Search

Background: Although individuals with dementia have a high risk of developing seizures, whether seizures are associated with cholinesterase inhibitors, which are commonly prescribed to treat individuals with dementia, remains unknown. This study investigated the risk of incident seizure following cholinesterase inhibitor use in patients with dementia., Methods: A nationwide, nested case-control study was conducted using data from the Korean Health Insurance Review and Assessment Service (HIRA) from 2014 through 2018. A total of 13,767 participants aged 65-95 years who experienced incident seizure were propensity score-matched for medical comorbidities and drug exposure at a 1:3 ratio with a control group of 39,084 participants. The study examined the incidence of seizures in patients diagnosed with dementia within one year after receiving cognitive enhancers. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for seizure incidence according to cholinesterase inhibitor use were analyzed using a multivariable conditional logistic regression model., Results: There was no statistically significant association between duration of cholinesterase inhibitors use and seizure risk. Although there was slight increased seizure risk in patient after receiving donepezil for 1 year compared to memantine, subgroup analyses stratified age and sex did not reveal any significant association between cholinesterase inhibitors use and late-onset seizure., Conclusions: Our findings suggest no immediate increase in seizure risk is associated with cholinesterase inhibitor use, although the risk of seizure in patients with dementia did increase after one year of continued medication intake. Further study is required to obtain confirmatory results on the seizure-related safety of cognitive enhancers in patients with dementia., (© 2022. The Author(s).)

Background: Although cholinesterase inhibitors (ChEIs) are the primary treatment for dementia, they are associated with overactive bladder (OAB), necessitating antimuscarinic use. Limited data exist regarding the risk of OAB across individual ChEIs in dementia. This study evaluated the risk of OAB associated with individual ChEIs in older adults with dementia., Methods: This was a new user retrospective cohort study using Medicare claims data involving Parts A, B, and D claims dataset from 2013 to 2015. The study included older adults (aged 65 and older) with a diagnosis of dementia using donepezil, galantamine, or rivastigmine. New ChEI claims were identified with a 6-month baseline washout period. Patients with OAB diagnosis or any antimuscarinic or mirabegron use in the baseline period were excluded. The primary outcome of interest was OAB diagnosis or prescription of antimuscarinics or mirabegron within 6 months of ChEI initiation. Multivariable cox proportional hazards regression with propensity scores (PS) as covariates and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of OAB among donepezil, galantamine, and rivastigmine users., Results: The study included 524,975 older adults with dementia who were incident users of ChEIs (donepezil 80.72%, rivastigmine 16.41%, galantamine 2.87%). Overall, OAB diagnosis/antimuscarinic/mirabegron prescription was observed in 5.07% of the cohort within 6 months of ChEIs prescription. The Cox regression model with PS as covariate approach found that donepezil use increased the risk of OAB compared to rivastigmine (aHR, 1.13; 95% CI, 1.08-1.28; p < 0.0001). However, there was no differential risk of OAB between galantamine and rivastigmine. The findings were consistent with the generalized boosted models., Conclusions: The study found that the risk of OAB varies across individual ChEIs with an increased risk of OAB with donepezil compared to rivastigmine. The study findings suggest the need to understand and manage medication-related morbidity in older adults with dementia., (© 2021 The American Geriatrics Society.)

Background: Acetylcholinesterase inhibitors (AChEIs) have been associated with an increased risk of starting antimuscarinic treatment to treat overactive bladder (OAB)-an example of a prescribing cascade. Limited comparative data exist regarding the prescribing cascade of antimuscarinics across individual AChEIs in older adults with dementia., Objective: This study examined the association between individual AChEI use and antimuscarinic cascade in older adults with dementia., Methods: We conducted a new user retrospective cohort study from January 2005 to December 2018 using data from the TriNetX electronic medical record database, a federated electronic medical records network in the US. The cohort included patients 65 years or older with a diagnosis of dementia using AChEIs (donepezil, galantamine, or rivastigmine). Individual AChEIs were identified with index dates from 1 January 2006 to 31 June 2018, with a 1-year washout period. The study excluded patients with any antimuscarinic use and OAB diagnosis 1 year before the AChEI index date. The primary outcome of interest was the prescription of antimuscarinics within 6 months of the AChEI index date. A Cox proportional hazard model was used to assess the association between individual incident AChEI use and antimuscarinic prescribing cascade after controlling for several covariates., Results: The study included 47,059 older adults with dementia who were incident users of AChEIs. Most of these patients were initiated with donepezil (83.1%), followed by rivastigmine (12.3%) and galantamine (4.6%). Overall, 8.16% of the study cohort had incident OAB diagnosis or antimuscarinic prescription. Antimuscarinics were initiated by 1725 (3.7%) older adults with dementia within 6 months of AChEI prescription, and cascade varied widely across individual agents-donepezil (3.9%), rivastigmine (2.6%), and galantamine (2.9%). Cox proportional hazard analyses revealed that donepezil users had an increased risk of receiving antimuscarinics (adjusted hazard ratio 1.55, 95% confidence interval 1.31-1.83) compared with rivastigmine. The findings were consistent in sensitivity analyses., Conclusion: This study found that donepezil use is more likely to lead to antimuscarinic cascade than rivastigmine. Future studies are needed to determine the potential consequences of this cascade in dementia.

Objective: To investigate mortality and hospitalization outcomes associated with medication misadventure (including medication errors [MEs], such as the use of potentially inappropriate medications [PIMs], and adverse drug events [ADEs]) among people with cognitive impairment or dementia., Data Sources: Ovid MEDLINE, Ovid EMBASE, Ovid International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials were searched from inception to December 2019., Study Selection and Data Extraction: Relevant studies using any study design were included. Reviewers independently performed critical appraisal and extracted relevant data., Data Synthesis: The systematic review included 10 studies that reported the outcomes of mortality or hospitalization associated with medication misadventure, including PIMs (n=5), ADEs (n=2), a combination of MEs and ADEs (n=2), and drug interactions (n=1). Five studies examining the association between PIMs and mortality/hospitalization were included in the meta-analyses. Exposure to PIMs was not associated with either mortality (odds ratio [OR]=1.36; 95%CI=0.79-2.35) or hospitalization (OR=1.02; 95%CI=0.83-1.26). In contrast, single studies indicated that ADEs with cholinesterase inhibitors were associated with mortality and hospitalization., Relevance to Patient Care and Clinical Practice: Individuals with cognitive impairment or dementia are at increased risk of medication misadventure; based on relatively limited published data, this does not necessarily translate to increased mortality and hospitalization., Conclusions: Overall, medication misadventure was not associated with mortality or hospitalization in people with cognitive impairment or dementia, noting the limited number of studies, difficulty in controlling potential confounding variables, and that most studies focus on PIMs.

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment., Objectives: To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes., Search Methods: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources., Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs., Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods., Main Results: We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review., Authors' Conclusions: This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background/objective: Reevaluation of the appropriateness of acetylcholinesterase inhibitors (AChEIs) is recommended in older adults with severe dementia, given the lack of strong evidence to support their continued effectiveness and risk for medication-induced adverse events. We sought to evaluate the impact of deprescribing AChEIs on risk of all-cause events (hospitalizations, emergency department visits, and mortality) and serious falls or fractures in older nursing home (NH) residents with severe dementia., Design: Analysis of 2015 to 2016 data from Medicare claims, Part D prescriptions, Minimum Data Set (MDS) version 3.0, Area Health Resource File, and Nursing Home Compare. Marginal structural models with inverse probability of treatment weights were used to evaluate the association of deprescribing AChEIs and all-cause negative events as well as serious falls or fractures., Setting: US Medicare-certified NHs., Participants: Nonskilled NH residents, aged 65 years and older, with severe dementia receiving AChEIs within the first 14 days of an MDS assessment in 2016 (n = 37 106)., Results: The sample was primarily white (78.7%), female (75.5%), and aged 80 years or older (77.4%). Deprescribing AChEIs was associated with an increased likelihood of all-cause negative events in unadjusted models (odds ratio [OR] = 1.17; 95% confidence interval [CI] = 1.11-1.23; P < .01), but not in fully adjusted models (adjusted OR [aOR] = 1.00; 95% CI = 0.94-1.06; P = .94). By contrast, deprescribing was associated with a reduced likelihood of serious falls or fractures in unadjusted models (OR = 0.59; 95% CI = 0.52-0.66; P < .001) and remained significant in adjusted models (aOR = 0.64; 95% CI = 0.56-0.73; P < .001)., Conclusion: Deprescribing AChEIs was not associated with a significant increase in the likelihood for all-cause negative events and was associated with a reduced likelihood of falls and fractures in older NH residents with dementia. Our findings suggest that deprescribing AChEIs is a reasonable approach to reduce the risk of serious falls or fractures without increasing the risk for all-cause events. J Am Geriatr Soc 68:699-707, 2020., (© 2019 The American Geriatrics Society.)

Background: Antidementia drugs (cholinesterase inhibitors and memantine) are still widely prescribed despite their controversial effects and 2011 guidelines that no longer encourage their prescription. The objective was to assess which factors remained determinants of antidementia drug prescriptions., Methods: A cross-sectional study was performed in 2013. Patients suffering from dementia, aged 65 and over, identified in the French national health insurance database were included. Because we anticipated a high correlation between age, comorbidities, and health care use, we first identified the patients' health status by a latent class analysis. Second, we performed adjusted logistic regression models. The explanatory variables were patients' health status, gender, prescription of nonpharmacological treatments (physical and speech therapies), prescription of psychotropic drugs, and access to health care., Results: Among the 3873 patients included, 38% received antidementia drugs. Three latent classes of patients with different health status were identified. Patients with poor health status received significantly fewer antidementia drugs (P < .001). Patients with speech therapy or antidepressant drugs received significantly more antidementia drugs (P < .001), whereas patients with physical therapy received significantly fewer antidementia drugs (P = .006)., Conclusion: Antidementia drugs were less likely to be prescribed for patients with poor health status. This result is encouraging for these frail patients who are more vulnerable to the adverse effects of treatments. At the same time, this result encourage targeting specifically patients in good health status for the use of a decision aid, in an attempt to limit prescriptions by involving patients and families., (© 2020 John Wiley & Sons Ltd.)

Importance: Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million., Observations: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia., Conclusions and Relevance: Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.

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.)

ABSTRACTObjectives:Visual hallucinations are a common symptom in dementia and Parkinson's disease and have been associated with greater cognitive and functional decline, but optimal management strategies are unclear. We review the frequency and pathogenesis of visual hallucinations in dementia and Parkinson's disease and examine the evidence base for their management., Design: We undertook a systematic review of the visual hallucinations in dementia, searching studies published between January 1980 and July 2017 using PubMed with the search terms visual hallucinations AND review AND (dementia OR parkinson*)., Results: We found 645 articles and screened them for relevance, finally including 89 papers (11 meta-analyses, 34 randomized controlled trials, six other trials and a number of relevant review articles). Only six of the trials reported visual hallucination outcomes separately from other neuropsychiatric symptoms., Conclusions: Atypical antipsychotics were frequently studied, but with the exception of clozapine in Parkinson's disease dementia, results were equivocal. There was some evidence that acetylcholinesterase inhibitors may help visual hallucinations. Overall, effect sizes for most treatments were small and there were few studies with long term follow up. Treatments need to be carefully weighed up with the risks and reviewed often, and many patients improved without treatment. There is a lack of data regarding visual hallucinations due to the grouping of psychotic symptoms together in commonly used rating scales. The lack of a specific rating scales, or analyzable items within other scales, for visual hallucinations, limited efficacy of current and small evidence base with short follow up are important areas for future studies to address.

Background: There is considerable uncertainty surrounding the medications used to delay the progression of dementia, especially their long-term efficacy and when to withdraw treatment with these agents. Current research regarding the optimal use of antidementia medication is limited, contributing to variability in practice guidelines and in clinicians' prescribing practices. Little is currently known about the experiences encountered by caregivers of people with dementia after antidementia medication is withdrawn., Aim: To investigate the experiences and perspectives of carers and family members when antidementia medications (cholinesterase inhibitors and/or memantine) are stopped, by analysing archived threads and posts of an online discussion forum for people affected by dementia., Methods: Archived discussions from Talking Point, an online discussion forum hosted by the Alzheimer's Society UK, were searched for threads discussing antidementia medication withdrawal and relevant threads were analysed thematically using the Framework method. Participant demographics were not established due to usernames which ensured anonymity., Results: Four key themes emerged: (1) expectations about withdrawal, (2) method of withdrawal, (3) clinical condition on withdrawal, and (4) the effect of withdrawal on caregivers., Conclusions: Online discussion forums such as Talking Point provide dementia carers with an outlet to seek help, offer advice and share experiences with other members. The study findings highlight the complexity surrounding optimising dementia pharmacotherapy and antidementia medication withdrawal, highlighting the need for treatment to be person-centred and highly individualised.

In dementia, specific drugs and psychotropic drugs used for psychotic and behavioral symptoms have limited efficacy. Adverse effects may be important given the age and comorbidity of the patients. It is necessary, frequently, its withdrawal, planned together with the family, monitoring the response and offering non-pharmacological treatment alternatives. Chronic pain is suffered by 25-76% of the elderly who live in a community and is more frequent in women. The treatment is multidisciplinary, establishing realistic objectives, individualizing it, starting with lower doses of drugs and continuously reevaluating to control side effects and to get the correct level of analgesia. The prevalence of atrial fibrillation increases with age and is underdiagnosed. ACO is recommended with dicoumarin or direct oral anticoagulants not antagonists of vitamin K, in patients with AF older than 65 years unless contraindicated, to reduce embolic risk, confirming subgroup analyzes similar efficacy in prevention of stroke., (Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

This study examined the use of potentially inappropriate medicines that may affect cognition (PIMcog) in people with dementia and its associated factors. Medical records of all outpatients with dementia attending a tertiary hospital in Vietnam between January 1, 2015, and December 31, 2016, were examined. Medicine use was assessed against a list of PIMcog. Variables associated with having a PIMcog were assessed using a multiple logistic regression. Of the 128 patients, 41% used a PIMcog, 39.1% used cholinesterase inhibitors (CEIs) concomitantly with anticholinergics, and 18% used antipsychotics. The number of hospital visits (adjusted odds ratio [OR]: 1.08; 95% confidence interval [CI]: 1.02-1.16) and number of treating specialists (adjusted OR: 0.61; 95% CI: 0.45-0.83) were associated with PIMcog use. This study highlights a high-level use of medicines that can further impair cognition or reduce the effectiveness of CEIs in people with dementia. Efforts to improve quality use of medicines for this population are warranted.

Objectives: To evaluate the cardiovascular (CV) effects of acetylcholinesterase inhibitors (AChEIs) in individuals with dementia DESIGN: Systematic review and meta-analysis., Setting: Two authors independently searched major electronic databases from inception until June 17, 2017, for longitudinal (without a control group) and cohort (with a control group) studies reporting CV outcomes in relation to AChEIs. Randomized controlled trials were excluded because they included relatively healthy subjects., Participants: Individuals with dementia and controls., Measurements: Changes in CV parameters were summarized using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Event rates were used to assess incidence of hypertension and bradycardia. Incidence of CV events in demented patients versus in healthy controls were compared using hazard ratios (HRs)., Results: Of 4,588 initial hits, 31 studies including 258,540 individuals with dementia and 2,246,592 controls were analyzed. In longitudinal and open-label studies, AChEIs were associated with a significantly greater incidence of hypertension (n=1,573, 4%, 95% CI=2-8%, I 2 =47%) and bradycardia (n=13,703, 2%, 95% CI=1-6%, I 2 =98%). AChEIs were associated with a decrease in heart rate (SMD=-1.77, 95% CI=-3.58-0.03, I 2 =78%) and an increase in PR interval (SMD=0.10, 95% CI=0.008-0.19, I 2 =3%) from baseline. During a median follow-up of 116 weeks, AChEIs were associated with a significantly lower risk of CV events (stroke, acute coronary syndrome, CV mortality; HR=0.63, 95% CI=0.45-0.88, I 2 =18%), without a significantly greater risk of bradycardic events (HR=1.40, 95% CI=0.76-2.59, I 2 =98%)., Conclusion: AChEI therapy may be associated with negative chronotropic and hypertensive effects but also with lower risk of CV events., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Background: The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline., Objective: To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures., Methods: A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund., Results: In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01-2.05], p = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000., Conclusion: Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given.

Objectives: To improve the value of research for older adults, we examine sex-specific reporting of data from drug trials for the management of dementia. These data are important because they may influence considerations ranging from the health of populations to shared decision-making by individual patient and caregiver about the risk and benefit of a drug therapy., Methods: Randomized controlled trials of cholinesterase inhibitors (i.e., donepezil, rivastigmine, or galantamine) with clinical outcomes were identified from searches of MEDLINE, EMBASE, and the Cochrane Library. Sex-specific data were extracted from nine sections (title, abstract, introduction, methods, outcomes, results, discussion, limitations, and conclusion). Among the donepezil trials only, more detailed harms data were obtained., Findings: Thirty-three randomized controlled trials were identified evaluating 15,971 participants (9,103 (57%) female). Trials were highly cited (median citations 158, interquartile range 62-441) and published in high impact journals (median impact factor 7.4, interquartile range 3.4-8.2). Sex was not mentioned in the title, introduction, limitations, or conclusion section of any trial. Only three trials (9%) mentioned sex in the abstract (all as a demographic characteristic), and 8 (24%) in the methods. Almost all (32 (97%)) trials mentioned sex in the results as a demographic variable. One trial reported a sex difference for a secondary outcome. Among the 16 trials studying donepezil, adverse events were frequently reported and often dose-related. No trial provided sex-specific reporting of adverse events., Conclusions: There is an almost complete lack of sex-specific reporting of data in clinical trials for dementia drug therapies, and no sex-specific reporting of adverse events. Sex-specific reporting of data should be required in drug trials to increase research value and ultimately inform more tailored prescribing for older adults., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Introduction: The prevalence of Alzheimer's disease (AD) continues to rise, while treatment options for cognitive impairment are limited. Acetylcholinesterase inhibitors (AChEIs) aim to provide symptomatic benefit for cognitive decline, however these drugs are not without adverse events (AEs). The safety profile of each drug must be taken carefully into consideration before being prescribed, as new dosages and formulations have recently been approved. Areas covered: Donepezil, galantamine and rivastigmine are the three AChEIs approved for the treatment of varying stages of AD. Numerous clinical trials and post-marketing studies have evaluated the safety of these medications. This article will review the safety, efficacy and tolerability of these drugs in treating AD. Topics including pharmacovigilance databases, concomitant drug interactions, prescribing cascades, and treatment discontinuation are also covered. Expert opinion: AChEI use in those with mild, moderate or severe AD provide modest improvements in cognition, function and behavior. The pharmacological treatment of AD using AChEIs is associated with generally mild AEs. Differences in drug formulations should be taken into account when determining the most appropriate route of administration for each individual. Furthermore, discontinuation of AChEIs must be carefully monitored as it may be associated with worsening cognitive impairment.

Depression in the context of dementia is common and contributes to poorer outcomes in individuals and those who care for them. Non-pharmacological treatments are the preferred initial approach to managing these symptoms but data in support of these are scarce. There are a number of pharmacological treatment options available to clinicians but efficacy is uncertain and concern about potential side effects in an aging and vulnerable population needs to be taken into consideration. This review aims to provide a concise overview of pharmacological treatments for depression in dementia. Antidepressants are the mainstay of pharmacological treatment for clinically significant depression in the general population but evidence to support their use in dementia is mixed. Trials of antidepressants should generally be reserved for individuals with depression where the symptoms are distressing and surpass the threshold for major depression. Acetylcholinesterase inhibitors and memantine are effective in the symptomatic treatment of Alzheimer's disease but current evidence does not support their use to treat depressive symptoms in dementia. Similarly, antipsychotics and mood stabilizers have no proven efficacy for depression and the risk of adverse effects seems to outweigh any potential benefit. Pain can be a frequent problem in dementia and may have significant effects on behavior and mood. Preliminary evidence supports a role of adequate analgesia in improving mood in people with dementia.

The number of patients with dementia continues to increase worldwide, mainly due to the demographic developments. Early diagnosis and individualized therapy offers the chance of healing in secondary dementias. The therapy of the more common primary neurodegenerative forms is able to improve the course of the disease. As part of a multimodal management the therapy of dementias includes pharmacological treatment, nondrug treatment strategies, and psychosocial interventions. The treatment is administered depending on dementia form and stage. Antidementive medication and differentiated pharmacological therapy of frequent mental and behavioral symptoms corresponding to current guidelines contribute decisively to stabilize quality of life and activities of daily living, delaying the progression, and thus improving the care situation of patients and caregivers.

The evidence base to guide withdrawal of antidementia medications in older people with dementia is limited; while some randomised controlled studies have considered discontinuation of cholinesterase inhibitors (ChEIs), no such studies examining discontinuation of the N-methyl-D-aspartate receptor antagonist memantine have been conducted to date. The purpose of this opinion article was to summarise the existing evidence on withdrawal of cholinesterase inhibitors and memantine, to highlight the key considerations for clinicians when making these prescribing decisions and to offer guidance as to when and how treatment might be discontinued. Until the evidence base is enhanced by the findings of large-scale, randomised controlled discontinuation trials of ChEIs and memantine that use multiple, clinically relevant, cognitive, functional and behavioural outcome measures, clinicians' prescribing decisions involve balancing the risks of discontinuation with side effects and costs of continued treatment. Such decisions must be highly individualised and patient-centred.

Cholinesterase inhibitors and memantine are the only classes of drugs approved for the treatment of dementia due to Alzheimer's disease. This article provides evidence-based recommendations to address the issues regarding the use of cholinesterase inhibitors and memantine in clinical practice. It includes their efficacy, timing, assessment, use in institutionalized patients, combined use, and use in other dementia types. However, most of the studies are of short duration (<1 year) and are mainly focused on cognitive and global improvement, whereas the practical issue of their use in daily practice such as optimal duration of treatment, long-term efficacy and delaying institutionalization are limited.

Background: Chronic obstructive pulmonary disease (COPD) is a nonreversible inflammatory condition of the lungs. Acetylcholine is a neurotransmitter involved in autonomic regulation of the airways, resulting in bronchoconstriction and mucous production. Cholinesterase inhibitors (ChEIs), a cornerstone therapy of dementia treatment, increase acetylcholine. Theoretically, ChEI use in patients with COPD can place patients at increased risk of exacerbation secondary to increased acetylcholine activity., Methods: A retrospective chart review was performed comparing veterans with dementia and COPD who received ChEIs with those who did not at the Veterans Affairs North Texas Health Care System. Frequency of exacerbation in the first 90 days following ChEI initiation was compared. Secondary outcomes assessed exacerbation severity and a potential protective effect of inhaled anticholinergics., Results: A total of 94 patients were eligible for the study; 52 received a ChEI and 42 did not. The risk of exacerbation over 90 days was higher in the ChEI users with 10 (19%) experiencing an exacerbation compared with 3 (7%) in the nonusers (P = 0.133), showing a clinically significant trend. Of the patients experiencing an exacerbation, 2 patients on ChEIs had multiple exacerbations over the 90 days. The use of inhaled anticholinergics was not found to decrease the risk of exacerbation., Conclusion: The use of ChEIs may increase the risk of COPD exacerbation in the first 90 days of therapy in patients with dementia and COPD. This finding is clinically significant as previous studies have indicated no risk.

Objectives: Nutritional status is one of the factors that affects disease progression, morbidity and mortality in elderly patients with dementia. The present study aimed to evaluate the effect of acetylcholinesterase inhibitor (AchEI) therapy on nutritional status and food intake in the elderly., Design, Setting and Participants: Newly diagnosed patients with dementia, who underwent comprehensive geriatric assessment (CGA) and were followed at regular intervals, were retrospectively evaluated. A total of 116 patients, who began to receive AchEI therapy and completed 6-month follow-up period under this treatment, were enrolled in the study., Measurements: Socio-demographic characteristics and data on comorbidity, polypharmacy, cognitive function, depression, activities of daily living and nutritional status (weight, Body Mass Index (BMI), Mini Nutritional Assessment (MNA)-Short Form) were recorded., Results: The mean age of the patients was 78.0±8.9 years. There was no significant difference between baseline and 6-month BMI, weight and MNA scores of dementia patients who received AchEI therapy (p>0.05). With regard to the relation between changes in BMI, weight and MNA on the 6th month versus baseline, and donepezil, rivastigmine and galantamine therapies, no difference was determined (p>0.05). However, no worsening in food intake was observed (kappa: 0.377). When the effects of each AchEI on food intake were compared, food intake in rivastigmine treated patients was not decreased as much as it was in galantamine or donepezil treated patients (p<0.05)., Conclusion: AchEI therapy has no unfavorable effect on nutritional status or weight in elderly patients with different types of dementia, but it seems that food intake is better in those treated by rivastigmine patch.

Background: There has been limited research into potentially inappropriate medication (PIM) use and anticholinergic burden in patients attending memory clinics., Objectives: The aim of this study was to explore the use of PIMs related to cognitive impairment (PIMcog), anticholinergic cognitive burden (ACB) and concomitant use of anticholinergic medications with cholinesterase inhibitors (ChEIs) in patients attending memory clinics., Methods: Cross-sectional analysis of baseline data from the Prospective Research In MEmory clinics (PRIME) study was performed. Participants were community-dwelling patients who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog were defined as any medication considered potentially inappropriate for patients with cognitive impairment according to the Beers or STOPP criteria. Clinically significant ACB was defined as total score of ≥3 on the ACB scale., Results: A total of 964 patients, mean age 77.6 years, were included. PIMcog were used by 206 (21.4%) patients. Anticholinergics and sedatives were the most common PIMcog. PIMcog use was associated with higher number of medications (adjusted OR 1.26; 95% CI 1.19-1.33) and with not having completed secondary level education (adjusted OR 1.71; 95% CI 1.01-2.89). One hundred and thirteen (11.7%) patients had a clinically significant ACB score (≥3). ChEIs were used by 575 patients and 65 (11.3%) of these had an ACB score ≥3. There was no statistically significant difference in ChEI use between patients with and without an ACB score ≥3., Conclusion: PIMcog use, clinically significant anticholinergic burden, and concurrent use of anticholinergics with ChEIs were prevalent in patients attending memory clinics. Efforts are needed to improve prescribing for people with cognitive impairment.

This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.

The study aimed to investigate the association of acetylcholinesterase inhibitors (AChEIs) use with the risk of acute coronary syndrome (ACS). We conducted a population-based retrospective cohort study of dementia patients during 1 January 1999 to 31 December 2008 using the National Health Insurance Database in Taiwan. New AChEI users during the study period were matched with AChEI nonusers in age-matched and gender-matched cohorts. The risk of ACS associated with use of AChEIs was analyzed using modified Kaplan-Meier analysis and Cox proportional hazard models after adjustment for competing death risk. Use of AChEIs was associated with a lower incidence of ACS (212.8/10,000 person-years) compared to the matched reference cohort (268.7/10,000 person-years). The adjusted hazard ratio for ACS in patients with dementia treated with AChEIs was 0.836 (95% confidence interval, 0.750-0.933; P < 0.001). Further sensitivity analysis of different study populations demonstrated consistent results. A statistical dose-response relationship for AChEI use and ACS risk was significant for the patients with dementia. In patients with dementia, AChEI treatment was associated with decreased risk of ACS.

Objectives: To determine whether initiation of cholinesterase inhibitors is associated with significant weight loss in a real-word clinical setting., Design: Retrospective cohort study from 2007 to 2010 comparing weight loss in individuals with dementia newly prescribed cholinesterase inhibitors and those newly prescribed other chronic medications., Setting: National Veterans Affairs data., Participants: Individuals aged 65 and older with a diagnosis of dementia who received a new prescription for a cholinesterase inhibitor or other new chronic medication., Measurements: The primary outcome was time to 10-pound weight loss over 12 months. Propensity score matching was used to control for the likelihood of receiving a cholinesterase inhibitor based on baseline characteristics. Data were analyzed in a priori defined subgroups according to age, comorbid burden, and initial weight., Results: Of 6,504 individuals that met study criteria, 1,188 started on cholinesterase inhibitors were matched to 2,189 started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Participants initiated on cholinesterase inhibitors had a higher risk of weight loss than matched controls at 12 months (hazard ratio = 1.23, 95% confidence interval (CI) = 1.07-1.41). At 12 months, 29.3% of participants taking cholinesterase inhibitors had experienced weight loss, compared with 22.8% of nonusers, corresponding to a number needed to harm of 21.2 (95% CI = 12.5-71.4) over 1 year. There were no significant differences in the risk of weight loss within subgroups., Conclusion: These results are consistent with the available data from randomized controlled trials. Clinicians should consider the risk of weight loss when prescribing cholinesterase inhibitors., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Background: There is no cure for dementia, and no treatments exist to halt or reverse the course of the disease. Treatments are aimed at improving cognitive and functional outcomes., Objective: Our objective was to review the basis of pharmacological treatments for dementia and to summarize the benefits and risks of dementia treatments., Methods: We performed a systematic literature search of MEDLINE through November 2014, for English-language trials and observational studies on treatment of dementia and mild cognitive impairment. Additional references were identified by searching bibliographies of relevant publications. Whenever possible, pooled data from meta-analyses or systematic reviews were obtained. Studies were included for review if they were randomized trials or observational studies on dementia or mild cognitive impairment that evaluated efficacy outcomes or adverse outcomes associated with treatment. Studies were excluded if they evaluated non-FDA approved treatments, or if they evaluated treatment in disorders other than dementia and mild cognitive impairment., Results: The literature search found 540 potentially relevant studies, of which 257 were included in the systematic review. In pooled trial data, cholinesterase inhibitors (ChEIs) produce small improvements in cognitive, functional, and global benefits in patients with mild to moderate Alzheimer's and Lewy body dementia, but the clinical significance of these effects are unclear. There is no significant benefit seen for vascular dementia. The efficacy of ChEI treatment appears to wane over time, with minimal benefit seen after 1 year. There is no evidence for benefit for those with advanced disease or those aged over 85 years. Adverse effects are significantly increased with ChEIs, in a dose-dependent manner. A two- to fivefold increased risk for gastrointestinal, neurological, and cardiovascular side effects is related to cholinergic stimulation, the most serious being weight loss, debility, and syncope. Those aged over 85 years have double the risk of adverse events compared with younger patients. Memantine monotherapy may provide some cognitive benefit for patients with moderate to severe Alzheimer's and vascular dementia, but the benefit is small and may wane over the course of several months. Memantine exhibits no significant benefit in mild dementia or Lewy body dementia or as an add-on treatment with ChEIs. Memantine has a relatively favorable side-effect profile, at least under controlled trial conditions., Conclusions: ChEIs produce small, short-lived improvements in cognitive function in mild to moderate dementia, which may not translate into clinically meaningful effects. Marginal benefits are seen with severe disease, long-term treatment, and advanced age. Cholinergic side effects, including weight loss, debility, and syncope, are clinically significant and could be especially detrimental in the frail elderly population, in which the risks of treatment outweigh the benefits. Memantine monotherapy may have minimal benefits in moderate to severe dementia, balanced by minimal adverse effects.

Objectives: To compare the risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine for dementia., Design: Retrospective cohort study., Setting: Nationally representative 5% sample of Medicare databases., Participants: Medicare beneficiaries aged 65 and older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009., Measurements: Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. Cox proportional hazards models were used to estimate the risk of pneumonia. Subgroup analyses and sensitivity analyses were conducted using alternative pneumonia definitions and adjustments using high-dimensional propensity scores to test the robustness of the results., Results: The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person-years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR)=0.75, 95% confidence interval (CI)=0.60-0.93). Risk in galantamine users (HR=0.87, 95% CI=0.62-1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results., Conclusion: The risk of pneumonia was lower in individuals receiving rivastigmine than in those receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and in users of galantamine., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

The updated Dementia guideline of the Dutch Geriatrics Society (NVKG) recommends additional testing (e.g. EEG, cerebrospinal fluid, CT/MRI or SPECT scans) only in cases of persisting significant diagnostic uncertainty. This more parsimonious use of tests appears to contrast with the current trend for specialist memory assessment services to favour full test batteries for all patients, and may be more efficient and less burdensome for patients. However, unlike the benchmark Dementia guideline of the Dutch College of General Practitioners (NHG), the NVKG guideline recommends treatment of Alzheimer's disease patients with cholinesterase inhibitors or memantine. Although meta-analyses yield significant beneficial treatment effects, in our opinion these are not clinically relevant and are mostly short-lived and counterbalanced by the burden of adverse effects. Nevertheless, the NVKG guideline also devotes considerable attention to psychosocial interventions that are valuable for the quality of life of both patients and their carers.

Introduction: Some treatments are inappropriate for patients with cognitive decline. We analyse their use in 500 patients and present a literature review., Development: Benzodiazepines produce dependence, and reduce attention, memory, and motor ability. They can cause disinhibition or aggressive behaviour, facilitate the appearance of delirium, and increase accident and mortality rates in people older than 60. In subjects over 65, low systolic blood pressure is associated with cognitive decline. Maintaining this figure between 130 and 140 mm Hg (145 in patients older than 80) is recommended. Hypocholesterolaemia < 160 mg/dl is associated with increased morbidity and mortality, aggressiveness, and suicide; HDL-cholesterol<40 mg/dl is associated with memory loss and increased vascular and mortality risks. Old age is a predisposing factor for developing cognitive disorders or delirium when taking opioids. The risks of prescribing anticholinesterases and memantine to patients with non-Alzheimer dementia that is not associated with Parkinson disease, mild cognitive impairment, or psychiatric disorders probably outweigh the benefits. Anticholinergic drugs acting preferentially on the peripheral system can also induce cognitive side effects. Practitioners should be aware of steroid-induced dementia and steroid-induced psychosis, and know that risk of delirium increases with polypharmacy. Of 500 patients with cognitive impairment, 70.4% were on multiple medications and 42% were taking benzodiazepines. Both conditions were present in 74.3% of all suspected iatrogenic cases., Conclusions: Polypharmacy should be avoided, if it is not essential, especially in elderly patients and those with cognitive impairment. Benzodiazepines, opioids and anticholinergics often elicit cognitive and behavioural disorders. Moreover, systolic blood pressure must be kept above 130 mm Hg, total cholesterol levels over 160 mg/dl, and HDL-cholesterol over 40 mg/dl in this population., (Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Background: The benefits of escalating the dose of donepezil in patients who are already receiving long-term treatment with it have not been well evaluated. Therefore, an exploratory study to assess the effects of donepezil dose escalation in patients with Parkinson's disease with dementia, and specifically on patients receiving long-term treatment with donepezil, was performed., Methods: Patients treated with 5-mg/day donepezil for at least 3 months and having a Mini-Mental State Examination (MMSE) score between 10 and 26 were included in this study. Donepezil dosage was then increased to 10 mg/day for 12 weeks. The outcome measures were a modified form of the Neuropsychiatric Inventory (NPI) with an extra domain for additional evaluation of fluctuation in cognitive functions (NPI-11) and the MMSE., Results: Of the nine patients enrolled, two withdrew because of nausea and inability to be assessed on the predetermined date; this left seven participants (four men and three women) with a mean age of 74.6 ± 6.9 years, a mean period of Parkinson's disease of 11.7 ± 7.5 years, and median donepezil use of 7 months (range: 3-56 months). At baseline, the mean total NPI-11 and mean MMSE scores were 18.3 ± 5.6 points and 21.3 ± 5.3 points, respectively. At week 12, they improved by 8.3 points (P < 0.01) and 3.0 points (P = 0.08), respectively, from the baseline. The NPI symptom domains that improved by 1 or more points were hallucination (1.3 points), depression (1.0 points), anxiety (1.6 points), and aberrant motor behaviour (1.7 points). None of the patients withdrew because of worsening of parkinsonism., Conclusions: The present results suggest that treatment with dose escalation of donepezil from 5 mg/day to 10 mg/day may be therapeutically useful for patients with Parkinson's disease with dementia who have taken donepezil 5 mg/day in the long term., (© 2014 The Authors. Psychogeriatrics © 2014 Japanese Psychogeriatric Society.)

Background: The purpose of this study was to investigate the risk of death among elderly outpatients (>65 years) with a dementia diagnosis treated with atypical antipsychotics., Methods: We conducted a cohort study of 696 patients who entered the Unit of Alzheimer Evaluation (UVA) of Teramo Hospital in Central Italy, during a 3-year period (January 2007-December 2009). Among these patients, 375 were treated with atypical antipsychotics (quetiapine, risperidone and olanzapine). Data were collected from record files sent to the pharmaceutical service of the hospital., Results: Patients taking atypical antipsychotic medication were associated with a significantly higher mortality rate than patients not taking antipsychotics. The relative risk of death in patients treated with antipsychotics compared to control patients was 2.354 (95% CI 1.704-3.279). The greatest increases in mortality rate occurred close to the last drug supply, and declined exponentially as time passed from the last drug supply in patients who stopped drug assumption. Quetiapine was the most commonly prescribed drug and higher doses of this drug were associated with higher mortality rates., Conclusions: These results are in line with the April 2005 warning of the Food and Drug Administration (FDA) that among elderly patients with dementia, the treatment of behavioural disorders with atypical antipsychotics is associated with a higher mortality rate. Given the potential risks of mortality with antipsychotics, and since antipsychotic medications may benefit only a minority of patients, new approaches are clearly needed to manage the neuropsychiatric symptoms of dementia.

The drugs currently available for the treatment of Alzheimer's disease and other dementias can provide limited symptomatic improvement. The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine and the NMDA-receptor antagonist memantine have produced modest but apparently persistent improvements in cognition, activities of daily living, and behavior in patients with disease severity ranging from mild to severe. Among the acetylcholinesterase inhibitors, transdermal rivastigmine causes fewer gastrointestinal side effects than the oral formulation. Whether adding memantine to an acetylcholinesterase inhibitor is more effective than an acetylcholinesterase inhibitor alone remains to be established; clinical trial results have been mixed. None of these agents have been shown to stop or reverse the underlying neurodegenerative process.

Background: Medications are frequently prescribed for neuropsychiatric symptoms (NPS) associated with dementia, although information on the efficacy and safety of medications for NPS specifically in long-term care (LTC) settings is limited. The objective of this study was to provide a current review of the efficacy and safety of pharmacological treatments for NPS in LTC., Methods: We searched MEDLINE, EMBASE, PsychINFO, and the Cochrane Library for randomized controlled trials comparing medications with either placebo or other interventions in LTC. Study quality was described using the Cochrane collaboration risk of bias tool. The efficacy of medications was evaluated using NPS symptom rating scales. Safety was evaluated through rates of trial withdrawals, trial withdrawals due to adverse events, and mortality., Results: A total of 29 studies met inclusion criteria. The most common medications evaluated in studies were atypical antipsychotics (N = 15), typical antipsychotics (N = 7), anticonvulsants (N = 4), and cholinesterase inhibitors (N = 3). Statistically significant improvements in NPS were noted in some studies evaluating risperidone, olanzapine, and single studies of aripiprazole, carbamazepine, estrogen, cyproterone, propranolol, and prazosin. Study quality was difficult to rate in many cases due to incomplete reporting of details. Some studies reported higher rates of trial withdrawals, adverse events, and mortality associated with medications., Conclusions: We conclude that there is limited evidence to support the use of some atypical antipsychotics and other medications for NPS in LTC populations. However, the generally modest efficacy and risks of adverse events highlight the need for the development of safe and effective pharmacological and non-pharmacological interventions for this population.

Objective: To clarify whether hospitalized patients with behavioral and psychological symptoms of dementia (BPSD) show gender differences in manifested symptoms and outcomes., Method: A chart review study of patients hospitalized from April 2006 to March 2008 for the treatment of BPSD was conducted. We evaluated the prevalence of symptoms in each of 7 clusters constituting a subscale of the Behavioral Pathology in Alzheimer's Disease Rating Scale and the incidence of favorable discharge, defined as discharge to the patient's own home or care facility. Dementia was diagnosed according to DSM-IV., Results: The study cohort comprised 122 men and 170 women. The men were more likely than the women to present with aggressiveness (78% vs 52%, P < .001) and diurnal rhythm disturbances (89% vs 79%, P < .05) and less likely to present with paranoid, delusional ideation (12% vs 41%, P < .001); hallucination (7% vs 29%, P < .001); affective disturbances (20% vs 40%, P < .001); and anxieties and phobias (15% vs 44%, P < .001). Incidence of favorable discharge was lower in the men (58% vs 77%, P = .001). Even after matching for age, sociodemographic factors, and physical and cognitive functions, the differences in these symptoms persisted, with the exception of diurnal rhythm disturbances. Incidence of favorable discharge was lower in the men (60% vs 77%, P = .0173)., Conclusion: The data demonstrated gender differences in BPSD and outcomes among hospitalized patients. The findings should be considered when deciding on the optimal management plan for patients with BPSD., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

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., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Aims: The aim of this study was to assess, in a natural setting, the development of cognitive, behavioral and functional performance of elderly dementia patients treated with cholinesterase inhibitors (ChEIs) during a 21-month follow-up. Another aim was to compare patterns of clinical changes in relation to patients' level of cognitive impairment at the beginning of therapy., Method: Of the 1987 elderly demented patients seen at our unit, 143 met the inclusion/ exclusion criteria, were followed for at least 21 months, and were thus included in the study. At baseline and each control point (up to 21 months), patients were scored for Mini Mental State Examination (MMSE), Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL)., Results: After 21 months' treatment with ChEIs, patients showed a significant reduction in MMSE, ADL and IADL values. The MMSE score decreased by 1.7 points/year (95% CI -2.1; -1.3), irrespective of initial cognitive level, and was lower than that expected in non-treated patients (-3/-4 points/year)., Conclusion: ChEI therapy is effective in slowing the progression of dementia, even in the long term, irrespective of baseline cognitive level.

Background: Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement., Objectives: To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease)., Search Methods: The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials., Selection Criteria: Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD)., Data Collection and Analysis: Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0., Main Results: Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03)., Authors' Conclusions: The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Background: Cholinesterase inhibitors (ChEIs) are a mainstay treatment for individuals with dementia. ChEIs may worsen airflow obstruction because of their pro-cholinergic properties., Objective: The objective of this study was to evaluate the risk of serious pulmonary complications in the elderly with concomitant chronic obstructive pulmonary disease (COPD) and dementia who were receiving ChEIs., Methods: This was a population-based, cohort study conducted between 2003 and 2010 in residents of Ontario, Canada. Subjects were over the age of 66 years and had concomitant dementia and COPD, identified using linked administrative databases. Exposure to ChEIs was determined using a drug benefits database. The primary outcome was an emergency room (ER) visit or hospitalization for COPD. The risk difference at 60 days and the relative risk (RR) for study outcomes were estimated in the propensity score-matched sample., Results: Of 266,840 individuals with COPD, 45,503 had a concomitant diagnosis of dementia. A total of 7166 unexposed subjects were matched to subjects newly exposed to ChEIs. New users of ChEIs were not at significantly higher risk of ER visits or hospitalizations for COPD (RR 0.90; 95% CI 0.76, 1.07) or COPD exacerbations (RR 1.02; 95% CI 0.91, 1.15). Furthermore, ER visits for any respiratory diagnoses were not increased among new users of ChEIs (RR 1.02; 95% CI 0.87, 1.19) when compared with non-users. Sub-group analyses were consistent with the main analysis., Conclusions: In a large cohort of elderly individuals with COPD and dementia, new users of ChEIs had a similar risk for adverse pulmonary outcomes as those who were not receiving ChEIs.