Search

Given the high rate of depression associated with narcolepsy or obstructive sleep apnea (OSA), this analysis compared effects of solriamfetol treatment of excessive daytime sleepiness (EDS) in participants with/without a history of depression (DHx+/DHx-). This secondary analysis included data from two randomized, controlled trials in which participants were randomized to 12 weeks placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300mg/day. Efficacy/safety (combined solriamfetol doses) was summarized for DHx+/DHx-subgroups. 27.5% (65/236) with narcolepsy and 23.4% (111/474) with OSA were DHx+. In narcolepsy (DHx+ and DHx-), 40-min Maintenance of Wakefulness Test (MWT40) mean sleep latency increased (5.4 and 7.0min), Epworth Sleepiness Scale (ESS) score decreased (3.8 and 3.5 points), and percentage of participants improved on Patient Global Impression of Change (PGI-C) was higher (31.7% and 39.4%) relative to placebo. In OSA (DHx+ and DHx-), MWT40 mean sleep latency increased (7.7 and 10.7min), ESS decreased (3.5 and 3.7 points), and percentage of participants improved on PGI-C was higher (41.1% and 29.4%) relative to placebo. Common treatment-emergent adverse events (headache, decreased appetite, nausea, anxiety) were similar in DHx+/DHx-. This study suggests that safety and efficacy of solriamfetol for treating EDS in narcolepsy and OSA are not affected by depression history. Moreover, the findings emphasize the high prevalence of depression in people with sleep disorders and suggest that increased awareness of this association may have clinical significance.

Introduction Progress reducing suicide death will require randomized clinical trials (RCTs) specifically targeting suicide risk. Even large RCTs may not stipulate suicide death as the primary outcome, as suicide death is relatively uncommon. Therefore, RCTs may need to specify suicidal ideation as a proxy indicator of risk. There is no consensus on the best tool for measuring suicidal ideation within RCTs. We contrasted the psychometric performance of three suicidal ideation measures to address this need. Methods We applied item response theory to the Beck Scale for Suicide Ideation (BSSI), the Columbia-Suicide Severity Rating Scale (C-SSRS), and the suicide item of the Hamilton Rating Scale for Depression (HRSD) for 101 outpatients with depression and suicidal ideation participating in a RCT with suicidal ideation as the primary outcome. Results All measures of suicidal ideation were equally able to detect low and very high levels of suicidal ideation. Conclusions The choice of the specific measure of suicidal ideation in a clinical trial may be dictated by time and financial resources versus the need for granularity in the interpretation of the scores.

Study Objectives Fast frequency sleep spindles are reduced in aging and Alzheimer’s disease (AD), but the mechanisms and functional relevance of these deficits remain unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD. Methods Fifty-eight cognitively unimpaired, β-amyloid-negative, older adults (mean ± SD; 61.4 ± 6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high-density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13 to Results Glial activation was associated with prefrontal fast frequency sleep spindle expression deficits. While adjusting for sex, APOE ε4 genotype, apnea–hypopnea index, and time between CSF sampling and sleep study, serial mediation models detected indirect effects of age on fast sleep spindle expression through microglial activation markers and then tau phosphorylation and synaptic degeneration markers. Sleep spindle expression at these electrodes was also associated with overnight memory retention in multiple regression models adjusting for covariates. Conclusions These findings point toward microglia dysfunction as associated with tau phosphorylation, synaptic loss, sleep spindle deficits, and memory impairment even prior to β-amyloid positivity, thus offering a promising candidate therapeutic target to arrest cognitive decline associated with aging and AD.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by disrupting motor enactments during REM sleep, but also cognitive impairments across several domains. In addition to REM sleep abnormalities, we hypothesized that RBD patients may also display EEG abnormalities during NREM sleep. We collected all-night recordings with 256-channel high-density EEG in nine RBD patients, predominantly early-onset medicated individuals, nine sex- and age- matched healthy controls, and nine additional controls with matched medications and comorbidities. Power spectra in delta to gamma frequency bands were compared during both REM and NREM sleep, between phasic and tonic REM sleep, and between the first versus last cycle of NREM sleep. Controls, but not RBD patients, displayed a decrease in beta power during phasic compared to tonic REM sleep. Compared to controls, RBD patients displayed a reduced decline in SWA from early to late NREM sleep. Overnight changes in the distribution of the amplitude of slow waves were also reduced in RBD patients. Without suppression of beta rhythms during phasic REM sleep, RBD patients might demonstrate heightened cortical arousal, favoring the emergence of behavioral episodes. A blunted difference between REM sleep sub-stages may constitute a sensitive biomarker for RBD. Moreover, reduced overnight decline in SWA suggests a reduced capacity for synaptic plasticity in RBD patients, which may favor progression towards neurodegenerative diseases.

Study Objectives To determine whether subjective measures of exercise and sleep are associated with cognitive complaints and whether exercise effects are mediated by sleep. Methods This study analyzed questionnaire data from adults (18–89) enrolled in a recruitment registry. The Cognitive Function Instrument (CFI) assessed cognitive complaints. Medical Outcomes Study Sleep Scale (MOS-SS) subscales and factor scores assessed sleep quality, daytime sleepiness, nighttime disturbance, and insomnia and obstructive sleep apnea (OSA)-like symptoms. Exercise frequency was defined as the weekly number of exercise sessions. Exercise frequency, MOS-SS subscales, and factor scores were examined as predictors of CFI score, adjusting for age, body mass index, education, sex, cancer diagnosis, antidepressant usage, psychiatric conditions, and medical comorbidities. Analyses of covariance examined the relationship between sleep duration groups (short, mid-range, and long) and CFI score, adjusting for covariates. Mediation by sleep in the exercise-CFI score relationship was tested. Results Data from 2106 adults were analyzed. Exercise and MOS-SS subscales and factor scores were associated with CFI score. Higher Sleep Adequacy scores were associated with fewer cognitive complaints, whereas higher Sleep Somnolence, Sleep Disturbance, Sleep Problems Index I, Sleep Problems Index II, and factor scores were associated with more cognitive complaints. MOS-SS subscales and factor scores, except Sleep Disturbance and the insomnia factor score, mediated the association between exercise and cognitive complaints. Conclusions The relationship between exercise frequency and subjective cognitive performance is mediated by sleep. In particular, the mediation effect appears to be driven by symptoms possibly suggestive of OSA which are negatively associated with exercise engagement, sleep quality, daytime sleepiness, and subjective cognitive performance.

Objectives Information is lacking regarding how commonly unblinding of treatment assignment occurs in hypnotic randomized clinic trials (RCTs). We now report the "best guesses" of clinical trial participants, versus study coordinators, versus study physicians in the study Reducing Suicidal Ideation Through Insomnia Treatment (REST-IT). Methods REST-IT, a, 8-week double-blind RCT, compared zolpidem extended-release (ER) versus placebo at bedtime in 103 adults with major depressive disorder with insomnia and suicidal ideation, and who received open label selective serotonin reuptake inhibitors. At the conclusion of study participation, 89 of the participants in this study, the study coordinators, and the study physicians each independently recorded their "best guess" of the treatment assigned. Results Patients guessed correctly 58.4% of the time, coordinators 53.9% of the time, and physicians 49.4% of the time, and none were different from chance alone. Agreement between patient/coordinator, patient/doctor, and coordinator/doctor dyads were 75%-78% with no significant differences in agreement between the dyads. Conclusions "Best guesses" of all parties were not different from chance, suggesting that the blind was maintained and that assessment bias was minimized in this RCT of zolpidem ER versus placebo. Our results may not apply to other hypnotics or other RCT designs.

Introduction Insomnia diagnosis has been associated with a significant clinical and economic burden on patients and healthcare systems. This study examined changes in healthcare resource use (HCRU) and costs in insomnia patients before and after initiation of suvorexant treatment. Methods This retrospective cohort study analyzed Optum Clinformatics Data Mart claims data (Jan 2010–Dec 2018). Patients with ≥ 2 insomnia diagnosis claims and ≥ 1 prescription for suvorexant were included. Prevalent and incident insomnia patients were analyzed separately. The change in the trends of HCRU and costs were examined for 12 months before and 12 months after suvorexant initiation. An interrupted time series (ITS) analysis was conducted to assess the level and slope changes. Subgroups of patients with mental health comorbidities were examined. Results The study included 18,919 and 5939 patients in the prevalent and incident insomnia cohorts, respectively. For the prevalent cohort, mean (SD) age was 64.5 (14.1) years, 65% were female, 74% had Medicare Advantage coverage, and 61% had a Charlson comorbidity index score ≥ 1. Characteristics for the incident cohort were similar. The ITS results suggested that the trend for monthly total healthcare cost (THC) was increasing before suvorexant initiation (US$52.51 in the prevalent cohort, $74.93 in incident insomnia cohort), but, after suvorexant initiation, the monthly total cost showed a decreasing trend in both cohorts. The decrease in slope for THC after suvorexant initiation were $72.66 and $112.07 per month in the prevalent and incident cohorts, respectively. The monthly trends in HCRU rates also decreased. The subgroup analysis showed that decreases were 1.5–3 times greater for patients with mental health comorbidities. Conclusions In this real-world study, suvorexant initiation was associated with immediate and continued decreases in HCRU and costs in insomnia patients. Further research is needed to understand the effect of suvorexant initiation on direct medical costs as well as costs associated with lost productivity in other real-world settings. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01891-8.

Major Depressive Disorder, characterized by cognitive affective biases, is a considerable public health challenge. Past work has shown that higher depressive symptoms are associated with augmented memory of negative stimuli. In contrast, anxiety symptoms have been associated with overgeneralization of emotional memories. Given the high comorbidity of depression and anxiety, it is critical to understand how cognitive affective biases are differentially associated with clinical symptoms.We used continuous measures of depression (Beck Depression Inventory [BDI-II]) and anxiety (Beck Anxiety Inventory [BAI]) to evaluate an adult sample (N = 79; 18-41 years old, 58 female). Emotional memory discrimination and recognition memory were tested using an emotional discrimination task. We applied exploratory factor analysis to questions from the BAI and BDI-II to uncover latent constructs consisting of negative affect, anhedonia, somatic anxiety, and cognitive anxiety.We report evidence that anxious symptoms were associated with impaired recognition of negative items after accounting for age and sex. Our exploratory factor analysis revealed that impaired negative item recognition is largely associated with somatic and cognitive anxiety factors.Interpretations in a mixed pathology sample, especially given collinearity among factors, may be difficult.We provide evidence that somatic and cognitive anxiety are related to impaired recognition memory for negative stimuli. Future clinical investigations should uncover the neurobiological basis supporting the link between recognition of negative stimuli and somatic/cognitive symptoms of anxiety.

The authors sought to determine whether targeted treatment of insomnia with controlled-release zolpidem (zolpidem-CR) in suicidal adults with insomnia would provide a reduction in suicidal ideation superior to placebo.Reducing Suicidal Ideation Through Insomnia Treatment was an 8-week three-site double-blind placebo-controlled parallel-group randomized controlled trial of zolpidem-CR hypnotic therapy compared with placebo, in conjunction with an open-label selective serotonin reuptake inhibitor. Participants were medication-free 18- to 65-year-olds with major depressive disorder, insomnia, and suicidal ideation. Suicidal ideation was the main outcome, measured first by the Scale for Suicide Ideation and second by the Columbia-Suicide Severity Rating Scale (C-SSRS).A total of 103 participants were randomly assigned to receive zolpidem-CR (N=51) or placebo (N=52) (64 women and 39 men; mean age=40.5 years). Zolpidem-CR had a robust anti-insomnia effect, especially in patients with the most severe insomnia symptoms. No significant treatment effect was observed on the Scale for Suicide Ideation (least squares mean estimate=-0.56, SE=0.83, 95% CI=-2.19, 1.08), but the reduction in scores was significantly positively related to improvement in insomnia after accounting for the effect of other depression symptoms. The C-SSRS indicated that zolpidem-CR had a significant treatment effect (least squares mean estimate=-0.26, SE=0.12, 95% CI=-0.50, -0.02). The advantage for zolpidem-CR in reducing suicidal ideation on the C-SSRS was greater in patients with more severe insomnia. No deaths or suicide attempts occurred.Although the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpatients, especially in patients with severe insomnia.

Emotion processing abnormalities and sleep pathology are central to the phenomenology of paediatric posttraumatic stress disorder, and sleep disturbance has been linked to the development, maintenance and severity of the disorder. Given emerging evidence indicating a role for sleep in emotional brain function, it has been proposed that dysfunctional processing of emotional experiences during sleep may play a significant role in affective disorders, including posttraumatic stress disorder. Here we sought to examine the relationship between sleep and emotion processing in typically developing youth, and youth with a diagnosis of posttraumatic stress disorder . We use high-density electroencephalogram to compare baseline sleep with sleep following performance on a task designed to assess both memory for and reactivity to negative and neutral imagery in 10 youths with posttraumatic stress disorder, and 10 age- and sex-matched non-traumatized typically developing youths. Subjective ratings of arousal to negative imagery (ΔArousal=post-sleep minus pre-sleep arousal ratings) remain unchanged in youth with posttraumatic stress disorder following sleep (mean increase 0.15, CI -0.28 to +0.58), but decreased in TD youth (mean decrease -1.0, 95% CI -1.44 to -0.58). ΔArousal, or affective habituation, was negatively correlated with global change in slow-wave activity power (ρ=-0.58, p=.008). When considered topographically, the correlation between Δslow-wave activity power and affective habituation was most significant in a frontal cluster of 27 electrodes (Spearman, ρ=-0.51, p=.021). Our results highlight the importance of slow-wave sleep for adaptive emotional processing in youth, and have implications for symptom persistence in paediatric posttraumatic stress disorder. Impairments in slow-wave activity may represent a modifiable risk factor in paediatric posttraumatic stress disorder.

Although mandibular advancement device (MAD) treatment of adults with obstructive sleep apnea (OSA) is generally less efficacious than positive airway pressure (PAP), the two treatments are associated, with similar clinical outcomes. As a sub-analysis of a randomized trial comparing the effect of MAD versus PAP on blood pressure, this study compared objectively measured adherence to MAD versus PAP treatment in adults with OSA. Adults with OSA (age 54.1 ± 11.2 [standard deviation] years, 71.1% male, apnea-hypopnea index 31.6 ± 22.7 events/h) were randomized to MAD (n = 89) or PAP (n = 91) treatment for 3-6 months. Objective adherence was assessed with a thermal sensor embedded in the MAD and a pressure sensor in the PAP unit. In a per protocol analysis, no difference was observed in average daily hours of use over all days in participants on MAD (n = 35, 4.4 ± 2.9 h) versus PAP (n = 51, 4.7 ± 1.6 h, p = .597) treatment when days with missing adherence data were included as no use. MAD was used on a lower percentage of days (62.5 ± 36.4% versus 79.9 ± 19.8%, p = .047), but with greater average daily hours of use on days used (6.4 ± 1.9 h versus 5.7 ± 1.2 h, p = .013). Average daily hours of use in the first week were associated with long-term adherence to MAD (p < .0001) and PAP (p = .0009) treatment. Similar results were obtained when excluding days with missing adherence data. In conclusion, no significant difference was observed in objectively measured average daily hours of MAD and PAP adherence in adults with OSA, despite differences in the patterns of use. MAD adherence in the first week predicted long-term use.

Sleep apnea is a condition with significant health risks and increased risk of mortality and is prevalent in patients with chronic kidney disease. This paper describes the detrimental cardiovascular sequelae of sleep-disordered breathing and explores the bidirectional relationship between chronic kidney disease and obstructive sleep apnea. Obstructive sleep apnea-related hypoxia produces a range of harmful systemic effects including oxidative stress, inflammation, and sympathetic activation that collectively worsen the progression of renal disease. In turn, chronic kidney disease can result in increased severity of sleep apnea through inducing (1) uremic neuropathy and myopathy, (2) altered chemosensitivity, and (3) hypervolemia. Continuous positive airway pressure therapy remains the mainstay of treatment for reversing the health risks of apnea. Other strategies aimed at decreasing the high prevalence and associated morbidity of sleep apnea include weight loss, oral appliances, and corrective surgery in the case of airway obstruction.

Aims Nearly a third of U.S. veterans who deployed in support of the 1990–1991 Persian Gulf War are affected by Gulf War illness (GWI). Here we aimed to characterize whether subjective sleep complaints in GWI veterans are associated with objective sleep EEG disturbances relative to healthy veterans and controls; and whether Gulf War veterans show alterations in neural activity during sleep that differentiate them from healthy subjects. Main methods We used high-density EEG (HDEEG) to assess regional patterns of rapid eye movement (REM) sleep and non-REM (NREM) sleep between three groups: Gulf War male veterans with fatigue and GWI, Gulf War male veterans without fatigue or GWI, and control males. The groups were matched relative to age, sex and obstructive sleep apnea. Topographic comparisons of nocturnal NREM and REM sleep were made between groups for all frequency bands. Key findings Topographic analysis revealed a broadband reduction in EEG power in a circumscribed region overlying the frontal lobe in both groups of Gulf War veterans, regardless of GWI and fatigue. This frontal reduction in neural activity was present, to some extent, across all frequency bands in NREM and REM sleep. Significance Given that our findings were observed in all Gulf War veterans, it appears unlikely that frontal sleep HDEEG power reductions prove wholly responsible for fatigue symptoms. These results provide avenues for research which may someday contribute to improved clinical care of formerly deployed veterans of the Persian Gulf War.

Objective:To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife.Methods:We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal. Sleep quality was measured with the Medical Outcomes Study Sleep Scale. CSF was assayed for biomarkers of amyloid metabolism and plaques (β-amyloid 42 [Aβ42]), tau pathology (phosphorylated tau [p-tau] 181), neuronal/axonal degeneration (total tau [t-tau], neurofilament light [NFL]), neuroinflammation/astroglial activation (monocyte chemoattractant protein–1 [MCP-1], chitinase-3-like protein 1 [YKL-40]), and synaptic dysfunction/degeneration (neurogranin). To adjust for individual differences in total amyloid production, Aβ42 was expressed relative to Aβ40. To assess cumulative pathology, CSF biomarkers were expressed in ratio to Aβ42. Relationships among sleep scores and CSF biomarkers were assessed with multiple regression, controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch.Results:Worse subjective sleep quality, more sleep problems, and daytime somnolence were associated with greater AD pathology, indicated by lower CSF Aβ42/Aβ40 and higher t-tau/Aβ42, p-tau/Aβ42, MCP-1/Aβ42, and YKL-40/Aβ42. There were no significant associations between sleep and NFL or neurogranin.Conclusions:Self-report of poor sleep was associated with greater AD-related pathology in cognitively healthy adults at risk for AD. Effective strategies exist for improving sleep; therefore sleep health may be a tractable target for early intervention to attenuate AD pathogenesis.

Objective Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10–20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. Methods Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured. Results Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo). Conclusion Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813).

Sex-related differences in the clinical profiles of some insomnia medications have been previously reported. To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups. Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18–64 years) insomnia patients. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg. The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo). Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

ObjectiveInsomnia is associated with increased risk for suicide. The Food and Drug Administration (FDA) has mandated that warnings regarding suicide be included in the prescribing information for hypnotic medications. The authors conducted a review of the evidence for and against the claim that hypnotics increase the risk of suicide.MethodThis review focused on modern, FDA-approved hypnotics, beginning with the introduction of benzodiazepines, limiting its findings to adults. PubMed and Web of Science were searched, crossing the terms "suicide" and "suicidal" with each of the modern FDA-approved hypnotics. The FDA web site was searched for postmarketing safety reviews, and the FDA was contacted with requests to provide detailed case reports for hypnotic-related suicide deaths reported through its Adverse Event Reporting System.ResultsEpidemiological studies show that hypnotics are associated with an increased risk for suicide. However, none of these studies adequately controlled for depression or other psychiatric disorders that may be linked with insomnia. Suicide deaths have been reported from single-agent hypnotic overdoses. A separate concern is that benzodiazepine receptor agonist hypnotics can cause parasomnias, which in rare cases may lead to suicidal ideation or suicidal behavior in persons who were not known to be suicidal. On the other hand, ongoing research is testing whether treatment of insomnia may reduce suicidality in adults with depression.ConclusionsThe review findings indicate that hypnotic medications are associated with suicidal ideation. Future studies should be designed to assess whether increases in suicidality result from CNS impairments from a given hypnotic medication or whether such medication decreases suicidality because of improvements in insomnia.

Sleep problems occur commonly in normal and pathologic aging. Older adults typically have more difficulty falling asleep and remaining asleep, report more daytime napping, and have an increased prevalence of primary sleep disorders such as insomnia, parasomnias, sleep apnea, and sleep-related movement disorders. Medical and psychiatric disorders as well as medications used to treat them also contribute to sleep disturbances in aging. Patients with mild cognitive impairment and dementia have more severe sleep problems, and disturbed sleep and sleep disorders contribute to earlier onset and more rapid progression of neurodegenerative disorders. Approaches to diagnosing and treating sleep disorders in the elderly are discussed.

In this paper, we report the rate of previously undiagnosed obstructive sleep apnea (OSA) in a randomized clinical trial (RCT) of suicidal patients with major depressive disorder (MDD). One hundred and twenty-five suicidal adults with MDD were recruited into a RCT. None were suspected to have OSA. Fourteen percent met diagnostic criteria for OSA. The Apnea Hypopnea Index (AHI) was predicted by increasing age, male sex, and higher Body Mass Index. However, neither the degree of daytime sleepiness nor the degree of insomnia predicted AHI severity. A high degree of suspicion is warranted for OSA in suicidal patients with MDD, and for patients with treatment-resistant depression. ClinicalTrials.gov identifier: NCT01689909.

The objective of the study was to determine if sleep disorder, depression or anxiety screening status was associated with safety outcomes in a diverse population of hospital workers. A sample of shift workers at four hospitals participated in a prospective cohort study. Participants were screened for five sleep disorders, depression and anxiety at baseline, then completed prospective monthly surveys for the next 6months to capture motor vehicle crashes, near-miss crashes, occupational exposures and medical errors. We tested the associations between sleep disorders, depression and anxiety and adverse safety outcomes using incidence rate ratios adjusted for potentially confounding factors in a multivariable negative binomial regression model. Of the 416 hospital workers who participated, two in five (40.9%) screened positive for a sleep disorder and 21.6% screened positive for depression or anxiety. After multivariable adjustment, screening positive for a sleep disorder was associated with 83% increased incidence of adverse safety outcomes. Screening positive for depression or anxiety increased the risk by 63%. Sleep disorders and mood disorders were independently associated with adverse outcomes and contributed additively to risk. Our findings suggest that screening for sleep disorders and mental health screening can help identify individuals who are vulnerable to adverse safety outcomes. Future research should evaluate sleep and mental health screening, evaluation and treatment programmes that may improve safety.

Study objectives To examine scalp and source power topography in sleep arousals disorders (SADs) using high-density EEG (hdEEG). Methods Fifteen adult subjects with sleep arousal disorders (SADs) and 15 age- and gender-matched good sleeping healthy controls were recorded in a sleep laboratory setting using a 256 channel EEG system. Results Scalp EEG analysis of all night NREM sleep revealed a localized decrease in slow wave activity (SWA) power (1-4 Hz) over centro-parietal regions relative to the rest of the brain in SADs compared to good sleeping healthy controls. Source modelling analysis of 5-minute segments taken from N3 during the first half of the night revealed that the local decrease in SWA power was prominent at the level of the cingulate, motor, and sensori-motor associative cortices. Similar patterns were also evident during REM sleep and wake. These differences in local sleep were present in the absence of any detectable clinical or electrophysiological sign of arousal. Conclusions Overall, results suggest the presence of local sleep differences in the brain of SADs patients during nights without clinical episodes. The persistence of similar topographical changes in local EEG power during REM sleep and wakefulness points to trait-like functional changes that cross the boundaries of NREM sleep. The regions identified by source imaging are consistent with the current neurophysiological understanding of SADs as a disorder caused by local arousals in motor and cingulate cortices. Persistent localized changes in neuronal excitability may predispose affected subjects to clinical episodes.

Study objectivesSuvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.MethodsPrespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints.ResultsSuvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.ConclusionsSuvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.Clinical trial registrationClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.

Context: Complications following lung transplantation are common and significantly reduce quality of life, and increase morbidity and mortality. Increasing evidence suggests sleep disorders are prevalent following lung transplantation, but factors associated with their development are not known. Objectives: We sought to evaluate the prevalence of restless legs syndrome (RLS) in a lung transplant population and determine if a relationship exists between RLS and exposure to immunosuppressant medications. Design, Setting, and Participants: Subjects were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (N = 81) completed sleep questionnaires, including the four RLS diagnostic criteria, insomnia severity index, and Sheehan disability scale. Cumulative tacrolimus exposure was determined in 62 subjects by calculating an area under the curve (AUC) to assess for a relationship with restless legs syndrome. Results: Prevalence of RLS was 35 percent. Cumulative mean ± SEM tacrolimus exposure was similar in patients with RLS versus those without RLS (17446±1855 ng days/mL vs. 15303 ± 1643 ng days/mL, respectively; p = 0.42). Insomnia severity index scores (12.5 ± 1.0 vs 6.8 ± 0.7, p < 0.0001) and Sheehan disability scores (7.8 ± 1.3 vs 3.6 ± 0.6, p = 0.003) were significantly higher in those with vs those without RLS symptoms, respectively. Conclusions: Our data confirms increased prevalence of RLS following lung transplantation reported by previous studies. RLS symptoms were not related to estimated tacrolimus exposure. Predictors of RLS following lung transplantation need to be further investigated to better identify and control RLS symptoms and reduce associated insomnia and disability.

Study objectives To examine nonrapid eye movement (NREM) sleep in insomnia using high-density electroencephalography (EEG). Methods All-night sleep recordings with 256 channel high-density EEG were analyzed for 8 insomnia subjects (5 females) and 8 sex and age-matched controls without sleep complaints. Spectral analyses were conducted using unpaired t-tests and topographical differences between groups were assessed using statistical non-parametric mapping. Five minute segments of deep NREM sleep were further analyzed using sLORETA cortical source imaging. Results The initial topographic analysis of all-night NREM sleep EEG revealed that insomnia subjects had more high-frequency EEG activity (> 16 Hz) compared to good sleeping controls and that the difference between groups was widespread across the scalp. In addition, the analysis also showed that there was a more circumscribed difference in theta (4-8 Hz) and alpha (8-12 Hz) power bands between groups. When deep NREM sleep (N3) was examined separately, the high-frequency difference between groups diminished, whereas the higher regional alpha activity in insomnia subjects persisted. Source imaging analysis demonstrated that sensory and sensorimotor cortical areas consistently exhibited elevated levels of alpha activity during deep NREM sleep in insomnia subjects relative to good sleeping controls. Conclusions These results suggest that even during the deepest stage of sleep, sensory and sensorimotor areas in insomnia subjects may still be relatively active compared to control subjects and to the rest of the sleeping brain.

Slow waves are characteristic waveforms that occur during non-rapid eye movement (NREM) sleep that play an integral role in sleep quality and brain plasticity. Benzodiazepines are commonly used medications that alter slow waves, however, their effects may depend on the time of night and measure used to characterize slow waves. Prior investigations have utilized minimal scalp derivations to evaluate the effects of benzodiazepines on slow waves, and thus the topography of changes to slow waves induced by benzodiazepines has yet to be fully elucidated. This study used high-density electroencephalography (hdEEG) to evaluate the effects of oral temazepam on slow wave activity, incidence, and morphology during NREM sleep in 18 healthy adults relative to placebo. Temazepam was associated with significant decreases in slow wave activity and incidence, which were most prominent in the latter portions of the sleep period. However, temazepam was also associated with a decrease in the magnitude of high-amplitude slow waves and their slopes in the first NREM sleep episode, which was most prominent in frontal derivations. These findings suggest that benzodiazepines produce changes in slow waves throughout the night that vary depending on cortical topography and measures used to characterize slow waves. Further research that explores the relationships between benzodiazepine-induced changes to slow waves and the functional effects of these waveforms is indicated.

The article provides an overview of common and differentiating self-reported and objective sleep disturbances seen in mood-disordered populations. The importance of considering sleep disturbances in the context of mood disorders is emphasized, because a large body of evidence supports the notion that sleep disturbances are a risk factor for onset, exacerbation, and relapse of mood disorders. In addition, potential mechanisms for sleep disturbance in depression, other primary sleep disorders that often occur with mood disorders, effects of antidepressant and mood-stabilizing drugs on sleep, and the adjunctive effect of treating sleep in patients with mood disorders are discussed.

Evidence suggests that abnormalities in circadian rhythms might prove causally or pathophysiologically significant in psychiatric illness. The circadian regulation of hormonal and behavioral timekeeping processes is often altered in patients with major depression, bipolar disorder, and schizophrenia, and a susceptibility to rhythm instability may contribute to the functional impairment. For some patients, interventions that stabilize or resynchronize circadian rhythms prove therapeutically effective. Circadian disruption in the clinical profiles of most psychiatric illnesses and the treatment efficacy of chronobiological interventions suggest that attention to circadian phenotypes in a range of psychiatric disorders may help to uncover shared pathophysiologic mechanisms.

Older adults with mild cognitive impairment (MCI) are at-risk of developing dementia, particularly Alzheimer's disease. While some research suggests that alterations in sleep architecture may mediate cognitive decline, the nature and magnitude of changes to sleep macro- (sleep stages) and micro-architecture (electroencephalography (EEG) oscillations) in MCI is not yet clear. This study aimed to systematically review and meta-analyse case-control studies objectively measuring sleep in MCI. A systematic search was conducted using PubMed, Scopus, Web of Science, Embase and Psycinfo databases and after review, a total of 10 studies met inclusion criteria. Of these, all reported sleep macro-architecture and four reported micro-architecture outcomes. A combined total of 430 participants (209 with and 221 without MCI) underwent objective sleep assessments in the included full text articles. Findings show that compared to healthy controls, those with MCI have pronounced changes in sleep macro-architecture with greater wake after sleep onset, reduced total sleep time, lower sleep efficiency, longer sleep onset latency, longer rapid eye movement sleep (REM) latency, reduced REM sleep, greater N1 sleep, and worse severity of hypoxemia. Pooling of sleep micro-architecture EEG measures was not possible due to limited studies, however reduced spindles in non-REM sleep and greater EEG slowing in REM sleep were reported.

Depression and sleep problems are highly prevalent disorders that are often comorbid with other medical disorders. We evaluated the prevalence and associations of these conditions in patients presenting to a Men’s Health clinic. In this retrospective study, 124 patients presenting to a Men’s Health clinic completed three urological questionnaires (International Index of Erectile Function [IIEF-5], International Prostate Symptom Score [IPSS], and Androgen Deficiency in Aging Males [ADAM]); and four non-urological questionnaires (Patient Health Questionnaire for depression [PHQ-9], STOP-BANG Sleep Apnea [OSA STOP-BANG], Insomnia Severity Index [ISI], and Epworth Sleepiness Scale [ESS]). Questionnaire results were evaluated in conjunction with patient clinical history and associated laboratory values via univariate and multivariate analysis. The mean age of the study participants was 54.1 years (SD 16). Comorbidities included hypertension (22.5%), vascular disease (15%), and diabetes mellitus (13.3%). Body Mass Index (BMI) was >25 in 77.3%. IIEF-5 scores were moderate-severe in 47.9%, ADAM questionnaire was positive in 79%, and IPSS scores were moderate-severe in 42.9% of patients. PHQ-9 demonstrated mild-severe depression in 38.6%, STOP-BANG showed intermediate-high risk for sleep apnea in 55.2%, ISI indicated moderate-severe insomnia in 18.1%, and ESS revealed mild-severe sleepiness in 16.6% of participants. On univariate analysis, BMI was associated with scores on the PHQ-9 (p = 0.035), STOP-BANG (p

Listen to this podcast as experts discuss 2 patient cases focusing on diagnosing and treating co-occurring insomnia and mental illness. The first case features a 32-year-old man with bipolar disorder who is experiencing psychiatric symptoms and poor sleep, and the second case involves a 27-year-old man with schizophrenia who is having auditory hallucinations as well as chronic issues with insomnia.

​​ Insomnia is a common feature of many psychiatric disorders but can also be a comorbid disorder, often contributing to poor outcomes and treatment failure. For some patients who do respond to psychiatric treatment, their insomnia persists after their mood symptoms have remitted, indicating that their insomnia needs to be a separate focus of treatment. In this CME Academic Highlights, Drs Ruth Benca and Daniel Buysse discuss how to effectively evaluate patients with psychiatric disorders for comorbid insomnia, as well as how to safely and effectively implement both behavioral and pharmacologic treatments. ​​​​​​​.

Midlife may be an ideal window for intervention in Alzheimer's disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using positron emission tomography with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale and the Medical Outcomes Study Sleep Scale in 98 cognitively healthy adults (aged 62.4 ± 5.7 years) from the Wisconsin Registry for Alzheimer's Prevention. We used multiple regressions to test the extent to which sleep scores predicted regional amyloid burden. Participants reporting less adequate sleep, more sleep problems, and greater somnolence on the Medical Outcomes Study had greater amyloid burden in AD-sensitive brain regions (angular gyrus, frontal medial orbital cortex, cingulate gyrus, and precuneus). Amyloid was not associated with reported sleep amount, symptoms of sleep-disordered breathing, trouble falling asleep, or Epworth Sleepiness Scale. Poor sleep may be a risk factor for AD and a potential early marker of AD or target for preventative interventions in midlife.

Background/aims: Suicide is a major public health concern, yet there are very few randomized clinical trials that have been conducted to reduce suicidal ideation in patients at risk of suicide. We describe the rationale and refinements of such a trial that is designed to assess the effect of a hypnotic medication on suicidal ideation in adult outpatients currently experiencing suicidal ideation. Methods: “Reducing Suicidal Ideation Through Insomnia Treatment” is a multi-site randomized clinical trial that includes three recruiting sites and one data management site. This 4-year study is in its second year of recruitment. The purpose of the study is to compare hypnotic medication versus placebo as an add-on treatment to a selective serotonin reuptake inhibitor as a means of reducing suicidal ideation in depressed adult outpatients with insomnia and suicidal ideation. The safety features of the study follow the 2001 National Institutes of Health guidelines for studies that include patients at risk of suicide. Results: In total, 584 potential participants have undergone telephone screening; 67% of these failed the phone screen, most often due to an absence of expressed suicidal ideation (26% of the telephone screen fails). A total of 115 people appeared for a face-to-face baseline assessment, and 40 of these had completed a taper off of their ineffective psychotropic medications before the baseline assessments. In all, 64% of those who completed baseline assessments failed to proceed to randomization, most commonly because of no clinically significant suicidal ideation (51% of those excluded at baseline). One participant was offered and accepted voluntary psychiatric hospitalization in lieu of study participation. Thus far, 40 participants have been randomized into the study and 88.7% of scheduled visits have been attended, with 93.8% adherence to the selective serotonin reuptake inhibitor and 91.6% adherence to the randomized hypnotic versus placebo. None of the randomized participants have required hospitalization or had a suicide attempt. Conclusion: By carefully considering the inclusion and exclusion criteria and other safety features, the safe conduct of randomized clinical trials in suicidal adult patients is possible, including the inclusion of participants who have undergone a prescribed tapering off of psychotropic medications prior to baseline assessment.

Study objectives Measures of health-related quality of life (HRQL) specific for sleep disorders have had limited psychometric evaluation in the context of randomized controlled trials (RCTs). We investigated the psychometric properties of the Functional Outcomes of Sleep Questionnaire (FOSQ) and Sleep Apnea Quality of Life Instrument (SAQLI). We evaluated the FOSQ and SAQLI construct and criterion validity, determined a minimally important difference, and assessed for associations of responsiveness to baseline subject characteristics and continuous positive airway pressure (CPAP) adherence in a RCT population. Design Secondary analysis of data collected in a multisite RCT of home versus laboratory-based diagnosis and treatment of obstructive sleep apnea (HomePAP trial). Participants Individuals enrolled in the HomePAP trial (n = 335). Interventions N/A. Measurement and results The FOSQ and SAQLI subscores demonstrated high reliability and criterion validity, correlating with Medical Outcomes Study 36-Item Short Form Survey domains. Correlations were weaker with the Epworth Sleepiness Scale (ESS). Both the FOSQ and SAQLI scores improved after 3 mo with CPAP therapy. Averaging 4 h or more of CPAP use was associated with an increase in the FOSQ beyond the minimally important difference. Baseline depressive symptoms and sleepiness predicted FOSQ and SAQLI responsiveness; demographic, objective obstructive sleep apnea (OSA) severity and sleep habits were not predictive in linear regression. Conclusions The FOSQ and SAQLI are responsive to CPAP intervention, with the FOSQ being more sensitive to differences in CPAP adherence than the SAQLI. These instruments provide unique information about health outcomes beyond that provided by changes in physiological measures of OSA severity (apnea-hypopnea index). Clinical trial information Portable Monitoring for Diagnosis and Management of Sleep Apnea (HomePAP) URL: http://clinicaltrials.gov/show/NCT00642486. NIH clinical trials registry number: NCT00642486.

Background: Lung transplant recipients are at high risk of developing sleep disorders such as insomnia, but the prevalence and features are currently poorly characterized within this population. Since these disorders are associated with increased morbidity and mortality, it is important to identify them to optimize the care of lung transplant recipients. We sought to evaluate the prevalence of insomnia within our university-based lung transplant clinic and determine whether a relationship exists between insomnia and exposure to immunosuppressant medications following transplantation. Methods: Participants were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (n = 92) completed the adult sleep history questionnaire, which included the Insomnia Severity Index (ISI) to assess for insomnia (defined as ISI score >10). Cumulative tacrolimus exposure was determined in 73 patients by performing an area under the curve calculation to assess for a potential relationship between tacrolimus exposure and insomnia. Results: The prevalence of insomnia was 40% within this population. Although no difference in time since transplant was found, cumulative mean ± standard error of the mean tacrolimus exposure was significantly higher in patients with insomnia versus those without insomnia (17 190 ± 1673 ng·d/mL vs 12 130 ± 1630 ng·d/mL, respectively; P = .04). Estimated tacrolimus exposure was not greater with increasing frequency of insomnia complaints (analysis of variance P = .54). Conclusion: In our population, insomnia is common after lung transplantation, with prevalence greater than the general population. Higher cumulative exposure to tacrolimus may contribute to insomnia in this group. Future research should investigate the relationship between immunosuppressant therapy and development of sleep disorders.

ObjectiveDepression is often associated with disruptions in sleep and circadian rhythms. We aimed to confirm these relationships via actigraphic assessment in a large, population-based sample and test whether sex moderates these relationships.MethodsA total of 418 participants (age = 35-85 years, mean [standard deviation] = 57.04 [11.47]) completed questionnaires and 1 week of actigraphy, used to calculate sleep and rest-activity statistics including mesor (mean activity level), amplitude (height of rhythm), and acrophase (time of day that rhythm peaks).ResultsDepressive symptoms, assessed via Center for Epidemiologic Studies Depression Scale, were associated with disrupted sleep and rest-activity rhythms. Furthermore, men demonstrated longer sleep onset latency (SOL, B = -13.28, p < .001), longer wake time after sleep onset (B = -6.26, p < .01), lower sleep efficiency (B = 5.91, p < .001), and lower total sleep time (TST, B = 33.16, p < .001) than women. Sex moderated the relationship between depression and SOL, TST, mesor, and amplitude; sex-stratified models revealed that higher depression scores were associated with greater SOL (B = 1.05, p < .001) and less TST (B = -0.87, p < .10) for women with higher depressive symptoms, but lower mesor (B = -1.75, p < .01) and amplitude (B = -1.94, p < .01) for men with higher depressive symptoms.ConclusionsDepressive symptoms were related to disrupted sleep continuity and rest-activity rhythms in this population-based sample; however, these relationships differed by sex. Women with greater depressive symptoms exhibited difficulty with sleep continuity, whereas men with greater depressive symptoms demonstrated disruption throughout the 24-hour rhythm.

Summary Background Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment. Methods We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813. Findings 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p vs −8·4 min, difference −9·5, −14·6 to −4·5; p=0·0002). Interpretation Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance. Funding Merck & Co Inc.

STUDY OBJECTIVES: To examine the patterns of insomnia and sleep-related movement from ages 4.5 to 9 years, their concurrent associations with mental health symptoms in childhood, and the longitudinal associations of sleep-problem persistence with mental health symptoms at ages 9 and 18 years. DESIGN: A 14-year prospective follow-up study. Assessments included maternal report on the Children's Sleep Habits Questionnaire at ages 4.5 and 9, and child mental health symptoms via maternal report at age 4.5, multi-informant (child, teacher, mother) report at age 9, and adolescent report at age 18. SETTING: Community. PARTICIPANTS: A total of 396 children (51% female). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep problems were more common at age 4.5 than 9; symptoms of insomnia and abnormal sleep movement both had persistence rates of 9-10%. At age 4.5, insomnia was associated with hostile-aggressive and hyperactive-distractible behavior, but there were no significant associations for sleep movement. At age 9, both insomnia and sleep movement were associated with symptoms of depression, externalizing, and attention deficit hyperactivity disorder (ADHD). Insomnia persistence was associated with symptoms of depression, externalizing, and ADHD at age 9 and anxiety and externalizing at age 18; sleep- movement persistence was associated with externalizing and ADHD at age 9, and ADHD at age 18. The age 18 persistence effects for insomnia and anxiety and for sleep movement and ADHD were significant when controlling for earlier mental health. CONCLUSIONS: Childhood insomnia and sleep movement are common and associated with mental health symptoms. Their persistence from middle to late childhood predicts associations with specific types of mental health symptoms at age 18. CITATION: Armstrong JM, Ruttle PL, Klein MH, Essex MJ, Benca RM. Associations of child insomnia, sleep movement, and their persistence with mental health symptoms in childhood and adolescence. SLEEP 2014;37(5):901-909. Language: en

Prior investigations have suggested sleep homeostasis is altered in major depressive disorder (MDD). Low frequency activity (LFA) in the electroencephalogram during waking has been correlated with sleep slow wave activity (SWA), suggesting that waking LFA reflects sleep homeostasis in healthy individuals. This study investigated whether the overnight change in waking LFA and its relationship with sleep SWA are altered in MDD.256-channel high-density electroencephalography (hdEEG) recordings during waking (pre- and post-sleep) and during sleep were collected in 14 unmedicated, unipolar MDD subjects (9 women) and age- and sex-matched healthy controls (HC).Waking LFA (3.25-6.25 Hz) declined significantly overnight in the HC group, but not in the group of MDD subjects. Overnight decline of waking LFA correlated with sleep SWA in frontal brain regions in HC, but a comparable relationship was not found in MDD.This study is not able to definitely segregate overnight changes in the waking EEG that may occur due to homeostatic and/or circadian factors.MDD involves altered overnight modulation of waking low frequency EEG activity that may reflect altered sleep homeostasis in the disorder. Future research is required to determine the functional significance and clinical implications of these findings.

Objective Menopause is widely believed to be an established cause of sleep disorders, but evidence for this theory is inconclusive. Attributing any sleep problem to normal processes of menopause may lead to underdiagnosis of treatable sleep disorders in midlife women. This study uses detailed longitudinal data on sleep and menopausal health from participants in the Sleep in Midlife Women Study to investigate whether risk and severity of sleep-disordered breathing increase with progression through menopause, accounting for changes in age and body habitus. Methods A total of 219 women aged 38 to 62 years were recruited from participants in the Wisconsin Sleep Cohort Study. Menopause status was determined from daily diaries in which participants reported menstrual flow, hot flashes, and use of hormonal medications. Each participant underwent in-home polysomnography studies every 6 months, to measure the apneahypopnea index (AHI) (N = 1,667 studies). Linear models with empirical standard errors were fit for logarithm of AHI on menopause status and years in menopause, adjusting for age, body mass index, waist girth, and neck girth. Results Compared with women in premenopause, AHI was 21% higher among participants in perimenopause (95% CI, −4 to 54), 31% higher among participants in postmenopause (95% CI, 2-68), and 41% higher among participants whose menopausal stage could not be distinguished between peri- and postmenopause (95% CI, 8-82). Among women who had begun perimenopause, each additional year in menopause was associated with 4% greater AHI (95% CI, 2-6). Conclusions Progression through menopause is associated with greater sleep-disordered breathing severity. This association is independent of aging and changes in body habitus.

Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12 h and 24 h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12 h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24 h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites.

Background The cardiovascular effects of positive airway pressure ( PAP ) therapy in obstructive sleep apnea ( OSA ) patients are not clear because of confounding by comorbid conditions. Methods and Results Prospective interventional study of PAP therapy and withdrawal. Apnea Hypopnea Index ( AHI ; events/hour of sleep) was determined from polysomnography. Central aortic blood pressures ( BPs ), Aortic Augmentation Index ( AAI x), and central ( PWV c‐f ) and peripheral pulse wave ( PWV c‐r ) velocities were determined by applanation tonometry. Echocardiography and brachial artery reactivity testing were performed at baseline, after 4 and 12 weeks of PAP therapy, and 1 week after PAP withdrawal. The 84 participants were mean (SD) 41.1 (7.6) years old and had 39.8 (24.5) AHI events/hour. After 4 weeks post‐ PAP initiation and sustained after 12 weeks, subjects experienced decreases in central systolic BP ( P =0.008), diastolic BP , mean BP , AAI x, and PWV c‐r , and brachial artery dilation (all P PAP use (hours/night) predicted reductions in diastolic BP (β=−0.65 [SE, 0.32] mm Hg/hour; P =0.045), AAI x (β=−0.53 [0.27] %/hour; P =0.049) and PWV c‐r (β=−0.13 [0.05] m·s −1 /hour; P =0.007), and improved brachial artery flow‐mediated dilation (β=0.31 [0.14] %/hour use; P =0.015). After 1 week of PAP withdrawal, brachial diameter, diastolic BP , mean BP , AAI x, and heart rate increased ( P ≤0.05). Conclusions PAP therapy reduces arterial tone and improves endothelial and diastolic function in young to middle‐aged adults. This positive effect is observed after 4 weeks and depends on hours of use, but reverts quickly with PAP withdrawal. Clinical Trial Registration URL: https://clinicaltrials.gov/ . Unique identifier: NCT 01317329.

Tune in to this podcast as experts discuss 2 patient cases-one involving co-occurring insomnia and depression and another comprising PTSD, substance abuse, insomnia, and nightmares. Drs Benca and Buysse explain how to effectively diagnose and manage these complex cases based on the latest diagnostic criteria and evidence from clinical trials.

Whether insomnia, a known correlate of depression, predicts depression longitudinally warrants elucidation. The authors examined 555 Wisconsin Sleep Cohort Study participants aged 33-71 years without baseline depression or antidepressant use who completed baseline and follow-up overnight polysomnography and had complete questionnaire-based data on insomnia and depression for 1998-2006. Using Poisson regression, they estimated relative risks for depression (Zung scale scoreor =50) at 4-year (average) follow-up according to baseline insomnia symptoms and polysomnographic markers. Twenty-six participants (4.7%) developed depression by follow-up. Having 3-4 insomnia symptoms versus none predicted depression risk (age-, sex-, and comorbidity-adjusted relative risk (RR) = 3.2, 95% confidence interval: 1.1, 9.6). After multiple adjustments, frequent difficulty falling asleep (RR = 5.3, 95% confidence interval: 1.1, 27.9) and polysomnographically assessed (upper or lower quartiles) sleep latency, continuity, and duration (RRs = 2.2-4.7; P'sor = 0.05) predicted depression. Graded trends (P-trendor = 0.05) were observed with increasing number of symptoms, difficulty falling asleep, and difficulty returning to sleep. Given the small number of events using Zungor =50 (depression cutpoint), a limitation that may bias multivariable estimates, continuous depression scores were analyzed; mean values were largely consistent with dichotomous findings. Insomnia symptoms or markers increased depression risk 2.2- to 5.3-fold. These results support prior findings based on self-reported insomnia and may extend similar conclusions to objective markers. Heightened recognition and treatment of insomnia may prevent subsequent depression.

It is clear that insomnia and depression are intimately related, which may suggest an overlapping neurobiology. Although much progress has been made toward understanding how these disorders relate to each other, the exact neurobiological mechanisms that link them remain elusive. Sleep changes in depression may be associated with abnormal neurotransmission, genetic polymorphisms, HPA overactivity, impaired plasticity, or most likely a combination of factors. It is therefore crucial that sleep assessments go beyond traditional polysomnography to include a more expanded set of objective measures in the hope that these will uncover the common neurobiology that is thought to underlie insomnia and depression.

Sleep disturbances are among the most common symptoms in patients with acute episodes of mood disorders, and patients with mood disorders exhibit higher rates of sleep disturbances than the general population. Insomnia and hypersomnia are associated with an increased risk for the development or recurrence of mood disorders and increased severity of psychiatric symptoms. Primary sleep disorders are also associated with an increased incidence of depression. Sleep electroencephalogram recordings have identified objective abnormalities associated with mood disorders, providing insight into the neurobiologic relationships between mood and sleep. Future studies will continue to investigate this association, and potentially improve the treatment of both sleep and mood disorders.

Benzodiazepines are commonly used medications that alter sleep spindles during non-rapid eye movement (NREM) sleep, however the topographic changes to these functionally significant waveforms have yet to be fully elucidated. This study utilized high-density electroencephalography (hdEEG) to investigate topographic changes in sleep spindles and spindle-range activity caused by temazepam during NREM sleep in 18 healthy adults. After an accommodation night, sleep for all participants was recorded on two separate nights after taking either placebo or oral temazepam 15 mg. Sleep was monitored using 256-channel hdEEG. Spectral analysis and spindle waveform detection of sleep EEG data were performed for each participant night. Global and topographic data were subsequently compared between temazepam and placebo conditions. Temazepam was associated with significant increases in spectral power from 10.33 to 13.83 Hz. Within this frequency band, temazepam broadly increased sleep spindle duration, and topographically increased spindle amplitude and density in frontal and central-posterior regions, respectively. Higher frequency sleep spindles demonstrated increased spindle amplitude and a paradoxical decrease in spindle density in frontal and centroparietal regions. Further analysis demonstrated temazepam both slowed the average frequency of spindle waveforms and increased the relative proportion of spindles at peak frequencies in frontal and centroparietal regions. These findings suggest that benzodiazepines have diverse effects on sleep spindles that vary by frequency and cortical topography. Further research that explores the relationships between topographic and frequency-dependent changes in pharmacologically-induced sleep spindles and the functional effects of these waveforms is indicated.

PurposeObservational studies suggest that menopausal hormone therapy protects against sleep-disordered breathing, but such findings may be biased by a "healthy user effect." When the Women's Health Initiative Study reported in 2002 that estrogen-progestin therapy increases heart disease risk, many women discontinued hormone therapy. We investigate healthy user bias in the association of hormone therapy with sleep-disordered breathing in the Sleep in Midlife Women Study.MethodsA total of 228 women aged 38 to 62 years were recruited from the Wisconsin Sleep Cohort Study. They underwent polysomnography to measure apnea-hypopnea index, at home semiannually from 1997 to 2006, and in the sleep laboratory every four years (n = 1828 studies). Hormone therapy was recorded monthly. Linear models with empirical standard errors regressed logarithm of apnea-hypopnea index on hormone use with a pre- or post-July 2002 interaction, adjusting for menopause and age.ResultsThe association of hormone therapy and sleep-disordered breathing was heterogeneous (P < .01); apnea-hypopnea index among users was 15% lower in the early period (95% confidence interval, -27% to -1%), but similar to nonusers in the late.ConclusionsHormone therapy was negatively associated with sleep-disordered breathing only until the Women's Health Initiative results were publicized. Hormone therapy may have been a marker for healthfulness in the early period, creating a spurious association with sleep-disordered breathing.

Sleeping brain activity reflects brain anatomy and physiology. The aim of this study was to use high density (256 channel) electroencephalography (EEG) during sleep to characterize topographic changes in sleep EEG power across normal aging, with high spatial resolution. Sleep was evaluated in 92 healthy adults aged 18-65 years old using full polysomnography and high density EEG. After artifact removal, spectral power density was calculated for standard frequency bands for all channels, averaged across the NREM periods of the first 3 sleep cycles. To quantify topographic changes with age, maps were generated of the Pearson's coefficient of the correlation between power and age at each electrode. Significant correlations were determined by statistical non-parametric mapping. Absolute slow wave power declined significantly with increasing age across the entire scalp, whereas declines in theta and sigma power were significant only in frontal regions. Power in fast spindle frequencies declined significantly with increasing age frontally, whereas absolute power of slow spindle frequencies showed no significant change with age. When EEG power was normalized across the scalp, a left centro-parietal region showed significantly less age-related decline in power than the rest of the scalp. This partial preservation was particularly significant in the slow wave and sigma bands. The effect of age on sleep EEG varies substantially by region and frequency band. This non-uniformity should inform the design of future investigations of aging and sleep. This study provides normative data on the effect of age on sleep EEG topography, and provides a basis from which to explore the mechanisms of normal aging as well as neurodegenerative disorders for which age is a risk factor.

Study objectivesDepression has been identified as the most common condition comorbid to insomnia, with findings pointing to the possibility that these disorders may be causally related to each other or may share common mechanisms. Some have suggested that comorbid insomnia and depression may have a different clinical course than either condition alone, and may thus require specific treatment procedures. In this report we examined the clinical characteristics of individuals referred to an academic sleep center who report comorbid symptoms of insomnia and depression and those with symptoms of insomnia outside the context of meaningful depression, and we identified differences between these groups with regard to several cognitive-related variables.MethodsLogistic regression analyses examined whether past week worry, dysfunctional beliefs about sleep, and insomnia symptom-focused rumination predicted group membership.ResultsIndividuals with comorbid symptoms of insomnia and depression reported more past-week worry, dysfunctional beliefs about sleep, and insomnia symptom-focused rumination, than those with symptoms of insomnia without significant depression symptoms. When including all three cognitive-related variables in our model, those with comorbid symptoms reported more severe insomnia symptom-focused rumination, even when controlling for insomnia and mental health severity, among other relevant covariates.ConclusionThe findings contribute to our understanding of the complex nature of comorbid symptoms of insomnia and depression and the specific symptom burden experienced by those with significant depression symptoms in the presence of insomnia. The findings also highlight the need for increased clinical attention to the sleep-focused rumination reported by these patients.