Assessment of the effect of amantadine in patients with traumatic brain injury: A meta-analysis.

BACKGROUND: Traumatic brain injury is a global burden. We aimed to perform a meta-analysis to determine the efficacy of amantadine for cognitive performance after traumatic brain injury. METHODS: The systematic review was prospectively registered on the International Prospective Register of Systematic Reviews website under the registration number CRD42017080044. We used Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to report the steps of meta-analysis. The search included electronic databases (PubMed, PsycINFO, Embase, Cochrane Library databases, CENTRAL, ProQuest and ClinicalTrials.gov trial registry). Critical care medicine journals and clinical neurology specialty were searched using www.scimagojr.com. There was no publication date restriction. Two authors assessed studies' relevance and extracted data. Studies were assessed for quality using the Cochrane risk of bias tool. Data were analyzed using Comprehensive Meta-analysis Program versions 2.0 and 3.0. RESULTS: Twenty-six studies out of 3,440 records were included in the systematic review, of which only 14 clinical trials and 6 observational studies were included in the meta-analysis. Amantadine significantly enhanced the cognitive function relative to control group (mean difference [MD], 0.50; 95% confidence interval [CI], 0.33-0.66; p < 0.001, 16 studies, 1,127 participants, low certainty evidence). Consistent significant difference in favor of amantadine relative to control group was found (MD of 0.79 [95% CI, 0.34-1.24], very low certainty evidence, for cohort studies vs. MD of 0.40 [95% CI, 0.25-0.56], moderate certainty evidence, for RCTS). Starting amantadine in the first week after TBI had a significant effect on improving cognitive function (MD, 0.97; 95% CI, 0.45-1.49; 16 studies, 1,127 participants, low certainty). Amantadine showed a better effect when administered for less than 1 month (MD, 0.83; 95% CI, 0.56-1.11; low certainty) and to patients below 18 years of age (MD, 0.66; 95% CI, 0.32-0.99; low certainty) or to patients with less severe traumatic brain injury (MD, 0.40; 95% CI, 0.18-0.62; low certainty). No statistically significant difference existed between amantadine and the control concerning the adverse events (OR, 1.74; 95% CI, 0.88-3.44; p = 0.11, moderate certainty). Metaregression of the different clinical parameters, which are onset of treatment, age, and severity of traumatic brain injury, showed a statistically significant relation between onset of treatment and the effect size of amantadine. The relation between the other two parameters and the effect size of amantadine showed a marginal statistical significance. CONCLUSION: Amantadine may improve the cognitive function when used after TBI. Further research with high validity is needed to reach a solid conclusion about the use of amantadine in traumatic brain injury. LEVEL OF EVIDENCE: Systematic review/meta-analysis, level III.

The Cost of Gait Slowness: Can Persons with Parkinson's Disease Save Energy by Walking Faster?

BACKGROUND: Gait slowing is a common feature of Parkinson's disease (PD). Many therapies aim to improve gait speed in persons with PD, but goals are often imprecise. How fast should each patient walk? And how do persons with PD benefit from walking faster? There is an important need to understand how walking speed affects fundamental aspects of gait-including energy cost and stability-that could guide individualized therapy decisions in persons with PD. OBJECTIVE: We investigated how changes in walking speed affected energy cost and spatiotemporal gait parameters in persons with PD. We compared these effects between dopaminergic medication states and to those observed in age-matched control participants. METHODS: Twelve persons with PD and twelve control participants performed treadmill walking trials spanning at least five different speeds (seven speeds were desired, but not all participants could walk at the fastest speeds). Persons with PD participated in two walking sessions on separate days (once while optimally medicated, once after 12-hour withdrawal from dopaminergic medication). We measured kinematic and metabolic data across all trials. RESULTS: Persons with PD significantly reduced energy cost by walking faster than their preferred speeds. This held true across medication conditions and was not observed in control participants. The patient-specific walking speeds that reduced energy cost did not significantly affect gait variability metrics (used as proxies for gait stability). CONCLUSION: The gait slowing that occurs with PD results in energetically suboptimal walking. Rehabilitation strategies that target patient-specific increases in walking speed could result in a less effortful gait.

Differential dopaminergic modulation of spontaneous cortico-subthalamic activity in Parkinson's disease.

Pathological oscillations including elevated beta activity in the subthalamic nucleus (STN) and between STN and cortical areas are a hallmark of neural activity in Parkinson's disease (PD). Oscillations also play an important role in normal physiological processes and serve distinct functional roles at different points in time. We characterised the effect of dopaminergic medication on oscillatory whole-brain networks in PD in a time-resolved manner by employing a hidden Markov model on combined STN local field potentials and magnetoencephalography (MEG) recordings from 17 PD patients. Dopaminergic medication led to coherence within the medial and orbitofrontal cortex in the delta/theta frequency range. This is in line with known side effects of dopamine treatment such as deteriorated executive functions in PD. In addition, dopamine caused the beta band activity to switch from an STN-mediated motor network to a frontoparietal-mediated one. In contrast, dopamine did not modify local STN-STN coherence in PD. STN-STN synchrony emerged both on and off medication. By providing electrophysiological evidence for the differential effects of dopaminergic medication on the discovered networks, our findings open further avenues for electrical and pharmacological interventions in PD.

Parkinson's disease medication state and severity assessment based on coordination during walking.

Walking is a complex motor function requiring coordination of all body parts. Parkinson's disease (PD) motor signs such as rigidity, bradykinesia, and impaired balance affect movements including walking. Here, we propose a computational method to objectively assess the effects of Parkinson's disease pathology on coordination between trunk, shoulder and limbs during the gait cycle to assess medication state and disease severity. Movements during a scripted walking task were extracted from wearable devices placed at six different body locations in participants with PD and healthy participants. Three-axis accelerometer data from each device was synchronized at the beginning of either left or right steps. Canonical templates of movements were then extracted from each body location. Movements projected on those templates created a reduced dimensionality space, where complex movements are represented as discrete values. These projections enabled us to relate the body coordination in people with PD to disease severity. Our results show that the velocity profile of the right wrist and right foot during right steps correlated with the participant's total score on the gold standard Unified Parkinson's Disease Rating Scale (UPRDS) with an r2 up to 0.46. Left-right symmetry of feet, trunk and wrists also correlated with the total UPDRS score with an r2 up to 0.3. In addition, we demonstrate that binary dopamine replacement therapy medication states (self-reported 'ON' or 'OFF') can be discriminated in PD participants. In conclusion, we showed that during walking, the movement of body parts individually and in coordination with one another changes in predictable ways that vary with disease severity and medication state.

Pharmaceutical Treatment for Alzheimer's Disease and Related Dementias: Utilization and Disparities.

BACKGROUND: Four prescription drugs (donepezil, galantamine, memantine, and rivastigmine) are approved by the US FDA to treat symptoms of Alzheimer's disease (AD). Even modest effectiveness could potentially reduce the population-level burden of AD and related dementias (ADRD), especially for women and racial/ethnic minorities who have higher incidence of ADRD. OBJECTIVE: Describe the prevalence of antidementia drug use and timing of initiation relative to ADRD diagnosis among a nationally representative group of older Americans, and if there are disparities in prevalence and timing by sex and race/ethnicity. METHODS: Descriptive analyses and logistic regressions of Medicare claims (2008-2016) for beneficiaries who had an ADRD or dementia-related symptom diagnosis, or use of an FDA approved drug for AD. We investigate prevalence of use and timing of treatment initiation relative to ADRD diagnosis across time and beneficiary characteristics (age, sex, race/ethnicity, socioeconomic status, comorbidities). RESULTS: Among persons diagnosed with ADRD or related symptoms, 33.3% used an approved drug over the study period. Odds of use was higher among Whites than non-Whites. Among ADRD drug users, 40% initiated use within 6 months of the initial ADRD or related symptoms diagnosis, and 16% initiated prior to a diagnosis. We observed disparities by race/ethnicity: 28% of Asians, 24% of Hispanics, 16% of Blacks, and 15% of Whites initiated prior to diagnosis. CONCLUSIONS: The use of antidementia drugs is relatively low and varies widely by race/ethnicity. Heterogeneity in timing of initiation and use may affect health and cost outcomes, but these effects merit further study.

A pharmacoeconomic evaluation of cholinesterase inhibitors and memantine for the treatment of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) results in progressively worsening cognitive decline, leading to loss of functional ability, behavior/mood disturbances, institutionalization, and death. Current pharmaceutical therapies only treat the symptoms of cognitive decline yet can be expensive for payers. Areas covered: The authors undertook a systematic review of economic evaluations of pharmaceutical therapies for AD. The literature search encompassed English-language studies indexed in PubMed (Medline), Cochrane Library Current, and Web of Science. The search included articles published between 1 January 1995 and 10 February 2018. The literature suggested AD medications generally dominated comparator treatments (e.g. placebo). Expert opinion: The authors noted several limitations of the included economic evaluations. These limitations suggest the results of the economic evaluations should be interpreted with caution. Many economic models were not transparent with respect to sources of probabilities and cost data, and data collected in certain jurisdictions were applied to other jurisdictions without considering the validity of such applications. Measuring health utilities in cognitively impaired populations raises questions about the validity of quality-adjusted life years, but this issue was unaddressed in the included studies. Most included studies were sponsored by industry and the results tended to overwhelmingly support the manufacturer's product.

Relevance of sleep quality on caregiver burden in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder which affects the quality of life of patient and their family. Sleep disorders appear in 80-90% of PD patients and have a great impact on the PD well-being. We examined the relationship of patients' sleep quality and depression on burden, mood, quality of life, and quality of sleep of their caregivers. A multicenter, regional (Veneto), observational, cross-sectional study that included 55 patient-caregiver pairs was conducted. Patients were assessed using Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS) for sleep disorders, Beck Depression Inventory (BDI) as a measure of depression, and Parkinson's Disease Questionnaire (PDQ-39) as a measure of quality of life. Caregivers were evaluated by the Caregiver Burden Inventory (CBI) a measure of burden, BDI, SF-36 Health Survey as measures of HRQoL, and Medical Outcomes Study-Sleep Scale (MOS-SS) for quality of sleep. CBI, HRQoL, MOS-SS, and BDI scores displayed no association with patients' age, cognition (Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB)), disease duration, and Hoehn and Yahr (H&Y), and UPDRS III scales whereas were significantly correlated with patients' quality of sleep, depression, and quality life. CBI and HRQoL were also associated respectively with patients' ESS and L-dopa daily dose. This study underscores the presence of a significant relationship between patient and caregiver quality of life. Interestingly, sleep quality and depression rather than motor disability best predicted caregivers' well-being.

Fatigue in Patients with Major Depressive Disorder: Prevalence, Burden and Pharmacological Approaches to Management.

Fatigue is a frequently reported symptom in major depressive disorder, occurring in over 90% of patients. Clinical presentations of fatigue within major depressive disorder encompass overlapping physical, cognitive and emotional aspects. While this review addresses the epidemiology, burden, functional impact and management of fatigue in major depressive disorder, the main focus is on available pharmacotherapy options and their comparative efficacies. Our review of the effects of pharmacological treatments on fatigue in major depressive disorder found that medications with dopaminergic and/or noradrenergic action such as modafinil, flupenthixol and atomoxetine were most effective in improving symptoms of fatigue and low energy. However, significant variation across studies in assessment tools and study inclusion/exclusion criteria may have contributed to inconsistent findings. The efficacy of non-pharmacological interventions is also discussed, including light therapy and exercise.

Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer's Disease: Systematic Review and Network Metaanalysis.

BACKGROUND/OBJECTIVES: To examine the comparative effectiveness and safety of cognitive enhancers for Alzheimer's disease (AD). DESIGN: Systematic review and Bayesian network metaanalysis (NMA). SETTING: MEDLINE, EMBASE, Cochrane Library, CINAHL, Ageline (inception-March 2016). PARTICIPANTS: Individuals with AD in randomized controlled trials (RCTs), quasi-RCTs, and nonrandomized studies. INTERVENTION: Any combination of donepezil, rivastigmine, galantamine, or memantine. MEASUREMENTS: Two reviewers independently screened titles, abstracts, and full-texts; abstracted data; and appraised risk of bias. RESULTS: Twenty thousand three hundred forty-three citations were screened, and 142 studies were included (110 RCTs, 21 non-RCTs, 11 cohort studies). NMA found that donepezil (Mini-Mental State Examination: mean difference (MD) = 1.39, 95% credible interval (CrI) = 0.53-2.24), donepezil+memantine (2.59, 95% CrI = 0.12-4.98), and transdermal rivastigmine (2.02, 95% CrI = 0.02-4.08) improved cognition more than placebo. NMA found that donepezil (Alzheimer's Disease Assessment Scale-cognitive: MD = -3.29, 95% CrI = -4.57 to -1.99) and galantamine (MD = -2.13, 95% CrI = -3.91 to -0.27) improved cognition more than placebo. NMA found that donepezil+memantine (MD = -5.23, 95% CrI = -8.72 to -1.56) improved behavior more than placebo. NMA found that donepezil (MD = -0.32, 95% CrI = -0.46 to -0.19), donepezil+memantine (MD = -0.57, 95% CrI = -0.95 to -0.21), oral rivastigmine (MD = -0.38, 95% CrI = -0.56 to -0.17), and galantamine (MD = -3.79, 95% CrI = -6.98 to -0.59) improved global status more than placebo. NMA found that galantamine decreased the odds of mortality (odds ratio = 0.56, 95% CrI = 0.36-0.87). No agent increased risk of serious adverse events, falls, or bradycardia. Some increased risk of headache (oral rivastigmine), diarrhea (oral rivastigmine, donepezil), nausea (oral rivastigmine, donepezil, galantamine), and vomiting (oral rivastigmine, donepezil, galantamine). CONCLUSION: An exhaustive review of the literature involving 142 studies demonstrated that cognitive enhancers in general have minimal effects on cognition according to minimal clinically important difference and global ratings. The drugs appear safe, but this must be interpreted cautiously because trial participants may have less comorbidity and fewer adverse effects than those treated with these drugs in clinical practice.

Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.

Assessment and treatment of mental fatigue after a traumatic brain injury.

Mental fatigue is a frequently occurring symptom after mild, moderate or severe traumatic brain injury (TBI). Such mental fatigue may become a long-lasting problem, irrespective of severity and even after recovery from other neurological or psychiatric symptoms. Two characteristics of this mental fatigue are that patients easily become exhausted and there is generally a long recovery time. There is a need to increase knowledge and awareness of mental fatigue as it interferes considerably with work, studies, and social activities. Assessment is difficult and few treatment studies have been carried out. For the purposes of assessment, the development of the Mental Fatigue Scale is described here, and we also summarise the few treatment studies found for fatigue after TBI. Symptom alleviation is reported through Mindfulness-Based Stress Reduction (MBSR), light therapy and for the psychostimulant methylphenidate and the dopamine stabiliser (-)-OSU6162. However, more knowledge of the origin of mental fatigue and its underlying mechanisms is needed for development of more efficient therapeutic methods. Prospective randomised trials focusing on long-term outcomes are warranted and should include both pharmacological and non-pharmacological treatments.

Brain dopamine neurone 'damage': methamphetamine users vs. Parkinson's disease - a critical assessment of the evidence.

The objective of this review is to evaluate the evidence that recreational methamphetamine exposure might damage dopamine neurones in human brain, as predicted by experimental animal findings. Brain dopamine marker data in methamphetamine users can now be compared with those in Parkinson's disease, for which the Oleh Hornykiewicz discovery in Vienna of a brain dopamine deficiency is established. Whereas all examined striatal (caudate and putamen) dopamine neuronal markers are decreased in Parkinson's disease, levels of only some (dopamine, dopamine transporter) but not others (dopamine metabolites, synthetic enzymes, vesicular monoamine transporter 2) are below normal in methamphetamine users. This suggests that loss of dopamine neurones might not be characteristic of methamphetamine exposure in at least some human drug users. In methamphetamine users, dopamine loss was more marked in caudate than in putamen, whereas in Parkinson's disease, the putamen is distinctly more affected. Substantia nigra loss of dopamine-containing cell bodies is characteristic of Parkinson's disease, but similar neuropathological studies have yet to be conducted in methamphetamine users. Similarly, it is uncertain whether brain gliosis, a common feature of brain damage, occurs after methamphetamine exposure in humans. Preliminary epidemiological findings suggest that methamphetamine use might increase risk of subsequent development of Parkinson's disease. We conclude that the available literature is insufficient to indicate that recreational methamphetamine exposure likely causes loss of dopamine neurones in humans but does suggest presence of a striatal dopamine deficiency that, in principle, could be corrected by dopamine substitution medication if safety and subject selection considerations can be resolved.

Lower urinary tract symptoms in Parkinson's disease: Prevalence, aetiology and management.

Lower urinary tract symptoms (LUTS) are common in Parkinson's disease (PD), effecting 27-85% of patients with PD. Irritative symptoms predominate and urodynamic studies confirm high prevalence of detrusor overactivity in PD. LUTS are present early in PD and are more common in PD than in age matched controls. The assessment of LUTS in PD is complicated by coexisting bradykinesia and cognitive impairment. Although LUTS become more troublesome as PD progresses it remains unclear if LUTS severity correlates with motor symptoms and/or duration of PD. The underlying cause of LUTS in PD remains to be fully elucidated. Animal and human studies suggest the net effect of the basal ganglia is to supress micturition. Although LUTS are a common in PD, few studies have examined the assessment and management of LUTS specifically in patients with PD. Pilot studies have suggested that bladder training, antimuscarinic drugs and intravesical botulinum toxin maybe helpful but these trials have been small and frequently lacked a suitable control group making them vulnerable to the placebo effect. Furthermore the adverse effects of antimuscarinic drugs on cognitive and gastrointestinal function may limit the use of these drugs in PD. In this review we summarise the literature describing the prevalence of LUTS in PD, discuss the emerging data delineating the underlying pathophysiology of LUTS and examine interventions helpful in the management of LUTS in people with PD.

The assessment of cognitive impairment suspected of dementia in Polish elderly people: results of the population-based PolSenior Study.

The growing incidence of dementia in ageing societies is a major concern of health care organizations. Because of its detrimental influence on the mental and functional statuses of elderly people, it leads to increased economic burdens caused by the social and financial needs of patients with dementia and their caregivers. There has been no data concerning the prevalence of dementia in the elderly in the general Polish community so far. The main aim of the study was to assess the prevalence of cognitive impairment suspected of dementia among the Polish elderly and the relationships between cognitive performance and age, gender, place of residence and educational status. The presented data was the result of nationwide, multicentre PolSenior Study conducted from 2007 to 2011 in the Polish elderly population. Cognitive functions were evaluated using Mini-Mental State Examination (MMSE) performed by pre-trained nurses. The result of MMSE lower than 24 points was classified as cognitive impairment suspected of dementia and divided according to its severity into three stages: mild, moderate and severe dementia. The results were analysed in two ways: raw MMSE and MMSE scores after Mungas adjustment (MMSEadj), that is, corrected for age and educational level, and these were compared. To verify the suspicion of dementia an assessment was complemented by an interview of carers for the occurrence and course of memory disorders, treatment of dementia and by functional status assessment. In order to assess the prevalence of suspicion of dementia in the general Polish population, statistical analyses based on weighting were done. The suspicion of dementia on the basis of raw MMSE was made in 20.4% of respondents aged 65years and more, and after Mungas adjustment in 12.1% of older subjects. The prevalence of cognitive impairment grew with increasing age, as well as depending on the educational status of elderly respondents in both types of analyses; raw MMSE and MMSEadj. There was no significant difference in the prevalence of cognitive impairment according to gender in the general population (raw MMSE); however in analyses including MMSEadj results, the suspicion of dementia was made more often among men. Suspicion of dementia based on raw MMSE and MMSEadj results was made significantly more often among men than women at the age of 65-69years, and significantly more often among the oldest women, aged 90years and more. Suspicion of dementia was diagnosed more often in respondents living in rural communities (based on raw MMSE, but not on MMSEadj), which might be related to the differences in their educational status.

Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014.

The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

Memantine improves goal attainment and reduces caregiver burden in Parkinson's disease with dementia.

OBJECTIVE: Memantine, an uncompetitive antagonist of N-methyl-d-aspartate receptors, may have a role in managing symptoms associated with dementia in Parkinson's disease (PDD), although its role in improving patient-reported outcomes (PROs) has not been extensively investigated. PROs may be more sensitive than standard psychometric measures for detecting change in complex conditions such as PDD. The aim of this study was to examine the effect of memantine on PROs: individually determined goals and health-related quality of life. We also examined memantine's effect on caregiver burden. METHODS: This 22-week double-blind randomised controlled trial evaluated participants with PDD on 20 mg of memantine or placebo. Outcome measures were Goal Attainment Scaling (GAS), the Parkinson's Disease Questionnaire-8 and the Zarit Burden Inventory. RESULTS: A significantly greater proportion of participants on memantine (64%) had better than expected GAS outcomes compared with those on placebo (7%) (p = 0.007). Furthermore, the improvement in mean GAS score, as well as mean caregiver burden score, from baseline to drug discontinuation was significantly greater in those on memantine compared with those on placebo (p = 0.03 and 0.04, respectively). Significant differences in quality of life were not seen. CONCLUSIONS: In this study, memantine improved individually set goals and caregiver burden in PDD. This suggests that clinimetric measures such as GAS may be more sensitive than conventional psychometric measures in detecting improvements in people with PDD.

Estimating the excess of inappropriate prescriptions of anti-dopaminergic anti-emetics during acute gastroenteritis epidemics in France.

PURPOSE: Anti-dopaminergic anti-emetics (ADA) use for the treatment of nausea associated with gastroenteritis (GE) can be considered inappropriate, as their effects are not supported by evidence of clinical efficacy and can potentially induce serious adverse events. OBJECTIVE: This study quantifies the suboptimal consumption of ADA attributable to seasonal GE epidemics in France and its cost. METHODS: GE epidemiological data were collected and transmitted by the general practitioners (GPs) of Sentinelles network. Epidemic periods were identified by periodic regression. Drug sales data were obtained from pharmacies, and costs data were obtained from the French National Social Security. The ADA use and costs incurred by seasonal GE epidemics were calculated. RESULTS: During the epidemic periods considered in this study, the median age of patients seen by GPs for GE was 24 years old. During each epidemic, a sale increase by 14% for domperidone, by 15% for metoclopramide and 30% for metopimazine was observed. The average cost attributable to seasonal GE epidemic was 5,030,000 Euros, of which 2,160,000 Euros were incurred by the French National Social Security. CONCLUSION: Linking epidemiological databases helped to identify and quantify inappropriate ADA prescriptions. GE treatment guidelines should be disseminated more widely.

Alzheimer's dementia: budget impact and cost-utility analysis of a combination treatment of a cholinesterase inhibitor and memantine in Switzerland.

QUESTIONS UNDER STUDY: The objective of this study was to estimate the potential budget impact and cost-effectiveness of the combination treatment of a cholinesterase inhibitor and memantine in Switzerland. METHODS: The prevalence of dementia according to European sources and future Swiss population data were used to estimate the number of patients with Alzheimer's dementia in Switzerland. Both direct and indirect costs calculated from Swiss sources were included. Utility estimates and transition probabilities were obtained from the published literature. A Markov model was used for the cost-utility analysis in order to calculate incremental cost-effectiveness ratios from a health care and a societal perspective. RESULTS: Assuming mono treatment (either a cholinesterase inhibitor or memantine), treatment costs would increase from CHF 22.7 million in 2012 to CHF 26.1 million in 2016, the additional yearly treatment costs for the combination treatment (cholinesterase inhibitor and memantine) would be between CHF 1.7 million and CHF 1.9 million. The Markov model compared health care costs of the mono treatment to costs of the combination treatment over five years. From a health care perspective, the combination treatment saved CHF 27,655 per patient over five years and CHF 248,895/quality adjusted life year compared to the mono treatment. CONCLUSIONS: Implementation of the reimbursed combination treatment would incur additional treatment costs of about CHF 10 million over five years. From a health care perspective, the combination treatment would decrease costs over five years by CHF 50 million. Based on long term considerations, the combination treatment was the dominant strategy over the mono treatment.