The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial.

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

Zopiclone to treat insomnia in older adults: A systematic review.

Considering the global increase in use of Z-drugs to treat insomnia, the study objective was to conduct a systematic review on the efficacy and safety of zopiclone to treat sleep disorders in older adults compared to other sedative-hypnotics, to placebo or to non-pharmacological interventions. The literature search for original reports - clinical trials, cohort studies and cross-sectional, observational investigations - was done in eleven databases and web search engines followed PRISMA guidelines, and methodological quality was assessed using the Risk of Bias tool in the Cochrane Reviewers' Handbook. The search resulted in 12 randomized, placebo-controlled clinical trials along with 2 open studies and 2 observational reports. Overall, the studies suggest that zopiclone is effective to treat insomnia by reducing sleep latency, nocturnal awakenings and wake time after sleep onset while increasing total sleep time, with probable effects on sleep architecture. Zopiclone was found to be fairly tolerated, to induce a low rate of adverse events with non-severe impact on psychomotor or cognitive performance and to produce no major harm to the overall well-being and daily living abilities. However, the quality of most studies was classified as low or unclear. Though the studies available support benefits from zopiclone use, there is still a need for further evidence on long-term effects, tolerability and safety in the treatment of older adults by means of high-quality trials.

More than a quarter century of the most prescribed sleeping pill: Systematic review of zolpidem use by older adults.

Zolpidem is widely used to treat insomnia of older adults despite that few randomized controlled studies were conducted in this group. We systematically reviewed the relevant literature on efficacy/effectiveness and safety of zolpidem use by elderly individuals in relevant databases completed with a manual search of key journals. Studies were required to include individuals aged ≥60 years under intervention with zolpidem compared to placebo or other hypnosedatives. Outcomes were either objectively- or subjectively-assessed improvements in specific sleep parameters and safety for clinical use. The 31 reports selected for review were mostly of low-quality. The evidence suggests that zolpidem is useful typically by reducing sleep latency and episodes of wake after sleep onset, and increasing total sleep time and sleep efficiency. Regarding safety and tolerability, analyses suggest a low risk of daytime sleepiness and of deleterious effects on memory or psychomotor performance, provided that recommended dosage and precautions are followed. Few retrospective studies associate zolpidem use with risk of falls, fractures, dementia, cancer, and stroke. Zolpidem appears effective at lower doses and for short-term treatment among the elderly. Rigorous, new clinical trials are warranted to further document the specific effects of zolpidem in older individuals.

Evidence for a contribution of the APOE (but not the ACE) gene to the sleep profile of non-demented elderly adults.

This study aims to investigate alleles of the human apolipoprotein E (APOE) and of the angiotensin-converting enzyme (ACE) genes as risk factors for poor quality of sleep in elderly individuals with no major cognitive decline. This cross-sectional, analytical study was conducted with 163 participants aged 75 years in average and 85% female. Sociodemographic, anthropometric and clinical data were gathered, and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth scale, with patient followed for years prior to these evaluations to rule out onset of major mental disorders. Genotyping of classic polymorphic sites for the ApoE (rs429358 and rs7412) and the ACE (rs4646994) genes used peripheral DNA. A total of 63% of the subjects reported poor quality of sleep assessed by the PSQI whereas 54 (33%) reported daytime sleepiness through the Epworth scale. A significant correlation was observed between APOE and PSQI, with a greater frequency of the poor nighttime sleep quality phenotype among ε2 carriers, whereas no correlation was found among any of the sleep scores and the ACE genotypes. Thus, we suggest a correlation between APOE alleles and scale-assessed sleep quality scores in older adults, with no implications for ACE alleles, in a context devoid of cognitive impairment.

Underdiagnosis of delirium in the elderly in acute care hospital settings: lessons not learned.

BACKGROUND: Delirium is a common and poorly diagnosed cause of behavioral change in elderly. This study aimed to estimate the prevalence, diagnostic accuracy and factors associated with the onset of delirium in the elderly admitted to an urgency unit. METHODS: Cross-sectional study including clinically stable subjects aged ≥60 years between April and June of 2014. Diagnosis of delirium based on the Confusion Assessment Method (CAM, gold standard) was compared to the subjective assessment made by physicians on duty as recorded in the medical chart. Association of sociodemographic, psychological/behavioural, and clinical variables with delirium was assessed using multivariate analysis. RESULTS: A sample of 110 participants with a mean age of 72.7 ± 8.3 years was studied. Of these, 56.4% were men and 28.2% had a diagnosis of delirium on CAM. Significant associations were observed between delirium and male gender (P-value = 0.019), poor or very poor self-perception of health (P-value = 0.033), previous diagnosis of dementia (P-value = 0.001), previous history of stroke (P-value = 0.014), and acute bacterial infection (P-value = 0.008). Physician diagnosis had a sensitivity of 35.5%, specificity of 100%, and accuracy of 81.8% to detect delirium. Rate of misdiagnosis was 64.5%. CONCLUSION: Delirium was underdiagnosed in this urgent care hospital setting.

Mirtazapine does not improve sleep disorders in Alzheimer's disease: results from a double-blind, placebo-controlled pilot study.

AIM: The aim of this study was to test the efficacy and safety of mirtazapine in the treatment of sleep disorders in patients with Alzheimer's disease by means of a randomized, double-blind, placebo-controlled trial. Measurements were obtained for 7 days before intervention (baseline) and for 2 weeks after the onset of treatment. METHODS: Alzheimer's disease patients with sleep disorders (n = 24) received 15-mg mirtazapine (n = 8) or placebo (n = 16) once daily at 2100 hours for 2 weeks. Patients were evaluated with actigraphy and structured scales before and after intervention. Historical control was employed. RESULTS: Treatment with mirtazapine or placebo had no effect on cognitive and functional status as assessed by the Mini-Mental State Examination and the Katz scale, respectively. There were no differences between groups in the frequency or severity of the adverse events reported. Compared with the placebo group, mirtazapine users showed increased daytime sleepiness but no improvement in the duration or efficiency of nocturnal sleep after treatment. CONCLUSIONS: This study showed no significant therapeutic effects of 15-mg mirtazapine in community-dwelling Alzheimer's disease patients with sleep disorders. Instead, this study found evidence of worsening of daytime sleep patterns.

Circadian rhythm in Alzheimer disease after trazodone use.

A circadian rhythm is a cycle of approximately 24 h, responsible for many physiological adjustments, and ageing of the circadian clock contributes to cognitive decline. Rhythmicity is severely impaired in Alzheimer disease (AD) and few therapeutic attempts succeeded in improving sleep disorders in such context. This study evaluated sleep parameters by actigraphy in 30 AD patients before and after trazodone use for 2 weeks, and we show a significant improvement in relative rhythm amplitude (RRA), compatible with a more stable daytime behavioral pattern. So, trazodone appears to produce a stabilization of the circadian rhythms in individuals with AD.

Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind, and placebo-controlled study.

OBJECTIVES: There are no randomized clinical trials regarding efficacy of trazodone in the treatment of sleep disturbances (SD) in patients with Alzheimer disease (AD). We tested the efficacy and safety of trazodone to treat SD in patients with AD. DESIGN: We conducted a double-blind, randomized and controlled trial during periods of 7-9 days at baseline and 2 weeks of treatment. SETTING: Geriatric medical center of the university's general hospital. PARTICIPANTS: Individuals with probable AD and SD. The complete analysis comprised 30 patients assigned to either the active treatment group (N = 15) or the placebo group (N = 15). INTERVENTION: Patients received 50 mg of trazodone once daily at 10:00 P.M. or placebo in a 1:1 ratio for 2 weeks. MEASUREMENTS: Patients were evaluated using actigraphy and structured scales before and after intervention. RESULTS: Compared with the placebo group, trazodone users slept 42.5 more minutes per night and had their nighttime percent sleep increased 8.5 percentage points according to actigraphic data post-treatment. Neither trazodone nor placebo induced significant daytime sleepiness or naps. The treatments with trazodone or placebo did not show any effects either on cognition (Mini-Mental State Examination, forward/backward digit span task, letter-number sequencing, arithmetic, digit symbol-coding, and symbol search) or functionality (Katz index). There were no differences in frequency or severity rating of adverse events between the groups. CONCLUSIONS: This study shows significant therapeutic effects of trazodone 50 mg in community-dwelling AD patients with SD.

Cytokine gene polymorphisms and Alzheimer's disease in Brazil.

BACKGROUND: Single-nucleotide polymorphisms in genes encoding immunological mediators can affect the biological activity of these molecules by regulating transcription, translation, or secretion, modulating the genetic risk of inflammatory damage in Alzheimer's disease (AD). Nonetheless, the Brazilian contingent is highly admixed, and few association trials performed herein with AD patients have considered genetic ancestry estimates as co-variables when investigating markers for this complex trait. METHODS: We analyzed polymorphisms in 10 inflammatory genes and compared the genotype distribution across outpatients with late-onset AD and noncognitively impaired subjects from Midwest Brazil under a strict criterion, and controlling for ancestry heritage and ApoE genotype. RESULTS: Our findings show an almost 40% lower chance of AD (p = 0.004) among homozygotes of the IL10 -1082A allele (rs1800896). Dichotomization to ApoE and mean ancestry levels did not affect protection, except among those with greater European or minor African heritage. CONCLUSION: The IL10 locus seems to affect the onset of AD in a context sensitive to the genetic ancestry of Brazilian older adults.

Wrist actigraphy for measuring sleep in intervention studies with Alzheimer's disease patients: application, usefulness, and challenges.

Sleep disorders are common in patients with Alzheimer's disease (AD). An important aspect of intervention studies in patients with sleep disorders is the choice of assessment strategy. This paper presents a literature review concerning assessment strategies for measuring sleep in intervention studies with AD patients, with a focus on actigraphy. Thirty-seven articles were selected for this review, having analysis of sleep/nocturnal rhythm disturbances by actigraphy as the primary or secondary outcome. The advantages and limitations of actigraphy were discussed vis-à-vis polysomnography and subjective interventions. The following methodological aspects were addressed: impact of experimental design and patient setting, inclusion and exclusion criteria, placement of the actigraphy device, adherence to the regimen, duration of recordings and the choice of sleep parameters. Our analyses suggest that the methods used in intervention studies encompassing sleep disorders and dementia could be improved by increasing accuracy of diagnosis, categorization of sleep disturbances, adherence to actigraphy, and by clearly defining the variables and endpoints in each study. Also, controlling variables that could interfere with sleep and describing the data processing and analysis might improve interpretation of results.

Amerindian genetic ancestry protects against Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide, and bears remarkable evidence for a differential prevalence among continental populations. In this scenario, estimating ancestry proportions in recently admixed populations is a strategy that can help increasing knowledge about the genetic structure of this complex trait. AIM/METHODS: Our purpose was to assess mean ancestry estimates for the three main parental contributors to the Brazilian contingent (European, African and Amerindian) using a panel of 12 ancestry informative markers. Outpatients with the late-onset form of AD (n = 120) were compared for ancestry levels with non-cognitively impaired subjects (n = 412) in the Midwest Brazil, controlling for classic clinical, social and anthropometric risk factors. RESULTS: Our findings show a 3-fold greater genetic Amerindian content among control subjects compared to AD patients (p < 0.001). CONCLUSION: Our results suggest that the allelic architecture of Native Americans can confer protection against the onset of the disease.