegradation rate of Dp-PLA-M/PC was also slower. In the Dp release experiment, Dp-PLA-M sustained Dp for longer compared with Dp-PLGA-M. Dp-PLA-M/PC exhibited a longer sustained release pattern of two months. In vivo bioavailability of Dp-PLA-M/PC was almost 1.4 times higher than that of Dp-PLA-M and 1.9 times higher than that of Dp-PLGA-M. The variations in the Dp release patterns of Dp-PLGA-M and Dp-PLA-M were explained by differences in the degradation rates of PLGA and PLA. The sustained release of Dp by Dp-PLA-M/PC was attributed to the fact that the PC hydrogel served as a wrapping matrix for Dp-PLA-M, which could slow down the biodegradation of PLA-M, thus delaying the release of Dp from Dp-PLA-M. Dp-PLGA-M induced a higher inflammatory response compared to Dp-PLA-M/PC, suggesting that the rapid degradation of PLGA triggered a strong inflammatory response. In conclusion, Dp-PLA-M/PC is a promising injectable Dp formulation that could be used to reduce the dosing frequency of Dp injections.

Optimal Formula of Angelica sinensis Ameliorates Memory Deficits in ß-amyloid Protein-induced Alzheimer's Disease Rat Model.

OBJECTIVE: Angelica (A.) sinensis is used as a traditional medical herb for the treatment of neurodegeneration, aging, and inflammation in Asia. A. sinensis optimal formula (AOF) is the best combination in A. sinensis that has been screened to rescue the cognitive ability in ß-amyloid peptide (Aß25-35)-treated Alzheimer's disease (AD) rats. The objective of this study was to investigate the effect of AOF on the learning and memory of AD rats as well as to explore the underlying mechanisms. METHODS: Male Wistar rats were infused with Aß25-35 for AD model induction or saline (negative control). Five groups of AD rats were fed on AOF at 20, 40, or 80 mL/kg every day, donepezil at 0.9 mg/kg every day (positive control), or an equal volume of water (AD model) intragastrically once a day for 4 weeks, while the negative control rats were fed on water. The Morris water maze test was used to evaluate the cognitive function of the rats. The Aß accumulation, cholinergic levels, and antioxidative ability were detected by ELISA. Additionally, the candidate mechanism was determined by gene sequencing and quantitative real-time polymerase chain reaction. RESULTS: The results showed that AOF administration significantly ameliorated Aß25-35-induced memory impairment. AOF decreased the levels of amyloid-ß precursor protein and Aß in the hippocampus, rescued the cholinergic levels, increased the activity of superoxide dismutase, and decreased the malondialdehyde level. In addition, AOF inhibited the expression of IL1b, Mpo, and Prkcg in the hippocampus. CONCLUSION: These experimental findings illustrate that AOF prevents the decrease in cognitive function and Aß deposits in Aß25-35-treated rats via modulating neuroinflammation and oxidative stress, thus highlighting a potential therapeutic avenue to promote the co-administration of formulas that act on different nodes to maximize beneficial effects and minimize negative side effects.

Targeting hippocampal amyloidogenesis with SV2A protein modulator levetiracetam.

Cerebral amyloid ß (Aß) proteostasis is compromised under neuronal overexcitation, long-term neuroinflammation and brain aging. Using the animal model of LPS-induced neuroinflammation we demonstrated that treatment with levetiracetam, a specific modulator of synaptic vesicle glycoprotein SV2A, rescues abnormal synaptic vesicle (SV) fusion and neurotransmitter release, decreasing elevated hippocampal APP levels in vivo. Therapy with levetiracetam upregulates the SV2A in hippocampus and restores the level of apolipoprotein E, involved in brain Aß aggregation/clearance and resolution of inflammation. We demonstrated that oligomers of Aß1-42 and Aß1-40 peptides promote SV clustering, which reduces the rate and plateau level of subsequent homo- and heterotypic SNARE-mediated SV fusion. Oligomeric Aß1-42 lowered ΔpH gradient across the vesicular membrane, thus affecting their neurotransmitter storage capacity. In contrast, monomers of Aß1-42 and Aß1-40 had negligible impact on studied processes. Our data suggests that in the course of progression of neuroinflammation oligomeric forms of Aß1-42 and Aß1-40 can compromise the SV fusion machinery and that antiepileptic agent levetiracetam, acting on SV recycling and restricting overexcitation, is able to affect APP processing and Aß generation within the hippocampus in vivo.

Assessing prevalence, knowledge and use of cognitive enhancers among university students in the United Arab Emirates: A quantitative study.

BACKGROUND: Cognitive enhancers (CE) are often used to improve memory, alertness and cognitive capacity. These products are commercially and pharmaceutically available. Due to high academic pressure, university students are at risk of CE misuse. However, data regarding this issue are limited, especially in the United Arab Emirates (UAE). AIMS: To assess the prevalence of CE intake; evaluate students' knowledge of these substances; and identify student characteristics associated with CE usage. METHOD: A cross sectional study based on a validated online survey that was distributed using university-licensed software (Qualtrics) as a direct web link via email and social media to all Medical, Pharmacy, Dentistry, Nursing and Engineering students enrolled in six UAE universities. Associations between student characteristics and CE use were investigated using the chi-squared test and multiple logistic regression. Reasons for CE use, temporal patterns of use, details regarding purchase and types of CE used were compared by gender. RESULTS: One quarter of students had used CEs. There was a clear difference between users and non-users in terms of gender (p<0.001). CE users were disproportionately represented by students from either UAE or other Arab countries (p<0.001), and by students of Medicine, followed by Pharmacy, Dentistry, and Engineering (p<0.001). CE use increased with year of study, reaching the highest level in the fourth year (p<0.001), which for most programmes is the final year. Modafinil was self-administered, especially in males, for concentration and alertness; B12 was typically taken by female students for academic performance and concentration; and high-dosage caffeine compounds were ingested to improve alertness levels. Use of the internet for both obtaining information and purchasing CEs was frequently reported. Multiple logistic regression analysis showed that gender, nationality, and year of study were associated with CE use among UAE university students. CONCLUSIONS: Universities need to address the prevalence of CE use amongst their students by providing effective support programs.

Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor.

BACKGROUND AND OBJECTIVE: Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin). METHODS: In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0-167 h (AUC0‒167; itraconazole), 0-168 h (AUC0‒168; rifampicin), or 0-infinity (AUC0-∞; rifampicin and itraconazole), maximum measured concentration (Cmax) of BI 425809, and adverse events. RESULTS: In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC0‒167: 265.3; AUC0-∞: 597.0; Cmax: 116.1) and lower in the presence of rifampicin (AUC0‒168: 10.3; AUC0-∞: 9.8; Cmax: 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated. CONCLUSIONS: Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809. TRIAL REGISTRATION NUMBER: NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017).

Prenatal choline supplementation during mouse pregnancy has differential effects in alcohol-exposed fetal organs.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are preventable adverse outcomes consequent to prenatal alcohol exposure. Supplemental choline confers neuroprotection to the alcohol-exposed offspring, but its actions outside the brain are unclear. We previously reported that prenatal exposure of mice to 4.5 g/kg of alcohol decreased placental weight in females only, but decreased body weight and liver-to-body weight ratio and increased brain-to-body weight ratio in both sexes. Here we test the hypotheses that a lower alcohol dose will elicit similar outcomes, and that concurrent choline treatment will mitigate these outcomes. METHODS: Pregnant C57BL/6J mice were gavaged with alcohol (3 g/kg; Alc) or maltodextrin (MD) from embryonic day (E) 8.5-17.5. Some also received a subcutaneous injection of 100 mg/kg choline chloride (Alc + Cho, MD + Cho). Outcomes were evaluated on E17.5. RESULTS: Alc dams had lower gestational weight gain than MD; this was normalized by choline. In males, Alc decreased placental weight whereas choline increased placental efficiency, and Alc + Cho (vs. MD) tended to further reduce placental weight and increase efficiency. Despite no significant alcohol effects on these measures, choline increased fetal body weight but not brain weight, thus reducing brain-to-body weight ratio in both sexes. This ratio was also lower in the Alc + Cho (vs. MD) fetuses. Alc reduced liver weight and the liver-to-body weight ratio; choline did not improve these. Placental weight and efficiency correlated with litter size, whereas placental efficiency correlated with fetal morphometric measurements. CONCLUSIONS: Choline prevents an alcohol-induced reduction in gestational weight gain and fetal body weight and corrects fetal brain sparing, consistent with clinical findings of improvements in alcohol-exposed children born to mothers receiving choline supplementation. Importantly, we show that choline enhances placental efficiency in the alcohol-exposed offspring but does not normalize fetal liver growth. Our findings support choline supplementation during pregnancy to mitigate the severity of FASD and emphasize the need to examine choline's actions in different organ systems.

Peroxisome proliferator-activated receptor gamma: a novel therapeutic target for cognitive impairment and mood disorders that functions via the regulation of adult neurogenesis.

The proliferation, differentiation, and migration of neural precursor cells occur not only during embryonic development but also within distinct regions of the adult brain through the process of adult neurogenesis. As neurogenesis can potentially regulate brain cognition and neuronal plasticity, the factors that enhance neurogenesis can be attractive therapeutic targets for improving cognitive function and regulating neurodegenerative and neuropsychiatric disorders, including affective and mood disorders. Peroxisome proliferator-activated receptors (PPARs) are a class of ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARγ is a target for insulin sensitizers and plays an essential role in regulating various metabolic processes, including adipogenesis and glucose homeostasis. Interestingly, evidence demonstrates the role of PPARγ activation in regulating neurogenesis. The pharmacological activation of PPARγ using specific ligands increases the proliferation and differentiation of neural stem cells in specific brain regions, including the hippocampus, and prevents neurodegeneration and improves cognition and anxiety/depression-like behaviors in animal models. We summarize here recent reports on the role of PPARγ in adult neurogenesis, as well as the mechanisms involved, and suggest that PPARγ can serve as a potential therapeutic target for neurological and/or neurodegenerative diseases.

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.

Repeated treatment with alpha 7 nicotinic acetylcholine receptor ligands enhances cognitive processes and stimulates Erk1/2 and Arc genes in rats.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the treatment of cognitive decline in patients with schizophrenia, Alzheimer's disease, and attention-deficit/hyperactivity disorder. Here we examined the promnesic activity of the α7 nAChR agonist (A582941), the type I (CCMI), and the type II (PNU120596) positive allosteric modulators (PAMs) in rats following single and repeated (once daily for seven days) treatment. To determine the neuronal mechanisms underlying the procognitive activity of the tested compounds, levels of the extracellular signal-regulated kinases (Erk1/2) and the activity-regulated cytoskeleton-associated protein (Arc) mRNAs were assessed in the frontal cortical and hippocampal brain regions. Using the novel object recognition test, we demonstrate that the lower doses of A582941 (0.1 mg/kg), CCMI (1 mg/kg), and PNU120596 (0.3 mg/kg) improved recognition memory after repeated but not single administration, suggesting a cumulative effect of repeated dosing. In contrast, the higher doses of A582941 (0.3 mg/kg), CCMI (3 mg/kg) and PNU120596 (1 mg/kg) demonstrated promnesic efficacy following both single and repeated administration. Subsequent in situ hybridization revealed that repeated treatment with A582941 and CCMI, but not PNU120596 enhanced mRNA expression of the Erk1/2 and Arc in the frontal cortex and hippocampus. Present data suggest that both the α7 nAChR agonist and PAMs exhibit procognitive effects after single and repeated administration. The increased level of the Erk1/2 and Arc genes is likely to be at least partially involved in this effect.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

Assessing Treatment Effects with Pharmacometric Models: A New Method that Addresses Problems with Standard Assessments.

Longitudinal pharmacometric models offer many advantages in the analysis of clinical trial data, but potentially inflated type I error and biased drug effect estimates, as a consequence of model misspecifications and multiple testing, are main drawbacks. In this work, we used real data to compare these aspects for a standard approach (STD) and a new one using mixture models, called individual model averaging (IMA). Placebo arm data sets were obtained from three clinical studies assessing ADAS-Cog scores, Likert pain scores, and seizure frequency. By randomly (1:1) assigning patients in the above data sets to "treatment" or "placebo," we created data sets where any significant drug effect was known to be a false positive. Repeating the process of random assignment and analysis for significant drug effect many times (N = 1000) for each of the 40 to 66 placebo-drug model combinations, statistics of the type I error and drug effect bias were obtained. Across all models and the three data types, the type I error was (5th, 25th, 50th, 75th, 95th percentiles) 4.1, 11.4, 40.6, 100.0, 100.0 for STD, and 1.6, 3.5, 4.3, 5.0, 6.0 for IMA. IMA showed no bias in the drug effect estimates, whereas in STD bias was frequently present. In conclusion, STD is associated with inflated type I error and risk of biased drug effect estimates. IMA demonstrated controlled type I error and no bias.

COgnitive enhancement and consumption of psychoactive Substances among Youth Students (COSYS): a cross-sectional study in France.

OBJECTIVES: This descriptive and analytical study investigated the consumption rates of psychoactive substances among individuals aged 18-25 years in France. More specifically, it enabled assessment of the extent of the neuroenhancement (NE) phenomenon among students in France (including study of the misuse of psychostimulant medicines). STUDY DESIGN: COgnitive enhancement and consumption of psychoactive Substances among Youth Students (COSYS) is a cross-sectional survey of students in France. METHODS: Between January and June 2017, a questionnaire was mailed to students. All questionnaires were completed anonymously and included questions regarding the use of all kind of psychoactive substances, motivations for use and socio-economic situations. Statistics for all variables and the results of a multiple correspondence analysis (MCA) are presented. RESULTS: This study recorded 46,203 respondents, mostly in universities (>60%), mostly women (63.4%), with an average age of 21.4 years. In terms of substance use, medications were cited in the third position after alcohol and tobacco by women (22.48%) and in the fourth position after alcohol, tobacco and cannabis by men (15.14%). Among medications, opiates were the most frequently used, followed by benzodiazepines. Students who declared a non-medical use (NMU) of drugs obtained these through various ways (e.g. family medicine cabinet, a friend, a dealer or via the Internet), or by increasing their recommended doses (e.g. codeine). In total, 18.6% of students consumed psychoactive substances for 'stress management' and 14.1% for 'sleep management'. Results indicated that NE in students is a problem, with 18.6% of students in the COSYS survey confirming the use of psychoactive substances for this reason. There was a very low prevalence for psychostimulant medications (0.57% of men), mostly NMU (67%). MCA yielded three different profiles (doping candidate, experimenter and psychiatric profile) of psychostimulant users, which complicates the implementation of prevention programmes. CONCLUSIONS: It is evident that NMU and 'conventional' use of medications are highly prevalent in French students, especially females. NMU is associated with substance use disorders, psychopathology and suicidality. Social norms and social media increase NMU of psychoactive substances, but also provide a potential platform for anti-NMU campaigns. CLINICAL TRIAL REGISTRATION NUMBER: NCT02954679.

Assessment of a Potential Synergistic Effect of Souvenaid® in Mild Alzheimer's Disease Patients on Treatment with Acetylcholinesterase Inhibitors: An Observational, Non-Interventional Study.

We evaluated the efficacy and safety of Souvenaid (a multinutrient supplement) in patients with mild Alzheimer's disease (AD) in real clinical practice and assessed a potential synergistic effect of acetylcholinesterase (AChE) inhibitors. Clinical Dementia Rating (CDR) scale was evaluated after six months follow-up. Patients were divided into 4 groups according to the treatment they received: Souvenaid + AChE inhibitors (n = 23); only Souvenaid (n = 8); only AChE inhibitors (n = 7); no treatment (n = 16). The Souvenaid + AChE inhibitors and Souvenaid alone groups were associated with significantly lower increases in CDR per month than the AChE inhibitors or no treatment ones. The efficacy of Souvenaid + AChE inhibitors tended to be higher than Souvenaid alone.

Stimulating meditation: a pre-registered randomised controlled experiment combining a single dose of the cognitive enhancer, modafinil, with brief mindfulness training.

BACKGROUND: Mindfulness-meditation has a variety of benefits on well-being. However, individuals with primary attentional impairments (e.g. attention deficit disorder) or attentional symptoms secondary to anxiety, depression or addiction, may be less likely to benefit, and require additional mindfulness-augmenting strategies. AIMS: To determine whether a single dose of the cognitive enhancer, modafinil, acutely increases subjective and behavioural indices of mindfulness, and augments brief mindfulness training. METHODS: A randomised, double-blind, placebo-controlled, 2 (drug: placebo, modafinil) × 2 (strategy: mindfulness, relaxation control) experiment was conducted. Seventy-nine meditation-naïve participants were assigned to: placebo-relaxation, placebo-mindfulness, modafinil-relaxation or modafinil-mindfulness. Pre-drug, post-drug and post-strategy state mindfulness, affect and autonomic activity, along with post-strategy sustained attention and mind-wandering were assessed within a single lab session. After the session, participants were instructed to practice their assigned behavioural strategy daily for one week, with no further drug administration, after which, follow-up measures were taken. RESULTS: As predicted, modafinil acutely increased state mindfulness and improved sustained attention. Differential acute strategy effects were found following mindfulness on autonomic activity but not state mindfulness. There were no strategy or drug effects on mind-wandering. However, exploratory analyses indicated that participants receiving modafinil engaged in more strategy practice across strategy conditions during follow-up. CONCLUSIONS: Modafinil acutely mimicked the effects of brief mindfulness training on state mindfulness but did not enhance the effects of this training. Limitations of the current study, and recommendations for future research examining modafinil as an adjunct to mindfulness- (or relaxation-) based treatments are discussed.

The Use of Methylphenidate for Cognitive Enhancement in Young Healthy Adults: The Clinical and Ethical Debates.

OBJECTIVE: Methylphenidate (MP), a drug of choice for attention-deficit/hyperactivity disorder (ADHD), is a federally restricted substance CII in the United States because of abuse and dependence, and similar restrictions are practiced in Canada and around the world. This designation is given to drugs with medical value that present a high potential for abuse. In view of these severe restrictions, it is concerning to find out that a large group of healthy young adults, at least as large as the ADHD group of patients, take MP for cognitive enhancement, in an attempt to improve their academic achievements during studies and examinations. These young adults buy MP illegally and consume it without any medical supervision. The objective of the present debate piece is to present the ethical and clinical issues that need to be addressed in an attempt to solve this dilemma. METHODS: The issues presented here are systematically reviewed and discussed along the following lines: MP effectiveness in enhancing cognitive achievements in healthy people; "As these are normal healthy people, what is the duty of physicians to 'treat' them?"; potential benefits of cognitive enhancement to healthy people; the risks of MP; "How do these young people get their MP?"; and "What can be done?" RESULTS: Methylphenidate is widely used for cognitive enhancement without medical supervision. The effectiveness of MP for cognitive enhancement is well documented along a dose-response curve. Congruent with the results of the randomized trials, repeated studies based on interviews suggest that numerous young people report that cognitive enhancement helps them in improving their academic achievements, and hence also improve their feeling of well-being. Presently, most regulatory and medical organizations limit the use of MP to ADHD and narcolepsy. Yet, the American Academy of Neurology ruled that there is a moral, ethical, and legal basis to prescribe the drug for cognitive enhancement. The drug has known dose-dependent adverse effects that can have serious ramifications and may often lead to poor adherence. The relative risk of MP causing sudden death/arrhythmia is 1.46 (95% confidence interval, 1.03-2.07), and there are estimated 20 million college and university students in the United States in 2020. The rate of sudden death/arrhythmias in this age group ranges between 1 and 10 per 100,000. This translates to an excess of 146 deaths caused by MP every year in the United States considering postsecondary students only. DISCUSSION: We propose that an ethical-clinical debate should be followed by an action plan to ensure that the present reality of millions of young people taking unsupervised MP is not accepted as a force majeure that cannot be changed.

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.