Sleep patterns change with aging, independent of other factors, and include advanced sleep timing, shortened nocturnal sleep duration, increased frequency of daytime naps, increased number of nocturnal awakenings and time spent awake during the night, and decreased slow wave sleep. Most of these changes seem to occur between young and middle adulthood; sleep parameters remain largely unchanged among healthy older adults. The circadian system and sleep homeostatic mechanisms become less robust with normal aging. The amount and pattern of sleep-related hormone secretion change as well. The causes of sleep disturbances in older adults are multifactorial.Copyright © 2017 Elsevier Inc. All rights reserved.

Previous researches have shown inconsistent findings on the relationship between sleep duration and cognitive disorders (including cognitive decline, dementia, Alzheimer's disease, and cognitive impairment). Furthermore, the possible dose-response association of sleep duration and cognitive disorders is still not clear.Two databases (PubMed and Embase) were searched for relevant studies from inception to May 4, 2016. We used the generic inverse-variance method to combine the outcomes with a random-effects model for the association between sleep duration (the shortest or longest vs. middle category) and cognitive disorders. Additionally, we used the generalized least-squares trend estimation model to estimate the potential dose-response association.Finally, nine eligible cohort studies involving 22,187 participants were included in the present systematic review and meta-analysis. Compared with the middle category, both short and long sleep duration were accompanied by a significantly higher incident risk of cognitive disorders, and the relative risks (RRs) and 95% confidence intervals (CIs) were 1.34 (1.15, 1.56) and 1.21 (1.06, 1.39), respectively. Moreover, an approximately "U-shaped" dose-response relationship was observed. Stratified analyses showed that the association between short sleep duration and cognitive disorders was more robust in the subgroup of the measurement of sleep duration based on self-report.The lowest incident risk of cognitive disorders was found at the sleep duration of 7-8 h per day. The present study includes a small number of studies, and the study participants mostly consist of Caucasian population. In the future, researches are also warranted to confirm the association in different groups of people.

Research interest in sleep as a risk factor for dementia has grown, warranting an update in advances over the last 18 months, particularly in the mild cognitive impairment (MCI) stage in which interventions may be best targeted.The current systematic review includes empiric research articles published since 2016 that have investigated sleep (excluding obstructive sleep apnea) in MCI. Published articles include case-control studies, those examining clinical correlates of sleep problems, sleep microarchitecture, neuroimaging studies and novel cerebrospinal and blood-based markers.Evidence accumulated since 2016 continues to demonstrate that people with MCI manifest sleep disturbance on self-report measures. Neurophysiologically, sleep disturbance in MCI appears to be associated with diminished sleep spindles, key processes involved in overnight memory consolidation. Those with both MCI and sleep disturbance appear to have more pronounced functional connectivity alterations in temporoparietal brain regions and higher levels of the wake-promoting neurotransmitter orexin in cerebrospinal fluid than those with MCI alone. Novel findings also suggest that sleep may mediate homocysteine and oxidative stress mechanisms, warranting further exploration. Further studies focusing on novel interventions for sleep and circadian disturbance in MCI are warranted, particularly those targeting sleep spindles, orexin/hypocretin and the oxidative stress system.

An important function of sleep is the consolidation of memories, and features of sleep, such as rapid eye movement (REM) or sleep spindles, have been shown to correlate with improvements in discrete memory domains. Because of the methodological difficulties in modulating sleep, however, a causal link between specific sleep features and human memory consolidation is lacking. Here, we experimentally manipulated specific sleep features during a daytime nap via direct pharmacological intervention. Using zolpidem (Ambien), a short-acting GABAA agonist hypnotic, we show increased sleep spindle density and decreased REM sleep compared with placebo and sodium oxybate (Xyrem). Naps with increased spindles produced significantly better verbal memory and significantly worse perceptual learning but did not affect motor learning. The experimental spindles were similar to control spindles in amplitude and frequency, suggesting that the experimental intervention enhanced normal sleep processes. Furthermore, using statistical methods, we demonstrate for the first time a critical role of spindles in human hippocampal memory performance. The gains in memory consolidation exceed sleep-alone or control conditions and demonstrate the potential for targeted, exceptional memory enhancement in healthy adults with pharmacologically modified sleep.

Benzodiazepines (BZDs) and Z-drugs have high potential for developing frequent adverse drug events in older adults (e.g., psychomotor sedation, drug-related dementia, deliria, drug dependence, etc.). Knowledge of the prevalence and patterns of the use of BZDs/Z-drugs in vulnerable older patients is important in order to prevent and reduce the burden caused by their drug-related complications. Our study focused on international comparisons of the prevalence, country-specific prescribing patterns and risk factors of regular BZD/Z-drug use in nursing home (NH) residents.This cross-sectional study retrospectively analysed data of 4156 NH residents, prospectively assessed in the Services and Health in the Elderly in Long TERm care (SHELTER) project conducted from 2009 to 2014. Residents aged 65+ in 57 NHs in 7 European countries and Israel were assessed by the InterRAI Long-Term Care Facilities instrument. Descriptive statistics and multiple logistic regression models were used to describe the country-specific prevalence, patterns and risk factors of BZD/Z-drug use.The mean age of the participants was 83.4 ± 9.4 years, 73% were female and 27.7% used BZDs/Z-drugs. The prevalence of BZD/Z-drug use differed significantly across countries, ranging from 44.1% in Israel to 14.5% in Germany. The most frequently prescribed were zopiclone (17.8%), lorazepam (17.1%) and oxazepam (16.3%). Lorazepam, oxazepam and diazepam were used in most of the countries. Brotizolam, temazepam and zolpidem showed highest prevalence in Israel (99.4% of all regular users of this medication in the sample), the Netherlands (72.6%) and France (50.0%), respectively. Residing in Israel was the most significant factor associated with the use of BZDs/Z-drugs or BZDs only (odds ratio [OR] 6.7; 95% confidence interval [CI] 4.8-9.2 and OR 9.7, 95%CI 6.5-14.5, respectively). The use of Z-drugs only was most significantly associated with residing in France (OR 21.0, 95%CI 9.0-48.9).Despite global recommendations and warnings, the preference for and extent of use of individual BZDs and Z-drugs in vulnerable NH residents differ significantly across countries. The strong association with country of residence compared to clinical and functional factors denotes that prescribing habits, social, cultural, behavioural, and regulatory factors still play an important role in the current diverse use of these medications.

A meta-analysis of a randomized placebo-controlled trial was used to evaluate the effectiveness and safety of Zolpidem in the treatment of insomnia disorder for one month.Searched from PubMed, EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials and web of science from inception to May 13, 2021. In addition, we also searched ClinicalTrials.gov trials register to obtain relevant research and related data. Include all randomized controlled trials that meet the criteria. The primary efficacy outcome were total sleep time and sleep latency. The secondary outcome was wake-time after sleep onset. And to evaluate the safety of Zolpidem in the treatment of insomnia.Total of 6 randomized placebo-controlled trials involving 1068 patients with insomnia disorder were included in our study. Our analysis results showed that compared with placebo, zolpidem treatment for one month was more effective in increasing the total sleep time of patients with insomnia disorder, reducing sleep latency and improving sleep quality. There was no significant statistical difference between the two groups in the amount of change in the wake after sleep onset. Meanwhile, there was no significant statistical difference in adverse events between Zolpidem and placebo after one month of treatment.Our meta-analysis showed that zolpidem is an effective and safe therapy option to treat insomnia disorder for one month. However, when using zolpidem to treat insomnia, its effect on sleep structure should be considered. In the future, large-scale clinical trials are needed to compare the effectiveness and safety of zolpidem in the treatment of insomnia from subjective and objective indicators combined with zolpidem on sleep structure.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

The imidazopyridine zolpidem (Ambien) is one of the most commonly prescribed sleep aids in the United States (Rush, 1998). Similar to classic benzodiazepines (BZDs), zolpidem binds at the extracellular N-terminal alpha/gamma subunit interface of the GABA-A receptor (GABAR). However, zolpidem differs significantly from classic BZDs in chemical structure and neuropharmacological properties. Thus, classic BZDs and zolpidem are likely to have different requirements for high-affinity binding to GABARs. To date, three residues--gamma2Met57, gamma2Phe77, and gamma2Met130--have been identified as necessary for high-affinity zolpidem binding (Proc Natl Acad Sci USA 94:8824-8829, 1997; Mol Pharmacol 52:874-881, 1997). In this study, we used radioligand binding techniques, gamma2/alpha1 chimeric subunits (chi), site-directed mutagenesis, and molecular modeling to identify additional gamma2 subunit residues important for high-affinity zolpidem binding. Whereas alpha1beta2chi receptors containing only the first 161 amino-terminal residues of the gamma2 subunit bind the classic BZD flunitrazepam with wild-type affinity, zolpidem affinity is decreased approximately 8-fold. By incrementally restoring gamma2 subunit sequence, we identified a seven-amino acid stretch in the gamma2 subunit loop F region (amino acids 186-192) that is required to confer high-affinity zolpidem binding to GABARs. When mapped to a homology model, these seven amino acids make up part of loop F located at the alpha/gamma interface. Based on in silico zolpidem docking, three residues within loop F, gamma2Glu189, gamma2Thr193, and gamma2Arg194, emerge as being important for stabilizing zolpidem in the BZD binding pocket and probably interact with other loop F residues to maintain the structural integrity of the BZD binding site.

This study explored two research questions: (a) Does sleep medication neutralize or provide a protective effect against the hazard of Alzheimer's disease (AD)? (b) Do apolipoprotein (APOE) e4 carriers reporting a sleep disturbance experience an increased risk of AD?This study is a secondary analysis of the National Alzheimer's Coordinating Center's Uniform Data Set ( n = 6,782) using Cox proportional hazards regression.Sleep disturbance was significantly associated with eventual AD development. Among the subset of participants taking general sleep medications, no relationship between sleep disturbance and eventual AD was observed. Among individuals not taking sleep medications, the increased hazard between the two variables remained. Among APOE e4 carriers, sleep disturbance and AD were significant, except among those taking zolpidem.Our findings support the emerging link between sleep disturbance and AD. Our findings also suggest a continued need to elucidate the mechanisms that offer protective factors against AD development.

Adverse effects of sedative-hypnotic medications on cognition are concerning. Past studies have examined benzodiazepine (BZD) use and cognitive outcomes; however, few studies have examined newer non-BZD hypnotic agents (nBHs; e.g. zolpidem). This systematic review examined observational studies assessing the association between nBH use and cognitive outcomes.Five studies met eligibility requirements and were included in the review. Most studies did not find an association between nBH use and dementia diagnosis; however, we found no studies assessing other cognitive outcomes such as cognitive performance (e.g., word recall tasks). Characterization of nBH use mostly consisted of incident new use; one study assessed nBH dosing; none examined duration of use. Studies included were of strong quality.This review found no association between nBH use and dementia diagnosis, although there is a need for more research on more cognitive outcomes and nBH use patterns.

Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia.We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates.The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66), and 1.88 (1.14-3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]).Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed.ENCePP e-register of studies, EUPAS18006.