[Pharmacological Cognitive Enhancement: Current Situation and Perspectives].

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

Diagnosing and treating dementia in German primary and specialized care between 2011 and 2015
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BACKGROUND: Whilst there was no upturn in detection rate of persons with dementia (PwD) in German general practitioner (GP) practices before 2012, dementia diagnoses markedly increased in 2013 and 2014. OBJECTIVE: (1) Verify the increase of dementia diagnoses in GP practices and neurologist/psychiatrist (NP) practices; (2) examine the subsequent prescription of antidementia drugs. MATERIALS AND METHODS: We performed a retrospective, longitudinal analysis of 874 GP and 141 NP practices collecting clinical data about 220,213 patients who received a dementia diagnosis (ICD-10: G30, F01, F03) between 2011 and 2015. RESULTS: In GP practices, documented dementia diagnoses increased by 73% between 2012 and 2014 (mean 6.4 - 11.1 PwD/practice) and decreased by 26% in 2015 (8.3 PwD/practice). This trend was mostly due to the subgroup of nonspecific (+63%) and vascular dementia (+170%). The upturn has been accompanied by a downturn of the proportion of PwD receiving antidementia drugs (2012: 13.9% vs. 2014: 7.8%). Neither of these trends was found in NP practices. CONCLUSION: The upturn parallels the introduction of monetary incentives for both patients and GPs. It should be examined if these monetary incentives will also lead to an improvement in treatment and care of PwD in the long run.
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Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients.

CONTEXT: Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. OBJECTIVE: The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. METHODS AND MATERIALS: The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. RESULTS AND DISCUSSION: Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. CONCLUSION: The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

Antidementia drug use among community-dwelling individuals with Alzheimer's disease in Finland: a nationwide register-based study.

The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006-2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer's disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295-1458) days and 1103 (interquartile range 489-1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22-1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15-1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer's disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.

Prohibition or coffee shops: regulation of amphetamine and methylphenidate for enhancement use by healthy adults.

This article analyzes appropriate public policies for enhancement use of two most important stimulant drugs: Ritalin (methylphenidate) and Adderall (mixed amphetamine salts). The author argues that appropriate regulation of cognition enhancement drugs cannot be a result of a general discussion on cognitive enhancements as such, but has to be made on a case-by-case basis. Starting from the recently proposed taxation approach to cognition enhancement drugs, the author analyzes available, moderately permissive models of regulation. After a thorough analysis of relevant characteristics of methylphenidate and amphetamine, the author concludes that a moderately liberal permissive regulation of enhancement use by healthy adults might be appropriate for extended release forms of methylphenidate. However, due to their danger profile, amphetamine and instant release forms of methylphenidate should not be made readily available to healthy adults and would need to be prohibited.

Comparative cardiovascular safety of dementia medications: a cross-national study.

OBJECTIVES: To compare the cardiovascular safety of currently marketed dementia medications in new users in the United States and Denmark. DESIGN: Retrospective cohort study. SETTING: Nationally representative sample of Medicare beneficiaries from 2006 through 2009 and nationwide Danish administrative registries from 1997 through 2007. PARTICIPANTS: Individuals treated with a dementia medication aged 65 and older. MEASUREMENTS: Hospitalizations for myocardial infarction (MI), heart failure, and syncope or atrioventricular block in both cohorts; fatal or nonfatal MI and cardiac death in the Danish cohort; and all-cause mortality in sensitivity analyses. RESULTS: In 46,737 Medicare beneficiaries and 29,496 Danish participants, donepezil was the most frequently used medication. There were no substantial differences in the risk of MI or heart failure between participants using donepezil and those using other cholinesterase inhibitors (all hazard ratios (HR) crossing 1). In the Danish cohort, memantine was associated with fatal or nonfatal MI (HR = 1.33, 95% confidence interval (CI) = 1.08-1.63), cardiac death (HR = 1.31, 95% CI = 1.12-1.53), and a trend toward higher rates of hospitalization for MI (HR = 1.31, 95% CI = 0.98-1.76). Memantine was also associated with greater risk of all-cause mortality in the Medicare (HR = 1.20, 95% CI = 1.13-1.28) and Danish (HR = 1.83, 95% CI = 1.73-1.94) cohorts, suggesting that sicker individuals were selected for memantine therapy. CONCLUSION: Cholinesterase inhibitors have similar cardiovascular risk profiles. Associations between memantine and fatal outcomes in Denmark may be related, in part, to selection of sicker individuals for memantine therapy.

Treatment of Alzheimer disease.

Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.

[Daily functioning in dementia: pharmacological and non-pharmacological interventions demonstrate small effects on heterogeneous scales]. / Alltagsbewältigung bei Demenz: Medikamentöse und nicht medikamentöse Interventionen zeigen kleine Effekte auf heterogenen Skalen.

OBJECTIVE: To assess the effects of pharmacological and non-pharmacological interventions on activities of daily living in dementia and the heterogeneity of the applied measurement instruments. METHODS: Four Health Technology Assessments (HTA) on dementia are summarized regarding to effects on activities of daily living. These HTA assessed RCTs on ACE-inhibitors, Memantin, Ginkgo and non-pharmacological interventions according to Cochrane standards. An overview over the domains of activities of daily living covered by the applied assessment instruments is provided. RESULTS: The analysis of 40 RCTs revealed indications of a beneficial effect of Donepezil, small positive effects of Galantamin, Rivastigmin and Memantin, positive effects of caregiver training in only one of five RCTs and no beneficial effects in seven RCTs on validation and reminiscence therapy, cognitive training procedures or activity-based interventions. CONCLUSION: The studies demonstrated a very heterogeneous methodological quality with regard to assessment instruments, measurement time points and report of study design and results. Harmonisation in research methods is imperative and further elaborated RCTs must be conducted.

[Memantine for treatment of behavioural disturbances and psychotic symptoms in moderate to moderately severe Alzheimer dementia: a naturalistic study in outpatient services in Austria]. / Memantin in der Behandlung von Verhaltensauffälligkeiten und psychotischen Symptomen bei moderater bis mittelschwerer Alzheimer-Demenz: Eine naturalistische Studie im ambulanten Bereich in Osterreich.

We conducted an open, 16-week study on the efficacy of memantine on behavioral disturbances and psychotic symptoms in moderate to moderately severe Alzheimer s disease in daily routine. Fifty-three patients of 20 outpatient centers in Austria were recruited. The Neuropsychiatric Inventory (NPI) was defined as main outcome measure. After 16 weeks the total NPI score improved by 4,6 points (p<0.01). The caregiver distress score was also significantly reduced. The most pronounced improvements were seen in the NPI components depression (-24,6%), aberrant motor behavior (-16,9%), agitation/agression, fear, apathy, disinhibition and disturbances in appetite and eating behavior (-11,3%, each). Our naturalistic study is in line with the results of controlled trials in moderate and severe Alzheimer dementia stages. Controlled clinical trials which have behavioral disturbances and psychotic symptoms as primary endpoint are needed to define the true potential of memantine in mild dementia stages.

How do we treat people with dementia in Croatia.

The current clinical view on pharmacological treatment and the Croatian reality regarding approved antidementia drugs is presented. Dementia is a syndrome of high incidence and Alzheimer's disease is the most common cause of dementia. New data show that dementia prevalence will nearly double every 20 years, and we believe that current estimated number of persons with dementia (PWD) for Croatia is more than 80,000. The standard treatment with antidementia drugs is unavailable in Croatia, for the majority of PWD, because antidementia drugs are not on the reimbursement list, although Croatian algorithm for psychopharmacological treatment and Alzheimer Disease Societies Croatia recommend early and adequate treatment. Alzheimer's dementia is becoming a world's health priority in 21st century, so we strongly believe that antidementia drugs should be reimbursed in Croatia.

Tense prescriptions? Alzheimer medications and the anthropology of uncertainty.

This article discusses the two major groups of Alzheimer medications, which are hotly debated in the specialized literature because of their doubtful efficacy. Examining this issue under the rubric of an ;anthropology of uncertainty,' this article seeks to address the question: how do doctors prescribe medications given tensions created by uncertainty? A partial answer is drawn from research conducted in Brazil with local psychogeriatricians, which has documented a high degree of certainty regarding Alzheimer drugs and their benefits. I argue that one reason for this certainty is that ;efficacy' has become increasingly non-specific in Alzheimer's disease through the broadening of outcome measures in clinical trials. While such measures previously focused on cognitive symptoms, they now encompass concepts such as functionality, quality of life and activities of daily living. The certainty of the Brazilian psychogeriatricians is further buttressed by three interacting elements: (i) the influence of the pharmaceutical industry; (ii) long-standing arguments for including non-cognitive symptoms in dementia care and research; and (iii) a specific discourse found in geriatrics and gerontology, which recognizes ;the person beyond cognition.'